mahiuddin alamgir
TRANSCRIPT
SYNTHESIS AND REACTIVITY OF
SOME ACTIVATED HETEROCYCLIC
COMPOUNDS
A thesis submitted in fulfilment of the requirements for the degree of
DOCTOR OF PHILOSOPHY
by
Mahiuddin Alamgir
School of Chemistry Faculty of Science
The University of New South Wales Sydney, Australia
March, 2007
PLEASE TYPE
THE UNIVERSITY OF NEW SOUTH WALES
Thesis/Dissertation Sheet
Surname or Family name: ALAMGIR
First name: MAHIUDDIN Other name/s:
Abbreviation for degree as given in the University calendar: PhD
School: CHEMISTRY Faculty: SCIENCE
Title: SYNTHESIS AND REACTIVITY OF SOME ACTIVATED HETEROCYCLIC COMPOUNDS
Abstract 350 words maximum: (PLEASE TYPE)
An alternate approach to the synthesis of calix[3]indoles has been demonstrated, but further attempted synthetic approaches to
calixindoles using new leaving groups led to uncharacterized polymeric products. The synthesis of new 7,7'-diindolylmethane-
2,2'-dicarbaldehydes gives potential for further ligand design and metal complex formation. In addition, 4,6-dimethoxyindole-7-
carbaldehydes have been effectively converted to a range of 6-methoxyindole-4,7-diones by Dakin oxidation.
Various electrophilic substitution reactions have been performed on the 4,6-dimethoxybenzimidazoles. Formylation, acylation,
acid catalyzed addition of formaldehyde and nitration revealed that the activated benzimidazoles are less reactive at the specified
C-7 position compared to the analogous indoles. The key starting material for a potential calixbenzimidazole was synthesized by
the selenium dioxide oxidation of 2-methyl-7-formyl-4,6-dimethoxybenzimidazole and by oxidative cleavage of 4,6-dimethoxy-
2-styrylbenzimidazole by Lemieux-Johnson reagent followed by reduction. Nevertheless, attempted preparation of
calixbenzimidazole from 2-hydroxymethyl-4,6-dimethoxy benzimidazole led to formation of a dibenzimidazolyl ether. The
synthesis of some novel activated bisbenzimidazoles has been developed. Furthermore, benzimidazoles were incorporated into
new ligand systems which have led to a wide range of acyclic quadridentate neutral metal complexes.
Activated benzimidazoles overall illustrate one electron irreversible oxidation to form a radical cation followed by multielectron
oxidations. On the other hand, the nickelII and cobaltII benzimidazole metal complexes investigated showed one electron ligand
centered reversible reduction. Irreversible radical cation oxidation followed by multielectron oxidation of the metal complexes
further demonstrates the rich electrochemical nature of the 4,6-dimethoxybenzimidazoles.
Some novel 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles were prepared with indolin-2-one and triflic anhydride and an alternate
procedure afforded 2-(4,6-dimethoxyindol-7-yl)-benzimidazoles from activated indoles and 2-benzimidazolinone.
Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-4,6-dimethoxybenzothiazoles were
synthesized via Jacobson cyclization. The two strategically placed electron donating methoxy groups activate these
benzothiazoles to undergo various electrophilic substitutions at the 4- and 7- positions respectively.
Declaration relating to disposition of project thesis/dissertation
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i
ORIGINALITY STATEMENT
I hereby declare that this submission is my own work and to the best of my
knowledge it contains no materials previously published or written by another
person, or substantial proportions of material which have been accepted for the
award of any other degree or diploma at UNSW or any other educational institution,
except where due acknowledgement is made in the thesis. Any contribution made to
the research by others, with whom I have worked at UNSW or elsewhere, is
explicitly acknowledged in the thesis. I also declare that the intellectual content of
this thesis is the product of my own work, except to the extent that assistance from
others in the project's design and conception or in style, presentation and linguistic
expression is acknowledged.’
Mahiuddin Alamgir
Date:
ii
ABSTRACT
An alternate approach to the synthesis of calix[3]indoles has been demonstrated, but further
attempted synthetic approaches to calixindoles using new leaving groups led to
uncharacterized polymeric products. The synthesis of new 7,7'-diindolylmethane-2,2'-
dicarbaldehydes gives potential for further ligand design and metal complex formation. In
addition, 4,6-dimethoxyindole-7-carbaldehydes have been effectively converted to a range
of 6-methoxyindole-4,7-diones by Dakin oxidation.
Various electrophilic substitution reactions have been performed on the 4,6-
dimethoxybenzimidazoles. Formylation, acylation, acid catalyzed addition of formaldehyde
and nitration revealed that the activated benzimidazoles are less reactive at the specified C-7
position compared to the analogous indoles. The key starting material for a potential
calixbenzimidazole was synthesized by the selenium dioxide oxidation of 2-methyl-7-
formyl-4,6-dimethoxybenzimidazole and by oxidative cleavage of 4,6-dimethoxy-2-
styrylbenzimidazole by Lemieux-Johnson reagent followed by reduction. Nevertheless,
attempted preparation of calixbenzimidazole from 2-hydroxymethyl-4,6-dimethoxy
benzimidazole led to formation of a dibenzimidazolyl ether. The synthesis of some novel
activated bisbenzimidazoles has been developed. Furthermore, benzimidazoles were
incorporated into new ligand systems which have led to a wide range of acyclic
quadridentate neutral metal complexes.
Activated benzimidazoles overall illustrate one electron irreversible oxidation to form a
radical cation followed by multielectron oxidations. On the other hand, the nickelII and
cobaltII benzimidazole metal complexes investigated showed one electron ligand centered
reversible reduction. Irreversible radical cation oxidation followed by multielectron
oxidation of the metal complexes further demonstrates the rich electrochemical nature of the
4,6-dimethoxybenzimidazoles.
Some novel 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles were prepared with indolin-2-one
and triflic anhydride and an alternate procedure afforded 2-(4,6-dimethoxyindol-7-yl)-
benzimidazoles from activated indoles and 2-benzimidazolinone.
Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-
4,6-dimethoxybenzothiazoles were synthesized via Jacobson cyclization. The two
strategically placed electron donating methoxy groups activate these benzothiazoles to
undergo various electrophilic substitutions at the 4- and 7- positions respectively.
iii
ACKNOWLEDGEMENTS
First of all, all praises be to Allah, The Exalted, The Most Gracious and Most
Merciful. The author also sends his darud and salam to the holy Prophet (Peace of
Allah be upon him).
I express my profound sense of gratitude to my respected supervisor, Professor
David St. Clair Black for his inspiration, constant guidance, valuable suggestions,
unparalleled encouragement and support made throughout the course of the study.
He always provided an endless source of ideas and motivation, and was always
approachable. He has allowed me the freedom to develop my own areas of interest
within the scope of this project, and made the research more enjoyable rather than
daunting.
I also express my deepest sense of appreciation and respect to my co-supervisor Dr.
Naresh Kumar for his keen interest, thoughtful suggestions, valuable guidance and
kind help in my research project. I acknowledge the effort and advice he has made in
the preparation of my thesis.
I am grateful to Dr. Steve Colbran and Dr. Sang Tae Lee for their help with the
electrochemical part of the thesis. I also thank A/Prof. Roger Read and Dr. Jason
Harper and for their interest and some suggestions in my study.
I wish to thank Dr. Jim Hook, Hilda Stender and Adelle Shasha for their help in
running the 2D NMR, Don Craig for performing the X-ray crystallography, Barry
Ward for his assistance with the IR and UV spectroscopy, Nicholas Proschogo and
Sarowar Chowdhury for processing the HRMS, Juan Arraya and Richard Burgess
for their help with fixing and organizing laboratory equipment, Ian Aldred and
Joseph Antoon for supplying the chemicals and solvents when needed, and Ken
McGuffin for administrative help. I am also grateful for the help I received from the
other staff members of the School of Chemistry. Thanks also go to Ms. Lydia Morris
for running some ESI and MALDI mass spectra. I give special thanks to Mrs.
Marianne Dick at the University of Otago for performing the microanalysis
determinations and running the EI mass spectra.
iv
Thanks to all past and present members of Prof. Black’s and Dr. Kumar’s group for
their cooperation. I am very happy and proud to be a member of this friendly group.
I especially remember Mandar, Tinnagon, Karin, Tutik, Wade, Wai Ching, Frank,
Kittiya, Kylie, Alex G, Kasey, Shari, Danielle, Taj, Alex D, William, George, Abel,
Valentina, Vi and Vanessa. I also had the pleasure of working with other group
members, namely Khuong, Danielle, Emily, Serin, Michael, Brad and Joan in our lab
during building renovations and transfer.
I am deeply grateful to my beloved parents for their continuous love, prayers and
encouragement for my success. I also thank my parents in law, my brothers, my
sisters and my nieces and nephew for their prayers, love and support without whose
good wishes I could not have completed this work. My father deserves special credit
for the inspiration that has led our three brothers to do Doctoral degrees. My elder
brother Dr. Ibrahim Khalil is always very caring about my study matters. Thanks to
all of my friends and other well wishers, particularly Saif for his accompany.
Words are inadequate to express my deepest admiration to my wife Sultana Rajia for
all the sacrifice she has made regarding my entire program. But for her trust and
belief in me and above all, encouragement and understanding, it would have been
difficult if not impossible, to undertake the program successfully. Similarly, I wish
successful completion of her PhD as well in Medicine. My love also goes to my little
daughter Aisha Sarah for giving me pleasure and fun in my spare time.
The financial support from the Australian Government in the form of an Endeavour
International Post Graduate Research Scholarship (EIPRS) and The University of
New South Wales for an International Postgraduate Award (UIPA) during my PhD
is gratefully acknowledged.
v
PUBLICATIONS
Part of this thesis work has been reported in the following conference presentation:
1. M. Alamgir, David St. C. Black, N. Kumar. Synthesis and reactivity of some
dimethoxy activated indoles, benzimidazoles and benzothiazoles. (Accepted)
21st International Congress for Heterocyclic Chemistry, University of New
South Wales, Sydney, Australia, July 15-20, 2007.
2. M. Alamgir, Peter S.R. Mitchell, N. Kumar, David St. C. Black. Synthesis of
4,7-indoloquinones from indole-7-carbaldehydes by Dakin oxidation. Annual
One Day Symposium, RACI Natural Products Group, NPG 06. University of
Wollongong, Wollongong, Australia, Abstract p. 14, September 29, 2006.
3. M. Alamgir, G.C. Condie, V. Martinovic, J. Wood, David St. C. Black.
Synthesis and reactivity of methoxy activated benzimidazoles. Apte, S.C.,
Kable S.H. (eds) CONNECT 2005, The 12th Royal Australian Chemical
Institute (RACI) Convention, Syndey, Australia, Abstract p. 216, July 3-7,
2005.
vi
TABLE OF CONTENTS
CERTIFICATE OF ORIGINALITY i
ABSTRACT ii
ACKNOWLEDGEMENTS iii
PUBLICATIONS v
TABLE OF CONTENTS vi
LIST OF ABBREVIATIONS x
CHAPTER 1. INTRODUCTION 1
CHAPTER 2. SYNTHESIS AND REACTIVITY OF ACTIVATED
INDOLES
2.1. Introduction 6
2.2. Calixarenes and calixindoles 7
2.3. Preparation of activated indoles 10
2.4. Reaction of indoles with thionyl chloride and sulfuryl chloride 12
2.5. Formylation of 3-aryl-4,6-dimethoxyindoles and reduction of the
corresponding indole aldehydes
14
2.6. Attempted conversion of activated hydroxymethylindoles into
bromomethylindoles
16
2.7. Attempted conversion of activated hydroxymethyl indoles to sulfonyl
derivatives
24
2.8. Attempted synthesis of oxazinoindoles 26
2.9. Future approaches towards calixindoles 28
2.10. Dakin oxidation of indole-7-carbaldehydes 29
2.11. Conclusions 34
vii
CHAPTER 3. SYNTHESIS AND REACTIVITY OF ACTIVATED
BENZIMIDAZOLES
3.1. Introduction 35
3.2. Preparation of 4,6-dimethoxybenzimidazoles 37
3.3. Formylation of 4,6-dimethoxybenzimidazoles and reduction of the
corresponding benzimidazole aldehydes
41
3.4. Synthesis of 7,7'-dibenzimidazolylmethanes 44
3.5. Acylation of 4,6-dimethoxybenzimidazoles 46
3.6. Attempted synthesis of benzimidazole glyoxyloyl chlorides 50
3.7. Nitration of 4,6-dimethoxybenzimidazoles 51
3.8. Benzoylation of a 4,6-dimethoxybenzimidazole using activated carbon 52
3.9. Preparation of imidazoloquinolines 55
3.10. Synthesis and N-allylation of 2,7-bisbenzimidazoles 57
3.11. Attempted synthesis of benzimidazole-4,7-diones 61
3.12. Synthesis of 4,6-dimethoxybenzimidazole aldoximes and ketoximes 61
3.13. Attempted synthesis of furobenzimidazoles 64
3.14. Investigation of some calixbenzimidazole precursors 70
3.14.1. Benzylic oxidation of 2-methyl-4,6-dimethoxybenzimidazole 72
3.14.2. Attempted preparation of halomethyl benzimidazoles 75
3.14.3. Synthesis and oxidation of 2-styryl benzimidazoles 77
3.15. Preparation of acyclic quadridentate metal complexes 81
3.16. Synthesis of 2,2' linked bisbenzimidazoles 87
3.17. Synthesis of bisbenzimidazol-1-ylmethanes 92
3.18. Conclusions 93
viii
CHAPTER 4. ELECTROCHEMICAL PROPERTIES OF SOME
ACTIVATED BENZIMIDAZOLES
4.1. Introduction 94
4.2. Electrochemistry of 2-substituted 4,6-dimethoxybenzimidazoles 95
4.3. Electrochemistry of some hydrogen bonded benzimidazoles 97
4.4. Electrochemistry of NiII and CoII benzimidazole complexes 104
4.5. Conclusions 110
CHAPTER 5. SYNTHESIS OF INDOLYLBENZIMIDAZOLES
5.1. Introduction 111
5.2. Reaction of a benzimidazole with indolin-2-one under Vilsmeier
conditions
112
5.3. Reaction of benzimidazoles with indolin-2-one using triflic anhydride 114
5.4. Reaction of indoles with 2-benzimidazolinone 117
5.5. Conclusions 121
CHAPTER 6. SYNTHESIS AND REACTIVITY OF ACTIVATED
BENZOTHIAZOLES
6.1. Introduction 122
6.2. Preparation of the dimethoxy activated benzothiazoles 123
6.3. Formylation of activated benzothiazoles and reduction of
benzothiazole aldehydes
133
6.4. Acylation of activated benzothiazoles 136
6.5. Nitration of activated benzothiazoles 137
6.6. Preparation of benzothiazolylbenzimidazoles 139
6.7. Conclusions 140
ix
CHAPTER 7. EXPERIMENTAL
7.1. General information 141
7.2. Electrochemistry 142
7.3. Quantum chemical calculation 143
7.4. Experimental details 143
REFERENCES 247
APPENDIX
X-ray crystallography data
Introduction 259
Structure determination 259
1. Crystal data for the compound 187 260
2. Crystal data for the compound 194 263
3. Crystal data for the compound 222 266
4. Crystal data for the compound 226 270
5. Crystal data for the compound 227 273
6. Crystal data for the compound 321 276
x
LIST OF ABBREVIATIONS
abs. absolute Ac acetyl Ac2O acetic anhydride AcOH acetic acid AIBN Azobisisobutyronitrile Ar aryl b.p. boiling point Boc tert-butoxycarbonyl Bu butyl CH3CN acetonitrile conc. concentrated CV cyclic voltammetry d day(s) DCM dichloromethane DDQ dichlorodicyanobenzoquinone dec. decomposition DMA N,N-dimethylacetamide DMAD dimethyl acetylenedicarboxylate DMF N,N-dimethylformamide DMS dimethyl sulfate DMSO dimethylsulfoxide DNA deoxyribonucleic acid E1/2 half cell potential EI electron impact Epa anodic peak potential Epc cathodic peak potential eq. equivalent(s) ESI electrospray ionization Et ethyl Et2O diethyl ether Et3N triethyl amine EtOH ethanol Fc/Fc+ ferrocene/ferrocenium h hour(s) HMBC heteronuclear multiple quantum coherence HMQC heteronuclear multiple bond coherence HRMS high resolution mass spectrometry Ipa anodic ionization potential IR infrared IUPAC international union of pure and applied chemistry k/cal kilo calorie KBr potassium bromide
xi
KOH potassium hydroxide lit. literature LRMS low resolution mass spectrum M molar m.p. melting point MALDI matrix assisted laser desorption ionization max maximum Me methyl MeO methoxy MeOH methanol min minute(s) mM milli mole mmol milli mole mol mole MS mass spectrum mV milli volt [nBu4N][PF6] tetra-n-butyl ammonium hexafluorophosphate NaOH sodium hydroxide NBS N-bromosuccinimide NMR nuclear magnetic resonance NOESY nuclear overhauser enhancement spectroscopy o/n over night Ph phenyl Ph3P triphenyl phosphine POCl3 phosphoryl chloride ppt precipitate p-TosOH p-toluenesulfonic acid r.t. room temperature t-Bu tert-butyl TEOF triethylorthoformate Tf2O triflic anhydride TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl Tos tosyl TosCl p-toluenesulfonyl chloride UV ultraviolet V volt
Ep peak seperation (Epa- Epc)Ho
f heat of formation
Chapter 1 1
CHAPTER 1
INTRODUCTION
Indole 1 normally undergoes electrophilic substitution and addition reactions
preferentially at C-3, and if that position is substituted as in compound 2 then reaction
is directed to the C-2 position. Specifically activated indoles 3 and 4 by the presence
of two methoxy substituents at C-4 and C-6 have shown some very interesting and
characteristic reactions which do not occur in the case of simple indoles. In these 4,6-
dimethoxyindoles 3 and 4, the reactivity at C-7 is markedly incre ased by the
presence of two electron donating methoxy groups into the ring system (Figure 1-
1).1,2 This substitution pattern not only activates C-7 in particular, but it enhances the
general reactivity of the indoles, so that new reactions can be observed. In addition,
given suitable substitution patterns, reaction can occur at C-7 alone, C-2 and C-7, C-2
and N-1, and C-7 and N-1. These reactions make the synthesis of new classes of
natural and unnatural indoles possible.2
NH
OMe
MeOE+
NH
NH
R
E+
E+ R
1 2 4
12
345
67
E+NH
OMe
MeOE+
R
3
R
Figure 1-1
A variety of reactions including formylation, acylation, halogenation, nitration,
oxidative dimerization, acid catalyzed addition of aldehydes and , -unsaturated
ketones, and imine formation has been performed exclusively at the C-7 position on
the 2,3-diphenyl-4,6-dimethoxyindole 3.1,3-5 The mono-substituents at C-3 result in an
activated indole nucleophile 4 capable of undergoing electrophilic substitution both at
the C-2 and C-7 positions.4-7 Recently, the reactivity of 2-methyl-3-aryl-4,6-
dimethoxyindoles to oxidation and intramolecular cyclization at C-7 has been
explored.8,9 Although a tremendous amount of work has been done in the past, new
patterns of reactivity of indoles are still being discovered.
Chapter 1 2
An added advantage of the 3-aryl-4,6-dimethoxyindoles is that they have two reactive
sites at both C-2 and C-7 and consequently form different types of calixindoles
(Figure 1-2). For example, the symmetrical calix[3]indole 5 and calix[4]indole 6 can
be prepared from 7-hydroxymethylindole by acid catalyzed reactions, where water is
eliminated in the mechanism of acid catalyzed formation of the macrocyclic
structures.10
NH
MeO OMe
R
HN OMe
OMe
R
NHMeO
R
NH
OMe
MeO
R
HN
MeO
R
HN
R
NH
MeO
OMe
R
OMe
OMe
OMe
5
OMe
6
Figure 1-2
The range of calixarenes was extended by application of the previous technique to
benzofurans, using strategically positioned methoxy groups to form symmetrical
calix[3]benzofuran 7 and calix[4]benzofuran 8, in addition to unsymmetrical
calix[3]benzofuran 9 by various acid catalyzed reactions (Figure 1-3).11,12
O
MeO OMe
R
O OMe
OMe
R
OMeO
R
O
OMe
MeO
R
O
MeO
R
O
R
O
MeO
OMe
R
OMe
OMe
OMe
7 8
OMe
OOMe
OMe
R
O
MeO
MeO
R
O
MeO
OMeR
9
Figure 1-3
Chapter 1 3
Thus, as part of a programme aimed at expanding the chemical reactivity of
dimethoxy activated heterocyclic systems we started working with activated indoles 4,
benzimidazoles 10 and benzothiazoles 11, 12 (Figure 1-4). Although, the planned
benzimidazole 10 and benzothiazoles 11, 12 have similar activation at the C-7
imposed by the dimethoxy groups, they have slightly different basicity compared to
the activated indoles 4. Hence, it would be interesting to study whether varieties of
reactions done on the activated indoles 3 and 4 are applicable to the proposed
dimethoxy activated benzimidazoles 10 and benzothiazoles 11, 12. These findings will
be valuable to compare their reactivity towards various electrophiles. In addition, this
would significantly develop their synthetic applications. Moreover, it is possible to
generate two reactive sites in these heterocyclic ring systems and investigate the
previous approach to prepare new calixarenes.
NH
OMe
MeOE+ E+
E+R
NH
N
OMe
MeOE+
N
S
OMe
MeOE+
S
N
OMe
MeOE+E+E+
4 10 11 12
Figure 1-4
Heterocyclic compounds related to indole 1 are widely distributed in nature and
possess significant biological activity. For example, the simple indole vasoconstrictor
serotonin 13 and the complex indole anticancer compound vincristine13 14 (Figure 1-
5) can play major pharmacological and important therapeutic roles. Very recently, a 5-
methoxyindoloquinone 15, of particular significance to this work, exhibited activity
against human pancreatic cancer.14
NH
NHO
Et
OMeO MeO
NCHO OMeO
H OHOAc
N EtH
H
Vincristine (14)
NH
Serotonin (13)
HO
NH2
N
Indoloquinone (15)
MeOMe
O
O
O
NO2
Me
Figure 1-5
Chapter 1 4
Benzimidazoles have been applied rather more as herbicides,15,16 fungicides,17,18 and
anthelmintics.19-21 For example, albendazole 16 and mebendazole 17 have proven
anthelmintic efficiency both for human and veterinary use (Figure 1-6). A 5,6-
dialkoxybenzimidazole 18 has shown significant anti-inflammatory activity.22 More
interestingly, some bisbenzimidazoles and indolylbenzimidazoles have been reported
to show significant antitumor cytotoxicity.23,24 Recently, benzimidazole derived metal
complexes have revealed antibacterial, antifungal and DNA intercalator activities.25
NH
N
Albendazole (16)
NH
OMe
O
SPrn
NH
N
Mebendazole (17)
NH
OMe
OO
N
N
Benzimidazole (18)
EtO
EtOSCH3
O Ph
Figure 1-6
On the other hand, benzothiazoles rarely occur as natural products, but they form part
of the molecular structure of many natural products, biocides, drugs, food flavours and
industrial chemicals.26-28 Recently a benzothiazole alkaloid violatinctamine 19 has
been isolated from the marine tunicate Cystodytes cf. violatinctus (Figure 1-7).29 A
more relevant compound dimethoxybenzothiazole 20 has dual inhibitory activity
against 5-lipoxygenase and thromboxane A2 (TXA2) synthetase,30 which are two
important enzymes for the inflammatory process. Whereas the
polyhydroxybenzothiazole 21 has potential cytotoxicity against various tumor cell
lines.31
N
S
Dimethoxybenzothiazole (20)
NHMeO
N
OMeHO
S
N
Dihydroxybenzothiazole (21)
HO
OH
OHN
S
Violatinctamine (19)
OH
HN
O
NMe2
Figure 1-7
Chapter 1 5
Considering the above scope and importance, the aim of the work presented in this
thesis was firstly to investigate the effects of the leaving group on the nature of
calixindole structure and to exploit some further reactivity of the 7-formyl-4,6-
dimethoxyindoles to produce a series of 6-methoxyindoloquinones (Chapter 2). The
second aim of this project was to investigate whether the C-7 position of the activated
4,6-dimethoxybenzimidazole 10 is similarly reactive as the related 4,6-
dimethoxyindole. However, fewer studies have been performed on this structure and
as a consequence the second objective was to synthesize a series of activated
benzimidazoles and compare their C-7 reactivity with analogous indoles. It is further
possible to generate some transition metal complexes and some precursors for the
possible synthesis of calixbenzimidazoles from 4,6-dimethoxybenzimidazole
(Chapter 3). Chapter 4 describes an investigation of the electrochemical behaviour
of some activated benzimidazoles, with particular attention given to the intramolecular
hydrogen bonding and the metal complex redox process. The fourth aspect involving
of the synthesis of indolylbenzimidazoles is described in Chapter 5. Chapter 6 deals
with the synthesis of two series of activated benzothiazoles, namely 2-substituted-5,7-
dimethoxybenzothiazole, eg. 11 and 2-substituted-4,6-dimethoxy benzothiazole, eg.
12 and a study of their reactivity towards some electrophiles.
Chapter 2 6
CHAPTER 2
SYNTHESIS AND REACTIVITY OF ACTIVATED INDOLES
2.1. Introduction
The indole alkaloids form an enormous class of important natural products, which in
many cases show potent biological activity.32 As a consequence of this, synthetic
studies related to indoles in general and indole alkaloids in particular continue to be
explored by many groups.2 For example, recently 4,6-dimethoxy-2-indoleamide
hydroxamic acid 22 and some other methoxy activated indoles have shown potent
inhibition of histone deacetylase and antiproliferative activity.33,34
NH
HN NHOH
O O
22
OMe
MeO
Many varied methods for the synthesis of indoles have been developed.35-38 Our group
has synthesized a wide range of 3-substituted-4,6-dimethoxyindoles 4 by a modified
Bischler procedure.39-41 Indoles normally undergo electrophilic substitution and
addition reactions at C-3, and if that position is substituted, reaction is directed to C-2.
Incorporation of the two electron donating methoxy groups has been shown to activate
the indole ring, particularly at the C-7 position.1 Thus 3-substituted-4,6-
dimethoxyindoles 4 are of particular interest as they have two activated sites, namely
C-2 and C-7, to enhance the reactivity of the indoles. Therefore, there has been
extensive study of the reactivity of 4,6-dimethoxyindoles towards aromatic
substitution.1,4,6,8,42-46 Furthermore, the use of activated indoles, has allowed the
preparation of some natural and unnatural indole derivatives and unusual macrocyclic
compounds,47 which would otherwise be inaccessible.
Chapter 2 7
2.2. Calixarenes and calixindoles
One of the most popular classes of macrocyclic compounds is the calixarenes.48 The
macrocyclic structure combines the molecular backbone (the parent calixarene) with a
large choice of functional groups. Other structural features include (i) the
conformation which may be rigid or flexible, (ii) a cavity with a size suitable for
inclusion of ions and small molecules, (iii) the possibility of complexing larger guests
in an extended cavity based on multiple interactions, (iv) the possibility to create
ditopic ligands with binding sites at the upper and lower rim of the parent compound,
and (v) the combination of ligating groups with signaling ones for molecular sensors
or switches.48 There are numerous reviews concerning synthesis,49,50 structural
features and host-guest interactions,51,52 chemical recognition and separation of
cations,53 and biochemical recognition.48 Calixarenes also show some biological
activity.54,55 Instead of the conventional phenol unit, indoles,56-58 pyrroles,59 furans,60
pyridines,61 naphthalenes62 and benzofurans12,63 have been used as building blocks to
prepare heterocalixarenes. An important requirement for the formation of calixarenes
is to have two activated sites, to form the macrocycle; 3-aryl-4,6-dimethoxyindoles 4
have both C-2 and C-7 activated positions making it possible for them to form
calixindoles.
The 2,7-functionalized indoles have the possibility to link in different ways to form
calixindoles, either with a symmetrical (i.e. 2,7;2,7;2,7) or unsymmetrical (i.e.
2,2;7,7;2,7) arrangement of linkages. The one-pot formation of calix[3]indoles 24 has
been carried out by reaction of indole 23 with an aryl aldehyde under reflux in
chloroform containing phosphoryl chloride, while the stepwise synthesis involves the
acid catalyzed conversion of indolylmethanol 25 at room temperature (Scheme 2-1).
Furthermore, symmetrical calix[3]indoles 28 and 29 have been prepared together with
calix[4]indoles 30 and 31 respectively from the hydroxymethylindoles 26 and 27 with
the treatment of acid10,56,58 (Scheme 2-2).
Chapter 2 8
Scheme 2-1
ArCHO
Ar
Ar
ArNH
MeO OMe
Me
HN OMe
OMe
Me
NH
OMe
MeO
Me
POCl3/CHCl3NH
OMe
MeO
Me
23 24
NH
OMe
MeO
Me1. ArCONMe2/POCl3
2. NaBH4 NH
OMe
MeO
Me
H+
Ar
OH
23 25
Scheme 2-2
H+
NH
MeO OMe
R
HN OMe
OMe
R
NHMeO
R
NH
OMe
MeO
R
HN
MeO
R
HN
R
NH
MeO
OMe
R +N
H
OMe
MeO
R
OH
OMe
OMe
OMe
26; R =4-BrC6H427; R = Ph
28; R = 4-BrC6H429; R = Ph
30; R = 4-BrC6H431; R = Ph
OMe
X-ray data for the flexible cyclo-trimers showed a flattened partial cone conformation,
while the more rigid cyclo-tetramers have 1,3-alternate stereochemistry.56
Unsymmetrically linked calix[3]indoles 35 can be prepared by stepwise synthesis.
(Scheme 2-3). For example, the indole-7-carbaldehyde 32 undergoes reaction with
formaldehyde in acetic acid to give the dialdehyde 33, which can be reduced to the
corresponding dialcohol 34. The diindolylmethanedimethanol 34 can be reacted with
3-aryl-4,6-dimethoxyindole 4 in acetic acid to produce the unsymmetrically oriented
Chapter 2 9
calix[3]indoles 35.58 The unsymmetrically linked calix[3]indole 35 shows a wedge
shaped structure controlled by the 2,2'-link.
Scheme 2-3
NH
OMe
OMe
Ar
O
NH
OMe
MeO
Ar
O
NH
OMe
MeO
Ar
O
HCHO, AcOH
NH
OMe
OMe
Ar
HO
NH
OMe
MeO
Ar
OH
AcOH, 4
32
33 34
NaBH4
35
HNOMe
OMe
Ar
NH
MeO
MeO
Ar
HN
MeO
OMeArH
H H
A range of 2' -and 7'-indolylglyoxylamides has been reduced to the corresponding
alcohols 36 and 37 and on treatment under a variety of acidic conditions, these
alcohols underwent trimerization to give the calix[3]indoles 38 (Scheme 2-4). These
cyclo-trimers were predominantly in the flattened partial cone conformations. In
addition, cone conformers have also been produced.57,64
Chapter 2 10
Scheme 2-4
NH
MeO OMe
Ar
HN OMe
OMe
NH
OMe
MeONH
OMe
MeO
38
OH
RH
O
NH
OMe
MeO
Ar
or
OHO
R
H
CORH
ROCH
CORAr
H
Ar
H+36
37
Ar
R=NHMe, NHBun, NHBut, NH2, NHMe2
The mechanism of acid catalyzed formation of the macrocyclic structures of
calixindoles from the above examples of hydroxymethylindoles, involves water as the
leaving group.10 It was of interest to investigate the effects of the leaving group on the
nature of the calixindole structure. For example, the bromomethylindole could provide
an alternate leaving group (Br-), which might lead to a calixindole of different
conformation, or regioselectivity as the result of variation of a mechanism. In addition
to the synthesis of the starting indoles, attempted synthesis of bromomethylindole,
other attempts to incorporate alternate leaving groups on indoles, and Dakin oxidation
of indoles are discussed in this chapter.
2.3. Preparation of activated indoles
The indoles 47 and 48 were prepared via the modified four-step Bischler synthesis41
(Scheme 2-5). Reaction of 3,5-dimethoxyaniline 39 with the -haloacetophenones 40
in refluxing absolute ethanol afforded the corresponding anilino-ketones 41 and 42.
An excess of sodium bicarbonate was needed to ensure that the reaction mixture
remained basic, to eliminate the possibility of acid catalyzed rearrangements. The
anilino-ketone intermediates 41 and 42 were then reacted with trifluoroacetic
anhydride to give the N-trifluoroacetyl derivatives 43 and 44, which were then
cyclized immediately in trifluoroacetic acid to give the N-trifluoroacetylindoles 45 and
46. The N-protection of the anilino-ketone was required before the cyclization to
prevent the Bischler rearrangement to give the 2-substituted indole. The crude N-
Chapter 2 11
trifluoroacetylindoles 45 and 46 were then deprotected with methanolic potassium
hydroxide to yield the desired indoles 47 and 48, which were purified by column
chromatography.
Scheme 2-5
NH
OMe
MeO
R
N
OMe
MeO
R
N
OMe
MeO
R
NH
OMe
MeO
R
O
OOMe
MeO NH2EtOH, NaHCO3
KOH, MeOHTFAr.t ; o/n
41; R = Br42; R = H
Br
OR
39
(CF3CO2)2O
RefluxTHF, Et3N
0oC
O CF3
OCF3
40
43; R = Br44; R = H
45; R = Br46; R = H
47; R = Br48; R = H
Recently, the indole 50 has been prepared by a one-pot procedure65 (Scheme 2-6). In
this procedure the synthesis of activated indoles based on electron rich anilines, e.g.
4,6-dimethoxyaniline, can be achieved in a one pot process by a direct cyclization of
an arylaminoketone, in the presence of lithium bromide and sodium bicarbonate,
under essentially neutral conditions. Lithium bromide is believed to exchange the
chloro group to facilitate the formation of anilino-ketone, but also acts as a Lewis acid
to allow cyclization without rearrangement at neutral conditions and moderate
temperature.65 A mixture of 3,5-dimethoxyaniline 39, 2-chloroacetophenone 49,
lithium bromide and sodium bicarbonate in 1-propanol was refluxed overnight to yield
the indole 50 in 61% yield (Scheme 2-6). In order to achieve the synthesis of indole
47 in a one step procedure, 3,5-dimethoxyaniline 39, bromophenacylbromide 40, and
sodium bicarbonate were carefully weighed in one equivalent amounts and refluxed
together in absolute ethanol for four hours, but only 10% of the desired indole 47 was
obtained after workup.
Chapter 2 12
Scheme 2-6
OMe
MeO NH21-propanol, Reflux
50Br
O
Cl
39 49
+ NH
OMe
MeO
Cl
NaHCO3, LiBr
Similarly, a mixture of 3-chloro-2-butanone 51 and 3,5-dimethoxyaniline 39 was
reacted in the presence of lithium bromide and sodium bicarbonate in absolute ethanol
to produce directly the 2,3-dimethylindole 52 in a moderate yield (Scheme 2-7). It is
believed that the intermediate anilino-ketone quickly cyclizes in the neutral reaction
mixture, because of the reactive carbonyl group.66 The very well known 2,3-
diphenylindole 53 was prepared reacting 3,5-dimethoxyaniline 39 with benzoin, and
acetic acid as described by Black et al.40
Scheme 2-7
OMe
MeO NH2
1-propanol, Reflux
52Cl
MeO
39
51
NaHCO3, LiBr
+
NH
OMe Me
MeOMe
Me
53
benzoinNH
OMe Ph
MeOPh
AcOH+
Reflux
2.4. Reaction of indoles with thionyl chloride and sulfuryl chloride
Since activated 3-substututed-4,6-dimethoxyindoles 3 react with aryl aldehydes and
phosphoryl chloride to form calixindoles, it was of interest to examine their reactivity
towards other electrophiles, such as thionyl chloride or sulfuryl chloride. A possible
outcome could be the formation of a new class of calixindoles, such as compound 54
containing sulfur linkages (Scheme 2-8). To check this possibility indole 47 was
reacted with thionyl chloride at room temperature. The crude 1H NMR spectrum
showed the presence of a polymeric material which could not be characterized. When
thionyl chloride was replaced by sulfuryl chloride no reaction occurred.
Chapter 2 13
Scheme 2-8
SOCl2
O
O
ONH
MeO OMe
HN OMe
OMe
NH
OMe
MeO
S
S
SNH
OMe
MeO
47 54
Br
Br
Br
Br
A more controlled reaction of indole 47 with thionyl chloride was carried out in the
presence of potassium carbonate in acetonitrile (Scheme 2-9). The reaction was
completed within minutes, but again the presence of polymeric compounds was shown
by the 1H NMR spectrum. The reaction was slowed down by cooling in an ice-salt
bath or dry ice but the same polymeric product resulted. It was considered that the
sulfinyl chloride 55 could have formed, but due to its high reactivity reacted further to
form the polymer. This is indicated as a crude reaction product showed a molecular
ion peak m/z (M+1) at 413 corresponding to the sulfinyl chloride 55. Attempts to
intercept the polymerization reaction by reacting the sulfinyl chloride with ammonia
to form a more stable sulfinamide 56, were unsuccessful and once again polymeric
material was isolated. It is also possible that thionyl chloride could have reacted with
the indole nitrogen atom to form a nitrogen sulfur bond.
Scheme 2-9
NH
OMe
MeO
Br
SO Cl
NH
OMe
MeO
Br
SO NH2
NH
OMe
MeO
Br
SOCl2K2CO3CH3CN
47 55 56
NH3
Chapter 2 14
2.5. Formylation of 3-aryl-4,6-dimethoxyindoles and reduction of the
corresponding indole aldehydes
3-Aryl-4,6-dimethoxyindoles on reaction with anhydrous N,N-dimethylformamide and
phosphoryl chloride undergo a direct Vilsmeier-Haack formylation preferentially at
the C-7 position at 0oC. Above 5oC, a mixture of 2- and 7-formyl indoles are obtained,
and at high temperature (60oC) disubstitution occurs.67
Treatment of indoles 47, 50, 52, and 53 with a slight excess of one equivalent
Vilsmeier formylating reagent at 0oC for 1-2 h afforded the indole-7-carbaldehydes
57, 58 and 60 in high yields (90-95%) and 59 in moderate yield (55%). On the other
hand, the use of excess phosphoryl chloride reagent with some warming of the
reaction of 47 and 48 results in the formation of only the 2,7-diformyl products 61 and
62 respectively in 86% and 92% yields (Scheme 2-10). The disappearance of the meta
coupled doublet of H-5 and, H-7 in their 1H NMR spectra and the presence of a sharp
singlet around ~9.5 ppm for the C-2 aldehyde and ~10.3 ppm for the C-7 aldehyde
protons were significant observations in the identification of the formylated products.
Scheme 2-10
NH
OMe R1
MeO NH
OMe R1
MeO
H O
R2 R2POCl3/DMF
60oC, 2-16 h
NH
OMe R1
MeO
H O
excess POCl3/DMF
0oC, 1-2 h
61; R1 = 4-BrC6H462; R1 = Ph
O
H
57; R1 = 4-BrC6H4, R2 = H58; R1 = 4-ClC6H4, R2 = H59; R1 , R2 = Me60; R1 , R2 = Ph
47; R1 = 4-BrC6H4, R2 = H48; R1 = Ph, R2 = H50; R1 = 4-ClC6H4, R2 = H52; R1, R2 = Me53; R1, R2 = Ph
Chapter 2 15
The indole-7-carbaldehydes were treated with excess sodium borohydride in methanol
or tetrahydrofuran/absolute ethanol (1:1) under reflux for 1-2 h and gave the
corresponding alcohols 26 and 63, and dimethanols 64 and 65 as white solids in
quantitative yields (Scheme 2-11).58
Scheme 2-11
NH
OMe R
MeO
H O
61; R = 4-BrC6H462; R = Ph
NH
OMe R
MeO
OH
O
H
64; R = 4-BrC6H465; R = Ph
OH
NH
OMe R1
MeO
H O
57; R1 = 4-BrC6H4, R2 = H60; R1 , R2 = Ph
reflux, 2 h
NaBH4/MeOH
NH
OMe R1
MeO
OH
26; R1 = 4-BrC6H4, R2 = H63; R1 , R2 = Ph
R2 R2
reflux, 2 h
NaBH4/MeOH
The alcohol 26 with a drop of hydrochloric acid in tetrahydrofuran gave a precipitate
of the known calix[4]indole56 30 in low yield (Scheme 2-12).
Scheme 2-12
30
NH
OMe
MeO
Br
H+
THF
OH
26
NH
OMe
MeOHN
MeO
HN
NH
MeO
OMe
OMe
OMe
OMe
Br
Br
Br
Br
Chapter 2 16
2.6. Attempted conversion of activated hydroxymethylindoles into
bromomethylindoles
In order to prepare the calixindoles, synthesis of 7-bromomethylindole 73 was
attempted to provide an alternative precursor. It was expected that the 7-
bromomethylindole 72 would undergo base catalyzed reaction to form the calixindoles
and this variation of conditions could alter the conformation or regioselectivity of the
calixindoles.
The conversion of 3-hydroxymethylindole to 3-bromomethylindole has been reported
by Oliveira and Coelho68 (Scheme 2-13), who have used an adaptation of
methodology described by Schöllkopf et al..69 The indole-3-aldehyde 66 was N-
protected by a Boc group to give compound 67, which was reduced to alcohol 68. In
the next step, N-Boc protected hydroxymethylindole 68 was reacted with bromine in
the presence of triphenylphosphine and triethylamine in carbon tetrachloride at room
temperature for 3 days to give bromomethylindole 69 in 83% yield.
Scheme 2-13
NH
NaOH, DCM
Boc2O,(Bu)4NHSO4
N
OH
OH
BocN
OH
BocN
Br
Boc
Br2, PPh3
CCl4, r.t, 3d
66 696867
NaBH4EtOH
The indole-7-carbaldehyde 57 was first reacted with di-tert-butyl dicarbonate in the
presence of tetrabutylammonium hydrogen sulfate and sodium hydroxide in dry
dichloromethane to protect the indole nitrogen. After several days no change of the
reaction was observed in the TLC of the reaction mixture. The steric hindrance of the
Boc group was initially considered as the reason for this inactivity. Therefore, the
indole 57 was reacted with a smaller protecting group trimethylsilylchloride, under
different conditions of triethylamine/dichloromethane, sodium
hydroxide/dimethylsulfoxide, and sodium hydride/tetrahydrofuran. However, no
reaction progress was observed by TLC over 24 h, and only starting material was
recovered from the reaction mixtures. Another attempt was made starting with 7-
hydroxymethylindole 26, but the same reaction conditions also failed to substitute the
Chapter 2 17
nitrogen of the indole 26 (Scheme 2-14). This result is possibly caused by steric
hindrance from the buttressing effect caused by all of the substituents present on the
indole ring. In addition, the hydrogen bonding between the indole NH and the 7-
carbaldehyde 57 or 7-alcohol 26 could also account for this failure. Furthermore, the
absence of reactivity could also result from deactivation of the indole nitrogen by the
electron withdrawing 7-formyl group.
Scheme 2-14
NH
OMe
MeO N
OMe
MeOR1
R2R
26; R = CH2OH57; R = CHO
Br Br conditions i) Boc2O,(Bu)4NHSO4, NaOH, DCM or ii) TMCS, Et3N, DCM or iii) TMCS, NaOH, DMSO or iv) TMCS, NaH, THF
70; R1 = CH2OH, R2 = Boc, TMS71; R1 = CHO, R2 = Boc, TMS
Having failed to protect the indole nitrogen, the next step was attempted to continue
the bromination reaction without protecting the nitrogen. This was considered, as there
was evidence of the conversion of a hydroxymethyl compound to a bromomethyl
derivative, without protecting the nitrogen using carbon tetrabromide and
triphenylphosphine in tetrahydrofuran.70 Thus the 7-hydroxymethylindole 26 was
reacted using the above conditions, the resulting phosphonium salt was filtered off and
the residue was worked up. However, after workup the reaction failed to yield any
isolable products for characterization (Scheme 2-15).
Recently, Jin and Williams has reported the conversion of methoxy activated benzyl
alcohol to benzyl bromide by carbon tetrabromide and triphenylphosphine in
tetrahydrofuran in high yield (94%).71 Preparation of benzyl chloride from benzyl
alcohol has also been reported by other groups using carbon tetrachloride and
triphenylphosphine.72-74 The use of carbon tetrachloride has the advantage to serve
both as reagent and solvent. The reaction between carbon tetrachloride and
triphenylphosphine is very fast, so is carried out only in the presence of substrate. The
reactive intermediates are very susceptible to hydrolysis, making it necessary to use a
carefully dried solvent. The above mentioned procedures were used with necessary
Chapter 2 18
precautions for the reaction of 26, but the halogenated product 72 could not be isolated
(Scheme 2-15). Loic et al. stated that the 2,4-dimethoxybenzylacohol reacts with N-
halosuccinimide in ether to produce the benzylhalide,75 but the reaction of 26 with N-
bromosuccinimide in diethyl ether did not generate the brominated compound 72.
Scheme 2-15
NH
OMe
MeO NH
OMe
MeO
26
Br Br conditions: i) Br2, PPh3, CBr4, Et3N, THFor ii) PPh3, CBr4,THFor iii) PPh3, CCl4or iv) NBS, Et2O
OH Br72
The findings were not unexpected as the 3-bromomethylindole 69 displayed very
unstable characteristics68 and the activated indole system 72 with the two methoxy
groups at C-4 and C-6 should be more reactive then compound 69, as there is a
reactive C-2 position in 72. The desired compound 72 was considered to be too
reactive and therefore vulnerable to rapid decomposition during isolation. At this
point, it was considered that the 2,7-dibromomethylindoles 73, 74 would be less
reactive and might be stable enough to be isolated under normal conditions. However,
all the attempts to isolate the products 73, 74 from 2,7-dihydroxymethylindoles 64, 65
using a variety of conditions as outlined below failed (Scheme 2-16).
Scheme 2-16
NH
OMe
MeO NH
OMe R
MeO
conditions: i) Br2, PPh3, CBr4, Et3N, THFor ii) PPh3, CBr4,THFor iii) PPh3, CCl4or iv) NBS, THF
OH Br
OH Br
64; R = 4-BrC6H465; R = Ph
R
73; R = 4-BrC6H474; R = Ph
Chapter 2 19
Unexpectedly, the reaction of 64 and 65 with N-bromosuccinimide yielded
respectively 7,7'-diindolylmethane-2,2'-dicarbaldehydes 75 and 76 (Scheme 2-17).
The disappearance of the one CH2 and OH protons in the 1H NMR spectra and the
presence of a new CH2 and CHO correspond to the compounds 75 and 76. The
position of the C-2 aldehyde proton at ~9.5 ppm was similar to the other indole C-2
aldehydes. In addition, the mass spectra clearly showed molecular ion peaks m/z at
732 and 575 to confirm the structures 75 and 76. The other spectroscopic and
analytical results are all consistent with their structures.
Scheme 2-17
HN
OMe
NH
MeO
OO
NH
OMe R
MeO
OH
OHRR
NBS/THF
OMe MeO
H H64; R = 4-BrC6H465; R = Ph
75; R = 4-BrC6H476; R = Ph
r.t., 1.5-2 h
Recently, the same compound 76 has been prepared via a different synthetic route
(Scheme 2-18),8 where the indole 79 was treated with acid to form the dimer 80,
which was then oxidized with selenium dioxide to give the product 76. However, the
synthesis of the 7,7'-diindolylmethane-2,2'-dicarbaldehyde 76 using N-
bromosuccinimide provides an alternate procedure.
Scheme 2-18
NH
OMe Ph
MeOMe
POCl3, DMF
NH
OMe Ph
MeO
O
NH
OMe Ph
MeOMe
OH
NaBH4
HN
OMe
NH
MeO
MeMe
PhPh
OMe MeO
H+
HN
OMe
NH
MeO
OO
PhPh
76
OMe MeO
80
77 78 79
SeO2
Dioxan
MeOHMe
H
H H
Chapter 2 20
The dimerization in the N-bromosuccinimide reaction was unpredicted as similar self-
condensations of hydroxymethylindoles to give diindolylmethanes were only observed
under acid-catalyzed conditions.10,58 In this case, the reaction starts off under neutral
conditions, but formation of hydrobromic acid during the oxidation step, could
catalyze the process presumably to that proposed by Black et al.10 Another possibility
is that the 7-bromomethylindole 73 could have been formed in the reaction and
reacted further to produce the diindolylmethane 76, as only one equivalent of the N-
bromosuccinimide was used in the reaction.
An interesting feature of the reaction is the oxidation of the C-2-alcohol by N-
bromosuccinimide. Although, it is not a common procedure for the oxidation of an
alcohol to an aldehyde, there exist some literature reports on this transformation.76,77
However, the mechanism of oxidation of alcohol by N-bromosuccinimide is at present
not fully understood.78 Most investigations into N-bromosuccinimide oxidation of
organic substances have assumed that the molecular N-bromosuccinimide acts only
through its positive polar end, producing bromonium ion Br+,79,80 which is
subsequently solvated. Thus, H2OBr+ has been considered an effective oxidizing
species of N-bromosuccinimide in acidic medium.78,79 Filler et al. reported the
positive halogen as the attacking species, but argued about the site of attack.76 He
suggested that alcohol forms a hypobromite which readily loses hydrogen bromide to
form the aldehyde; alternatively oxidation proceeded through bromide substitution of
hydrogen on the carbon atom bearing the hydroxyl group, with rapid loss of hydrogen
bromide. Recently, Hiran et al. 78 proposed two different mechanisms, firstly
involving a cyclic transition state with unprotonated N-bromosuccinimide in the
absence of acid, and secondly involving a noncyclic transition state with protonated N-
bromosuccinimide in the presence of acid.
Evaluating the above references and the reaction conditions, the following mechanism
(Scheme 2-19) was proposed for the formation of the products 75 and 76. It is known
that the C-7 alcohol forms a weak hydrogen bond with the NH proton. Thus, it was
assumed that the C-2 alcohol would be oxidized preferentially over the C-7 alcohol by
N-bromosuccinimide. The postulated mechanism involves attack of N-
bromosuccinimide on the C-2 alcohol group and the loss of hydrobromic acid for
Chapter 2 21
example to give the 2-aldehyde 81. This hydrobromic acid could protonate the C-7
alcohol group, and subsequent loss of a water molecule would produce a benzylic
cation, which then could undergo electrophilic attack from another indole at position
C-7. Loss of a proton and formaldehyde would restore the aromaticity to the molecule,
and yield the observed product 76.
Scheme 2-19
NH
OMe Ph
MeO ONBr
NH
OMe Ph
MeONH
-HBr
NBS
NH
OMe Ph
MeO
H+
-H2O
OH
H
H
H
OH
H
O
H
NH
OMe Ph
MeO O
H
H H
HN
OMe Ph
MeO H
O
CH2
NH
OMe
MeO
Ph
HN
OMe Ph
MeOHO
H
O
O
H
HO
-H+
-HCHO HN
OMe
NH
MeO
OO
Ph
OMe MeO
Ph
HH
-
76
65
OH2
O
81
The 7,7'-diindolylmethane-2,2'-dicarbaldehydes 75 and 76 were then reduced in high
yields respectively to the 7,7'-diindolylmethane-2,2'-dialcohols 82 and 83 (Scheme 2-
20). The dialcohols 82 and 83 were notably identified by the absence of aldehyde
protons and the presence of hydroxyl and methylene protons in the 1H NMR spectra.
The 7,7'-diindolylmethane-2,2'-dialcohol 82 was then reacted with acetic acid in
Chapter 2 22
anhydrous tetrahydrofuran for attempted synthesis of calix[4]indole 84 by acid
catalyzed condition.
Scheme 2-20
NH
OMe
HN
OMe
O
O
R
MeO
MeO
RH
H
NH
OMe
HN
OMe
OH
OH
R
MeO
MeO
R
NaBH4NH
OMe
HN
OMe R
MeO
MeO
R
NH
OMe
HN
OMeR
OMe
OMe
R
84
H+
75; R = Br76; R = H
82; R = Br83; R = H
6-18 hMeOH
However, under the applied acidic conditions the reaction yielded a polymer
suggested to have structure 85 (Scheme 2-21). This result is not unanticipated and
very likely to happen to this highly activated molecule.
Scheme 2-21
NH
HN
HO
MeO
OMe
NH
MeO
HN
OH
MeO
OMeBr
Br
Br
Br
NH
OMe
HN
OMe
OH
OHMeO
MeO
82
AcOH
Br
Br
OMe
OMeMeO
85
THF6 h
On the other hand, the unsymmetrical calix[3]indole 86 was prepared by reacting the
7,7'-diindolylmethane-2,2'-dialcohol 82 with a molecule of indole 47 in 64 % yield
(Scheme 2-22). This is an alternate approach to that shown in Scheme 2-3. A
molecular ion at m/z 1032 in the MALDI mass spectrum in 4HCCA matrix confirms
the formation of the calix[3]indole 86 (Figure 2-1).
Chapter 2 23
Scheme 2-22
AcOHNH
OMe
HN
OMe
OH
OHMeO
MeO
82
Br
Br
NH
OMe
MeO
Br
+
NH
OMe
HN
OMe
MeO
MeO
Br
Br
HN OMe
OMe
Br
86
47
THF, 1 h
Figure 2-1 MALDI mass spectrum of calix[3]indole in a matrix of -cyano-4-
hydroxycinnamic acid
The 7,7'-diindolylmethane-2,2'-dicarbaldehyde 76 is an important intermediate and
can also potentially serve as a precursor for a variety of ligand synthesis, for example
the ligands 87 and 88 using different equivalents of 1,2-diaminobenzene (Scheme 2-
23) and similarly various other diamines. So, there is now a new scope for a future
exploration of ligand synthesis and their metal complexation properties.
10 1 7 .0 1 0 22 .6 1 02 8 .2 1 03 3 .8 1 0 39 .4 1 04 5 .0Mas s (m/z )
66 9 .1
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
% In
tens
ity
Vo yag er Sp ec #1= > BC= > BC[BP = 212.1, 27882]
1 0 32 .09
1 0 33 .1 110 3 1 .1 41 0 30 .1 1
1 02 9 .1 0
1 03 4 .1 1
10 3 5 .0 4
1 02 8 .1 71 0 17 .1 6
1 04 3 .2 8
10 2 4 .9 2
Chapter 2 24
Scheme 2-23
NH2
NH2
1 eq.
NH2
NH2
2 eq.
HN
OMe
NH
MeO
PhPh
OMe MeO
NHN NHN
Metal complexes
76
88
87
MII salts
MIV salts
HN
OMe
NH
MeO
OO
Ph
OMe MeO
Ph
HH
HN
OMe
NH
MeO
NN
Ph
OMe MeO
Ph
HH
2.7. Attempted conversion of activated hydroxymethyl indoles to sulfonyl
derivatives
Sohar et al. reported the preparation of oxathiazine ring systems 90, 91 by reacting
amino alcohol 89, respectively with thionyl chloride and sulfuryl chloride in the
presence of triethylamine (Scheme 2-24).81 These types of oxathiazine compounds are
highly sensitive to nucleophilic attack.82-84
Scheme 2-24 MeO
MeONH
OHR1
R2R1 = H, MeR2 = H, Me MeO
MeON
OR1
R2R1 = H, MeR2 = H, Me
SO
O
MeO
MeON
OR1
R2R1 = H, MeR2 = H, Me
SO
SOCl2, Et3NSO2Cl2, Et3N
89
90 91
Chapter 2 25
Therefore, if similar compounds such as the indole oxathiazines 92 and 93 could be
prepared, they might act as new precursors of new structures 94 yielding calixindoles
(Scheme 2-25). Attempts to prepare the oxathiazinoindoles 92 and 93 by reactions of
7-hydroxymethylindole 26 with thionyl chloride and sulfuryl chloride led to the
isolation of green polymeric products, which could not be characterized. Direct
reactions and those in the presence of bases such as potassium carbonate or
triethylamine gave similar results. Either polymeric compounds or unseparable
complex mixtures were obtained from these reactions.
Scheme 2-25
SO
NH
OMe
MeO
OH
Br
N
OMe
MeO
O
Br
N
OMe
MeO
O
Br
SOCl2 SO2Cl2
S O
ONu- Nu-
N
OMe
MeO
Br
SN
OMe
MeO
Br
SONu Nu O
OO O
NH
OMe
MeO
Br
Nu
-SO2
H+H+
-SO3
26
94
9392
Thereafter, reactions of dihydroxymethylindole 64 with thionyl chloride and sulfuryl
chloride were also investigated in an attempt to achieve a less reactive product and
also to observe any reactivity preference towards the C-2 or C-7 alcohol. However,
after the reactions with thionyl chloride and sulfuryl chloride, with or without the
potassium carbonate/triethylamine base none of the desired products could be isolated.
Chapter 2 26
2.8. Attempted synthesis of oxazinoindoles
Using a similar approach, the preparation of the 4,6-dimethoxyoxazinoindole 95
(Scheme 2-26) could also generate compounds suitable to undergo nucleophilic
attack,85 and therefore provide an alternate leaving group at the C-7 methylene
position of the indole 94 as shown in the following scheme.
Scheme 2-26
NH
OMe
MeO
OH
Br
N
OMe
MeO
O
Br
Cl3COCOCl
Nu-
NH
OMe
MeO
Br
Nu
H+
-CO2
26 95
O
N
OMe
MeO
Br
Nu O O
94
The approach undertaken for the synthesis of the oxazinoindole 95 from the 7-
hydroxymethylindole 26, was similar to the procedure of Heydenreich et al. 86 and
Sohar et al..87 It has been reported that treatment of an electron rich aromatic amino
alcohol 96 with formaldehyde directly gave oxazinoisoquinoline 97. The oxo
derivative 98 was obtained from 96 either A) in a two step reaction, firstly with ethyl
chloroformate and sodium bicarbonate in toluene and water, secondly with sodium
methoxide; or B) in a one step reaction with phosgene (Scheme 2-27).86,87
Scheme 2-27
NH
MeO
MeOOH
N
MeO
MeOO
N
MeO
MeOO
O
HCHO, MeOH, H2O
A) i) ClCOOC2H5, NaHCO3, H2O, toluene ii) NaOMeor B) Phosgene
r.t., 1h
96
98
97
Chapter 2 27
Kurahashi et al. reported that 7-hydroxymethyl-2,3-dihydroindole and
trichloromethylchloroformate in ethyl acetate under reflux gave the respective oxazine
derivative.88 Coppola and others have used trichloromethylchloroformate
(diphosgene) or phosgene with aqueous base to prepare the oxazines.85,89,90 In the case
of an indole, the nitrogen anion must first be formed by reaction with base. In an
attempt to prepare the oxazinoindole 95, 7-hydroxymethylindole 26 was reacted with
trichloromethylchloroformate in the presence of bases such as potassium carbonate or
triethylamine, but a complex mixture of compounds was obtained, from which no pure
product could be isolated.
On the other hand, the reaction of 7-hydroxymethylindole 26 with formaldehyde in a
solution of methanol overnight, surprisingly gave an ether linked dimer 99 (Scheme
2-28). The 1H NMR spectrum exhibited a symmetrical structure and methylene
protons which are indicative of the compound 99. An ether peak at 1202 cm-1 was
seen in the infrared spectrum of the compound. An HRMS molecular ion peak m/z at
729.0323 for [M+Na]+ represents the confirmation of the diindolyl ether 99.
Scheme 2-28
NHMeO
OMe
OH
HCHO/MeOH
26
Br
99
HN
OMe
MeO
BrNH
MeO
OMe
Br
O
r.t., 24 h
It is assumed that the benzylic cation 100 reacted with another molecule of 7-
hydroxymethylindole 26 to form the diindolyl ether 99 (Scheme 2-29). Conversion of
an alcohol to the corresponding ether is a widely used functional transformation in
organic synthesis. Most commonly the O-alkylation reactions are carried out by using
alkyl halides (Williamson ether synthesis).91 Recently, a synthetic method has been
reported to prepare symmetrical and unsymmetrical ethers by coupling two alcohols
via oxidation-reduction condensation using fluoranil.92 The easy procedure outlined
above can be an addition to these syntheses, but needs further attention and
explanation.
Chapter 2 28
Scheme 2-29
99
HN
OMe
MeO
Br
NH
OMe
MeO
Br
O
NHMeO
OMe
OH
HCHO
MeOH
26
Br
NHMeO
CH2
OMe
Br
100
2.9. Future approaches towards calixindoles
Although the attempts so far made have failed to yield an indole with an alternate
leaving group, there are still other possibilities that could be investigated in future. A
likely precursor for calixindoles could be the indole-7-methylacetate 101, which could
possibly be synthesized from 7-hydroxymethylindole 26 with acetyl chloride (Scheme
2-30).
Scheme 2-30
NH
OMe Ar
MeONH
OMe Ar
MeO
OH
CH3COCl Calixindole ??
10126OCOCH3
Another potential precursor for calixindoles could be the trimethylammonium salt
104. This could be synthesized from indole 47 by reaction with tetramethylurea and
phosphoryl chloride to form the carboxamide 102, which could then be reduced to the
corresponding dimethylmethanamine 103 by lithium aluminium hydride, and then be
methylated to produce the ammonium salt 104. The salt 104 could then possibly lead
to calixindoles on treatment with base. The indole-7-carboxamide 102 could also be
prepared from 7-trichloroacetylindole 105 and dimethylamine. In alternate approach
Chapter 2 29
to compound 102 could be from the indole-7-carboxylic acid 107, by reaction with
phosphoryl chloride and dimethylamine, the acid being prepared from 7-
trifluoroacetylindole 106 by base treatment (Scheme 2-31). However, this sequence
was not studied due to time constraints.
Scheme 2-31
NH
OMe Ar
MeO NH
OMe Ar
MeO
NMe2
Me2NCONMe2
POCl3
O
LiAlH4
NH
OMe Ar
MeO
NMe2
NH
OMe Ar
MeO
NMe3
MeI
NaOEt
Calixindole ??
102 103
104
47
NH
OMe Ar
MeO
105
NH
OMe Ar
MeO
47
O CCl3
Me2NH
Cl3CCOCl
NH
OMe Ar
MeO
107
NH
OMe Ar
MeO
106
O OH
KOH
O CF3
(COCF3)2O
POCl3Me2NH
2.10. Dakin oxidation of indole-7-carbaldehydes
Indoloquinones are an interesting and important class of bioreductive alkylating
agents because they and their derivatives play a vital role in some biosynthetic
process.93 Moreover, these compounds are found as structural units of natural
compounds such as in antibiotics (e.g. kinamycin C 108),94 compounds having
antifungal and cytotoxic activity (e.g. isobatzellin C 109),95 and antitumor activity
(e.g. discorhabdin C 110, mitomycin C 111)96-98 (Figure 2-2). As a consequence of
this the indoloquinones have been subjected to intense analogue development by
Chapter 2 30
different synthetic groups for many years, and a range of 4,7-indoloquinones has been
synthesized as potential antitumor agents.99-103
NH
N
ONH
OBrBr
Discorhabdin C (110)
NCN
O
O
N
O
H3COOH
OAc
CH3
OH
OAcAcO
Kinamycin C (108)
H2N OMe
NH
ONH2
O
Mitomycin C (111)
N
N
O
Cl
H2N
Isobatzellin C (109)
CH3
Figure 2-2. Structures of some natural bioactive indoloquinones
Examples of some synthetic 4,7-indoloquinones are shown in the Figure 2-3. Saa et
al. reported the synthesis of 6-methoxy-3-methylindoloquinone 112 from 4-formyl-7-
hydroxy-6-methoxyindole by reaction with Fremy’s salt.101 Whereas, several series of
potential antitumor compounds such as cyclopentindoloquinone 113 and
indoloquinone E09 114 have also been synthesized by Skibo et al. from the 4-
aminoindoles by Fremy’s salt oxidation.99 However, these procedures bear some
limitations. For example, several steps are required by Saa’s approach, while Skibo’s
methods required a nitration step, which sometimes lacks selectivity. Thus, an
alternate general method for the preparation of 4,7-indoloquinones is a desirable goal.
NH
O
NO
Cyclopentindoloquinone (113)
N
O
O
NOH
OH
Me
Indoloquinone E09 (114)
NH
O Me
MeOO
6-methoxyindoloquinone (112)
Figure 2-3. Structures of some synthetic 4,7-indoloquinones
Dakin oxidation allows the preparation of phenols from aryl aldehydes or aryl ketones
via oxidation with hydrogen peroxide. Some preliminary studies on the application of
the Dakin reaction on the 2,3-diphenyl-4,6-dimethoxyindole-7-carbaldehyde 60 have
been carried out by Mitchell.104 The reaction of 2,3-diphenyl-4,6-dimethoxyindole-7-
carbaldehyde 60 with hydrochloric acid and hydrogen peroxide in a solution of
Chapter 2 31
methanol and tetrahydrofuran in two hours gave the 6-methoxy-4,7-indoloquinone
118 as a crude product in 80% yield and in a moderate yield (57%) after
recrystallization (Scheme 2-32). Further oxidation of the indoloquinone 118 was not
observed in the presence of excess hydrogen peroxide. In a similar way, 4,6-
dimethoxyindole-7-carbaldehydes 59, 115, and 116 produced respectively the desired
6-methoxy-4,7-indoloquinones 117, 119 and 120 in 70-80% crude yields and 47-59%
yields after recrystallization from ethanol. Treatment of base during workup was not
required as described earlier.
Scheme 2-32
59; R1 = CH3; R2 = CH360; R1 = Ph ; R2 = Ph115; R1 = CH3; R2 = Ph116; R1 = H; R2 = CH3
NH
R2
MeO NH
O R2
MeOO
H2O2/HCl
MeOH/THF
OMe
O
R1 R1
117; R1 = CH3; R2 = CH3118; R1 = Ph ; R2 = Ph119; R1 = CH3; R2 = Ph120; R1 = H; R2 = CH3
H
r.t., 2 h
The modified Dakin method was found to be quite general for other 3-aryl-4,6-
dimethoxyindole-7-carbaldehydes 57, 58, 121, 122 and 123. Although, these indoles
contain a reactive C-2 position, the reaction proceeded smoothly and the desired 4,7-
indoloquinones 124-128 were obtained as analytically pure compounds from the
corresponding indole-7-carbaldehydes in moderate yields (50-65%) after
recrystallization from ethanol/methanol (Scheme 2-33).
Scheme 2-33
r.t., 2 hNHMeO N
H
O
MeOO
H2O2/HCl
MeOH/THF
OMe
O
57; R = Br58; R = Cl121; R = MeO122; R = tert-butyl123; R = Ph
RR
124; R = Br125; R = Cl126; R = MeO127; R = tert-butyl128; R = Ph
H
Chapter 2 32
Similarly, the tetrahydrocarbazole-1-carbaldehyde 130, when reacted with hydrogen
peroxide in the presence of hydrochloric acid, in methanol and tetrahydrofuran
solution produced the 1,4-dione 131 in 50% yield (Scheme 2-34). As reported
previously105, the tetrahydrocarbazole-1-carbaldehyde 130 was synthesized from the
corresponding indole 129 by Vilsmeier formylation in 80% yield.
Scheme 2-34
r.t., 2 hNHMeO
H2O2/HCl
MeOH/THF
OMe
O
NH
O
MeOO
130 131
H
NHMeO
OMe
129
POCl3/DMF
1 h
The 7,7'-dicarbaldehyde-2,2'-bisindolyl 132 can also be oxidized to give the
bisindoloquinone 133 (Scheme 2-35). However, in this case a longer time (four hours)
is required compared to the previous indoles for the completion of the reaction.
Scheme 2-35
r.t., 4 h
H2O2/HCl
MeOH/THF
NHMeO N
H OMe
OMe
BrBr
NHMeO
O
NH OMe
O
O O
BrBr
OMe
O O
132 133
H H
The indoloquinones were mostly orange to bright red or deep burgundy solids and
showed high melting points. The structures were identified particularly by the
disappearance of the sharp methoxy and aldehyde proton resonances in the 1H NMR
spectra and the upfield shift of the H-5 proton resonances to ~5.7 ppm. In the 13C
NMR spectra of the products it was significant to observe the presence of a single
methoxy carbon at ~56 ppm. The carbonyl resonance at ~183 ppm represents the C-4
carbonyl carbon, that of ~171 ppm represents the C-7 carbonyl carbon, and that of
~159 ppm represents the C-6 carbon. The infrared bands at ~1660 cm-1and ~1630 cm-1
represent the carbonyl group frequencies of the quinone functionality (Table 2-1).
Chapter 2 33
Table 2-1. Significant H and C chemical shift and C=O values of the indoloquinones.
Indoloquinone O-Me H5 H2 N-H C4 C6 C7 C=O (cm-1)
117 3.71 5.63 - 12.35 184.98 160.19 172.70 1666/1633
118 3.76 5.74 - 13.07 183.28 159.70 171.25 1660/1640
119 3.73 5.67 - 12.71 183.48 159.46 170.70 1665/1637
120 3.71 5.67 6.34 12.23 184.91 N/A 172.70 1661/1637
124 3.75 5.80 7.51 13.01 183.50 159.26 171.66 1665/1628
125 3.84 5.80 7.54 13.01 183.52 159.25 171.66 1663/1624
126 3.75 5.78 7.44 12.91 183.51 159.26 171.49 1665/1634
127 3.75 5.79 7.56 12.89 183.51 159.27 171.26 1662/1632
128 3.77 5.83 7.58 13.02 183.53 159.27 172.80 1664/1631
131 3.77 5.60 - 9.57 184.62 159.97 170.38 1661/1628
The mechanism for the formation of the indoloquinone could involve a peroxy hemi-
acetal intermediate106 135 produced in the acidic environment of the methanolic
solution (Scheme 2-36). The intermediate 135 is then thought to be oxidized to the
indolophenol 136, and further oxidation by the excess hydrogen peroxide leads to the
6-methoxy-4,7-indoloquinone 137.
Scheme 2-36
NH
Ar
MeO
OMe
O
NH
Ar
MeO
OMe
H OCH3OOH
H
H2O2/H+
NH
Ar
MeO
OMe
H OCH3O
H+
NH
Ar
MeOOH
OMe
NH
O Ar
MeOO
H2O2
OHH
aryl migration
135134
137 136
MeOH
Chapter 2 34
2.11. Conclusions
Whilst the aim of this part of the project relating to the synthesis of indole
macrocycles via alternate leaving groups has not been achieved, an alternate way to
prepare calix[3]indole 86 was demonstrated. In addition, the synthesis of new 7,7'-
diindolylmethane-2,2'-dicarbaldehydes 75, 76 gives potential for new ligand design
and metal complex formation. Finally, the synthesis of indoloquinones by Dakin
oxidation of indole-7-carbaldehydes was found to be general and can be applied to a
variety of functionalized indoles, yielding products which are inaccessible by other
methods.
Chapter 3 35
CHAPTER 3
SYNTHESIS AND REACTIVITY OF ACTIVATED BENZIMIDAZOLES
3.1. Introduction
Benzimidazole is the fused aromatic imidazole ring system, where a benzene ring is
fused to the 4 and 5 positions of an imidazole ring. Benzimidazoles are sometimes
called by other names such as benziminazole and 1,3-benzodiazole. They possess both
acidic and basic characteristics. The –NH- group in benzimidazole is very weakly
basic and relatively strongly acidic, and benzimidazoles are able to form salts.107,108 A
set of resonance structures drawn for benzimidazole shows its amphoteric nature, and
implies that electrophilic attack will be either at N-1 or in the benzene ring;
nucleophilic attack at C-2 is predicted (Figure 3-1).108
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
N
Figure 3-1. Resonance structures for benzimidazole
Evidence of tautomerism in the benzimidazole ring has been reported.107
Benzimidazoles unsubstituted on nitrogen exhibit fast prototropic tautomerism, which
leads to equilibrium mixtures of unsymmetrically substituted compounds. For
example, 4,6-dimethoxybenzimidazole 10 tautomerises to a non-identical structure
5,7-dimethoxybenzimidazole 138 (Figure 3-2).
NH
N
OMe
MeO
HN
N
10 138
OMe
MeO
Figure 3-2. Tautomerism of 4,6-dimethoxybenzimidazole 10.
Chapter 3 36
It has been reported earlier that 3-substituted-4,6-dimethoxyindoles 4 have two
activated sites at C-2 and C-7 for electrophilic aromatic substitution.1 4,6-
Dimethoxybenzimidazoles 10 are similarly active at C-7, but the C-2 position is not
nucleophilic enough for electrophilic aromatic substitution. Therefore, similar
reactions to those carried out on indoles at their C-7 positions could be applied to 4,6-
dimethoxybenzimidazole 10. Replacement of the C-3 aryl group in indoles with a
nitrogen atom in benzimidazoles provides different steric features and basicity to the
molecule, and therefore could influence its chemistry, making it different from the
indoles. Therefore, it was of interest to investigate the C-7 reactivity of this new ring
system towards formylation, acylation, nitration, oxidation and metal complex
formation in addition to comparing the results with those for the related indoles.
NH
OMe
MeO
4
NH
N
OMe
MeO
10
R
Figure 3-3. Chemical structure of activated indole 4 and benzimidazole 10.
Benzimidazole compounds have a wide range of biological activities, ranging from
widely used anthelmintics109 to anticancer properties.110 The spectrum of the
pharmacological activity of benzimidazoles has been reviewed by several authors.111-
114 For example, the 4,6-dimethoxybenzimidazole 139 and 5,7-
dimethoxybenzimidazole 140 derivatives of 6,11-dihydrodibenzoxepin-2-carboxylic
acid (Figure 3-4) showed non-prostanoid thromboxane A2 (TXA2) receptor
antagonist behaviour.115
NN
MeO
OMe
NN
OMe
MeO
COOH
O
COOH
O
139 140
Figure 3-4. Activated benzimidazole derivatives as TXA2 receptor antagonists
Chapter 3 37
3.2. Preparation of 4,6-dimethoxybenzimidazoles
Previous researchers in our laboratories have synthesized a series of 2-substituted-4,6-
dimethoxybenzimidazoles 10, 141-144 (Figure 3-5). Bowyer116 first did the initial
studies on the preparation of 4,6-dimethoxybenzimidazoles, whereas Martinovic,117
Wood118 and Condie119 have synthesized a series of 4,6-dimethoxybenzimidazoles and
studied mainly their 7-formylation, reduction of the resulting 7-aldehydes to alcohol
and acid catalyzed conversion of the alcohols to 7,7'-dibenzimidazolylmethanes.
Furthermore, Condie119 studied the N-substitution of the benzimidazoles, and prepared
a 4,5,6 trimethoxybenzimidazole 145, while Sholohin120 prepared 2,2'-
dibenzimidazolylmethanes 146, 147 and investigated the synthesis of cyclic metal
complexes prepared from compound 147 as epoxidation catalysts.
NH
N
OMe
MeOR
10; R = H141; R = CH3142; R = Ph143; R = CH2Ph144; R = t-butyl
N
NHMeO
OMe
N
NH OMe
OMeR R
146; R = H147; R = CH3
NH
N
OMe
MeOPh
MeO
145
Figure 3-5. Structures of some 4,6-dimethoxybenzimidazoles
Various methods have been described for the synthesis of benzimidazoles.108
Benzimidazoles have most commonly been prepared from 1,2-diaminobenzenes
reacting with carboxylic acids or acid derivatives.107 An alternative method involves
the cyclization of a 2-aminoanilide derivative.108 However, synthesis of the 4,6-
dimethoxybenzimidazoles in this thesis was carried out using the procedure developed
by Bowyer116 and Martinovic117 (Scheme 3-1) with minor modifications.
The amino group of 3,5-dimethoxyaniline 39 was first formylated with an excess of
formic acid to protect the molecule from the next nitration step. Nitration of the
formanilide 148 at the C-2 position was carried out using nitric acid in acetic
anhydride to give the 2-nitroformanilide 149. The formyl group was removed by
Claisen’s base (methanolic potassium hydroxide) to give the 2-nitroaniline 150, which
Chapter 3 38
was then reduced to the 1,2-diaminobenzene 151 by palladium-catalyzed hydrazine
reduction. The 4,6-dimethoxybenzimidazole 10 was prepared by reacting the
diaminobenzene 151 with formic acid in 73 % yield (Scheme 3-1). The formanilide
148 exists in two geometric isomeric forms, due to restricted rotation of the amide
bond as evidenced by the 1H NMR spectrum. These isomers are usually not separable
due to the relatively low barrier to rotation (20 kcal/mole).121 The preparation of this
formanilide was observed to be fast even at room temperature, the reaction was
complete within half an hour and does not require four hours refluxing conditions as
used previously.
Scheme 3-1
NH2
OMe
MeO NH
OMe
MeO
NH2
NO2
OMe
MeONH2
NH2
OMe
MeONH
N
OMe
MeO
O NH
OMe
MeO O
NO2HCOOH HNO3/Ac2O
KOH/MeOHreflux, 1 h
Pd/CNH2NH2.H2OHCOOH
39 148 149
15015110
H H
EtOH, reflux, 1 h
r.t., 0.5 h 0oC, 0.5 h
100oC, 2 h
Use of a large excess of the solvent acetic anhydride in the nitration step and a longer
stirring time during aqueous workup resulted in the hydrolysis of 2-nitroformanilide
149 in situ and yielded the 2-nitroaniline 150 in 67 % yield.
The other 2-substituted benzimidazoles were prepared via a slightly different route
(Scheme 3-2). In this modified route the 3,5-dimethoxyaniline 39 was first acylated
with respective acid chlorides to give the amides 152-154 in moderate to high yields.
These could then be nitrated, using nitric acid in acetic anhydride to produce the 2-
nitroanilides 155-157 in usually high yields 70-83%. The 2-nitroanilides were then
reduced to 2-aminoanilides 158-160 with palladium-catalyzed hydrazine reduction,
and were immediately cyclized by acid catalysis to give the corresponding 2-
substituted-4,6-dimethoxybenzimidazoles 141, 142 and 161 in high yields 75-87%.
Chapter 3 39
Scheme 3-2
EtOH, Reflux, 1-2 h
0oC, 0.5 hNH2
OMe
MeO NH
OMe
MeO
NH
NH2
OMe
MeONH
N
OMe
MeO
O NH
OMe
MeO
NO2RCOCl, K2CO3 HNO3/Ac2O
Pd/CNH2NH2.H2O
39 152; R = Me153; R = Ph154; R = 4-MeOC6H4
155; R = Me156; R = Ph157; R = 4-MeOC6H4
R
O R
O R158; R = Me159; R = Ph160; R = 4-MeOC6H4
141; R = Me142; R = Ph161; R = 4-MeOC6H4
H+/EtOHR
DCM, 2 h
Reflux, 3-8 h
The following table (Table 3-1) displays the significant chemical shift values ( H) of
the benzimidazoles and their starting anilides.
Table 3-1. Chemical shift values ( H) of the benzimidazoles and starting anilides.
Product Yields (%) O-Me H2,H6/H7 H4/H5 N-H
148 85 3.78, 3.78 6.25,6.76 6.20 7.08,7.49
152 91 3.77 6.73 6.23 7.10
153 83 3.80 6.89 6.28 7.74
Anilide
154 69 3.77 6.89 6.25 7.79
149 90 3.88, 3.90 7.74 6.32 9.15
155 70 3.86, 3.88 7.69 6.27 9.15
156 73 3.92, 3.93 7.99 6.32 10.32
Nitroanilide
157 83 3.90, 3.91 7.97 6.28 10.26
Aminoanilide 158 90 3.77, 3.81 5.79 5.70 8.33
159 90 3.78, 3.84 7.08 6.34 8.35
160 98 3.80, 3.83 6.89 6.29 8.39
10 73 3.84, 3.96 6.71 6.39 -
141 75 3.80, 3.89 6.61 6.33 9.00
142 87 3.77, 3.87 6.67 6.35 10.31
Benzimidazole
161 79 3.78, 3.85 6.58 6.32 10.28
Chapter 3 40
It is essential that the nitration step should be carried out carefully at 0-5oC and slow
addition of the nitrating agent is important to avoid di-nitration. Use of a previously
cooled and mixed nitric acid in acetic anhydride, and use of an ice/salt bath as a
cooling medium improved the temperature control, which resulted in significantly
reduced yield of the di-nitrated products. However, a very small amount of di-nitrated
product was observed on the TLC and in the 1H NMR spectrum of the crude product,
which however could be purified easily by recrystallization from ethanol/water. The
acetanilide 152 can be prepared both from acetyl chloride or acetic anhydride, the
latter procedure being preferred for easy recovery of the product, and also because the
subsequent nitration step could be done in the same pot without purification of the
acetanilide 152.
Martinovic and Wood prepared the benzimidazole 142, in a different way117,118
(Scheme 3-3), to that described above. They started with nitroaniline 150, reacting it
with benzoyl chloride to get the nitrobenzamide 156. Reduction of amide 156 gave the
aminoanilide 159 which was cyclized to the benzimidazole 142 by refluxing in
ethanolic hydrochloric acid. This procedure is also general, compared to that shown in
Scheme 3-2 but has two additional steps. The aminoanilides 158-160 were isolated
and characterized, but usually the subsequent cyclization reaction can be carried out
directly and without their purification.
Scheme 3-3
NH2
OMe
MeO
NH
NH2
OMe
MeO
NH
OMe
MeO
NO2PhCOCl
Pd/CNH2NH2.H2OEtOH
150 156O Ph
O Ph159
HCl/EtOH
NO2
NH
N
OMe
MeO
142
Ph
Chapter 3 41
In an attempt to find an alternate and quick reduction and cyclization sequence for the
2-nitroanilides 155-157, the 2-nitrobenzamide 156 was reacted with stannous chloride
dihydrate and hydrochloric acid in a single step, and after workup and
chromatography gave the benzimidazole 142 in low yield. Although this sequence
(Scheme 3-4) has the advantages of limited number of steps and time, it was not
considered further due to low yields (18 %) and need for chromatography to isolate
the products.
Scheme 3-4
NH
N
OMe
MeO
142
PhNH
OMe
MeO
NO2
156O Ph
SnCl2.2H2O/ HCl
EtOH, reflux, 3-8 h
In the case of benzimidazole 10, a tautomeric mixture of benzimidazoles 10 and 138
was observed in a 9:1 ratio in the 1H NMR spectrum using CDCl3, and the NH proton
could not be observed. Usually the NH protons were observed as broad singlets, but
sometimes they were not visible. However, it was found that the 4,6-tautomer 10 was
dominant over the 5,7-tautomer 138 (Figure 3-2). The H-5 and H-7 protons of the
benzimidazoles appeared in the 1H NMR spectra as meta coupled doublets. The
phenyl protons in the benzimidazole 161 were observed as an AB system,
characteristic of 1,4-disubstituted benzenes.
3.3. Formylation of 4,6-dimethoxybenzimidazoles and reduction of the
corresponding benzimidazole aldehydes
Sun et al. reported122 the preparation of 5-formylbenzimidazole, accomplished by
reduction of benzimidazole-5-carboxylic acid to 5-hydroxymethylbenzimidazole by
lithium aluminium hydride, followed by oxidation of the benzylic alcohol with
tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide. The procedure
is long and not general; however we have previously shown that the Vilsmeier-Haack
reaction is effective for the formylation of activated indoles (Scheme 2-10).
Vilsmeier-Haack formylation of the 3-arylindoles with one equivalent of reagent at
0oC for one hour gave a predominance of the 7-carbaldehyde over the 2-carbaldehyde,
Chapter 3 42
while two equivalents of reagent produced the corresponding 2,7-dicarbaldehyde.58
Formylation of 2,3-diphenylindole exclusively occurs at C-7 to give the 7-
carbaldehyde in 82% yield,1 which is more similar to the 4,6-dimethoxy-2-substituted-
benzimidazoles, as they both have only one reactive site at C-7.
Treatment of the 4,6-dimethoxybenzimidazoles 10, 141, 142 and 161 with Vilsmeier
formylating reagent respectively afforded the benzimidazole-7-carbaldehydes 162-165
(Scheme 3-5). It was observed that the benzimidazoles required more vigorous
reaction conditions than the indoles. They required two equivalents of the formylating
reagent, higher reaction temperatures (65-70oC), and longer reaction times (12-24 h),
when compared to the indole cases (Table 3-2). An exception of 2-
methylbenzimidazole 141, can be only formylated with 1.1 equivalent of the
formylating reagent, as the presence of two equivalents results in side reactions at the
active 2-methyl functional group. Formylation of benzimidazoles with 2-aryl
substituents generally afforded higher yields (75-80%).
Scheme 3-5
NH
N
OMe
MeORPOCl3/DMF
NH
N
OMe
MeO
10; R = H141; R = Me142; R = Ph161; R = 4-MeOC6H4
R
OH
162; R = H163; R = Me164; R = Ph165; R= 4-MeOC6H4
65-70oC, 18-24 h
Evidence for the formation of benzimidazole-7-carbaldehydes 162-165 was obtained
from their 1H NMR spectra showing the disappearance of the meta coupled doublets
~6.60 ppm corresponding to H-7 of the starting benzimidazoles, and the presence of
the 7-formyl proton near ~10.30 ppm. The H-5 protons now appeared as singlets in
the benzimidazole-7-carbaldehydes 162-165. The carbonyl absorption frequencies
were observed at ~1631 cm-1in the infrared spectra.
Chapter 3 43
NH
N
OMe
MeOR
OH
NH
OMe
MeOR2
OH
R1
BenzimidazoleIndole
Table 3-2. Comparison of the formylation of indoles and benzimidazoles.
65-70oC 0oC CHO (ppm)
Indoles
57; R1=4-BrC6H4,R2 =H - 1.5 h, 1.1 eq., 94% 10.38
58; R1=4-ClC6H4,R2 =H - 1.5 h, 1.1 eq., 93% 10.39
59; R1,R2 = Me - 1.5 h, 1.1 eq., 55% 10.30
60; R1,R2 = Ph - 2 h, 1.1 eq., 87% 10.40
61;R1=4-BrC6H4,
R2 =CHO
16 h, 5 eq., 86% - 10.38, 9.55
62;R1= Ph, R2 =CHO 2 h, 2.2 eq., 92% - 10.39, 9.56
Benzimidazoles
162; R = H 18 h, 2 eq., 51% - 10.30
163; R = CH3 24 h, 1.1 eq., 49% - 10.28
164; R = Ph 18 h, 2 eq., 82% - 10.33
165; R = 4-MeOC6H4 18 h, 2 eq., 80% - 10.30
Tautomerism was not observed in the case of 4,6-dimethoxybenzimidazole-7-
carbaldehydes 162-165. The reason could be that the NH is hydrogen bonded to the
formyl oxygen (Figure 3-6), to give the 4,6-dimethoxy tautomer more stability, which
is not possible to the alternate 5,7-dimethoxy tautomer.
N
N
OMe
MeOR
OH
N
HN
OMe
MeOR
OHH
4,6-dimethoxy tautomer 5,7-dimethoxy tautomer
Figure 3-6. Hydrogen bonding of the 7-formyl-4,6-dimethoxybenzimidazole
Chapter 3 44
The benzimidazole-7-carbaldehydes 164 and 165 when treated with excess sodium
borohydride in methanol under reflux for one hour gave the 7-
hydroxymethylbenzimidazoles 166 and 167 respectively as white solids in high yields
(Scheme 3-6). The reactions were simple and the products precipitated out after
dilution with water and were characterized by analytical and spectroscopic data. The
disappearance of the 7-aldehyde proton peak and appearance of the methylene protons
are characteristic observations in the 1H NMR spectra. NH is probably hydrogen
bonded to the hydroxyl oxygen to give a single tautomeric compound.
Scheme 3-6
NH
N
OMe
MeOR
OH
166; R = Ph167; R= 4-OMeC6H4
NH
N
OMe
MeOR
OH
NaBH4/ MeOH
164; R = Ph165; R= 4-OMeC6H4
reflux, 1 h
3.4. Synthesis of 7,7'-dibenzimidazolylmethanes
Initially, the reaction of 4,6-dimethoxybenzimidazole 142 with formaldehyde in a
solution of methanol or tetrahydrofuran under the acidic conditions of hydrochloric
acid gave the salt of the starting benzimidazole at room temperature or under heating.
The treatment of formaldehyde in the presence of glacial acetic acid did not proceed
even after longer reaction times and heating. However, the 7,7'-
dibenzimidazolylmethane 170 was finally prepared in high yields by adding the
formaldehyde to a hot solution of the benzimidazole 142 in glacial acetic acid
followed by few drops of concentrated hydrochloric acid and overnight heating
(Scheme 3-7). The critical point for the reaction to proceed is that the reactants have
to be mixed under warm/hot conditions. By comparison, similar reactions of activated
indoles produced the 7,7'-diindolylmethanes in three hours at room temperature.1 The
7,7'-dibenzimidazolylmethanes 168, 169 and 171 were also prepared by the above
mentioned procedure in moderate to high yields 50-87%. In the 1H NMR spectra the
two identical H-5 protons were found as a singlet at 6.42-6.73 ppm and characteristic
methylene protons at 4.17-4.51 ppm, whereas the methylene carbon resonances
Chapter 3 45
appeared at the ~20 ppm in the 13C NMR spectra. Correct mass spectra and elemental
analysis confirmed the structures of the compounds.
Scheme 3-7
NH
N
OMe
MeOR
OH
166; R = Ph167; R = 4-MeOC6H4
NH
N
OMe
MeOR HCHO
168; R = H169; R = Me170; R = Ph171; R = 4-MeOC6H4
1. POCl3/DMF2. NaBH4/MeOH
NH
N
OMe
MeO
HN
N
OMe
MeO
R
R
AcOH/HCl
AcOHTHF
10; R = H141; R = Me142; R = Ph161; R = 4-MeOC6H4
100oC, o/n
The 7,7'-dibenzimidazolylmethanes 170 and 171 were also prepared from the reaction
of 4,6-dimethoxy-7-hydroxymethylbenzimidazoles 166 and 167 in tetrahydrofuran
with glacial acetic acid at room temperature for 6 h. The postulated mechanism
involves protonation of alcohol 166 and loss of water to form a carbocation, which
after electrophilic attack on another benzimidazole and extrusion of formaldehyde
resulted in the observed product 170 (Scheme 3-8).
Scheme 3-8
NH
N
OMe
MeO
AcOH
OH
NH
N
OMe
MeO
H H
N
HN
OMe
MeO
CH2
N
NH
OMe
MeO
N
HN
OMe
MeOHOHO
-H+
-HCHO
NH
N
OMe
HN
N
OMe
MeO
MeO
Ph
Ph
Ph
Ph
PhPh
Ph
H+, -H2O
166 170
Chapter 3 46
3.5. Acylation of 4,6-dimethoxybenzimidazoles
The modified Vilsmeier-Haack reaction conditions, using phosphoryl chloride and
N,N-dimethylacetamide have been used to acylate the activated indoles at their C-7
positions in high yields.123 Using 1.1 equivalents of the Vilsmeier reagent to the
benzimidazole 142 leads to no visible reaction even after heating at 60oC for 24 h. Use
of ten equivalents of the Vilsmeier reagent and heating the reaction near reflux or
using phosphoryl chloride as solvent also failed to show any signs of reaction with the
activated benzimidazole 142 (Scheme 3-9). It has been found earlier that the modified
Vilsmeier acetylation of indoles was much slower than the corresponding Vilsmeier
formylation reactions.124 Therefore, since the Vilsmeier formylation of
benzimidazoles was much slower than that of the indoles as discussed earlier in
section 3.3, the failure of this reaction shows again that the C-7 position in the
activated benzimidazoles is not as nucleophilic as that in the related indoles.
Scheme 3-9
NH
N
OMe
MeOPh
NH
N
OMe
MeOPh
O
DMA/POCl3
142 172Me
The alternatives for acylation of the benzimidazoles could be Friedel-Crafts acylation
or reaction with acetic anhydride with boron-trifluoride etherate.125 A modified
Friedel-Crafts acylation to the benzimidazole 142 using acetyl chloride and antimony
pentachloride as catalyst gave the desired 7-acetylbenzimidazole 172 in 61% yield
after 48 h (Scheme 3-10). As expected, the reaction was found to be slow compared to
the indole examples, where reaction was complete within 80 min.119 When
benzimidazole 142 was reacted with four equivalents of the Friedel-Crafts reagent, a
70 % yield of 172 and a quick reaction within two hours were achieved. Likewise, the
benzimidazoles 141 and 161 were also acylated using four equivalents of Friedel-
Crafts reagent in two hours and afforded the desired 7-acetylbenzimidazoles 173 and
174 in 98% and 61% yields respectively.
Chapter 3 47
Scheme 3-10
NH
N
OMe
MeOR
NH
N
OMe
MeOR
O
CH3COCl/SbCl5
141; R = Me142; R = Ph161; R = 4-MeOC6H4
173; R = Me172; R = Ph174; R = 4-MeOC6H4
Me0oC, 2 h
The characteristic evidence for the acylated compounds 172-174 was given by 1H
NMR spectroscopy indicating the presence of an acetyl group at ~2.6 ppm, and the
disappearance of the H-7 proton. Similar to the 7-formylbenzimidazoles 162-165, 7-
acetylbenzimidazoles 172-174 were also found as a single tautomer, again showing
the presence of hydrogen bonding between the acetyl carbonyl oxygen and the
nitrogen proton. The typical C=O bands of the acetyl functionality were observed at
~1630 cm-1. Correct microanalytical data for the acetyl compounds 173 and 174 could
not be achieved and in lieu HRMS data were collected.
Acylation of benzimidazole 142 using trifluoroacetic anhydride successfully afforded
the desired 7-trifluoroacetylbenzimidazole 175 in 80% yield (Scheme 3-11). Similar
hydrogen bonding between the carbonyl oxygen and nitrogen proton presumably
stabilizes the single tautomer observed in the 1H NMR spectrum. The disappearance
of the H-7 proton, appearance of H-5 proton as a singlet in the 1H NMR spectrum, and
tertiary carbon peaks at 100 ppm in 13C NMR spectrum indicated the presence of the
trifluoroacetyl group. The EI mass spectrum revealed molecular ions m/z (M+1) at
351 consistent with formation of the desired compound 175 along with an ion at 255
corresponding to (M-COCF3). The carbonyl (C=O) band absorption in the infrared
spectrum was seen at 1636 cm-1. In a similar way, 7-trifluoroacetylbenzimidazole 176
was also prepared by the above mentioned procedure under 5 days refluxing
conditions in 83 % yield. Just like the 7-acetylbenzimidazoles 172-174, the 7-
trifluoroacetylbenzimidazoles 175 and 176 indicated the hydrogen bonding between
the nitrogen proton and the carbonyl oxygen to give a single tautomer. Conversely, the
similar reaction to the indole occurred in 8 h at room temperature,126 whereas, the
Chapter 3 48
reaction of the benzimidazoles required 5-7 days under refluxing conditions for
completion indicates low reactivity of the benzimidazoles.
Scheme 3-11
NH
N
OMe
MeOR
NH
N
OMe
MeOR
O
175; R = Ph176; R = 4-MeOC6H4
(CF3CO)2O/ THF
reflux, 5-7 d
142; R = Ph161; R = 4-MeOC6H4
F3C
When the benzimidazoles 142 and 161 were refluxed with trifluoroacetic anhydride in
tetrahydrofuran for longer time 10 days, the major products observed were the
disubstituted benzimidazoles 177 and 178 in 70 and 77 % yield as white coarse
powders (Scheme 3-12). This was not unexpected as the reactions were conducted
over extended periods of time and excess of the reagent was used in the reactions.
There were no NH protons observed in the 1H NMR spectra. The molecular ions in
their mass spectra m/z (M+1) at 448 and 477 conform to the compounds 177 and 178
respectively. The infrared absorption band at 3448 cm-1 of the compound 178 was
assigned for the presence of water as supported by the elemental analysis. The
disubstituted compound 178 was easily N-deprotected by methanolic potassium
hydroxide solution at room temperature to give the 7-trifluoroacetylbenzimidazole 176
in 78% yield.
Scheme 3-12
NH
N
OMe
MeOR (CF3CO)2O
N
N
OMe
MeOR
F3C OO
F3C
176; R = 4-MeOC6H4
NH
N
OMe
MeOR
F3C OTHF, 10 d
KOHMeOH
142; R = Ph161; R = 4-MeOC6H4
177; R = Ph178; R = 4-MeOC6H4
reflux r.t., o/n
The following Table 3-3 displays the comparison of acylation of an indole and
benzimidazoles, which clearly expressed the lower reactivity of the benzimidazoles.
Chapter 3 49
NH
N
OMe
MeOR
OH3C
NH
OMe
MeOR2
OH3C
R1
BenzimidazoleIndole
Table 3-3. Comparison of the acylation of indole and benzimidazole.
Modified Vilsmeier
acylation
Friedel Crafts
acylation Trifluoroacylation
Indole
53; R1, R2 = Ph30 eq.; 48 h;
40-60oC; 88% 124
1.6 eq.; 15-18 h;
0-5 oC; 53% 124 8h ; 0 oC; 100%1
Benzimidazole
141; R = CH3 Not reactive 4 eq.; 2 h; r.t. ; 98% 5d ; reflux ; 83%
142; R = Ph Not reactive 1.1 eq.; 48h; r.t.; 61% 7d ; reflux ; 80%
4 eq.; 2 h; r.t. ; 70%
161; R = 4-MeOC6H4 Not reactive 4 eq.; 2 h; r.t. ; 61% -
In contrast to the above results, trichloroacetic anhydride failed to yield the desired
compound 179 (Scheme 3-13). However, this result is consistent with the fact that
trichloroacetic anhydride was also unreactive to the activated indoles.126 Instead,
trichloroacetyl chloride was used for the preparation of the indole trichloroacetyl
derivatives. Unfortunately, attempted reaction of the activated benzimidazoles with
trichloroacetyl chloride gave back the starting material.
Scheme 3-13
NH
N
OMe
MeOPh
NH
N
OMe
MeOPh
OCl3C
142 179
CCl3COCl/ DCM(CCl3CO)2O/ THF or
Chapter 3 50
The 7-trifluoroacetylbenzimidazoles 175 and 176 were hydrolyzed to the
corresponding benzimidazole-7-carboxylic acids 180 and 181 respectively in 77% and
80% yields by treatment with ethanolic potassium hydroxide solution (Scheme 3-14).
Once again, hydrogen bonding between the NH and carbonyl oxygen is suspected to
form single tautomers of the benzimidazole-7-carboxylic acids 180 and 181. The
carbonyl infrared frequencies of the acid derivatives were observed at ~1700 cm-1 and 13C NMR resonances were observed at 165-168 ppm. Treatment of the benzimidazole-
7-carboxylic acids 180 and 181 with excess dimethylsulfate in acetone gave the N-
methylbenzimidazole-7-carboxylates 182 and 183. The strong characteristic carbonyl
absorptions of the carboxylates were seen at ~1705 cm-1in the infrared spectrum.
Molecular ions (M+1) m/z at 327 and 357 were consistent with compounds 182 and
183 respectively.
Scheme 3-14
NH
N
OMe
MeOR
NH
N
OMe
MeOR
O
KOH/EtOH
F3C ON
N
OMe
MeOR
O
DMS/Acetone
175; R = Ph176; R = 4-MeOC6H4
182; R = Ph183; R = 4-MeOC6H4
MeOHO Me
180; R = Ph181; R = 4-MeOC6H4
reflux, 4 h reflux, o/n
3.6. Attempted synthesis of benzimidazole glyoxyloyl chlorides
Oxalyl chloride has been shown in several reports to react with indoles to give the
glyoxyloyl chloride.1,6,8,127,128 These glyoxyloyl chloride could be easily converted to
their corresponding acids and in addition a range of esters and amides.1,6 In this
context, it was of interest to investigate the reaction of oxalyl chloride with 4,6-
dimethoxybenzimidazoles to prepare the glyoxyloyl chloride 184. The glyoxyloyl
chloride and their derivatives could then be used for further synthetic purposes.
The reaction of oxalyl chloride with the 4,6-dimethoxybenzimidazole 142 in dry
dichloromethane gave the starting benzimidazole back (Scheme 3-15). Using excess
of the reagent oxalyl chloride or oxalyl chloride alone as a solvent did not change the
situation. Subsequently, heating the above reaction mixture has no effect.
Chapter 3 51
Scheme 3-15
NH
N
OMe
MeO
O
NH
N
OMe
MeO
ClCOCOCl
142 Cl
O
184
The result of the oxalyl chloride reaction is quite different compared to the indole
cases where the reaction proceeds very fast within 15 min in dichloromethane.6 On the
other hand, no reaction progress was observed with benzimidazole under these
conditions.
3.7. Nitration of 4,6-dimethoxybenzimidazoles
Nitration is an important process to introduce additional functionality to an organic
molecule, especially as a potential source of amino derivatives. The usefulness of the
reactive C-7 position has now enabled electrophilic attack by nitronium ion. Synthesis
and conversion of the C-7 nitro functionality to an amino group of the benzimidazole
would result in a compound similar to adenine (Figure 3-7). These types of
compounds have previously shown significant growth inhibition activity and activity
against gastric acid secretion.129,130
Adenine
N
N
NH2
N
NH N
H
N
OMe
MeONO2
R
7-nitrobenzimidazole
NH
N
OMe
MeONH2
R
7-aminobenzimidazole
Figure 3-7. Similarity of adenine with benzimidazole
Usually, nitration of organic compounds is difficult to achieve in a clean and selective
manner. Although the C-7 position is the preferred site for electrophilic attack, there is
also the possibility to nitrate at the C-5 position. Having achieved selective mono-
nitration in the preparation of nitroamides 155-157, nitric acid/acetic anhydride in an
ice/salt bath was chosen for the controlled nitration reaction of benzimidazoles 142
Chapter 3 52
and 161. The desired 7-nitrobenzimidazoles 185 and 186 were isolated in 70% and
78% yields respectively as yellow crystals (Scheme 3-16). Further nitration products
were not observed by TLC and 1H NMR spectra. In the 1H NMR spectra the H-7
protons were absent, while the IR spectra showed the presence of NO2 groups at
~1590 cm-1 and ~1310 cm-1. The 13C NMR spectra clearly confirmed that the number
of resonances of phenyl carbons remained unchanged while there was one additional
quaternary aryl carbon resonance at the expense of an aryl CH indicating that nitration
had occurred. The elemental analysis and mass spectral ions m/z (M+1) at 300 and
330 further confirmed the synthesis of the 7-nitrobenzimidazoles 185 and 186.
Scheme 3-16
NH
N
OMe
MeOR
NO2
HNO3/ Ac2O
NH
N
OMe
MeOR
142; R = Ph161; R = 4-MeOC6H4
185; R = Ph186; R = 4-MeOC6H4
OoC, 2h
In the case of similarly activated 2-unsubstituted-3-substituted-4,6-dimethoxyindoles
4 nitration has been found to be very difficult to control. However, selective
mononitration can be achieved for indoles bearing electron withdrawing groups in
either the C-2 or C-7 position, using nitric acid adsorbed on silica or nitric acid in
acetonitrile.4 On the other hand, 2,3-disubstituted-4,6-dimethoxy activated indoles not
bearing electron withdrawing groups undergo oxidative dimerization at C-7.46 It was
found that the 4,6-dimethoxybenzimidazoles undergo facile nitration using
concentrated nitric acid in acetic anhydride. These observations represent that the
activated benzimidazoles are less nucleophilic than the related activated indole
examples and resemble more in activity to the related indoles having a deactivated
group.
3.8. Benzoylation of a 4,6-dimethoxybenzimidazole using activated carbon
Activated carbon has been available for many years as a purification system due to its
adsorption properties.131 In addition, activated carbon is a very common and effective
support for many catalysts (e.g., Pd, CuCl2, K). It has the advantages of being
Chapter 3 53
relatively facile to recover and moreover the carbon active sites can also affect the
catalytic activity.132 On the other hand, activated carbon fibers showed greatly
improved adsorption characteristics in comparison to the activated carbon granules 133
and have been reported as catalyst supports.134 Besides these agents, graphite has also
been used as a catalytic support medium and has been used to catalyze benzoylation of
an indole.135 We were attracted to study the catalytic activity of activated carbon
granules, activated carbon fibers, activated carbon wools and graphite towards the
benzoylation reaction of the 4,6-dimethoxybenzimidazole 142.
Treatment of the 4,6-dimethoxybenzimidazole 142 with benzoyl chloride in dry
dichloromethane in the presence of a Lewis acid catalyst antimony pentachloride gave
the desired benzoylated product 187 in 29% yield (Scheme 3-17). The reaction
progress was monitored to be slow and required stirring at room temperature for 3
days. The infrared band at 1619 cm-1 was assigned for the carbonyl (C=O) group. The 1H NMR spectra plainly represents the product as observed by the disappearance of
the H-7 proton and appearance of five additional aromatic protons. The other
spectroscopic and elemental analyses were all in accord with the structure of
compound 187.
Scheme 3-17
NH
N
OMe
MeO
ONH
N
OMe
MeO
PhCOCl, SbCl5
CH2Cl2, r.t., 3 d
187142
On the other hand, the reaction of 4,6-dimethoxybenzimidazole 142 and benzoyl
chloride in dry dichloromethane in the presence of graphite gave N-benzoylated
product 188 in 17 % yield instead of the compound 187 (Scheme 3-18). The result is
unlike the indole case where the substitution happened at C-7.135 This difference in
reactivity can be explained due to the increased basicity of the benzimidazole
molecule. When the activated carbon granules, activated carbon fiber and activated
carbon wool were used replacing the graphite the same N-benzoylated product 188
Chapter 3 54
was isolated after reaction and purification in a low yield (Table 3-4). Only the
activated carbon granules gave a better yield (40%) in a shorter time (1d) compared to
the fiber and wool. Even though the carbon fiber and wool has greater surface area
and improved adsorption characteristics, the low yield and longer reaction time can be
explained due to inefficient stirring of the reaction mixture arising from the bulkiness
of these products. Additionally, impregnating the benzoyl chloride in activated carbon
granules slightly improved the reaction yield (52%) of the product 188. Table 3-4 lists
the comparative results of benzoylation of benzimidazole 142 under different reaction
conditions. The product 188 showed five additional aryl protons, absence of the NH
proton, while the H-7 proton was still present in the 1H NMR spectrum, confirming
the formation of N-benzoylbenzimidazole. The infrared carbonyl group frequency was
observed at 1687 cm-1 and the structure was further characterized by analyzing other
spectroscopic and microanalytical data.
Scheme 3-18
NH
N
OMe
MeO
PhCOCl, Carbon
CH2Cl2, reflux, 1-3 d N
N
OMe
MeOO
188142
Table 3-4. Comparison of the benzoylation of benzimidazoles.
Catalyst C-7 benzoylation N-benzoylation
Antimony pentachloride r.t., 3 d, 29% -
Graphite - reflux, 3 d, 17%
Activated carbon granules - reflux, 1d, 40%
Activated carbon fibers - reflux, 3 d, 20%
Activated carbon wools - reflux, 3 d, 18%
Impregnated activated carbon
granules
- reflux, 1d, 52%
Chapter 3 55
The compound 187 has shown a single tautomer probably due to the hydrogen
bonding of the carbonyl oxygen to the NH. The alternate tautomer would be
unfavourable due to steric hindrance from the methoxy group. Significantly, the X-ray
crystal structure of the compound 187 illustrated the 4,6-dimethoxy tautomer and
confirmed weak hydrogen bonding between the carbonyl oxygen and imidazole
nitrogen bearing a distance 2.43 Å. The crystal structure further revealed the presence
of a water molecule strongly attached to the imidazole nitrogen and a distance 1.96 Å
from it (Figure 3-8). Interestingly, the energy minimized Chem 3D model very
closely fits with the actual X-ray structure, where the calculated distance in the model
between C=O and NH is 2.44 Å.
Figure 3-8. X-ray crystal structure of the 7-benzoylbenzimidazole 187.
3.9. Preparation of imidazoloquinolines
Pyrroloquinoline ring systems are common in nature and have been reported for a
variety of biological activities. In addition, their synthesis has been extensively
reviewed.136 Recently, Condie119 has prepared the pyrroloquinoline 189 (Scheme 3-
19) by intramolecular cyclization of 7-formylindole 53 following Yavari
methodology.137
Chapter 3 56
Scheme 3-19
N
OMe
MeONH
OMe
MeO
DMAD, Ph3P
CH2Cl2, 24 h
COOMeCOOMe
O
18953
H
The same technique was applied to prepare the benzimidazole analogues 190 and 191
of the pyrroloquinolines. The 7-formylbenzimidazoles 164 and 165 were reacted with
dimethyl acetylenedicarboxylate (DMAD) and triphenylphosphine in dry
dichloromethane to give the respective imidazoloquinolines 190 and 191 as yellow
powders in 72% and 76% yields (Scheme 3-20). The benzimidazole reactions were
slow in comparison to 7-formylindoles, and required significantly more time (5 days
vs 24 h) to go to completion.119 The 1H NMR spectra showed two additional methoxy
groups, the C-8 proton was observed at ~6.20 ppm and C-4 aliphatic proton at ~6.40
ppm, whereas the C-4 aliphatic carbon was seen at ~55 ppm in the 13C NMR spectra.
The strong infrared bands near 1740 cm-1 and 1700 cm-1 represent the C=O stretching
frequencies of the carboxylate groups of the compounds 190 and 191. The products
were finally identified by elemental analyses and other spectroscopic data.
Scheme 3-20
N
N
OMe
MeO
COOMeCOOMe
NH
N
OMe
MeO
DMAD, Ph3P
CH2Cl2, 5 d
O
R R
164; R = H165; R = MeO
190; R = H191; R = MeO
H
Chapter 3 57
The proposed mechanism (Scheme 3-21) considers the initial addition of
triphenylphosphine to the acetylenic ester and concomitant protonation of the adduct.
The benzimidazole anion is then thought to attack the vinyltriphenylphosphonium
cation to form the phosphorane, which undergoes an intramolecular Wittig reaction,
with loss of triphenylphosphine oxide to produce the desired imidazoloquinoline 190.
Scheme 3-21
N
N
OMe
MeO
COOMeCOOMe
NH
N
OMe
MeO
DMAD, Ph3P
CH2Cl2
O
164 190
MeO2C CO2Me
P(Ph3)
NH
N
OMe
MeO
O
MeO2C
(Ph3)H2PCO2Me
N
N
OMe
MeO
O
MeO2C
(Ph3)H2P CO2Me
N
N
OMe
MeO
O CO2Me
CO2Me(Ph3)P
P(O)(Ph3)
H
HH
H
3.10. Synthesis and N-allylation of 2,7-bisbenzimidazoles
Reaction of 7-formylbenzimidazoles 163-165 with 1,2-diaminobenzene gave a new
type of 2,7-bisbenzimidazole 193-195 by oxidative dehydrogenation in N,N-
dimethylformamide (Scheme 3-22). A similar oxidative dehydrogenation of
intermediate dihydrobenzimidazoles 192 has been observed with related 7-
formylindoles in N,N-dimethylformamide.5
Chapter 3 58
Scheme 3-22
NH
N
OMe
MeOR
HN NH
NH
N
OMe
MeOR
NH
N
OMe
MeOR
HN NO
H2N
H2N
DMF, 110oC, 24-48 h163; R = Me164; R = Ph165; R = 4-MeOC6H4 [O]
193; R = Me194; R = Ph195; R = 4-MeOC6H4
H
H
192
The X-ray crystallographic structure of the compound 194 (Figure 3-9) exhibited a
planar molecule with hydrogen bonding (d = 2.20 Å) between N1H to the N3 lone pair
electrons. The N4H is also hydrogen bonded to a water molecule. Thus, the presence
of a water molecule in elemental analysis of the bisbenzimidazole 194 was obvious.
The crystal structure is a clear further proof of the dominant nature of the 4,6-
dimethoxy tautomer over the 5,7-dimethoxy tautomer imposed by the hydrogen
bonding.
Figure 3-9. ORTEP drawing of the crystal structure of bisbenzimidazole 194.
Chapter 3 59
N-Allyl benzimidazoles 196-198 were previously prepared by Condie. The two
nitrogens in the N-allyl benzimidazoles 196, 197 could not be differentiated and
showed tautomerism indicated by the presence of the 4,6-dimethoxy 196 and 5,7-
dimethoxy 197 tautomers (Scheme 3-23), which made the 1H NMR spectrum of the
N-allyl benzimidazole quite complicated. However, formylation of the tautomers gave
a single isomer as 7-formyl-4,6-dimethoxy derivative 198 due to suspected steric
effects.117
Scheme 3-23
N
N
OMe
MeO N
N
OMe
MeO N
N
OMe
MeO
O196 197 198
NH
N
OMe
MeO
10
POCl3/DMF
Br
H
KOH+
N-Allylation of the bisbenzimidazole 194 was tentatively investigated in an attempt to
differentiate between the two NHs via selective reaction at either NH. It was
anticipated that N-allylation would favour the N-4 position rather than the N1 position
of the 4,6-dimethoxybenzimidazole 194, due to steric hindrance from the neighboring
phenyl and benzimidazole group. The reaction of the bisbenzimidazole 194 with either
one or two equivalents of allyl bromide gave a yellow oily mixture of compounds with
very close Rf values. None of the compounds could be purified for characterization
even after extensive chromatography or by recrystallization in different solvents. Even
the 1H NMR spectrum of the partially purified mixture was extremely complicated to
analyze. The low resolution mass spectrometry showed that the disubstituted allyl
derivatives are the major compounds, and there are two possible tautomeric forms 199
and 200 (Scheme 3-24). The monosubstituted allyl derivative could be of two types;
substitution of nitrogen on the simple benzimidazole would give product 201 or its
tautomer 202, whereas substitution of nitrogen on the dimethoxybenzimidazole would
give either 203 or 204.
Chapter 3 60
Scheme 3-24
N
HN
OMe
MeOPh
N N
NH
N
OMe
MeOPh
HN N
N
N
OMe
MeOPh
N N
NH
N
OMe
MeOPh
N N
N
N
OMe
MeOPh
HN N
Br
KOH/NaI/DMSO
+
+
N
N
OMe
MeOPh
N N
N
N
OMe
MeOPh
HN N
194 199 200
204 203 202
201
+
Furthermore, the bisbenzimidazoles 193-195 have potential as bidentate ligands and
divalent metal ions could combine two bisbenzimidazoles to make neutral metal
complexes. Refluxing the bisbenzimidazole 194 with metal(II) acetates in methanol
overnight gave the nickel(II), cobalt(II) and copper(II) complexes 205-207 in
moderate to high yields (Scheme 3-25).
Scheme 3-25
N
N
OMe
MeOPh
NHN N
N
OMe
OMePh
N NHNH
N
OMe
MeOPh
NHNMeOH, reflux, o/n
M(OAc)2.xH2OM
205, M = Ni(II)206, M = Co(II)207, M = Cu(II)
194
A simple 1H NMR spectrum of the nickel(II) complex 205 hinted at the square planar
geometry of the complex, similar to the indole example.138 Molecular model studies of
the nickel complex 205 support a square planar configuration. However, due to lack of
crystal structure this could not be confirmed in the case of benzimidazoles. Correct
Chapter 3 61
elemental analysis could only be obtained for the copper(II) complex 207 containing a
water molecule. The presence of corresponding molecular ions in their mass spectra
confirmed formation of the desired metal complexes 205-207.
3.11. Attempted synthesis of benzimidazole-4,7-diones
Previously in Chapter 2.10 we have effectively prepared a series of indoloquinones
by Dakin oxidation of 4,6-dimethoxyindole-7-carbaldehydes. The reaction was found
to be quite general and thus it was of interest to apply the same technique to the 4,6-
dimethoxybenzimidazole-7-carbaldehyde 164 to prepare the benzimidazole-4,7-dione
208. The treatment of 7-formylbenzimidazole 164 with hydrogen peroxide in the
presence of hydrochloric acid in a solution of methanol/tetrahydrofuran at room
temperature overnight was not sufficient for complete reaction, which required further
heating for two hours. However, in that case only decomposed products were
observed. Change of solvent to isopropanol or tetrahydrofuran gave the same result
(Scheme 3-26). Alternatively, use of peroxosulfuric acid as an oxidant showed no sign
of reaction progress as monitored by TLC even after longer periods of time. A similar
result was obtained from the 4'-methoxyphenyl analog 165.
Scheme 3-26
NH
N
O
MeOO
NH
N
OMe
MeO
164 208
H2O2/HCl orH2O2/H2SO4
MeOH/THF
OH
3.12. Synthesis of 4,6-dimethoxybenzimidazole aldoximes and ketoximes
It is well recognized that the reaction of aldehydes and ketones with hydroxylamine
hydrochloride in the presence of base can produce the aldoximes and ketoximes
respectively.45,139,140 Our group has previously shown that the treatment of indole-7-
carbaldehydes with hydroxylamine hydrochloride and sodium hydroxide under reflux
for two hours gave high yields of the indole 7-aldoximes. These aldoximes were
recently effectively converted to nitriles,45 which are useful functional groups for their
transformation into a range of heterocyclic systems. Besides their organic potential,
some benzimidazole oximes have been reported to show important biological
Chapter 3 62
activity.141,142 In addition, some metal complexes have been prepared from the
benzimidazole-2-oximes.142-144 Therefore, the synthesis of some benzimidazole-7-
oximes was of interest.
Treatment of 4,6-dimethoxybenzimidazole-7-aldehydes 164 and 165 with
hydroxylamine hydrochloride in 95% ethanol containing potassium hydroxide under
reflux for 8 h gave the corresponding benzimidazole-7-aldoximes 209 and 210 in good
to high yields as white solids (Scheme 3-27). These compounds in their 1H NMR
spectra exhibited characteristic imine resonances at ~8.5 ppm in acetone-d6 for the
corresponding anti-isomers.145 The imine resonances in the 13C NMR spectra were
observed at ~144 ppm. The infrared spectra also showed C=N stretches in the range of
~1611cm-1 corresponding to the anti-isomer.145 The OH stretching frequencies were
seen at 3358-3388 cm-1. Their mass spectra revealed the molecular ions (m/z) and also
peaks at M-18 resulting from the loss of water. In addition, the infrared spectra of all
compounds indicated the absence of the carbonyl group frequency of the starting
aldehyde.
Scheme 3-27
NH
N
OMe
MeOR
NOH
NH2OH.HCl / NaOH
EtOH, reflux, 8 hNH
N
OMe
MeOR
O
164; R = Ph165; R = 4-MeOC6H4
209; R = Ph210; R = 4-MeOC6H4
H H
In a similar way, the synthesis of the 4,6-dimethoxybenzimidazole-7-ketoximes 211
and 212 were carried out by refluxing the 7-acetylbenzimidazoles 172 and 173 with
hydroxylamine hydrochloride in the presence of potassium hydroxide for two days to
give the respective ketoximes as white solids in moderate yields of 64-69% (Scheme
3-28). The reactions were considerably slower than those for the related aldehydes and
indole examples. The 1H NMR spectra of the 7-ketoximes 211 and 212 showed that
the molecules only exist as a single isomer as there was only one singlet
corresponding to the C=N methyl proton. In these molecules C=N oxime infrared
stretching frequencies were observed at ~1610 cm-1 and those for OH groups were
Chapter 3 63
seen at 3244-3397 cm-1. As for the previous findings, NH is probably hydrogen
bonded to the hydroxyl oxygen to give a single tautomer and the corresponding
benzimidazole 7-ketoximes were considered to be anti-isomers. This was supported
by NOE experiments and by comparison with the analogous indole examples.9
Scheme 3-28
NH
N
OMe
MeOR
NOH
211; R = Ph212; R = Me
NH2OH.HCl/ NaOH
EtOH, reflux, 48 hNH
N
OMe
MeOR
O
172; R = Ph173; R = Me
Me Me
The oxime function, located adjacent to another donor atom in an organic molecule,
can act as a versatile chelating group and may make the molecule useful in the
separation and estimation of metal ions.142 Thus, the 7-ketoxime 212 was treated with
one equivalent of Ni(II) and Co(II) acetate tetrahydrate in a methanol solution under
reflux for overnight to give the metal complexes 213 and 214 (Scheme 3-29). In these
molecules the NOH infrared band was observed at 3300-3400 cm-1 while no NH
stretching frequency was observed, suggesting that the metals are coordinated through
the benzimidazole NH. The molecular ions m/z at 554 and 555 in the MALDI mass
spectra supports the formation of complexes 213 and 214. Moreover molecular ion
peaks at m/z 495 and 496 indicates the loss of the corresponding metals.
Scheme 3-29
NH
N
OMe
MeOMe
NOHMe
MII(OAc)2 4H2O
MeOH, reflux, o/n
213; M = Ni(II)214; M = Co(II)
N
N
OMe
MeOMe
N
N
N
OMe
OMeMe
NO
OM
H
HMe
Me
212
The 1H NMR spectrum of the nickel(II) complex 213 could not be obtained, probably
due to its paramagnetism. The complexes were expected to be of transoid orientation
Chapter 3 64
with tetrahedral geometry. Molecular dynamics calculations preferred the formation of
the complexes derived from deprotonation of the NH rather than the NOH, and further
support the proposed structures. An energy minimized 3D structure is shown in
Figure 3-10. Despite these findings, a conclusive structure can not be drawn due to
lack of a crystal structure.
Figure 3-10. Energy minimized structure of the Ni(II) complex 213.
3.13. Attempted synthesis of furobenzimidazoles
Recently, Pchlalek prepared a novel furoindole from 4-methoxy-6-hydroxyindole by
alkylation of the 6-hydroxyl group with -haloketones followed by base catalyzed
intramolecular cyclization to yield the 5 membered furoindole.146 A similar
methodology (Scheme 3-30) was approached to prepare the furobenzimidazole 219.
Chemoselective demethylation of methoxy group located ortho to a carbonyl was
reported using cerium (III) chloride and sodium iodide147 and used in Pchlalek’s
procedure.146 The N-protection was necessary to avoid the hydrogen bonding between
the carbonyl oxygen and benzimidazole NH to accomplish successful demethylation
and later to prevent alkylation of the benzimidazole NH.
Chapter 3 65
Scheme 3-30
NH
N
OMe
MeOPh
N
N
OMe
HOPh
N
N
OMe
MeOPh
N
N
OMe
MeOPh
NH
N
OMe
OPh
Me
Chloroacetone
KOH, DMSO
TosCl
O
POCl3DMF
Tos Tos
Tos
142 215 216
217
K2CO3
MeOH
KOH
219
NaI, CH3CNCeCl3. 7H2O
N
N
OMe
OPh
Me218
TosO
H
H
Initially, the 2-phenylbenzimidazole 142 was reacted with p-toluenesulfonyl chloride
in the presence of different base systems (KOH/DMSO, Et3N/CHCl3 and NaH/THF)
to prepare the N-tosylated product 215 (Scheme 3-31). However, the desired
compound was not observed under any of these conditions and only starting materials
were recovered from the reaction mixtures even under vigorous conditions and at
longer reaction times. Steric hindrance was assumed to be responsible for this
unreactivity. The alternate sequence of doing formylation prior to tosylation was not a
sensible option because the additional deactivating formyl group and its hydrogen
bonding to the nitrogen proton would be more restrictive than the previous case.
Scheme 3-31
NH
N
OMe
MeO N
N
OMe
MeO
Me
S OO
TosCl, KOH, DMSOTosCl, Et3N, CHCl3TosCl, NaH,THF
142 215
The energy minimized structure of the N-tosylated compound 215 by semi-empirical
AM1 method revealed that the 2-phenyl group would be highly rotated from the plane
compared to the parent benzimidazole molecule (Figure 3-11).
Chapter 3 66
Figure 3-11. Energy minimized structure of N-tosylated compound 215.
To investigate the issue of steric hindrance, the 2-phenylbenzimidazole 142 was
reacted with excess methyl iodide in dimethyl sulfoxide in the presence of potassium
hydroxide. Purification of the reaction mixture gave three different products (Scheme
3-32), which were identified as the expected isomers 220 and 221 as minor products
and an unexpected imidazole ring opened trimethoxy benzamide 222 in 67% yield as
the major product.
Scheme 3-32
NH
N
OMe
MeOPh
NMe
N
OMe
MeOPh
N
MeN
OMe
MeOPh+
+DMSO, 110oC, 3 h
MeI, KOH
N
OMe
MeO OMe
O
Me
142
220 221
222
The ring opened compound 222 showed three methoxy signals in the 1H NMR
spectrum and protons for the N-methyl group. A carbonyl group frequency was
observed at 1635 cm-1, while the mass spectrum showed a molecular ion m/z peak at
301 to match with the ring opened compound 222. Final proof of the structure 222
came from a X-ray crystal structure isolated from a solution of chloroform (Figure 3-
12).
Chapter 3 67
Figure 3-12. ORTEP drawing of X-ray crystal structure of trimethoxybenzamide 222.
Interestingly, the N-methylbenzimidazole isomers 220 and 221 could be separated by
column chromatography using dichloromethane/ethyl acetate (90:10) as eluent. The
isomers were identified by the careful analysis of the 2D NMR spectra. Both the
compounds showed direct C-H coupling in the HMQC correlation, while in the
HMBC the aromatic protons displayed up to 2 bond long range couplings. Important
HMBC correlations are shown in the (Figure 3-13). The compounds were clearly
distinguished by HMBC coupling of the N-methyl protons, whether to the C-7a or C-
3a.
N
MeN
OMe
MeONMe
N
OMe
MeO
220 221Figure 3-13
The trimethoxy ring opened product 222 was thought to be formed from the attack of
methoxide anion at C-7a in the di-methylated intermediate 223 (Scheme 3-33). The
di-methyl intermediate 223 was considered to be sterically more favourable than 224
for the proposed attack by the methoxide anion. The methoxide anion could arise in
the reaction conditions from the excess methyl iodide and potassium hydroxide. The
Chapter 3 68
intermediate 225 could easily hydrolyze to benzamide 222 during the reaction and
aqueous workup. The proposed mechanism is also supported by the reaction with one
equivalent of methyl iodide, where only the isomers 220 and 221 were isolated, and
no ring opened product 222 was observed.
Scheme 3-33
NH
N
OMe
MeO
OMe
N
N
OMe
MeO
H2O
N
N
OMe
MeO
+
+
Excess MeIKOH
N
OMe
MeO OMe
NMe
Me
225
N
OMe
MeO OMe
O
Me
222
142Me
Me
Me
Me
223
224
Subsequently, the N-tosylation of the benzimidazoles 10 and 141 with tosyl chloride
and triethylamine in chloroform yielded the desired N-tosylated benzimidazoles 226
and 227 in respectively 79% and 87% yields (Scheme 3-34). 4,6-Dimethoxy isomers
are considered favoured due to steric reasons.
Scheme 3-34
NH
N
OMe
MeOR
N
N
OMe
MeO
Me
RTosCl, Et3N, CHCl3
Reflux, 1-2 h
10; R = H141; R = Me
226; R = H227; R = Me
S OO
The X-ray crystal structures of N-tosylated benzimidazoles 226 and 227 were obtained
(Figure 3-14). As expected the structures were found similar and showed weak
hydrogen bonding (d = 2.53 Å, 226; d = 2.37 Å, 227) between the H-7 protons and the
sulfur oxygen (O4).
Chapter 3 69
Figure 3-14. ORTEP diagram of the X-ray crystal structure of N-tosylbenzimidazoles
226 and 227.
Attempted Vilsmeier formylation of the N-tosylated benzimidazoles 226 and 227 with
phosphoryl chloride and anhydrous N,N-dimethylformamide at room temperature
resulted in formation of deprotected benzimidazoles 10 and 141 respectively (Scheme
3-35) and N,N'-dimethyl-benzenesulfonamide 228. Intramolecular hydrogen bonding
of the H-7 to the sulfur oxygen; and steric hindrance are considered as the deactivating
factor towards the formylation of N-tosyl benzimidazoles 226 and 227.
Scheme 3-35
NH
N
OMe
MeOR
S
Me
NMeMe
+POCl3/DMF
r.t., 4 h
10; R = H141; R = Me
226; R = H227; R = Me
N
N
OMe
MeO
Me
R
S OO
228
OO
Other conditions were also used in order to formylate benzimidazole 226. These
included, Vilsmeier conditions at 75°C, trifluoroacetic acid and triethylorthoformate,
trifluoroacetic anhydride and anhydrous N,N-dimethylformamide, and , '-
dichloromethyl methyl ether and antimony pentachloride. Using these strong
conditions formylation of the benzimidazole 226 (Scheme 3-36) indeed occurred, but
also resulted in removal of the N-protection to give the 7-formyl product 162.
Chapter 3 70
Scheme 3-36
POCl3/DMF, 75oC, o/nTFA/TEOFTf2O/DMF
- -dichloromethyl methyl ether/SbCl5 NH
N
OMe
MeO
O
226
N
N
OMe
MeO
Me
S OO
162
H
Finally, demethylation of the 7-formylbenzimidazole 164 was attempted (Scheme 3-
37) without protecting the NH, assuming that the different basicity of benzimidazole
compared to the indole might be relevant. The reaction of the 7-formylbenzimidazole
164 with cerium(III)chloride in the presence of sodium iodide in acetonitrile resulted
in complex mixtures. Interestingly, 1H NMR spectrum of the partially purified sample
showed the presence of the demethylated product 229, and this was supported by a
molecular ion m/z (M+1) at 269 in the mass spectrum. However, several attempts to
purify the 6-hydroxybenzimidazole 229 failed, so the synthesis of furobenzimidazoles
was discontinued at this stage and further attempts were not investigated.
Scheme 3-37
NH
N
OMe
HO
O
NH
N
OMe
MeO
O
NaI, CH3CN
CeCl3.7H2O
164 229H H
reflux, 48 h
3.14. Investigation of some calixbenzimidazole precursors
It has been found earlier that 7-hydroxymethyl-4,6-dimethoxybenzimidazole 230 did
not produce the desired calix[3]benzimidazole 232 or calix[4]benzimidazole 233
because of the insufficient nucleophilicity of the C-2 position.117 Alternatively,
synthesis of a calixbenzimidazole might be achieved by the acid catalyzed reaction of
the 2-hydroxymethyl-4,6-dimethoxybenzimidazole 231 (Scheme 3-38), because the
reactive C-7 position would be free in this case for potential reaction. The new
calixbenzimidazole may confer different steric features and regioselectivity due to a
difference in basicity or reaction mechanism. Reaction of 2-
Chapter 3 71
hydroxymethylbenzimidazole 231 was expected to be slow compared to the analogous
indole and should favour the thermodynamically more stable calix[4]benzimidazole
233 over the kinetically favoured calix[3]benzimidazole 232
Scheme 3-38
NH
N
OMe
MeO
OH230
H+
NHN
MeO OMe
HNN
OMe
OMe
NH
N
MeO
NH
N
OMe
MeO
OMe
OH
231232
?
NH
N
OMe
MeOHN N
OMe
MeO
HN
NOMe
OMeNHN
MeO
OMe233
H+
Therefore, 2-hydroxymethyl-4,6-dimethoxybenzimidazole 231 was considered as the
prime precursor for the building of the symmetrical calixbenzimidazoles 232 and 233.
Earlier attempts to prepare the 2-hydroxymethylbenzimidazole 231 from 1,2-diamino-
3,5-dimethoxybenzene 151 and glycolic acid have been unsuccessful.117 Although
several approaches could be considered for the preparation of this target molecule 231,
the following options were regarded to generate the 2-hydroxymethylbenzimidazole
231 (Scheme 3-39). The first approach was considered to be the oxidation of the 2-
methyl-4,6-dimethoxybenzimidazole 141 to 2-formylbenzimidazole 234, which could
be reduced easily to afford the desired 2-hydroxymethylbenzimidazole 231. A second
approach involved benzylic halogenation of the 2-methyl-4,6-
dimethoxybenzimidazole 141 to the halomethyl product 235 followed by base
hydrolysis to the 2-benzylalcohol 231. A third approach was the oxidation of the 2-
styrylbenzimidazole 236 to 2-formylbenzimidazole 234, followed by reduction as
above.
Chapter 3 72
Scheme 3-39
NH
N
OMe
MeO OH
NaBH4
NH
N
OMe
MeO ONH
N
OMe
MeO
[O]
Ph
NH
N
OMe
MeOMe
NH
N
OMe
MeO Br
KOHNBS/AIBN
234
141 235 231
236
[O]
H
Calixbenzimidazole ?
H+
3.14.1. Benzylic oxidation of 2-methyl-4,6-dimethoxybenzimidazole
There are numerous methods reported for the benzylic oxidation of a heterocyclic
methyl group to aldehyde.148-150 Dichlorodicyanobenzoquinone (DDQ) is a useful
selective side chain oxidant.148,149 However, the reaction of 2-methyl-4,6-
dimethoxybenzimidazole 141 with DDQ in tetrahydrofuran at room temperature or
under refluxing conditions for 24 h did not produce oxidized products, and instead
only the starting benzimidazole was recovered from the reaction mixture (Scheme 3-
40). Metallic oxidants like lead tetraacetate or palladium(II) acetate have been used
effectively for benzylic oxidation.150 However, the oxidation sometimes also results in
the formation of a benzylester.151 Use of aqueous acetic acid has been reported to
increase the yield of aldehyde over ester. Attempted oxidation using lead tetraacetate
and palladium(II) acetate in glacial acetic acid or aqueous acetic acid again failed to
oxidize the 2-methylbenzimidazole 141. None of the desired aldehyde 234 or ester
237 was detected. Either no reaction was noticed or complex mixtures of products
were obtained when varying the reaction conditions and time.
Scheme 3-40
NH
N
OMe
MeONH
N
OMe
MeOMe
141 234
NH
N
OMe
MeOO OAc
DDQLead tetraacetatePalladium(II) acetate H
240
+
Alternatively, methyl substituents of heterocyclic systems could be oxidized by
selenium dioxide to give carbaldehyde derivatives.152,153 In recent times, reaction of
Chapter 3 73
activated indoles with selenium dioxide under reflux converted the indole 238 to 2,2'-
diformyl-7,7'-diindolylselenide 239 as the oxidized product (Scheme 3-41).8
However, such selenium insertion at the reactive C-7 was avoided by using C-7
substituted indoles.
Scheme 3-41
NH
OMe Ph
MeOMe SeO2/dioxan
NH
OMe Ph
MeOSe
H
O
HN
OMe
MeO
PhH
O
238 239
reflux, 24 h
As mentioned previously the dimethoxy activated benzimidazole is less reactive at its
C-7 than the analogous indoles. Potentially, the reaction of the C-7-unsubstituted
benzimidazole 141 with selenium dioxide could give either 2-formylbenzimidazole
234 or 2,2'-diformyl-7,7'-dibenzimidazolylselenide 240 (Scheme 3-42).
Scheme 3-42
NH
N
OMe
MeOMe SeO2
NH
N
OMe
MeOSe
N
HN
OMe
MeO
141 240
NH
N
OMe
MeO
234
O
H O
O
H
H
or
However, refluxing a solution of the benzimidazole 141 with selenium dioxide for
three days gave a mixture from which a red solid was isolated after extensive
chromatography. The 1H NMR spectrum of the product showed a single H-5 proton
along with two methoxy groups, one methyl group and a NH proton. The H-7 proton
appeared to be missing, which suggests that a selenium atom could have inserted at C-
7 to produce the selenide 241 (Scheme 3-43). Even though elemental analysis could
Chapter 3 74
not be obtained, a molecular ion m/z at 461 in the mass spectrum proved that the
selenide 241 has been formed. However, in this case the 2-methyl substituent was not
oxidized. Although, the result indicates a different oxidation environment than the
indoles, it gives a clue that the C-7 position should be blocked to oxidize the C-2
methyl group and prevent selenide formation.
Scheme 3-43
NH
N
OMe
MeOMe SeO2/dioxan
NH
N
OMe
MeOSe
Me
N
HN
OMe
MeOMe
141 241
reflux, 3 d
Subsequently, oxidation of the 7-formyl-2-methylbenzimidazole 163 with selenium
dioxide in dry dioxan produced the desired 2,7-diformylbenzimidazole 242 in a
moderate yield of 68% after column chromatography (Scheme 3-44). The reaction
took three days under refluxing conditions to go to completion and is slow compared
to the indole oxidations, which required only one day.8 The result further demonstrates
that the 4,6-dimethoxybenzimidazoles do not produce the same electron donating
environment as the activated indoles and are overall less reactive. The 2,7-
diformylbenzimidazole 242 was reduced to the corresponding 2,7-dialcohol 243 in
69% yield by sodium borohydride in methanol under reflux for four hours.
Scheme 3-44
NH
N
OMe
MeOMe SeO2/dioxan
NH
N
OMe
MeO
H
O
163O O
242HH
NH
N
OMe
MeO
243
NaBH4/MeOH
OH
OHreflux, 3 d reflux, 4 h
The characteristic evidence for the formation of 2,7-diformylbenzimidazole 242 was
the clear presence of two sharp aldehyde peaks at 9.92 ppm (C-2) and 10.31 ppm (C-
7) and the absence of the starting C-2 methyl protons in the 1H NMR spectrum. The
Chapter 3 75
13C NMR and other spectroscopic data are in accord with the structure. Elemental
analysis and a molecular ion m/z (M+1) at 235 confirmed the synthesis of the 2,7-
diformylbenzimidazole 242. The dialcohol 243 showed two methylene protons at 4.56
ppm and 4.75 ppm corresponding to two hydroxymethyl groups and the characteristic
dialdehyde peaks of the starting product 242 were absent. Other spectroscopic
information also points to the structure 243. Furthermore, HRMS (+ESI) of the
compound 243 showed the exact mass m/z [M+Na]+ of the compound at 261.08457.
Synthesis of 2,7-dihydroxymethylbenzimidazole 243 is quite important as this
molecule now could be exploited to form the unsymmetrical calixbenzimidazole 247
or the mixed heterocalixarene 245 according the following scheme (Scheme 3-45).
Scheme 3-45
NH
N
OMe
MeOOH
OH
NH
OMe
MeO
Ar
H+
NH
MeO OMe
Ar
HNOMe
MeO
ArNH
N
OMe
MeO
ii) H+
NH
MeO OMe
Ar
HN OMe
OMe
Ar
NH
N
OMe
MeO
O
i) NaBH4
(2 eq) O
243
244
245
NH
NOMe
MeO NH
NOMe
OMe
NHN
MeO OMe
HNN
OMe
MeO
NH
N
OMe
MeO
247
H+
246
OH
HH
48
3.14.2. Attempted preparation of halomethyl benzimidazoles
Benzylic halogenation by N-bromosuccinimide is a standard method of synthesis of
bromomethyl aromatic compounds.154 Usually a dibenzoyldiperoxide, AIBN or UV
Chapter 3 76
light as a free radical initiator gave benzylic bromination, otherwise electrophilic ring
bromination occurred.155,156 Reaction of 2-methylbenzimidazole 141 with N-
bromosuccinimide in the presence of the free radical initiator AIBN gave a mixture of
7-bromobenzimidazole 248 and 5,7-dibromobenzimidazole 249. In the similar way,
treatment of 2-methylbenzimidazole 141 with N-bromosuccinimide without the free
radical initiator produced the electrophilic monobrominated product 248 and
dibrominated product 249 respectively in 56% and 23% yield (Scheme 3-46). The
disappearance of the H-7 proton in the monobrominated compound 248 and both H-5
and H-7 protons in the dibromo compound 249 were significant observations in their 1H NMR spectra. Molecular ions in the mass spectra m/z at 272 (M+1), and 351
(M+1) clearly show the respective formation of the mono and dibromo compounds
248 and 249.
Scheme 3-46
NH
N
OMe
MeOMe
Br
NH
N
OMe
MeOMe
NBS
141 248
NH
N
OMe
MeOMe
Br
Br
249
+ with or without AIBN
1 h
While, bromination using bromine and triethylamine leads to the formation of a single
dibrominated product 249 in high yield (88%) (Scheme 3-47).
Scheme 3-47
NH
N
OMe
MeOMe
Br
NH
N
OMe
MeOMe
Br2/Et3N
141 249
Br
CH2Cl215 min
It has been reported earlier that bromination of indoles containing a free NH, gave
only electrophilic bromination, whereas indoles containing a deactivating N-
substituent, gave only free radical bromination to produce bromomethylindole.157
Considering this indole example, N-tosylated benzimidazole 227 was reacted with N-
bromosuccinimide in the presence of AIBN. However in this case too, the reaction
Chapter 3 77
afforded the 5,7-dibromobenzimidazole 250 as the major product as a result of
electrophilic substitution (Scheme 3-48). In this product 250 the characteristic H-5
and H-7 were absent in the 1H NMR spectrum and a molecular ion (M) m/z at 349
corresponds to the presence of the dibromo product 250. The mass spectrum also
showed the characteristic pattern of the dibromo compound.
Scheme 3-48
NBS/AIBNCCl4, reflux, o/nN
N
OMe
MeOMe
227
N
N
OMe
MeOMe
Br
250Me
S OO
Me
S OO
Br
These results show that the activated benzimidazoles behave similarly to the related
activated indoles119 and favour electrophilic substitution on the benzoid ring rather
than free radical bromination of the methyl substituent.
3.14.3. Synthesis and oxidation of a 2-styryl benzimidazole
The synthesis of 4,6-dimethoxy-2-styrylbenzimidazole 236 was required to generate
the 2-formyl-4,6-dimethoxybenzimidazole 234. Two synthetic routes were followed
for the synthesis of 2-styrylbenzimidazole 236. In the first route (Scheme 3-49) the 2-
methylbenzimidazole 141 was reacted with benzaldehyde in acetic anhydride to form
the 2-styrylbenzimidazole 236. Heating the mixture of 2-methylbenzimidazole 141
and benzaldehyde in acetic anhydride for four hours gave a mixture of compounds.
The presence of a molecular ion m/z (M+1) at 281 in the mass spectrum of the
partially purified mixture showed the formation of the 2-styrylbenzimidazole 236.
However, pure compound could not be isolated for characterization.
Scheme 3-49
NH
N
OMe
MeOMe
PhCHO/Ac2O
141
NH
N
OMe
MeO
236(not isolated)
110oC, 4 h
Chapter 3 78
The second route followed the general synthetic scheme outlined for the synthesis of
benzimidazoles (Scheme 3-2). In this route 3,5-dimethoxyaniline 39 was first acylated
with cinnamoyl chloride to give the cinnamide 251 in 77% yield, which was then
nitrated using nitric acid in acetic anhydride to produce the 2-nitrocinnamide 252 in
80% yield. After that, the 2-nitrocinnamide 252 was reduced to 2-aminocinnamide
253 with palladium-catalyzed hydrazine reduction in 57% yield, and the product was
cyclized consequently by acid catalysis to give the 4,6-dimethoxy-2-styryl
benzimidazole 236 in a moderate yield of 41% (Scheme 3-50). In contrast to the other
amides, cinnamide 252 required dry ethanol and reaction conditions for the
hydrogenation. The desired styryl benzimidazole 236 exhibited the alkene (C=C)
absorption band at 1628 cm-1 in the infrared spectrum, while in the 1H NMR spectrum
the olefinic protons appeared at 7.08 ppm and 7.60 ppm with a coupling constant (J)
of 16.2 Hz. Molecular ion peak at m/z 281 symbolized to the presence of styryl
benzimidazole 236, which was further identified by the other spectroscopic data and
elemental analysis.
Scheme 3-50
NH2
OMe
MeO NH
OMe
MeO O
PhCH=CHCOCl
Pd/CNH2NH2.H2OEtOH
39
AcOH
NH
OMe
MeO O
NO2
NH
OMe
MeO O
NH2
NH
N
OMe
MeO
HNO3/AC2O
251 252
253236
K2CO3, DCM 0oC, 0.5 h
r.t., 4 h65oC, 3 h
The scission of the C=C double bond is a synthetically important reaction to break
large compounds or to introduce oxygen functionality into the molecules. For the
cleavage of alkenes to aldehydes a number of methods have been reported.158 To
obtain aldehydes from alkenes, ozonolysis followed by reductive workup159 or
oxidative cleavage with osmium tetroxide-sodium periodate (Lemieux-Johnson
reagent)160 are the two most frequently employed procedures.
Chapter 3 79
In the process of ozonolysis ozone (O3) reacts with alkenes to break the double bond
and form two carbonyl groups. When 2-styrylbenzimidazole 236 was reacted with
ozone at -78°C in dilute ethyl acetate solution, a quick reaction was observed and was
complete within 15 min. Reduction of the ozonides with dimethylsulfide and workup
only gave the decomposed products accordingly to the 1H NMR spectrum. It is
possible that, further oxidation of the aldehyde or multiple oxidation of the 2-
styrylbenzimidazole 236 could have happened to generate the decomposed materials.
In contrast, osmium tetroxide catalyzed sodium periodate oxidation has the advantages
of not proceeding beyond the aldehydic oxidation state, thus affording the same
products produced by ozonization followed by reductive cleavage.160 A catalytic
amount of osmium tetroxide is sufficient because periodate oxidizes osmium in its
lower valence forms to the tetroxide, thus regenerating the hydroxylating agent.
Hence, this combination of two well known reactions permits the use of relatively
small amounts of the expensive and poisonous hydroxylating agent. The 2-
styrylbenzimidazole 236 underwent oxidation very slowly (48 h) in aqueous dioxan
and produced 2-formylbenzimidazole 234 in 74% yield (Scheme 3-51). The
characteristic 2-formyl proton was observed at the 9.77 ppm in the 1H NMR spectrum,
while the infrared carbonyl absorption was seen at 1619 cm-1. A HRMS molecular ion
m/z [M+Na]+ at 229.0585 confirmed the presence of the 2-formylbenzimidazole 234.
The compound was seen as a single tautomer probably again due to the hydrogen
bonding of the carbonyl oxygen to the NH.
Scheme 3-51
236
NH
N
OMe
MeO
234
O
OsO4/NaIO4
NH
N
OMe
MeO OH
231
NaBH4
MeOH
H
NH
N
OMe
MeOdioxan
The 2-formyl benzimidazole 234 was reduced to the corresponding 2-alcohol 231 by
sodium borohydrate reduction in refluxing tetrahydrofuran/methanol solution. The
desired alcohol 231 showed the methylene protons at 4.56 ppm, whereas the aldehyde
peak was missing in the 1H NMR spectrum. A mass spectrum peak at m/z at 209
Chapter 3 80
corresponding to the molecular ion (M+1) verified the alcohol structure 231. In
attempts to prepare the desired calix[3]benzimidazole 232 or calix[4]benzimidazole
233 (Scheme 3-38), treatment of the alcohol 231 in warm acetic acid gave a complex
mixture of products, whereas treatment with p-toluenesulfonic acid in isopropanol
gave an unexpected ether linked product 254 (Scheme 3-52). The product 254
precipitated out from the reaction after cooling and the 1H NMR spectrum exhibited
the methylene protons at 4.68 ppm and the H-5 and H-7 protons were seen at 6.45
ppm and 6.60 ppm respectively. In the mass spectrum (m/z) a molecular ion (M+1) at
399 recognized the formation of the dibenzimidazolyl ether 254.
Scheme 3-52
NH
N
OMe
MeOIsopropanolp-TosOH
ONH
N
OMe
OMeNH
N
OMe
MeO OH
231 254
120oC, 4 h
The postulated mechanism of this formation was considered to be by formation of the
carbocation in the acidic conditions of the reaction (Scheme 3-53). This undergoes
attack by another molecule of hydroxymethyl benzimidazole to form the
dibenzimidazolyl ether 254, because of the comparatively less reactive nature of the
C-7 position. This result strengthens the findings in this thesis that the 4,6-dimethoxy
activated benzimidazoles are not as reactive as the C-7 position as that of the similarly
activated 4,6-dimethoxyindoles.
Scheme 3-53
NH
N
OMe
MeOO
NH
N
OMe
OMeNH
N
OMe
MeO OH
231
NH
N
OMe
MeO
H+
H
H
-H2O
HN N
OMe
MeO
OH
254
Chapter 3 81
3.15. Preparation of acyclic quadridentate metal complexes
Although excellent chelating agents, cyclic ligands impose certain structural
constraints on their complexes and have limited the generation of a series of ligands
where the spacer group can be expanded. Metal template reactions are ligand reactions
which are dependant on or can be significantly enhanced by, a particular geometrical
orientation imposed by metal coordination. In coordination chemistry, a
benzimidazole structure will be of interest to elucidate the properties of the acyclic
metal complexes in comparison with those of indole analogs. Moreover, a
benzimidazole copper complex has displayed antibacterial, antifungal properties and
interaction with the DNA.25
The 7-formylbenzimidazoles 164 and 165 were examined for their coordination
behaviour in some metal template reactions. 1,2-Diaminobenzene is ideal for
producing a coordination cavity with benzimidazole that will afford neutral square-
planar complexes in the acyclic cases. Treatment of the 7-formylbenzimidazoles 164
and 165 with half an equivalent of the divalent metal acetates nickel(II), cobalt(II),
copper(II), zinc(II) palladium(II) and manganese(II) acetates in a template reaction in
anhydrous methanol with 1,2-diaminobenzene at reflux afforded the desired metal
complexes 255-266 in each case ranging from 40-96% yield (Scheme 3-54).
Significant color changes from yellow of the starting materials to the colorful solution
indicating complex formation were observed during the reaction progress. The
reaction was monitored by TLC and continued under reflux for 2-16 h. In comparison
to the indole examples addition of triethylamine as a deprotonating agent was not
necessary. The basicity of the benzimidazole itself, the diamine or acetate ion could
effect deprotonation. The complexes normally precipitated from the refluxing solution
as the reaction proceeded. In general 2(4'-methoxyphenyl)benzimidazole afforded a
higher yield of the complexes than the 2-phenylbenzimidazole.
Chapter 3 82
Scheme 3-54
NH
N
OMe
MeOR
OH
NH2
NH2
M(OAc)2.xH2O/MeOH
N
NMeO
MeO N N
N
N OMe
OMe
M
R R
R NiII CoII CuII ZnII PdII MnII
Ph 255 256 257 258 259 2604-MeOC6H4 261 262 263 264 265 266
164; R = Ph165; R = 4-MeOC6H4
reflux, 2-16 h
Nickel(II), zinc(II) and palladium(II) complexes 255, 258, 259, 261, 264 and 265
exhibited simple characteristic 1H NMR spectra. The characteristic imine resonances
in the 1H NMR were observed at ~8.80 ppm and in the 13C NMR at ~172 ppm. Imine
absorptions (C=N) in the infrared spectra of the 2-phenylbenzimidazole derived
complexes 255-260 appeared at ~1595 cm-1, whereas those for the 2-(4'-
methoxyphenyl)benzimidazole derived complexes 261-266 were observed at ~1605
cm-1. The similarity in the imine band positions for different metals in both the 2-
phenylbenzimidazole and 2-(4'-methoxyphenyl)benzimidazole complexes shows that
the complexes are well structured to accommodate a range of transition metal cations.
Several electronic absorption bands usually with high molar absorptivities were
observed in the region 200 to 450 nm. The metal complexes are intensely colored with
the nickel(II), cobalt(II) and copper(II) complexes being usually dark brown, while the
zinc(II) complexes are orange-red, palladium(II) complexes are orange to brown and
the manganese(II) complexes are dark yellow. The complexes were sufficiently
volatile to give mass spectra showing peaks corresponding to the appropriate isotopic
molecular ions.
A comparison of 1H NMR spectra of the aldehyde ligand and its nickel(II) complex
255 and 261 exhibited a shifting of the resonances throughout the molecule. The H-5
proton appeared to shift upfield by ~0.18-0.22 ppm, while the methoxy signals remain
unchanged probably due to remoteness from the metal centre. Ortho phenyl protons
were seen to move downfield, whereas meta and para phenyl protons experienced an
upfield shift. On the other hand, the zinc(II) and palladium(II) complexes 258, 259,
Chapter 3 83
264 and 265 demonstrated a somewhat different pattern of resonance shifting. The H-
5 protons were moved to lowfield, ortho phenyl protons received an upfield shift,
whereas the meta and para phenyl protons were shielded. Interestingly, the (4'-
methoxy) protons displayed an upfield shift, most likely result of conformational
change and metal to ligand charge transfer effects.
In the case of four-coordinate metal complexes, the donor atoms lie at the corners of a
square or at the apices of a tetrahedron, with the metal ion at the centre of that square
or tetrahedron.161 It is known that d8 metal ion Ni(II) and Pd(II) give preferred square
planar configuration and afford diamagnetic complexes, whereas the d10 metal ion
Zn(II) has no electronic preference for geometry and affords diamagnetic complexes.
The Co(II) and Cu(II) complexes favour the tetrahedral geometry, while Mn(II) has a
preference for the trigonal bypyramidal configuration. Also these Co(II), Cu(II) and
Mn(II) complexes display paramagnetism and are difficult to observe by usual NMR
conditions. In this work, the nickel(II), zinc(II) and palladium(II) complexes displayed
simple characteristic resonances in the 1H NMR spectra suggesting symmetrical
orientation of the quadridentate metal complexes of neutral square-planar structure. In
the absence of three-dimensional X-ray structural analysis a rigorous structural
assignment for the complexes cannot be made. By way of analogy with the related
complexes derived from indole,138 on the basis of NMR and infrared spectroscopy and
molecular model studies, square planar structures are proposed for these quadridentate
complexes.
Satisfactory analytical data were obtained for the 255, 257-261, 263 and 264
complexes, but remained elusive for the other complexes. The correct microanalysis
could not always be obtained as a result of difficulties in recrystallization and as these
compounds usually contains water or other solvents within the cavities. The existence
of water molecules were also evidenced by the presence of wide bands at ~3400 cm-1
in their infrared spectra.
Chapter 3 84
1,2-Diaminoethane is a simple alkyl diamine spacer group that has been used
previously in template reactions.161 Template reactions of the 7-formylbenzimidazoles
164 and 165 with half an equivalent of the divalent metal acetates nickel(II), cobalt(II)
and palladium(II) acetates in anhydrous methanol with 1,2-diaminoethane similarly
affords the dark brown metal complexes 267-270 in relatively low yield ranging from
27-89 % than previous complexes (Scheme 3-55).
Scheme 3-55
reflux, 2-16 h
NH
N
OMe
MeOR
OH
H2N NH2
M(OAc)2.xH2O/MeOH
N
NMeO
MeO N N
N
N OMe
OMe
R R
R NiII CoII PdII
Ph 267 268 269 4-MeOC6H4 270 - -
M
164; R = Ph165; R = 4-MeOC6H4
The complex formation was noted by the presence of characteristic imine resonances
of the nickel(II) complexes 267 and 270 in the 1H NMR spectra at the ~8.2 ppm. The
compounds were too insoluble for measurement of 13C NMR spectra. The
palladium(II) complex 269 was also found not suitable even for 1H NMR spectrum,
most likely because of poor solubility. The infrared spectra of the complexes 267-269
exhibited characteristic imine absorption bands in the region ~1595 cm-1 and complex
270 at 1608 cm-1. The complexes were relatively less soluble in methanol as observed
in their molar absorptivities. None of these complexes give satisfactory
microanalytical results because of purification problems due to their poor solubility.
Therefore, mass spectra were obtained to authenticate the complex formation. Slightly
distorted neutral square planar/tetrahedral structures are proposed for these complexes
after analyzing their 1H NMR spectra and comparing them with previous examples.
An increase in cavity size was also investigated by using 1,3-diaminopropane and 1,4-
diaminobutane as spacer groups. 7-Formylbenzimidazole 164 underwent template
reaction with half an equivalent of the nickel(II) acetate tetrahydrate in anhydrous
methanol with 1,3-diaminopropane at reflux to afford the brown nickel(II)complex
271 in high yield 90% (Scheme 3-56). In the same way, treatment of the 7-
Chapter 3 85
formylbenzimidazole 164 and 1,4-diaminopropane with selected metal acetates,
namely nickel(II) or cobalt(II) in anhydrous methanol at reflux according to the
method described earlier formed the predicted quadridentate complexes 272 and 273
as brown solids in high yields of 90-92%.
Scheme 3-56
NH
N
OMe
MeOPh
164
OH
H2N NH2
M(OAc)2.4H2O/MeOH
N
NMeO
MeO N N
N
N OMe
OMe
Ph Ph
n NiII CoII
3 271 -4 272 273
M
(CH2)n
(CH2)n
reflux, 2 h
The characteristic imine resonance was observed at 8.86 ppm in the 1H NMR
spectrum of 271, while imine absorptions in the IR spectrum of the complex 271
appeared at 1595 cm-1. The complex 272 was too insoluble for characterization by 1H
NMR spectroscopy. Accurate elemental results were recorded only for the complex
271, but could not be obtained for the complexes 272 and 273. Nevertheless, they
exhibited the correct isotopic molecular ions (m/z) in the mass spectra to validate their
structures. The high yields of the complexes suggest that the increase in spacer group
favours the formation of the complexes because of the more flexible nature. As
mentioned earlier these complexes are also predicted to have a distorted square planar
geometry.
Selective physical and spectral observations of the metal complexes are recorded in
the Table 3-5.
Chapter 3 86
Table 3-5. Significant spectral and physical properties of the acyclic metal complexes.
Complex Metal IR C=N N=CH H5 Yields Color
255 Ni 1597 8.80 6.13 46 dark brown
256 Co 1597 - - 85 dark brown
257 Cu 1596 - - 40 dark blue
258 Zn 1590 9.53 6.62 79 orange red
259 Pd 1595 9.03 6.39 60 orange
260 Mn 1593 - - 90 yellow
261 Ni 1603 8.79 6.09 70 dark brown
262 Co 1610 - - 83 red
263 Cu 1608 - - 92 dark brown
264 Zn 1610 9.49 6.42 97 orange red
265 Pd 1608 8.99 6.41 63 light brown
266 Mn 1609 - - 91 yellow
267 Ni 1595 8.16 6.09 41 dark brown
268 Co 1595 - - 27 dark brown
269 Pd 1595 -* - 34 light green
270 Ni 1608 8.27 6.24 89 brown
271 Ni 1595 8.86 6.32 90 brown
272 Ni 1595 -* -* 92 dark brown
273 Co 1596 - - 92 dark brown
* sample too insoluble for 1H NMR
The 7-formylbenzimidazoles 164 and 165 are valid ligand precursors on their own
right, and have a deprotonable nitrogen (NH) for chelation and a lone pair donor
oxygen atom through the carbaldehyde group. It is expected that metal complexation
with the formyl ligands would be freer of the geometrical constraints imposed by the
spacer group and favour the transoid geometry. Treatment of the ligands 164 and 165
with half an equivalent of the metal acetates resulted in the formation of the metal
Chapter 3 87
complexes 274-278 in moderate yields (Scheme 3-57). The complexes are well
colored to distinguish from their starting materials during the reaction progress.
Scheme 3-57
NH
N
OMe
MeOR
OH
M(OAc)2.xH2O
R CuII PdII MnII
Ph 274 275 276 4-MeOC6H4 277 278 -
N
N
OMe
MeOR
OH
N
N
OMe
OMeR
O HMMeOH, reflux, 2 h
164; R = Ph165; R = 4-MeOC6H4
The infrared carbonyl group frequencies were observed at ~1600 cm-1 and the
resonances for the aldehyde peak in the 1H NMR of the palladium(II) complexes 275
and 278 appeared at ~10.30 ppm. Although the 1H NMR chemical resonance shift of
the complexes was not significant, a slight decrease in wave numbers in the IR of
C=O was noticed, which indicates chelation to the metal centre. Accurate elemental
analyses were found for the complexes 274 and 278 containing dichloromethane
solvent, but could not be obtained for the others due to difficulties in recrystallization
and inclusion of solvent molecules inside their cavities. However, correct mass spectra
of the complexes 274-278 were obtained to confirm the metal complex formation.
3.16. Synthesis of 2,2' linked bisbenzimidazoles
In this section, attempts were made to synthesize several dimethoxy activated 2,2'-
bisbenzimidazoles by the similar synthetic procedure established earlier in this thesis
for the preparation of benzimidazoles (Chapter 3.2). Following these procedures
malonyl chloride, succinyl chloride, phthaloyl chloride, isophthaloyl chloride and
terephthaloyl chloride were reacted with the nitroaniline 150 in
tetrahydrofuran/dichloromethane under argon to prepare the dinitroamides. The usual
sequence of preparation could not be followed because of the low solubility of the
amides in the nitration media and as multiple nitration products was observed in initial
attempts. The nitromalonamide 279, nitroisophthalamide 280 and
nitroterephthalamide 281 were isolated as yellow solids of low solubility in moderate
Chapter 3 88
yields (47-71%) (Scheme 3-58). The products were identified by their spectroscopic
data. The bis-2-nitroamides 279-281 were then reduced to bis-2-aminoanilides 282-
284 with palladium-catalyzed hydrazine reduction in good yields (72-84%), and were
isolated and characterized by spectroscopic measurements. The bis-2-aminoanilides
282-284 were then cyclized by acid catalysis to give the corresponding
bisbenzimidazoles 246, 285 and 286 in moderate yields 61-67%.
Scheme 3-58
NH2
OMe
MeO
ClCORCOCl
Pd/CNH2NH2.H2OEtOH, reflux, 3-20 h
150
H+, reflux
279; R = CH2280; R = 1,3-C6H4281; R = 1,4-C6H4
N
NHMeO
OMe
N
NH OMe
OMe
R
282; R = CH2283; R = 1,3-C6H4284; R = 1,4-C6H4
246; R = CH2285; R = 1,3-C6H4286; R = 1,4-C6H4
NO2
MeO
OMe
NH
NO2
RO
OMe
OMe
NH
O2NO
MeO
OMe
NH
NH2
RO
OMe
OMe
NH
H2NO
K2CO3, THF, 3 d
o/n
The compounds derived from isophthaloyl chloride and terephthaloyl chloride were
relatively insoluble in most organic compounds due to their rigid structure and hence
difficult to recrystallize. The carbonyl group frequencies for the nitroamides 279-281
were seen around 1690 cm-1, in addition to the amide NH absorptions from 3328-3379
cm-1 and the nitro bands at ~1550 cm-1 and ~1325 cm-1. The aminoamides 282-284
showed the characteristic carbonyl absorptions at ~1635 cm-1. The bisbenzimidazoles
285 and 286 showed tautomerism of the 4,6-dimethoxybenzimidazole 285, 287 and
5,7-dimethoxybenzimidazole 286, 288 in a ratio (1:0.34) according to the 1H NMR
spectra taken into DMSO-d6 (Figure 3-15). The 4,6-dimethoxy sets of peaks were
observed more dominant over the 5,7-dimethoxy signals in their spectra. As expected,
similar EI mass spectra were observed at m/z (M+1) 431 giving molecular ion base
peaks for the bisbenzimidazoles 285 and 286.
Chapter 3 89
N
NHMeO
OMe
N
NH OMe
OMeHN
NMeO
OMeHN
N OMe
OMe
N
NHMeO
OMe
N
NH OMe
OMeHN
NMeO
OMeHN
N OMe
OMe
285 287
286 288
Figure 3-15
Interestingly, DNA specific binding properties are well described 162,163 for some
bisbenzimidazoles (e.g., Hoechst 33258) related to the synthesized compounds 285
and 286. In addition, this kind of methoxy activated head to head 2,2'-
bisbenzimidazoles 285 and 286 having a phenyl spacer group are quite interesting for
further chemical reactivity towards electrophiles and formation of metal complexes.
These compounds could be adapted for acid catalyzed reaction by the following
scheme to give the calix[4]benzimidazole 291. However, it is also possible to form a
linear polymer 292 with these molecules (Scheme 3-59). It is expected that
formylation of this tautomeric benzimidazole 286 would give a more stable 4,6-
dimethoxy tautomer 289 due to hydrogen bonding, which could then be reduced easily
to alcohol 290, which on acid catalysis could give the calix[4]benzimidazole 291.
Another alternate one step procedure could be treatment of the bisbenzimidazole 286
with formaldehyde in the acidic conditions previously stated (section 3.4), to prepare
the calix[4]benzimidazole 291. It could also be possible to generate a similar kind of
calix[4]benzimidazole 291 from the bisbenzimidazole 286.
Chapter 3 90
Scheme 3-59
N
NHMeO
OMe
N
NH OMe
OMeN
NHMeO
OMe
N
NH OMe
OMe
286 289
N
NHMeO
OMe
N
NH OMe
OMeN
NHMeO
OMe
N
NH OMe
OMe
291
290
POCl3/DMF
OH HO
OH HO
NaBH4 / MeOH
H+
HCHO / AcOH
N
HN OMe
OMe
N
HNMeO
OMe H+
292
N
NHMeO
OMeN
NH OMe
OMe
N
HN OMe
OMeN
HNMeO
OMeN
HN OMe
OMeN
HNMeO
OMe
N
NHMeO
OMeN
NH OMe
OMe
In contrast to the previous findings, the reaction of succinyl chloride and phthaloyl
chloride with 2-nitroaniline 150 gave the unexpected imides 295 and 296 respectively
(Scheme 3-60). These result from the internal cyclization of the diacid chlorides on to
the amine 39 where the acid chloride groups were separated by two carbon units.
Chapter 3 91
Scheme 3-60
K2CO3, THF
NH2
OMe
MeO
ClCORCOCl
150 293; R = C2H4294; R = 1,2-C6H4
NO2
OMe
MeO NO
O
NO2
OMe
MeO NO
O
NO2
ClCORCOCl
295 296
MeO
OMe
NH
NO2
RO
OMe
OMe
NH
O2NO
However, attempted reduction and cyclization of the dione 296 to the
benzimidazoisoindolone 298 (Scheme 3-61) revealed the dione 296 to be unstable to
the various reduction conditions (e.g. Pd/C catalyzed hydrazine hydrate, hydrazine
hydrate, stannous chloride/hydrochloric acid, sodium borohydride, zinc/acetic acid
and iron dust/ammonium chloride) and produced the nitroaniline 150 as a result of
hydrolysis.
Scheme 3-61 OMe
MeO NO
O
NO2
296
OMe
MeO NO
O
NH2
297
N
NMeO
OMe
O
H+
298
Various reductions failed
Formation of the ketobisbenzimidazole 299 was attempted by oxidation of the
methylene bridge of the bisbenzimidazole 246 (Scheme 3-62). Following a similar
literature precedent164 the bisbenzimidazole 246 was submitted to air oxidation in
dimethyl sulfoxide for 7 days. However, no reaction was observed in air oxidation and
a similar observation was also noted in the case of attempted reaction with sodium
nitrite. Oxidation by sodium hypobromite solution165 yields a multitude of
uncharacterized products. Earlier nitric acid has been shown to be a mild oxidant for
methylene protons.166 Treatment of the bisbenzimidazole 246 by nitric acid in
acetonitrile indeed oxidized the methylene group to the ketone 299, along with further
Chapter 3 92
nitration at the C-7 positions. Infrared absorption bands at 1354 cm-1 and 1530 cm-1
indicate the presence of the nitro groups and this was later confirmed by the molecular
ion peak m/z at 473 in the EI mass spectrum and by HRMS data. Despite several
recrystallization attempts, the product could not be purified and a suitable 1H NMR
spectrum could not be obtained.
Scheme 3-62
N
NHMeO
OMe
N
NH OMe
OMeN
NHMeO
OMe
N
NH OMe
OMe
299246
HNO3
CH3CN
NO2 NO2
O
3.17. Synthesis of bisbenzimidazol-1-ylmethanes
Treatment of benzimidazole 141 in dry dimethyl sulfoxide with diiodomethane
produced a mixture of compounds with very close Rf values and they could not be
purified. However, the 1H NMR spectrum of the mixture revealed the presence of the
4,6-dimethoxy isomer 300 and the 5,7-dimethoxy isomer 301 in a ratio of 1:0.5
(Scheme 3-63). In this case also the 4,6-dimethoxy isomer prevailed over the 5,7-
dimethoxy isomer. The band at 3387 indicated the OH stretching frequency of the
water molecule present in the sample; this was also confirmed by elemental analysis.
Molecular ions m/z (M+1) at 397 (100%) provided further evidence for these isomeric
compounds 300 and 301.
Scheme 3-63
N
N
OMe
MeOMe
N
N
OMe
MeOMe
N
NMe
N
NMe
OMe
MeO
OMe
MeO
NH
N
OMe
MeOMe
DMSO, 2 h
CH2I2, KOH
141 300 301
+
(products were not seperated)
Because of the unsymmetrical position of methoxy groups the bisbenzimidazole 246
is tautomeric, but proton migration could be stopped by linking the two NH groups
Chapter 3 93
(Scheme 3-64). Thus attempted ring closure of the bisbenzimidazole 246 with
diiodomethane gave a polymer compound which could not be characterized.
Treatment of the bisbenzimidazole 246 with a slightly longer linker diiodoethane,
similarly gave an uncharacterized polymer and further attempts with longer and other
linkers were not investigated.
Scheme 3-64
N
NHMeO
OMe
N
NH OMe
OMeN
NMeO
OMe
N
N OMe
OMe
(CH2)n
302, n = 1, 2246
KOH/DMSOCH2I2 or C2H5I2
Another approach was to join the two benzimidazole nitrogens by reaction with
phosgene to give the compound 303 (Scheme 3-65). Treatment of half an equivalent
of phosgene to the benzimidazole 246 in a similar way gave uncharacterized polymer.
Scheme 3-65
N
NHMeO
OMe
N
NH OMe
OMeN
NMeO
MeON
NOMe
OMe
303246
COCl2CH2Cl2
O
3.18. Conclusions
In conclusion, some new dimethoxy activated benzimidazoles and bisbenzimidazoles
have been synthesized. On the whole, the varieties of reaction carried out on the
activated benzimidazoles revealed less reactivity at the specified C-7 and as well at
their functional groups compared to the analogous indoles. Thus the formation of
dibenzimidazolyl ether 254 in the attempted synthesis of calixbenzimidazole is
understandable. However, in future works the calix precursors still can be used to
form calixbenzimidazoles or mixed heterocalixarenes. Single 4,6-
dimethoxybenzimidazole tautomers can be obtained by designing structures with
suitable hydrogen bonding. Furthermore, benzimidazoles effectively demonstrated a
wide range of metal complexation, when incorporated into various ligand systems.
Chapter 4 94
CHAPTER 4
ELECTROCHEMICAL PROPERTIES OF SOME ACTIVATED
BENZIMIDAZOLES
4.1. Introduction
Hydrogen bonding is central to a range of intra- and intermolecular phenomena in the
natural world. The strength and directionality of these interactions direct protein
folding and stabilization, while the ability to encode information into hydrogen-
bonded networks allows for the storage and transfer of genetic data from DNA.
Biological systems also use hydrogen bonding to stabilize specific oxidation states of
pterins, quinines, nicotinamides, and flavins through specific interactions with a
protein scaffold.167 Studies on the hydrogen bond formation and redox potential
modulation of electroactive compounds could gain a greater understanding of the
underlying chemistry of the systems. Hydrogen bonds are known to have substantial
electrostatic character. Therefore, a reduction or oxidation process that leads to a
change in partial charge on one of the components in a hydrogen bond will have a
significant effect on the strength of that hydrogen bond. In particular, if the negative
charge on the hydrogen acceptor or the positive charge on the hydrogen donor is
decreased, the strength of the hydrogen bond will be decreased.168
The effect of hydrogen bonding on the electrochemical behaviour of some
electroactive benzimidazole compounds has been investigated previously.
Spectrophotometric and electrochemical investigations have shown that the bis-(2,2’-
bipyridine)(2,2’-pyridyl)-benzimidazole ruthenium RuII cation and its derivatives
interact with aromatic nitrogen heterocycles through hydrogen bonding.169 Some 2-
substituted benzimidazoles and their 1-methyl derivatives were investigated
theoretically with respect to their tendency to form an intramolecular hydrogen
bond.170 Hydrogen bonding interactions between poly (benzimidazole) and strong
acids in methanol were found to be responsible for thermal stability and proton
conductivity of the acid doped polymer complexes.171 Catalytic reduction of protons
through protonated benzimidazoles was observed in electroreduction studies of
benzimidazoles.172,173
Chapter 4 95
On the other hand, recently there has been interest in exploring the use of the metal
redox couple as a means of modulating the binding of a molecule to the minor groove
of the DNA helix, with a view to developing selective cytotoxins based on minor
groove targeted molecules.174,175 The use of transition metal chelates is central in the
effort to elucidate the mechanisms involved in the site specific recognition of DNA
and to determine the principles governing the recognition. Coordination of a minor
groove binding ligand to a metal ion was used to sterically exclude the ligand from the
narrow minor groove, in a reducing environment and thereby allowing the ligand to be
released to subsequently bind to DNA.174,175 Redox active co-ordination complexes of
either synthetic or natural origin, that induce DNA cleavages have been studied as
models for the site specific reactions and are useful tools in modern molecular biology
and in medicine. Thus, several CuII and RuII complexes have been interacted with
DNA.176-180 However, CoII complexes have not been extensively studied though they
possess interesting metallointercalation and DNA cleavage properties in addition to
binding selectivity.181
The aim of the present study is a preliminary investigation of electrochemical
behaviour of some newly developed activated benzimidazoles and benzimidazole
metal (NiII and CoII) complexes using cyclic voltammetry to evaluate the role of
hydrogen bonding of benzimidazoles in the redox process as well as the redox
behaviour of the benzimidazole metal complexes.
4.2. Electrochemistry of 2-substituted 4,6-dimethoxybenzimidazoles
The cyclic voltammetry (CV) studies were performed using 0.1 M tetra-n-
butylammonium hexafluorophosphate [nBu4N][PF6] in anhydrous acetonitrile as an
inert electrolyte solution. A conventional three electrode cell consisting of a glassy
carbon working electrode, a platinum wire counter electrode, and an Ag/AgCl
reference electrode were used for the measurement. Ferrocene/ferrocenium (Fc-Fc+)
redox couple served as a reference (a IUPAC reference) for the determination of redox
potentials.182
Initially, the CV experiments of the activated 4,6-dimethoxybenzimidazoles 141 and
142 were studied for their electrochemical behaviour. The voltammogram of the 2-
Chapter 4 96
methylbenzimidazole 141 on scanning to the positive potentials showed (Figure 4-1a)
two anodic peaks. The first anodic peak (Epa) was observed at +0.727 V with an
irreversible behaviour. The second anodic peak (Epa) appeared at +1.707 V with
subsequently a quasireverse peak (Epc) at +1.12 V. Therefore, the calculated peak
separation was Ep = 586 mV and the half cell potential was E1/2 = +1.41 V (in
acetonitrile 0.1 mM [nBu4N][PF6]). The 2-phenylbenzimidazole 142 showed (Figure
4-1b) an irreversible anodic peak at +0.573 V. There was a quasireversible behaviour
observed at anodic peak potential (Epa) at +1.18 V and cathodic peak potential (Epc) at
+1.053 V ( Ep = 127 mV; E1/2 = +1.11 V). Furthermore, a multielectron irreversible
oxidation (Epa) was observed at +1.394 V.
15x10-6
10
5
0
210-1Potential, V vs Fc
+- Fc
a)
NH
N
OMe
MeONH
N
OMe
MeO
30x10-6
20
10
0
210-1Potential, V vs Fc
+- Fc
b)
Figure 4-1. Cyclic voltammograms of a) 2 mM 2-methylbenzimidazole 141 and b) 2-phenylbenzimidazole 142 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100 mV/sec vs.Fc-Fc+ at 25 0C.
The first irreversible peaks of these two compounds are of one electron process and
suggested formation of a benzimidazole radical cation (Scheme 4-1). The subsequent
waves in the parent benzimidazoles are considered multielectron oxidation processes
of the benzimidazole radical cation. The numbers of electrons transferred in these
waves were determined using the oxidative peak current of the reversible one electron
ferrocene/ferrocenium couple as an internal standard. The irreversibility/
quasireversibility of the redox waves suggest chemical transformations following
electronic transfer(s). In addition, it was observed that the 2-methylbenzimidazole 141
has a higher oxidation potential compared to the 2-phenylbenzimidazole 142. For
instance, formation of the 7,7'-bisbenzimidazolyl 304 could take place via
dimerization of the radical cation resulting from the removal of one electron from the
benzimidazole 141 (Scheme 4-1).
Chapter 4 97
Scheme 4-1
NH
NOMe
MeOMe
NH
NOMe
MeOMe
NH
NOMe
MeOMe
-2H+
H
NH
N
OMe
MeOMe
HN
N
OMe
MeOMe
HH
NH
N
OMe
MeOMe
HN
N
OMe
MeOMe
304
141
-e-
4.3. Electrochemistry of some hydrogen bonded benzimidazoles
It has been demonstrated previously in Chapter 3 that NH is hydrogen bonded
(O···HN) with the carbonyl oxygen of 7-formylbenzimidazoles 163, 164 and 7-
acetylbenzimidazoles 172, 173 to give a single stable tautomer (Figure 4-2). Hence, it
was useful to examine their electrochemical behaviour as well as to investigate the
role of hydrogen bonding in the redox process.
NH
N
OMe
MeOMe
OMe
NH
N
OMe
MeOPh
OMe173172
NH
N
OMe
MeOMe
O
NH
N
OMe
MeOPh
O163 164
H H
Figure 4-2
First of all, on scanning to the positive potentials of the 7-formyl-2-
methylbenzimidazole 163 (Figure 4-3a-solid line) a minor oxidation product
appeared at +0.53 V, before an irreversible anodic peak (Epa) was observed at +0.886
V, and was assigned to the benzimidazole radical cation. A multielectron
quasireversible oxidation process was also observed at anodic peak potential at +1.45
V and cathodic peak potential (Epc) at +1.35 V ( Ep = 101 mV; E1/2 = +1.4 V).
Moreover, a fourth oxidation was observed at the anodic wave +1.75 V. These were
assumed to be the products of the benzimidazole radical cation. The 7-formyl-2-
Chapter 4 98
phenylbenzimidazole 164 showed (Figure 4-3b-solid line) three anodic peaks (Epa) at
+0.844 V, +1.274 V and +1.567 V. Among these three peaks, the first and the third
peaks were irreversible type and the second peak was observed with a quasireverse
cathodic peak (Epc) at +1.24 V. The first wave of these two 7-formylbenzimidazoles
163 and 164 represents the unstable benzimidazole radical cation as represented by the
multielectron oxidations of rapid chemical transformations. Quasireversibility of the
second oxidation waves hints to the stability of the electrochemically generated
intermediate following the second electronic transfer.
Addition of a strong acid, trifluoroacetic acid, to the 7-formylbenzimidazoles 163 and
164 has been used to protonate the benzimidazoles and investigate the electrochemical
behaviour. The acid addition shifted the first oxidation potential (Epa) of 163 to +1.276
V which is 0.39 V higher than the non acid treatment potential (Figure 4-3a-dashed
line). The first oxidation potential (Epa) of acid treated 164 shifted 0.195 V higher than
the original potential (Figure 4-3b-dashed line). The acid addition has moved the
first oxidation potentials towards the positive end. Thus, the finding of acid addition
suggests the compounds 163 and 164 are harder to oxidize in the acidic environment.
No major change was observed in the rest of the oxidation waves which are indicative
of multiple oxidation, except that the quasireversible second oxidation waves became
irreversible.
20x10-6
15
10
5
0
210-1
Potential, V vs Fc+- Fc
NH
N
OMe
MeO
O
a )30x10
-6
25
20
15
10
5
0
210-1
Potential, V vs Fc+- Fc
NH
N
OMe
MeO
O
b )
Figure 4-3. Cyclic voltammograms of 2 mM a) 7-formyl-2-methylbenzimidazole 163 and b) 7-formyl-2-phenylbenzimidazole 164 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C. (Solid line represents the voltammograms of 7-formylbenzimidazoles alone and dashed line represents the voltammograms of 7-formylbenzimidazoles with 10 eq trifluoroacetic acid.)
Chapter 4 99
Furthermore, we were curious to compare the approximate oxidation potential of the
non hydrogen bonded benzimidazoles 163 and 164. Some authors have estimated the
oxidation potential (Epa) by determining their ionization potentials (Ipa) by quantum
chemical calculations.183,184 Semi-empirical molecular orbital models (MNDO, AM1,
PM3) are the simplest quantum chemical techniques, whereas the Hartree-Fock (ab
initio) molecular orbital methods (STO-3G, 3-21G, 6-31G*, 6-311+G**, 6-311+G**)
remain a mainstay of quantum chemical techniques because of the wide range of
calculation. Each model has its own individual strengths and weaknesses as well as
limitations. However, Lal183 stated that semi-empirical calculations work better for
ionization potentials than ab initio and Yarligan170 showed the acid base properties
and hydrogen bonding of some 2-substituted benzimidazoles using semi-empirical
methods. More recently, Carter185 reported the semi-empirical model as a useful tool
for the study of redox potentials. Considering the above information, semi-empirical
AM1 model was chosen for the calculations. The ionization potentials and oxidation
potentials were estimated following the established procedure and correlation between
Ipa and Epa described in the references.183,184
According to the theoretical estimation of the oxidation potentials for the compounds
163 and 164, it can be seen from the Table 4-1 that hydrogen bonding in the
compounds 163 and 164 reduced the oxidation potentials by ~0.10-0.25 V than those
corresponding to the non-hydrogen bonded benzimidazoles. This finding is supported
by the other observation that oxidation potentials of hydrogen bonded enols were
0.29-0.51 V lower than non-hydrogen bonded enols.183 It was interesting to note that
the optimized structures showed planar geometry.
Table 4-1. AM1 calculated and experimental oxidation potentials of 163 and 164.
Compound
Hof
(neutral molecule)
(kcal/mol)
Hof
(radical cation)
(kcal/mol)
Ipa
(kcal/mol)
Epa (VFc)a
without
O···HN
Epa (VFc)b
with
O···HN
163 -51.657 127.875 179.532 1.134 0.886
164 -17.410 157.778 175.118 0.989 0.844
a Calculated183 from Ipab Experimental observation (Figure 4-3)
Chapter 4 100
There could be different ways to start the redox process, but the simplest mechanism
involves the intramolecular hydrogen bonding to form the benzimidazole radical
cation (Scheme 4-2). Considering the above experimental findings an intramolecular
proton migration is proposed to occur at its redox process with minimum nuclear
motion requirement.186
Scheme 4-2
163; R = Me164; R = Ph
NH
N
OMe
MeOR
O
N
N
OMe
MeOR
O
-e-
HH H
The cyclic voltammetry experiment of the 7-acetyl-2-phenylbenzimidazole 172 on
positively initiated scan revealed (Figure 4-4a) an anodic peak (Epa) at +0.7849 V
which was found to be irreversible, as no reverse peak was observed. The oxidation
was found to be a single electron process and afforded a similar benzimidazole radical
cation. This oxidation product probably undergoes further rapid oxidation or
decomposition leading to unknown products as evidenced from the multi-electron
irreversible oxidations observed at (Epa) +1.269 V and +1.142 V. The sharp cathodic
peak (Epc) at -1.099 V was assigned to the adsorption feature of the product, strongly
bound to the glassy carbon electrode. The benzimidazole radical anion
(Benzimidazole¯·) was observed at -0.107 V because the product appears in the scan
first to the negative potential (Figure 4-4b), but is not the product of the oxidation. In
addition, two minor oxidation products appeared at + 0.283 V and + 0.467 V, which
possibly resulted from the benzimidazole radical anion as these were not seen when
the oxidation was done first (Figure 4-4c). However, the overall system was found to
be reproducible. The broad anodic peaks (Epa) at -0.518 V and -0.352 V represent
multi electron oxidation or decomposition products (Figure 4-4a).
Chapter 4 101
20x10-6
15
10
5
0
-5
210-1Potential, V vs Fc
+-Fc
a)
b)
c)
NH
NOMe
MeOO
Figure 4-4. Cyclic voltammograms of 2 mM 7-acetyl-2-phenylbenzimidazole 172 inanhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
The benzimidazole radical anion (Benzimidazole¯·) can be attributed to the following
process (Scheme 4-3).
Scheme 4-3
NH
N
OMe
MeOR
NH
N
OMe
MeOR
+ e-
OMe OMe
172; R = Ph173; R = Me
A very similar kind of voltammogram was also observed in the case of 7-acetyl-2-
methylbenzimidazole 173 (Figure 4-5). The benzimidazole radical cation was
observed (Epa) at +1.43 V, whereas the benzimidazole radical anion was observed
(Epc) at -0.155 V. A sharp cathodic peak (Epa) of the compound arises at -1.14 V
indicative of adsorption of the compound to the electrode. Lastly, the broad anodic
peaks (Epa) at -0.84 V and -0.534 V represents multielectron oxidation or
decomposition.
Chapter 4 102
-10x10-6
-5
0
5
10
210-1
Potential, V vs Fc+
- Fc
NH
NOMe
MeOO
Figure 4-5. Cyclic voltammograms of 2 mM 7-acetyl-2-methylbenzimidazole 173 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
On the other hand, in the case of 7-ketoxime-2-methylbenzimidazole 212 and 2,7-
bisbenzimidazole 194 the NH is hydrogen bonded respectively with oxime nitrogen
and N3 of the 7-benzimidazole molecule. On these occasions, the NH is hydrogen
bonded (N···HN) to the lone pair of another nitrogen atom instead of the carbonyl
oxygen, unlike the previous cases.
NH
N
OMe
MeOMe
NMe
NH
N
OMe
MeOPh
HN N
212 194
OH
The 7-ketoxime-2-methylbenzimidazole 212 exhibits (Figure 4-6a) three oxidation
states in the cyclic voltammetry studies on positive potential scan. The first anodic
peak (Epa) observed at +0.479 V was irreversible and the second anodic peak (Epa) at
+1.13 V showed a quasireverse cathodic peak (Epc) at +0.975 V ( Ep = 157 mV; E1/2 =
+1.5 V), and the third anodic peak (Epa) at +1.552 V was again observed as
irreversible. To illustrate, the first oxidation wave represents the one electron
benzimidazole radical cation, which could be followed by multielectron oxidation to
give the next waves.
The 2-phenyl-2,7-bisbenzimidazole 194 showed (Figure 4-6b) an irreversible
oxidation peak (Epa) at +0.594 V, on oxidatively initiated scan, which was attributed to
the benzimidazole radical cation. The oxidation process was observed to be of one
Chapter 4 103
electron comparing with Fc-Fc+couple. Additionally, a minor oxidation peak (Epa)
appeared at +0.964 V and a quasireversible oxidation process was observed with an
anodic peak (Epa) at +1.17 V and cathodic peak (Epc) at +1.018 V ( Ep = 153 mV; E1/2
= +1.09 V). These are suggested as the multielectron oxidation products of the
benzimidazole radical cation. A similar (Scheme 4-2) intramolecular proton migration
is considered at its redox process with minimum nuclear motion requirement186 to
form the benzimidazole radical cation.
25x10-6
20
15
10
5
0
210-1Potential, V vs Fc
+-Fc
a)
NH
NOMe
MeO
NOH
15x10-6
10
5
0
210-1Potential, V vs Fc
+- Fc
b)
NH
NOMe
MeO
HN N
Figure 4-6. Cyclic voltammograms of 2 mM a) 7-ketoxime-2-methylbenzimidazole217 and b) 2-phenyl-2,7-bisbenzimidazole 194 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
Table 4-2. Electrochemical data (E=V) for the benzimidazole compounds.
Radical cation Quasireversible redox Compound
E pa E pa E pc E p E ½
141 0.727 1.707 1.121 0.586 1.414
142 0.573 1.180 1.053 0.127 1.116
163 0.886 1.451 1.350 0.101 1.400
164 0.844 1.274 1.240 0.034 1.257
194 0.594 1.171 1.018 0.153 1.094
212 0.479 1.132 0.975 0.157 1.053
Radical cation Radical anion Adsorption Broad peak
E pa E pc E pc E pa
172 0.789 -0.107 -1.098 -0.352, -0.518
173 1.43 -0.155 -1.14 -0.84, -0.534
Chapter 4 104
4.4. Electrochemistry of NiII and CoII benzimidazole complexes
Nickel is traditionally much harder to oxidize and NiII complexes containing soft
donors lend relative stabilization to NiI and are more likely to yield a reversible
NiII/NiI couple.187 Based on these concepts, the NiII complexes with benzimidazole
ligands were expected to display reversible NiII/NiI redox. On oxidatively initiated
scan the 2-phenylbenzimidazole NiII complex 255 displayed (Figure 4-7) three
successive oxidations involving one, two and one electron processes with the
respective anodic peaks (Epa) at +0.591 V, +0.781 V and +0.948 V and no reverse
peak was observed. This process represents the oxidation of the product leading to
unknown compounds. However, the reversible one electron process was observed at
anodic and cathodic peaks respectively (Epa) at -1.645 V and (Epc) at -1.711 V (E ½ = -
1.678 V in acetonitrile 0.1 mM nBu4NPF6). The separation of the anodic and cathodic
peak potential calculated was Ep = 66 mV.
This behaviour was attributed to the formation of a benzimidazole radical anion, and
not to metal reduction as it also appeared for the CoII complex 256 later at a similar
place. The one electron behaviour of this couple was established using the reversible
one electron couple of ferrocene/ferrocenium as an internal standard. In the presence
of a stoichiometric amount of ferrocene, the reductive peak current Ipc on
benzimidazole matches the oxidative peak Ipa on ferrocene, which confirms the one
electron character of the transfer. The second irreversible reduction wave is an
adsorption or pre wave as its position is dependent on the electrode conditions and the
presence of other substrates.188
15x10-6
10
5
0
-2 -1 0 1 2Potential, V vs Fc
+-Fc
NNMeO
MeO N N
NN OMe
OMe
Ni
Figure 4-7. Cyclic voltammograms of 2 mM 2-phenyl-benzimidazole NiII complex255 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
Chapter 4 105
The CoII complex 256 (Figure 4-8b) showed a quasireversible two electron oxidation
on scanning towards positive potentials at +0.815 V and a cathodic peak at +0.682 V,
hence the E1/2 was calculated as +0.748 V ( Ep= 133 mV). This behaviour was
considered to indicate formation of the benzimidazole radical cation. Similar to the
NiII complex 255, the CoII complex 256 was reduced in a reversible one electron
anodic wave at -1.616 V and a cathodic wave at -1.684 V ( E1/2 = -1.65 V ) (Figure 4-
8a). The separation of the anodic and cathodic peak potentials was Ep = 68 mV. In
comparison to the previous NiII complex 255 this behaviour was attributed to ligand
based reduction.
NNMeO
MeO N N
NN OMe
OMe
Co
15x10-6
10
5
0
210-1
Potential, V vs Fc+-Fc
a)3.0x10
-6
2.5
2.0
1.5
1.0
0.5
0.0
1.00.90.80.70.60.50.4
Potential, V vs Fc+-Fc
b)
Figure 4-8. Cyclic voltammograms of 2 mM 2-phenyl-benzimidazole CoII complex256 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
In the case of 2-(4'-methoxy)phenylbenzimidazole NiII complex 261 (Figure 4-9a) on
positively initiated scan the reversible one electron anodic peak (Epa) was observed at
-1.63 V with the respective cathodic peak (Epc) at -1.70 V (E1/2 = -1.67 V; Ep= 70
mV). Similar to the behaviour of the previous metal complexes 255,256, 2-(4-
methoxy)phenylbenzimidazole NiII complex 261 showed ligand centered reduction to
form the benzimidazole radical anion. Additionally, three successive oxidations were
observed (Figure 4-9b) at the following anodic waves at +0.53 V, +0.71 V and +0.86
V, but there was no reverse wave observed. The process is similar to the 2-phenyl-
benzimidazole NiII complex 255 and represents the oxidation of the product leading to
unknown compounds. Furthermore, a multielectron oxidation was noticed at +1.09 V.
Chapter 4 106
NN
MeO
MeO N N
NN
OMe
OMe
Ni
MeOOMe15x10-6
10
5
0
210-1Potential, V vs Fc
+-Fc
a)
3x10-6
2
1
0
1.21.00.80.60.40.2Potential, V vs Fc
+-Fc
b)
Figure 4-9. Cyclic voltammograms of 2 mM 2-(4'-methoxy)phenylbenzimidazole NiII
complex 261 in anhydrous acetonitrile in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
To improve the slight solubility of the benzimidazole metal complexes in dry
acetonitrile, anhydrous N,N-dimethylformamide was used as a solvent and also to
investigate the effect of solvent variation. The 2-phenylbenzimidazole NiII complex
255 indicated (Figure 4-10a) a more understandable voltammogram in the anhydrous
N,N-dimethylformamide. In a similar fashion, there was an anodic peak (Epa) observed
at 0.66 V with a corresponding cathodic peak (Epc) at -1.01 V representing ligand
centered oxidation. The very broad peak separation ( Ep = 1.67 V) corresponds to
proton dependent oxidation of the benzimidazole ligand. For instance, the reversible
anodic wave at -1.62 V with a corresponding cathodic wave observed at -1.72 V
suggested ligand centered reduction (E1/2 = -1.67 V; Ep = 100 mV) (Figure 4-10b).
Alternatives to this process are NiII/NiI couple or L/L-. couple. But the same process
occurred in the acetonitrile and also in the case of CoII and suggests this to be a ligand
centered reduction.
15x10-6
10
5
0
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0Potential, V vs Fc
+-Fc
a)
NNMeO
MeO N N
NN OMe
OMe
Ni
-2x10-6
-1
0
1
-2.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6
Potential, V vs Fc+
- Fc
b)
Figure 4-10. Cyclic voltammograms of 2 mM 2-phenylbenzimidazole NiII complex255 in anhydrous DMF in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
The CoII complex 256 in anhydrous N,N-dimethylformamide also exhibited (Figure
4-11a) two anodic oxidation states (Epa) at +0.139 V and at +0.783 V suggesting a
ligand centered process. Interestingly, the cathodic wave (Epc) at -0.259 V looks to be
a one electron oxidation process (Figure 4-11b,c). This behaviour was not observed
Chapter 4 107
before, with NiII analogue 255, suggesting it as CoII centered. Furthermore the
irreversibility of the process explains that the structure of the CoII centre must have
changed. The CoII coordinating environment is tetrahedral and usually this leads to
irreversible behaviour.
25x10-6
20
15
10
5
0
-1.5 -1.0 -0.5 0.0 0.5 1.0Potential, V vs Fc +-Fc
a)
b)
c)
d)
e)
NNMeO
MeO N N
NN OMe
OMe
Co
Figure 4-11. Cyclic voltammograms of 2 mM 2-phenylbenzimidazole CoII complex256 in anhydrous DMF in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
The process here also suggests that the substrate (S) might undergo sequential
oxidation to form an unstable (S n+) by electrochemical changes and by comparison
with the process at -1.60 V the number of electron (n) was suggested as one. But this
S n+ rapidly undergoes chemical transformation to the product (Pm+). Next, the product
(Pm+) could accept an electron at -0.26 V to convert it electrochemically to P(m-y)+ .
However, this could rapidly chemically decompose to unknown products or form the
substrate (S) again. The whole process can be drawn as:
S n+
S n+ P m+
P m+ P (m-y)+
P (m-y)+ S or unstable compound
0.14 V
rapid
-0.26 V
rapid
S
Additionally, the one electron reversible reduction process is observed at cathodic
peak (Epc) -1.686 V and anodic peak (Epa) at -1.566 V (E1/2 = -1.63 V; Ep = 120 mV)
(Figure 4-11d,e). Alternatives of this process are formation of a CoII/CoI couple or
L/L-. couple. It is curious that the same process was observed for NiII 255. So this is
Chapter 4 108
suggestive that the process is ligand centered. The reduction of the benzimidazole has
happened without altering the oxidation state of the metal NiII or CoII. This one
electron reversible reduction to form the radical anion could take place on the
benzimidazole N, but a delocalized structure could be produced (Scheme 4-4).189
Scheme 4-4
NN
MeOOMe
R N
NNN
MeOOMe
RM
NN
MeOOMe
R N
NNN
MeOOMe
RM
e-
NN
MeOOMe
R N
NNN
MeOOMe
RM
NN
MeOOMe
R N
NNN
MeOOMe
RM
NN
MeOOMe
R N
NNN
MeOOMe
RM
255; R = Ph ; M= Ni(II)256; R = Ph ; M= Co(II)261; R = 4-MeOC6H4; M= Ni(II)
The same kind of behaviour was noticed for the 2-(4-methoxy)phenylbenzimidazole
NiII complex 261 in anhydrous N,N-dimethylformamide (Figure 4-12a) as for the 2-
phenyl-benzimidazole NiII complex 255. An anodic peak (Epa) at +0.573 V represents
ligand centered oxidation and the reversible process (Epa) at -1.675 V and (Epc) at -
1.763 V represents ligand centered reduction (E1/2 = -1.72 V; Ep = 90 mV) (Figure
4-12b). This reveals that the introduction of an electron donating methoxy group at the
2-phenyl position of the benzimidazole ring does not have much influence in the
cyclic voltammetry of the metal complexes.
Chapter 4 109
5x10 -6
10
5
0
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0
Potential, V vs Fc+-Fc
a)
-1.5x10-6
-1.0
-0.5
0.0
0.5
1.0
-2.0 -1.8 -1.6 -1.4 -1.2
Potential, V vs Fc+- Fc
b)
Figure 4-12. Cyclic voltammograms of 2 mM 2-(4'-methoxy)phenylbenzimidazole NiII complex 261 in anhydrous DMF in the presence of 0.1 M [nBu4N][PF6] at a glassy carbon working electrode at a scan rate of 100mV/sec vs. Fc-Fc+ at 250C.
The behaviour of the NiII complex 255 in comparison to the CoII complex 256 is not
surprising as sometimes they displayed no observable electrochemical activity.190 It
has been reported that, in the presence of the donor amine nitrogen the NiII
complexes are more stabilized and this might be the reason for any observable nickel
redox in this study.191
Table 4-3. Electrochemical data (E = V) for benzimidazole metal complexes.
Acetonitrile N,N-dimethylformamide Compound
E pa E pc E p E ½ E pa E pc E p E ½
255 -1.645 -1.711 0.066 -1.67 -1.621 -1.720 0.100 -1.67
256 -1.616 -1.684 0.068 -1.65 -1.686 -1.566 0.120 -1.63
261 -1.630 -1.700 0.070 -1.67 -1.670 -1.760 0.090 -1.72
The higher Ep value 66-70 mV in acetonitrile and 90-120 mV in N,N-
dimethylformamide (Ep = 59 mV for a one electron Nernstian electron transfer
process) observed may result from kinetic complications during electron transfer and
uncompensated solution resistance.181 However, there was no significant solvent shift
observed due to differing interactions of the solvent with the benzimidazole. N,N-
Dimethylformamide has a greater donor number than acetonitrile and thereby lowered
the potential. In addition, N,N-dimethylformamide solvates the hydrogen bonding sites
much more effectively than acetonitrile 2. On the other hand, the half wave potential
was unchanged for the NiII complex 255 both in acetonitrile and N,N-
dimethylformamide. In contrast, the slight reduction of the E1/2 seen in N,N-
dimethylformamide compared with acetonitrile for the CoII complex 256 could
Chapter 4 110
represent the binding of the radical anion of benzimidazole to the solvent. Shifting, of
the E1/2 of the NiII complex 261 towards a more negative potential in N,N-
dimethylformamide compared to acetonitrile, indicates weaker binding of the
compound. The absence of multiple oxidations in the NiII complexes 255 in N,N-
dimethylformamide compared to acetonitrile hints to the stability of the
electrochemically generated cations in N,N-dimethylformamide.
4.5. Conclusions
The voltammograms of the activated benzimidazoles indicate their rich
electrochemical behaviour. The activated benzimidazole compounds in general
showed one electron irreversible oxidation to form a radical cation followed by
multielectron oxidation, representing electrochemical reactions followed by electronic
transfers. The reversibility of the second oxidation waves hints to the stability of the
electrochemically generated intermediate following the second electronic transfer. The
different redox potentials of the benzimidazole radical cations (Table 4-2) imply that
the redox process is not initiated by the same electron transfer mechanism. However,
hydrogen bonding might be involved in the initiation of the redox process to form the
radical cation. In addition, hydrogen bonding was found to alter oxidation potentials
of benzimidazoles. Interestingly, comparatively low oxidation potentials were
observed in the case of N···HN bonded benzimidazoles than O···HN bonded
benzimidazoles. Further experimental insights into the different electronic changes of
the benzimidazole radical cation state could be obtained through simultaneous
electrochemistry and SEPR/EPR studies.
In conclusion, the nickelII and cobaltII benzimidazole metal complexes investigated
showed one electron ligand centered reversible reduction. Only in the case of the CoII
complex in N,N-dimethylformamide was there a CoII based irreversible oxidation
observed. The metal complexes also exhibited an irreversible radical cation oxidation,
followed by multielectron oxidation, showing again the rich electrochemical nature of
the activated benzimidazoles. The redox activity of these coordination complexes
might induce DNA cleavages and further studies are suggested.
Chapter 5 111
CHAPTER 5
SYNTHESIS OF INDOLYLBENZIMIDAZOLES
5.1. Introduction
There has been considerable interest in the synthesis of indolylbenzimidazoles in
recent years. Different indolylbenzimidazoles 306 have been previously prepared
usually by condensation of indole aldehydes 305 5,192-194 or esters 24,195 with aromatic
1,2-diamines (Scheme 5-1). The indole units were linked mostly through their reactive
C-3 position,24,193,195,196 but also through C-2,24,192 C-5,24 C-624,194 or C-75 with the
corresponding benzimidazole link being at C-2.
Scheme 5-1
NH
NHN
NH
CHO NH2
NH2R2
R2
R1R1
305 306
Indole and benzimidazole are very useful and interesting chemical structures which
possess significant biological and medicinal activity. Recent interest has focused on
indolylbenzimidazoles as anticancer agents, antiviral agents and inhibitors of cell
signaling and signal transduction pathways.24 Some authors have reported that
indolylbenzimidazoles have anti-inflammatory activity,197 antiparasitic,198
insecticidal,199 anticoagulant,200 5-HT agonist201 and Protein Kinase C inhibitory
activity.202
Our group has previously reported the formation of a series of bi-indolyl systems via
Vilsmeier-Haack type reactions combining the indole 307 with indolin-2-one 308 in
anhydrous chloroform and phosphoryl chloride. Gentle reflux of the mixture for
several hours, base work up and chromatography produced novel 2,7-biindolyl 309
and 2,2-biindolyl 310 ring systems (Scheme 5-2).203,204
Chapter 5 112
Scheme 5-2
NH
MeOMe
MeO POCl3
NH
O
CHCl3
NH
MeOMe
NH NH
MeOMe
MeO NH
+ +
310309308
307 MeO
The success of this reaction motivated us to apply it to activated benzimidazole
molecules. 4,6-Dimethoxybenzimidazole 142 shows activity towards electrophilic
substitution at the C-7 position and it would be desirable to link the indole C-2
position with the benzimidazole C-7 to give a new 7-(2-indolyl)-benzimidazole 311
system (Scheme 5-3). Combination of an indole to the less reactive benzimidazole
could increase reactivity of the benzimidazole system.
Scheme 5-3
NH
N
OMe
MeO POCl3
NH
O
CHCl3
NH
N
OMe
NH+
311308
142 MeO
?
5.2. Reaction of a benzimidazole with indolin-2-one under Vilsmeier conditions
When 4,6-dimethoxybenzimidazole 142 was reacted with indolin-2-one 308 and
phosphoryl chloride, with overnight heating all the indolin-2-one 308 was consumed
but the benzimidazole 142 remained intact. After base work up and column
chromatography 2-chloroindole 312 and bi-indolyl 313 were isolated in 28% and 10%
yields respectively (Scheme 5-4). The starting benzimidazole 142 was recovered from
the reaction mixture whereas the desired indolylbenzimidazole 311 was not detected.
Chapter 5 113
Scheme 5-4
NH
N
OMe
MeO POCl3/CHCl3
NH
O
+
308
142NH
Cl
NH
Cl
NH+
312 313
reflux, o/n
Clearly the 2-chloroindole 312 arises from the reaction of indolin-2-one 308 and
phosphoryl chloride. Such compounds have been formed in other reactions involving
indolin-2-one 308 and phosphoryl chloride.204 Our group has previously shown that
2,3-diphenylindole 53 reacted with 3-methylindolin-2-one 314 and phosphoryl
chloride to give the desired bi-indolyl 316 together with 2-chloro-3-methylindole 315
(Scheme 5-5).204 A molecular ion m/z in the HRMS [M+H]+ at 267.0684 ( m=0.5
ppm) confirmed the presence of the bi-indolyl 313. In this case because the reactive 3
position of 2-chloroindole 312 was free for further substitution, the bi-indolyl 313 was
formed.
Scheme 5-5
POCl3
NH
O
CHCl3 NH
Cl
Me
316314
53+
315
NH
OMe
MeO
NHMe
NH
OMe
MeO
Me
There was also a small amount of the ter-indolyl 317 and quater-indolyl 318 observed
in the 1H NMR spectrum, but these compounds could not be purified and
characterized. The chlorinated compounds were found to be unstable and slowly
decomposed in air and light. However, the products could be stored under an inert
atmosphere, out of light and at low temperature to prevent decomposition. The ter-
Chapter 5 114
indolyl 317 could be simply derived from the compound 313, because the
unsubstituted 3- position on bi-indolyl 313 was free to react with another molecule of
2-chloroindole 312 and the reaction continues further to produce the quater-indolyl
318. The HRMS m/z [M+H]+ clearly showed the presence of these two compounds
317 and 318 respectively at 382.1104 and 497.1527. Moreover, a molecular ion m/z
[M+H]+ in the mass spectrum also revealed the presence of a trace amount of penta-
indolyl 319 at 612.1895.
317
NH
Cl
NHNH
318
NH
Cl
NHNH
NH
319
NH
Cl
NHNH
NHNH
Figure 5-1. Structures of ter-indolyl 317, quater-indolyl 318, and penta-indolyl 319.
Almost all of the unreacted benzimidazole 142 was recovered from the reaction. It
was not surprising that the benzimidazole remains unreactive because all the indolin-
2-one 308 had reacted with phosphoryl chloride. It has been discussed in the previous
chapter that the activated benzimidazoles are not as reactive as the related indoles at
their methoxy activated C-7 position. Therefore, more vigorous conditions are
required for reaction to occur with indolin-2-one 308. However, the use of excess
indolin-2-one 308 and phosphoryl chloride, or extended heating did not induce the
desired reaction. In all attempts, the phosphoryl chloride reacted with indolin-2-one
308 and formed mainly the 2-chloroindole 312 and bi-indolyl 313. These results
further show the reduced reactivity of the activated benzimidazoles at C-7 compared
to the activated indoles.
5.3. Reaction of benzimidazoles with indolin-2-one using triflic anhydride
Trifluoromethanesulfonic anhydride (triflic anhydride) can replace phosphoryl
chloride in the formylation of less reactive aromatic compounds in combination with
N,N-dimethylformamide.205 This approach was later used to combine the methoxy
Chapter 5 115
activated indoles 47 with indolin-2-one 308 and triflic anhydride in anhydrous
chloroform at room temperature to give high yields of 2,7-bi-indolyls 320 within an
hour (Scheme 5-6). The result was superior to that obtained from the reaction with
phosphoryl chloride and no chromatography was required.206
Scheme 5-6
NH
OMe
MeO Triflic anhydride
NH
O
CHCl3
NH
OMe
NH+
320308
47
BrBr
MeO
Consequently, benzimidazole 142 was treated with triflic anhydride and indolin-2-one
308 at room temperature under argon for 7 days, and produced the desired
indolylbenzimidazole 311 in very low yield (2%) after purification by column
chromatography (Scheme 5-7). The use of excess triflic anhydride did not improve the
reaction, and heating with triflic anhydride at 70°C for 7 days improved the yield of
compound 311 to a maximum of 10%.
Scheme 5-7
NH
N
OMe
MeOPh
NH
O
NH
N
OMe
NH
Ph
+
311308
142 Tf2O,CHCl3MeO
N
N
OMe
MeOPh
S C FF
OO
F
+
321
65-70oC, 7 d
The disappearance of the H-7 proton and appearance of five new aromatic protons
along with an NH in the 1H NMR spectrum indicated the presence of the
indolylbenzimidazole 311. A molecular ion m/z at 370 (M+1) and other spectral
observations authenticated formation of the structure 311.
Chapter 5 116
In addition to the desired product 311, a varied yield of 5-20% of a compound 321
was isolated as the first band during chromatography of the reaction mixture. The 1H
NMR spectrum exhibits the same number of protons as the starting benzimidazole 142
except for the NH. The methoxy, H-5 and H-7 protons were shifted to downfield,
whereas the 2-phenyl protons were shifted upfield. A molecular ion in the mass
spectrum m/z at 387 and further NMR studies revealed N-substitution had happened.
The final evidence of N-trifluoromethylsulfonylbenzimidazole 321 was given by the
X-ray crystal structure obtained from chloroform (Figure 5-2).
Figure 5-2. ORTEP drawing of the X-ray crystal structure of benzimidazole 321.
Thus the formation of N-trifluoromethylsulfonylbenzimidazole 321 during the
reaction indicates a basic characteristic of the benzimidazole 142. The reaction was
observed to be fast and hence reduced the yield of the desired indolylbenzimidazole
311.
In similar fashion, treatment of indolin-2-one 308 and triflic anhydride with
benzimidazoles 141 and 161 produced respectively the indolylbenzimidazoles 322 and
323 in 7% and 9% yield after extensive column chromatography (Scheme 5-8).
Chapter 5 117
Scheme 5-8
NH
N
OMe
MeOR
NH
O
NH
N
OMe
MeO
NH
R
+
308
322; R = CH3323; R = 4-MeOC6H4
Tf2O,CHCl3141; R = CH3161; R = 4-MeOC6H4
65-70oC,7 d
In addition to indolin-2-one 308, pyrrolidin-2-one 324, piperidin-2-one 325 and 4,6-
dimethoxyindolin-2-one 326 showed good reactivity with 2,3-diphenylindole 53 under
Vilsmeier conditions to produce the desired 7-indolylimines in high yields.3,206
However, the attempted reaction of benzimidazole 142 with the above molecules and
1-methylindolin-2-one 327, and 3-methyl-4,6-dimethoxyindolin-2-one 328 (Figure 5-
3) with phosphoryl chloride under a variety of conditions gave either no reactions or
complex mixtures from which no pure compounds could be isolated. The use of triflic
anhydride instead of phosphoryl chloride also gave similar results.
NO
MeNH
ONH O N
H
O
OMe
MeO
324 325 326 327
NH
O
OMe
MeO
Me
328
Figure 5-3
5.4. Reaction of indoles with 2-benzimidazolinone
Another approach to the synthesis of indolylbenzimidazoles would be to use 2-
benzimidazolinone 329 together with phosphoryl chloride or triflic anhydride in
reactions with activated indoles. Treatment of indole 53 and 2-benzimidazolinone 329
in anhydrous chloroform with phosphoryl chloride for one week resulted in formation
of the indolylbenzimidazole 330 in only a trace amount (1% yield) after extensive
column purification (Scheme 5-9). Mostly the unreacted starting indole 53 (62%) was
recovered from the reaction mixture.
Chapter 5 118
Scheme 5-9
65-70oC,7 d
POCl3 or Tf2O
NH
HN
O
CHCl3+
330329
53NH
OMe
MeO
N NH
NH
OMe
MeO
Phosphoryl chloride is known to form 2-chlorobenzimidazole 331 in reaction with 2-
benzimidazolinone 329.207 2-Chlorobenzimidazole 331 has been reported to be
susceptible to reaction with ultra violet light to give compound 332 (Scheme 5-10),207
and this might account for the low yield of the product 330. Wrapping the reaction
vessel with aluminium foil did not improve the yield much. However, when triflic
anhydride was applied to the same compounds, after seven days at room temperature
the product 330 was obtained in 12% after column chromatography.
Scheme 5-10
NH
HN
O
329
POCl3
NH
NCl
331
uv
NH
N
332
NHN
O
In a similar way, 2,3-dimethylindole 52 and 2-benzimidazolinone 329 in chloroform
with triflic anhydride at room temperature for 7 days produced the
indolylbenzimidazole 333 in a low yield (5%) after extensive column chromatography
(Scheme 5-11). In addition to the desired compound 333, 7,7'-bisindolylmethane 334
and 7,7'-bisindolyl 335 were isolated in 2% and 15% yields respectively.
Chapter 5 119
Scheme 5-11
r.t, 7 d
NH
OMe
MeO Tf2O
NH
HN
O
CHCl3
NH
MeOMe
MeO
NHN+
333329
52
Me
Me
MeNH
OMe
HN
OMe
Me
Me
Me
Me
MeO
MeO
NH
OMe
MeOMe
HN
OMe
MeOMe
Me
Me
334 335
+ +
The products 334 and 335 showed very simple 1H NMR spectra reflecting indole
containing molecules with two methoxy and two methyl peaks along with an H-5
aromatic proton and broad NH proton. The H-7 is missing in both the 334 and 335,
whereas 334 is accompanied by a suspected methylene singlet at 4.12 ppm. No other
protons were observed in the 1H NMR spectra of these two compounds. The integral
ratios and nature of the spectrum indicate C2-symmetric structure of both the
compounds 334 and 335, 13C NMR data further indicate a C2-symmetric structure, and
a DEPT 135 experiment confirms the presence of the bridging methylene unit in 334.
Correlation of the data leads to the identification of the products 334 as 7,7'-
bisindolylmethane and 335 as 7,7'-bisindolyl. Molecular ion peak (M+1) m/z at 423
and 409 clearly correspond to the assigned compounds 334 and 335 respectively.
The formation of the 7,7'-bisindolyl 335 could take place via similar oxidative
dimerization of a radical cation resulting from the removal of one electron from the
indole 52 as described in the 4,6-dimethoxy-2,3-diphenylindole 53.42 Phosphoryl
chloride might be chlorinating the C-7 position of the indole, followed by coupling or
by acting as an oxidant.67 Obviously, when a particular reaction is slow the competing
dimerization reaction is free to occur. The mechanism of the formation of 7,7'-
bisindolylmethane 334 is not clearly understood. Alternatively, the compound can be
easily prepared in high yield by the acid catalyzed reaction with formaldehyde.
The indolylbenzimidazoles 330 and 333 have been prepared previously from the
corresponding indole-7-carbaldehydes 60 and 59 with 1,2-diaminobenzene in high
yields (Scheme 5-12)5. Although this two-step sequence is clearly superior to the
Chapter 5 120
single-step 2-benzimidazolinone reaction, the latter provides an alternative approach
that warrants further study to optimize the reaction conditions and the yield. These
indolylbenzimidazoles 330 and 333 are structural analogs of 2,7’-biindolyls and have
metal chelating potential.
Scheme 5-12
330; R = Ph333; R = Me
NH2
NH2
60; R = Ph59; R = Me
NH
OMe
MeOR
R
N NHNH
OMe
MeOR
R
OH
DMF
Given the poor yield in reaction of 2-benzimidazolinone 329 with activated indoles, it
was not surprising that no reaction could be achieved with activated benzimidazole
142. When triflic anhydride was used instead of phosphoryl chloride, as expected the
N-trifluoromethylsulfonylbenzimidazole 321 was isolated in 28% yield.
Scheme 5-17
NH
N
OMe
MeO
NH
HN
O
CHCl3
NH
N
OMe
MeO
NHN+
194329
142POCl3 or Tf2O
In an alternative way, the product 194 was prepared in Chapter 3.10 from
benzimidazole-7-carbaldehyde 164 and 1,2-diaminobenzene in moderate yield
(Scheme 3-22).
Chapter 5 121
5.5. Conclusions
In summary, the reactions of activated indoles and benzimidazoles with indolin-2-one
308 and 2-benzimidazolinone 329 clearly show the difference in the reactivity at their
C-7 positions (Table 5-1). Activated indoles reacted easily with indolin-2-one 308,
whereas they required harsh conditions to react with 2-benzimidazolinone 329. Thus,
the less reactive benzimidazoles reacted with indolin-2-one 308 only under vigorous
conditions. Whereas, no observable reaction occurred with 2-benzimidazolinone 329
even under harsh conditions.
Table 5-1. The reactions of the activated indoles and benzimidazoles with indolin-2-
one 308 and 2-benzimidazolinone 329.
Reaction with indolin-2-one 308
Reaction with 2-benzimidazolinone 329
POCl3 Tf2O POCl3 Tf2O
Indoles
47 reflux,12h,5%206 r.t,0.5h,99%206 - -
52 - - - r.t.,7d,5%
53 reflux,12h,75%206 r.t.,0.5h,100%206 70°C,7d,1% r.t.,7d,12%
Benzimidazoles
141 - 70°C,7d,7% - -
142 NR 70°C,7d,10% NR NR
161 NR 70°C,7d,9% NR NR
NR = no reaction, - = not tested, r.t. = room temperature.
To conclude, a new 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles was prepared in
modest yield by the reaction of 4,6-dimethoxybenzimidazoles with indolin-2-one and
triflic anhydride. The preparation of 2-(4,6-dimethoxyindol-7-yl)-benzimidazoles
from 2-benzimidazolinone and activated indoles also gave poor yields. Although the
yields are not impressive, these reactions show new scope for future development.
Moreover, the finding further proves the less reactive nature of the activated
benzimidazoles towards some electrophiles.
Chapter 6 122
CHAPTER 6
SYNTHESIS AND REACTIVITY OF ACTIVATED BENZOTHIAZOLES
6.1. Introduction
Benzothiazoles are precursors of natural products, pharmaceutical agents and other
compounds that exhibit a wide spectrum of biological activity such as antitumor,
immunosuppressive, immunomodulatory and antiviral properties.208-210 For example,
polyhydroxylated 2-phenylbenzimidazoles 336 (Figure 6-1) showed potent in vitro
cytotoxicities against varieties of human tumor cell lines.31
N
SR1
R2
R1 = 4,6-OH; 5,6-OHR2 = H; 4-OH; 3,4-OH
336
Figure 6-1.
Previous work in our group has established that strategically positioned 4,6-dimethoxy
groups on indoles,1,8 benzofurans,11,12 and benzimidazoles117,119 activate the chemical
reactivity of the heterocyclic systems specifically at the C-7 position and on the 5,7-
dimethoxyindoles at C-4.128 It is well established that targeted reactivity at other sites
can expand the synthetic applications of these heterocyclic systems immensely.
Similarly, 5,7-dimethoxybenzothiazoles 337 and 4,6-dimethoxybenzothiazoles 338
both have the potential reactivity towards a range of electrophiles at specified
positions. Therefore the aim of this project is to synthesize a range of 2-substituted-
5,7-dimethoxybenzothiazoles 337 and 2-substituted-4,6-dimethoxybenzothiazoles
338, in addition to systemically investigate their chemical reactivity.
The numbering of benzothiazole ring designates the sulfur atom as position one .
N
S
3
165
4
OMe
MeO
7
S
N
1
356
7
OMe
MeO
4
337 338
R R2 2
Figure 6-2.
Chapter 6 123
6.2. Preparation of the dimethoxy activated benzothiazoles
Benzothiazoles are most commonly synthesized via one of two major routes. The
most commonly used direct methods involve the condensation of ortho
aminothiophenols 339 with electrophilic reagents. Substituted alkyl, aryl, and
heteroaryl aldehydes react with ortho aminothiophenols 339 in dimethyl sulfoxide to
give corresponding 2-substituted benzothiazoles 340 (Scheme 6-1). Similar reactions
with carboxylic acids, esters and acyl chlorides and nitriles have been reported.211,212
This method however suffers from limitations such as difficulties encountered in the
synthesis of readily oxidizable 2-aminothiophenols bearing substituents groups.
Scheme 6-1
SH
NH2
S
NRR-CHO+
339 340
Recently manganese(III) triacetate has been used as a one electron oxidant for the free
radical cyclization of phenylthioformamides to 2-arylbenzothiazoles in acetic acid
under microwave conditions.213 However, the reaction experienced poor yields in
conventional heating conditions. Instead, an effective route is based on the potassium
ferricyanide mediated radical cyclization in basic medium (Jacobson synthesis) of
thiobenzanilides 341 (Scheme 6-2). In this case, cyclization occurs on an
unsubstituted ortho position to the thioanilido nitrogen. This method is well used for
the preparation of substituted benzothiazoles.31,210
Scheme 6-2
S
NR
341 340
HN R
S
K3[Fe(CN)6]
NaOH
Alternatively, an intramolecular aromatic nucleophilic substitution has been used for
the preparation of 2-substituted benzothiazoles from ortho halothioanilides.214
Furthermore, oxidative coupling between thiophenols and aromatic nitriles in the
presence of ceric ammonium nitrate (CAN) leads to the synthesis of 2-
arylbenzothiazoles.212 However, they do not represent a convenient general route to
functionalized 2-substituted benzothiazoles and were not considered.
Chapter 6 124
Specifically, the 2-phenyl-4,6-dimethoxybenzothiazole 346 was prepared previously
form benzilmonoarylimine 344 via 2H-benzo-1,4-thiazine 345 (Scheme 6-3).215 The
reaction proceeds through the carbonyl sulfuration followed by an intramolecular
cyclization to achieve the 1,4-thiazine 345, which then undergoes oxidation leading to
benzothiazoles 346 by ring contraction with concomitant loss of benzaldehyde. It was
considered that in a similar way, 2-phenyl-5,7-dimethoxybenzothiazole 362 could be
prepared. However, the procedure has the probability to form indoles during
thionation by an intramolecular conjugate addition due to the presence of meta
methoxy groups in the initial aromatic amine 39.215
Scheme 6-3
S
N
OMe
MeOPh
AcOH
345
346
N
S
Ph
Ph
OMe
MeO
NH2
342
OMe
MeO
HN
344
OMe
MeOPh
Ph
O
O+
343
Ph
PhOEtOH
N
S
Ph
Ph
OMe
MeO
O2
P4S10Xylene
-ArCHO
O
OMe
MeO S O
NPh
PhH
OMe
MeO S
NPh
PhO
H S
HN
OMe
MeO
Ph
O
Ph
The preparation of the desired benzil monoarylimine 347 was accomplished by
condensation of benzil 343 with one equivalent of aromatic amine 39 and acetic acid
in boiling absolute ethanol. Purification of the crude product by column
chromatography gave the isolated yield of the benzilmonoarylimine 347 as 40%yield
in addition to 4,6-dimethoxy-2,3-diphenyl-3H-indol-3-ol 348 in 10% yield as a yellow
powder (Scheme 6-4).
Chapter 6 125
Scheme 6-4
AcOH/EtOH
39
OMe
MeO Ph
Ph
O
O+
343
NH2
OMe
N Ph
PhO
MeO
OMe
N Ph
Ph
MeO
HO
348
+
347
reflux, 24 h
The formation of the 2,3-diphenyl-3H-indol-3-ol 348 was considered to be the
rearrangement product of the benzyl monoarylimine 347 under the acidic medium
(Scheme 6-5). It is possible that 2,3-diphenyl-3H-indol-3-ol 348 could undergo
rearrangement to the diphenyl-1,2-dihydro-3H-indol-3-ones 350 under acidic
conditions,216 however the presence of the indol-3-ones 350 was not observed. The
absence of NH proton resonances in the 1H NMR spectrum and IR spectrum, and the
presence of a quaternary carbon at 87.77 ppm corresponding to the C-3 aryl carbon in
the 13C NMR spectrum are consistent with the structure as 4,6-dimethoxy-2,3-
diphenyl-3H-indol-3-ol 348. Furthermore, there was no carbonyl carbon resonance
observed in the 13C NMR spectrum.
Scheme 6-5 OMe
N Ph
PhO
MeO
OMe
N Ph
Ph
MeO
OHOMe
N Ph
Ph
MeO
HO
348347 349
OMe
NH
MeO
350
H+O
PhPh
The observed result is not surprising as stated earlier that the presence of a meta
methoxy group in the initial aromatic amine leads to the formation of indoles during
thionation with regioselectivity.215 The findings exemplify that having two meta
methoxy substituents is strong enough to induce an intramolecular conjugate addition
from benzilmonoarylimine 347. Thus, preparation of 5,7-dimethoxy benzothiazole
362 by the benzilarylaminoketone route looked very unlikely. Furthermore, this route
is not ready adaptable for other 2- substituted benzothiazoles.
Hence, the easiest route to prepare 4,6-dimethoxy or 5,7-dimethoxy benzothiazoles
with various 2-substitutents was considered to be the Jacobson synthesis. To follow
this procedure 3,5-dimethoxyaniline 39 was first acylated by the respective acid
Chapter 6 126
chlorides to the corresponding 3,5-dimethoxyanilides 351-353 in dichloromethane or
pyridine at room temperature conditions in 1-2 h in good to high yields (Scheme 6-6).
Synthesis of the anilides 148, 152, 153 and 154 has been described earlier in the
Chapter 3.2. The thionation of the anilides was accomplished either with Lawesson’s
reagent in refluxing toluene or by phosphorus pentasulfide (P4S10) in refluxing
pyridine for three hours to yield the thioamides 354-360. Jacobson synthesis of
benzothiazoles under basic conditions by the oxidant potassium ferricyanide
proceeded well in one hour to produce the corresponding 2-substituted-5,7-dimethoxy
benzothiazoles 11, 361-366.
Scheme 6-6
N
S
OMe
MeOR
MeO
OMe
NHCORMeO
OMe
NH2
ROCl, DCM or
148; R = H 152; R = CH3 153; R = Ph 154; R = 4-MeOC6H4351; R = 4-ClC6H4 352; R = 4-NO2C6H4353; R = 2-NO2C6H4
ROCl, Pyridine
r.t./ 1-2 h
P4S10, Pyridine orLawesson's reagent,toluene
Reflux/ 2-3 hrs
K3[Fe(CN)6], 30% NaOH
39
MeO
OMe
NHCSREtOH, 80-900C, 1 h
354; R = H 355; R = CH3 356; R = Ph 357; R = 4-MeOC6H4358; R = 4-ClC6H4 359; R = 4-NO2C6H4360; R = 2-NO2C6H4
11; R = H 361; R = CH3 362; R = Ph 363; R = 4-MeOC6H4364; R = 4-ClC6H4 365; R = 4-NO2C6H4366; R = 2-NO2C6H4
The series of 2-substituted-4,6-dimethoxybenzothiazoles 338 was synthesized
similarly to the above procedures (Scheme 6-7). The amides 367-373 were prepared
from 2,4-dimethoxyaniline 342 by reacting it with the respective acid chlorides in
dichloromethane or pyridine solution. In contrast, the formanilide 367 was prepared
from 2,4-dimethoxyaniline 342 and formic acid, whereas the acetamide 368 was
Chapter 6 127
obtained from reacting 2,4-dimethoxyaniline 342 and acetic anhydride. The amides
367-373 were then transformed into their corresponding thioamides 374-380 by
treatment with Lawesson’s reagent in refluxing toluene or by phosphorus pentasulfide
(P4S10) in refluxing pyridine for three hours. The thioamides 374-380 were oxidatively
cyclized to the corresponding 4,6-dimethoxybenzothiazoles 12, 346, 381-385 using
potassium ferricyanide in aqueous sodium hydroxide solution.
Scheme 6-7
S
N
OMe
MeOR
MeO
OMe
MeO
OMe ROCl, DCM orROCl, Pyridine
r.t./ 1-2 hrs
P4S10, Pyridine orLawesson's reagent,Toluene
Reflux/ 2-3 hrs
K3[Fe(CN)6], 30% NaOH
342
MeO
OMe
EtOH, 80-900C, 1 h
NH2 NHCOR
NHCSR
367; R = H 368; R = CH3 369; R = Ph 370; R = 4-MeOC6H4371; R = 4-ClC6H4 372; R = 4-NO2C6H4373; R = 2-NO2C6H4
374; R = H 375; R = CH3 376; R = Ph 377; R = 4-MeOC6H4378; R = 4-ClC6H4 379; R = 4-NO2C6H4380; R = 2-NO2C6H4
12; R = H 346; R = Ph 381; R = CH3 382; R = 4-MeOC6H4383; R = 4-ClC6H4 384; R = 4-NO2C6H4385; R = 2-NO2C6H4
Usually, the acylation reactions were performed in dry dichloromethane containing
anhydrous potassium carbonate. In this condition, the nitrobenzamides 352, 353, 372
and 373 were obtained in low yields in comparison to the other acylations in
dichloromethane, due to the presence of electron withdrawing ortho or para
substituents in the 2 phenyl ring (Table 6-1). However, formation of nitrobenzanilides
was achieved better in pyridine than in dichloromethane solution.
Chapter 6 128
Table 6-1. Comparison of nitrobenzanilides synthesis in different solvents.
Solvent (% Yields) Anilide
Dichloromethane Pyridine
352 22 86
353 16 86
372 54 96
373 39 51
The amides were identified easily by spectroscopic and elemental data. Infrared
carbonyl bands were observed at 1623-1683 cm-1, whereas the carbonyl carbon
resonances appeared at 159-167 ppm in the 13C NMR spectra. In addition, the NH
proton was noticed at 7.10-8.38 ppm in their 1H NMR spectra. A significant solvent
induced downfield shift of NH from 7.75 ppm (in CDCl3) to 9.73 ppm was observed
when the 1H NMR spectrum of amide 352 was recorded into acetone-d6. Therefore,
the peak at 9.70 ppm (in acetone-d6) of the amide 353 is considered to be solvent
induced. Significant spectral data and yields of the amides are recorded below.
Table 6-2. The characteristic spectroscopic data and yields of the amides.
Amide C=O NH C=O NH % Yields
148 1683 3501,3449 159.34, 162.67 7.08,7.49 85
152 1670119 3240117 161.43 7.10 91
153 1659217 3250217 161.02 7.74 83
154 1642 3313 161.00 7.79 69
351 1627 3486 164.71 7.92 62
352 1652 3264 161.03 7.75 86 3,5-
dim
etho
xyam
ides
353 1662 3266 161.10 9.70 86
367 1680 3245 162.22 7.49 97
368 1662 3283 167.84 7.52 53
369 1650 3240 164.87 8.33 74
370 1640 3323 164.44 8.25 72
371 1661 3436 163.77 8.26 78
372 1679 3432 162.64 8.38 96 2,4-
dim
etho
xyam
ides
373 1651 3293 163.51 7.86 51
Chapter 6 129
Thionation of the amide carbonyl with Lawesson’s reagent was usually superior to use
of phosphorus pentasulfide (P4S10) in terms of reaction time, recovery of the product
and product yield. Lawesson’s reagent gave higher yields of the thioamides 355-357
compared to phosphorus pentasulfide and the products could be purified by
recrystallization (Table 6-3). In the case of phosphorus pentasulfide, recrystallization
was not always sufficient to get a pure compound and short column chromatography
was necessary to obtain a pure product. However, Lawesson’s reagent did not give the
thioamide 360, probably due to the deactivating effect of the ortho nitro group, and
the steric effect of the bulky Lawesson’s reagent could also account for this. On the
other hand, the thioanilides 354 and 374 were observed in trace amounts when the
corresponding anilides were reacted with phosphorus pentasulfide. However, when
sulfuration was done with Lawesson’s reagent they could be isolated in low yields
after column chromatography.
Table 6-3. Comparative yield of thionation between phosphorus pentasulfide and
Lawesson’s reagent.
Thioamide Phosphorus pentasulfide/Pyridine Lawesson’s reagent/Toluene
354 trace 9
355 40 76
356 59 81
357 30 77
360 41 -
374 trace 6
Infrared stretching bands at ~1150 cm-1 represents the thiocarbonyl groups of the 3,5-
dimethoxythioamides 354-360. Similarly, bands at ~1125 cm-1 indicate the
thiocarbonyl group of the 2,4-dimethoxythioamides 374-380. The NH bands were
detected around 3162-3361 cm-1. In the 1H NMR spectra the NH protons were noticed
to shift downfield (average NH ~9.10 ppm) from their corresponding starting amides
in the proton NMR spectra. The more significant differences were observed in their 13C NMR spectra where the thiocarbonyl carbons appeared at ~192 ppm (~30 ppm
downfield shift). Correct mass spectral and elemental analysis data further confirmed
Chapter 6 130
their structures. Representative spectroscopic data and yields of the thioamides are
displayed in the following Table 6-4.
Table 6-4. The characteristic spectroscopic data and yields of the thioamides.
Thioamide C=S NH C=S NH % Yields
354 1155 3290 187.35 9.22 9
355 1163 3212 188.80 9.79 76
356 1155 3212 198.10 9.01 81
357 1158 3162 197.41 8.92 77
358 1150 3243 196.50 9.20 66
359 1164 3251 195.07 8.99 69 3,5-
dim
etho
xyth
ioam
ides
360 1149 3304 170.11 7.04 41
374 1121 3225 185.25 9.44 6
375 1125 3361 204.88 9.12 53
376 1126 3347 195.11 9.43 77
377 1124 3366 197.46 9.34 79
378 1125 3355 193.42 9.38 60
379 1118 3356 191.80 9.45 79
2,4-
dim
etho
xyth
ioam
ides
380 1110 3190 191.71 9.13 46
The hindered rotation about the C-N bond in amides and their thiocarbonyl analogues
results in some intriguing stereochemical and spectroscopic consequences. In the
absence of any improper symmetry axis they can exist in two geometric isomers and
are usually not separable due to the relatively low barrier to rotation (20 kcal/mole).121
Furthermore, it has been found that ortho substituted benzamides exhibited barriers to
rotation which were considerably higher than those for any meta or para substituted
benzamides.121 Molecular models and other studies suggest that that there could be
three resonance structures of the amide bonds218 (Figure 6-3).
CO
NCO
NCS
NCS
NCO
NCS
N
Figure 6-3
Chapter 6 131
The formamides 148, 367 and their respective thioformamides 354, 374 revealed the
restricted rotation around the C-N bond by observing doubling of the signals in their 1H NMR spectra. On the other hand, only the thioacetamides 355 and 375
demonstrated the hindered rotation. This is because the rotational barrier in thioamides
is ca. 5 kcal/mol higher than in the related amides due to greater contribution of the
bipolar resonance structure that increases double bond character of the C(S)-N
linkage.219 The possible geometric forms for amides 148, 367 and thioamides 354, 374
are drawn below (Figure 6-4). The arylamides presumably have lower torsional
barriers than those of alkylamides due to greater stability by charge delocalization into
the aromatic ring.
OMe
MeO
NH
OH OMe
MeO
NH
HO
OMe
MeO NH
OH
OMe
MeO NH
HO
syn antisyn anti
OMe
MeO
NH
SH OMe
MeO
NH
HS
OMe
MeO NH
SH
OMe
MeO NH
HS
syn antisyn anti
148 367
374354
Figure 6-4
Hydrogen bonding represents the most versatile means to discriminate between syn
and anti conformations of RCONH-aryl bonds. Restrictions of the aryl-amide bond
rotations can also be imposed by steric hindrance, using bulky substituents at ortho
positions to the amide group. However, these conformations can be characterized by
chemical shift comparisons, solvent shift comparisons, lanthanide induced shifts and
by single crystal structure determination.220 Little information is available in the
literature to differentiate between the favoured and disfavoured conformations of these
amides and thioamides. Further studies are beyond the scope of the thesis and are not
considered.
Significant differences were not observed between the chemical shifts of the H-5(H-6)
protons of the 5,7-dimethoxybenzothiazoles 11, 361-366 and 4,6-
dimethoxybenzothiazoles 12, 346, 381-385 as they appeared around the same places
(6.45-6.58 ppm) in their 1H NMR spectra. However, noticeable differences were
Chapter 6 132
observed as anticipated in the chemical shifts of the H-7(H-4) protons. The H-4
protons in the 5,7-dimethoxybenzothiazoles were downfield to ~7.1 ppm because of
their closeness to the more electronegative nitrogen atom compared to the sulfur atom
in the 4,6-dimethoxybenzothiaozoles, which averaged at ~6.9 ppm (H-7). The
benzothiazoles were further characterized by other spectroscopic information.
Accurate elemental analyses were obtained for all benzothiazoles except compounds
11 and 12. A selection of significant 1H NMR values and percentage yields of the
benzothiazoles is given in Table 6-5. The ortho nitrophenylbenzothiazoles 366 and
385 were isolated in low yields probably due to the deactivating effect of the ortho
nitro group.
Table 6-5. Important 1H NMR shift values ( H) and % yields of the benzothiazoles.
Benzothiazole H6(H5) H4(H7) OMe % Yields
11 6.47 7.06 3.78/3.85 19
361 6.45 7.06 3.86/3.96 55
362 6.49 7.19 3.89/3.95 74
363 6.47 7.17 3.89/3.95 95
364 6.50 7.17 3.89/3.96 91
365 6.55 7.21 3.91/3.98 96
5,7-
dim
etho
xybe
nzot
hiaz
oles
366 6.53 7.16 3.88/3.98 20
12 6.53 6.76 3.90/3.95 25
346 6.55 6.93 3.88/4.04 78
381 6.48 6.82 3.82/3.96 27
382 6.53 6.90 3.86/4.02 71
383 6.55 6.92 3.88/4.03 87
384 6.58 6.96 3.90/4.06 86
4,6-
dim
etho
xybe
nzot
hiaz
oles
385 6.54 6.91 3.80/3.98 25
The mechanism of the cyclization of thioamides 386 probably involves a one electron
oxidation of the thiolate anion 387 to give thiol radicals 388 which then attack the
unoccupied ortho position in the substrates (Scheme 6-8). Elimination of a hydrogen
radical from the reactive intermediates 389 effects aromatization to the benzothiazoles
337.
Chapter 6 133
Scheme 6-8
N
S
OMe
MeOR
MeO
OMe
NH
NaOH
R
S Na+
K3[Fe(CN)6]
MeO
OMe
N R
S
-H
N
S
OMe
MeOR
H
386 387
337 389
388
MeO
OMe
N R
S
6.3. Formylation of activated benzothiazoles and reduction of benzothiazole
aldehydes
The Vilsmeier-Haack formylation reaction normally occurs in high yields and there is
often a significant difference in the conditions needed to achieve the formylation.47
The reaction is particularly useful for determining the reactivity of nucleophilic site
(C-7/C-4) of dimethoxyactivated benzothiazoles. It is also important to compare this
reactivity with the dimethoxy activated indoles and benzimidazoles. The formylation
reaction was carried out using a similar method as described earlier for the indoles
(Chapter 2.5) and benzimidazoles (Chapter 3.3). The Vilsmeier formylation of 362
did not work well at room temperature with overnight stirring. However, using one
and half an equivalents of the formylating reagent at 70°C for three hours gave the 4-
formylbenzothiazole 390 in 90% yield (Scheme 6-9). Similarly, the 4(7)-
formylbenzothiazoles 391-394 were prepared by Vilsmeier formylation in 75-92 %
yields. Interestingly, no differences were observed in the reactivity of 5,7-
dimethoxybenzothiazoles 390-392 and 4,6- dimethoxybenzothiazoles 393 and 394 in
respect to the duration or yield of the reaction. The formylation of benzothiazoles was
found to be slower than the related activated indoles, but faster than the corresponding
benzimidazoles. This result indicates a more reactive nucleophilic site than that in the
activated benzimidazoles.
Chapter 6 134
Scheme 6-9
N
S
OMe
MeO N
S
OMe
MeOR R
POCl3/DMF
70oC/2-3 h
390; R = Ph 391; R = 4-MeOC6H4392; R = 4-ClC6H4
OH362; R = Ph 363; R = 4-MeOC6H4364; R = 4-ClC6H4
S
N
OMe
MeO S
N
OMe
MeOR R
POCl3/DMF
70oC/2 h
393; R = Ph 394; R = 4-ClC6H4
OH
346; R = Ph 383; R = 4-ClC6H4
As predicted, the 4-formyl-5,7-dimethoxybenzothiazoles 390-392 exhibited the
characteristic aldehyde peaks comparatively lowfield at ~10.90 ppm due to the
electron withdrawing nitrogen atom, whereas the 7-formyl-4,6-
dimethoxybenzothiazoles 393, 394 appeared at a slightly upfield position ~10.40 ppm
in the 1H NMR spectra (Table 6-6). The carbonyl carbon resonances in the 13C NMR
spectra of the 5,7-dimethoxy compounds 390-392 were seen at ~188 ppm, and in the
4,6-dimethoxy compound 393 appeared slightly upfield position at ~185 ppm. The IR
bands around 1655-1691 cm-1were assigned to the carbonyl absorptions. The bands at
~3430 cm-1 in the compounds 392 and 394 indicate the water molecule present in the
sample, which is supported by the elemental analysis. Further spectroscopy and
microanalysis data confirmed the formation of the desired aldehydes.
Table 6-6. Important spectral properties and yields of formylbenzothiazoles.
Aldehyde Time CHO C=O C=O % Yields
390 3 h 10.96 188.80 1673 90
391 2 h 10.92 188.90 1676 92
392 2 h 10.92 188.67 1691 89
393 2 h 10.42 185.83 1677 75
394 2 h 10.43 too insoluble 1655 82
Chapter 6 135
The formylbenzothiazoles 390, 391 and 393 were effectively reduced to the
corresponding alcohols 395-397 by sodium borohydride under reflux in methanol for
1.5-3 h in high yields (80-98 %) as white solids (Scheme 6-10). In the 1H NMR
spectra the methylene protons appeared at 5.19-4.86 ppm and the products were
further characterized by elemental and other spectroscopic information.
Scheme 6-10
N
S
OMe
MeO N
S
OMe
MeOR R
395; R = Ph 396; R = 4-MeOC6H4
OH
390; R = Ph 391; R = 4-MeOC6H4
S
N
OMe
MeO S
N
OMe
MeOR R
397; R = Ph
OH
393; R = Ph
OH
OH
NaBH4 / MeOHreflux / 1.5-3 h
NaBH4 / MeOHreflux / 1.5 h
The hydroxymethylbenzothiazoles 395 and 397 underwent a facile acid catalyzed
addition reaction in acetic acid at 80°C within two hours to produce the
dibenzothiazolylmethane derivatives 398 and 399 respectively in 88% and 93 % yields
again as white solids (Scheme 6-11). In the 1H NMR spectra of 395-397 the
methylene protons were found at lowfield positions compared with the starting
alcohols. Molecular ion peaks at m/z 556 (M+1) for both the compounds provided
evidence for the formation of the dibenzothiazolylmethanes 398 and 399.
Chapter 6 136
Scheme 6-11
N
S
OMe
MeOPh
395
S
N
OMe
MeOPh
OH
OH
80oC/2 h
N
S
OMe
MeO
N
S
OMe
MeO
Ph
Ph
S
N
OMe
MeO
S
N
OMe
MeO
Ph
Ph
398
397 399
AcOH
AcOH
80oC/2 h
6.4. Acylation of activated benzothiazoles
The modified Vilsmeier-Haack acylation reaction of the benzothiazole 362 using
phosphoryl chloride and N,N-dimethylacetamide was found to be unsuccessful despite
the treatment with a large excess of the reagent and heating the reaction mixture at
60°C for a week. Instead, the acetylated compounds 400 and 401 were prepared in
moderate yields by the Friedel-Crafts reaction with acetyl chloride using antimony
pentachloride as the Lewis acid catalyst (Scheme 6-12). On this occasion, the Friedel-
Crafts acylation reactivity of benzothiazoles is again less than the corresponding
indoles, but similar to the activated benzimidazoles. The carbonyl peaks in the
infrared spectra of the compounds 400 and 401 appeared at 1602 cm-1 and 1599 cm-1
respectively. Disappearance of the H-4/H-7 protons in the 1H NMR spectra and peaks
for additional acetyl protons at ~2.75 ppm indicated the acetyl derivatives 400 and
401. Molecular ions in the mass spectra at m/z 314 (M+1) confirmed the formation of
the desired acetyl derivatives 400 and 401.
Chapter 6 137
Scheme 6-12
N
S
OMe
MeO N
S
OMe
MeOPh Ph
CH3COCl/SbCl5
OMe
S
N
OMe
MeO S
N
OMe
MeOPh Ph
OMe
CHCl3, 24 h
CH3COCl/SbCl5CHCl3, 24 h
362 400
346 401
6.5. Nitration of activated benzothiazoles
As discussed earlier (Chapter 3.7) nitration is a significant reaction to build
supplementary derivatives on molecules. Treatment of benzothiazoles 362 and 346
with nitric acid in a cool solution of acetic anhydride resulted in the formation of the
desired 4-nitrobenzothiazole 402 in 24 % yield and the 7-nitrobenzothiazole 404 in 64
% yield, both as yellow crystals (Scheme 6-13). In addition to the 4-
nitrobenzothiazole 402 a product identified as the 4,7-dione 403 was also isolated in
25 yield % after column chromatography.
Scheme 6-13
N
S
OMe
MeO N
S
OMe
MeOPh Ph
HNO3/Ac2O
S
N
OMe
MeO S
N
OMe
MeONO2
Ph Ph
0oC, 1 h
362 402
346 404
HNO3/Ac2O0oC, 1 h
NO2
N
S
O
MeOPh+
403
O
Chapter 6 138
Disappearance of the H-4/H-7 proton in the 1H NMR spectra of 402 and 404 indicated
the introduction of a nitro substituents at C-4/C-7, which was supported by the
infrared bands for the nitro functional group respectively at 1572 cm-1, 1349 cm-1 and
at 1563 cm-1, 1348 cm-1. Elemental, mass and other spectral observations further
attested to the synthesis of the nitrobenzothiazoles 402 and 404.
The 4,7-dione 403 showed only one group of methoxy protons in its 1H NMR
spectrum and a singlet resonance at 6.06 ppm corresponding to the H-6 proton.
Infrared bands at 1697 cm-1 and 1639 cm-1 indicated the presence of carbonyl
functionality in the molecule, and this is further supported by 13C NMR spectral
resonances at 173 ppm and 179 ppm. A molecular ion at m/z 272 (M+1) and elemental
analysis gave the ultimate proof of the 4,7-dione structure 403.
The formation of the 4,7-dione 403 during nitration thus explained the low yield of the
4-nitrobenzothiazole 402. It is considered that 4,7-dione 403 was produced by the
further oxidation of 4-nitrobenzothiazole 402 by nitric acid oxidation.221
As stated above, the low yield of the 4-nitrobenzothiazole 402 and its further
oxidation to the 4,7-dione 403 shows the more reactive nature of the 5,7-
dimethoxybenzothiazole 362 compared to the 4,6-dimethoxybenzothiazole 346.
However, in comparison with the high reactivity towards nitration of activated indoles
by the similar nitric acid/acetic anhydride conditions, again shows the reduced
reactivity of the benzothiazoles.
Alternatively, the 4,7-dione 403 could be prepared in moderate yield from the 4-
formylbenzothiazole 390 by the modified Dakin oxidation method using hydrogen
peroxide in a solution of tetrahydrofuran/methanol under acidic conditions (Scheme
6-14) as described earlier in the thesis Chapter 2.10.
Chapter 6 139
Scheme 6-14
N
S
OMe
MeOPh
H2O2/HClMeOH/THF
390
N
S
O
MeOPh
403
OOH
The synthesis of benzothiazole-4,7-dione 403 is quite interesting as the same Dakin
oxidation failed in the case of the related 7-formylbenzimidazole 164 (Chapter 3.11).
This further shows the superior reactivity of activated benzothiazoles over similar
benzimidazoles. Heterocyclic quinones represent an important class of bioactive
molecules and some benzothiazole-4,7-diones have been reported to have
antimicrobial activities.222,223
6.6. Preparation of benzothiazolylbenzimidazoles
Treatment of the 4-formylbenzothiazoles 390 and 391 with one equivalent of 1,2-
diaminobenzene in N,N-dimethylformamide under overnight heating gave the desired
benzothiazolylbenzimidazoles 404 and 405 in moderate to good yields after
recrystallization from ethanol (52-68%) (Scheme 6-15). In the 1H NMR spectra the
compounds exhibited the absence of H-4 protons and have the additional aromatic
protons of the benzimidazole nucleus. The NH resonances were observed at ~11.70
ppm. Other spectroscopic data and EI mass spectra m/z at 388 (M+1) and 418 (M+1)
established the structures of the compounds respectively as the benzothiazolyl
benzimidazoles 404 and 405.
Scheme 6-15
N
S
OMe
MeOR
DMF/110oC/16 h N
S
OMe
MeOR
OH N NH
404; R = Ph 405; R = 4-MeOC6H4
390; R = Ph 391; R = 4-MeOC6H4
H2N
H2N
Chapter 6 140
The benzothiazolylbenzimidazoles 404 and 405 are presumably formed by the
oxidative dehydrogenation of dihydrobenzimidazoles in N,N-dimethylformamide as
described for the related indoles5 and benzimidazole compounds (Scheme 3-22).
There are numerous examples of indolylbenzimidazoles and bisbenzimidazoles in the
literature and these have been described earlier in the thesis. However, only a few
examples of benzothiazolylbenzimidazoles have been found, and these relate to 5-(2-
benzothiazolyl)benzimidazoles.224,225 Hence, the 2-(4-benzothiazolyl)-benzimidazoles
404 and 405 are new examples of benzothiazole where the 4 position of a
benzothiazole is linked a to a benzimidazole moiety at its 2 position. Such an addition
of two highly bioactive molecules could be of profound interest for the search for a
new class of bioactive compounds. Besides their biological potential the
benzothiazolylbenzimidazoles 404 and 405 are also prospective bidentate ligands.
6.7. Conclusions
Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-
substituted-4,6-dimethoxybenzothiazoles were effectively synthesized by Jacobson
cyclization of corresponding thioamides. These dimethoxy activated benzothiazoles
undergo regioselective formylation, acylation and nitration to the specific activated
position. In addition, the formylbenzothiazoles can be reduced to the corresponding
alcohols, which can be converted to dibenzothiazolylmethanes by acid catalyzed
conditions. A 5-methoxybenzothiazole-4,7-dione and benzothiazolyl benzimidazoles
were also synthesized from the corresponding formylbenzothiazoles. These reactions
demonstrated a less reactive nature of activated benzothiazoles compared to the
corresponding indoles but superior reactivity over the related activated benzimidazoles
towards various electrophiles.
Experimental 141
CHAPTER 7
EXPERIMENTAL
7.1. General information
Melting points were measured using a Mel-Temp melting point apparatus, and are
uncorrected. Microanalyses were performed by Marianne Dick at on a Carlo Erba
Elemental Analyzer EA 1108 at the Campbell Microanalytical Laboratory,
Department of Chemistry, University of Otago, New Zealand.
1H NMR spectra were recorded in the designated solvents on a Bruker DPX300 (300
MHz) /Brucker AC 300F spectrometer at the designated frequency and were internally
referenced to the solvent peaks. 1H NMR spectra data are reported as follows:
chemical shift measured in parts per million (ppm) downfield from TMS ( );
multiplicity; observed coupling constant ( ) in Hertz (Hz); proton count; assignment.
Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), quintet (p),
multiplet (m), broad (br), and combinations of these. 13C NMR spectra were recorded
in the designated solvents on a Bruker AC 300F (75 MHz) and chemical shifts are
reported in ppm downfield from TMS ( ), and identifiable carbons are given.
The mass spectra were recorded on either:
a Shimadzu LCMS QP 8000 (EI) at the University of Otago, New Zealand,
a Bruker Daltonics Bio Apex II FTICR MS (HRMS-ESI) at UNSW,
a Voyager DE STR MALDI TOF Applied Biosystems (MALDI) at UNSW,
a Q-TOF Ultima API Micromass (ESI) at UNSW.
The principal ion peaks m/z are reported together with their percentage intensities
relative to the assigned base peak.
Infrared spectra were recorded with a Thermo Nicolet 370 FTIR
Spectrometer/Mattson Genesis series FTIR spectrometer using potassium bromide
(KBr) discs. Ultraviolet-visible spectra were recorded using a Varian Cary 100 Scan
Spectrometer, and the absorbance maxima together with the log of the molar
absorptivity ( ), are reported and refers to the solution in absolute methanol.
Experimental 142
All reactions requiring anhydrous conditions were performed under an argon
atmosphere and dry solvents were prepared as follows: chloroform and
dichloromethane were distilled from calcium hydride when required. N,N-
dimethylformamide (DMF) was dried over calcium hydride prior to being distilled at
atmospheric pressure and stored over 4 Å molecular sieves. Analytical grade diethyl
ether, tetrahydrofuran (THF) and toluene were refluxed over sodium and
benzophenone under argon, until a deep purple color appeared, and were maintained
in this condition under nitrogen and distilled when required. Dry ethanol was prepared
by distilling absolute ethanol under argon and storing solvents over 4 Å molecular
sieves. Dry acetonitrile, ethyl acetate and methanol were prepared by storing
analytical grade solvents over 4 Å molecular sieves. Dimethylsulfoxide (DMSO) was
stirred over activated 4 Å molecular sieves for 4 h and stored over the 4 Å molecular
sieves. Light petroleum refers to the fraction boiling between 60-80 °C.
Flash column chromatography was performed using Merck 60H silica gel and refers
to the technique of applying suction at the base of the column. Column
chromatography was carried out using Merck 230-400 mesh ASTM silica gel.
Preparative thin layer chromatography was carried out on 3×200×200 mm glass plates
using Merck 7730 and 60GF254 silica gel. Reactions were monitored using thin layer
chromatography, performed on Merck DC aluminium foil pre-coated with silica gel
F254. Compounds were detected by short and long wavelength ultraviolet light and
with iodine vapor.
7.2. Electrochemistry
A computer controlled electroanalysis system was used for all the cyclic voltammetric
measurements. Cyclic voltammogram experiments were run with a Pine Instrument
Co. AFCBPI Bio potentiostat interfaced to and controlled by a Pentium III personal
computer. All the currents were digitally integrated. A conventional three electrode
cell consisting of a glassy carbon working electrode (0.5 mm diameter), a platinum
wire counter electrode and an Ag/AgCl (3 M KCl) reference electrode was housed in a
Faraday cage. 0.1 M tetra-n-butylammonium hexafluorophosphate [nBu4N][PF6] in
anhydrous acetonitrile (Sure/SealTM Aldrich Chemical Co.) or anhydrous N,N-
dimethylformamide (Sure/SealTM Aldrich Chemical Co.) served as an inert electrolyte.
Experimental 143
Solutions were deoxygenated by purging with argon gas for 15 min prior to
measurements and during the experiment a stream of argon gas was passed over the
solution. The experiments were carried out at room temperature. All solutions (c. 2
mM) of benzimidazoles for electrochemical analyses were made by dissolving the
appropriate amount of the compound in the nBu4NPF6 electrolyte solution. The glassy
carbon electrodes were scanned between the anodic and cathodic solvent discharges in
solvent-electrolyte alone, prior to running CVs of the sample to ensure reproducible
CVs. An electrochemical scan of the solvent-electrolyte system was always recorded
prior to the addition of the compound to ensure that there were no spurious signals.
The potential of the reference electrode was calibrated against the
ferrocene/ferrocenium (Fc-Fc+) redox couple by using the cyclic voltammetry of 2
mM ferrocene in the electrolyte solution. The half cell potential for
ferrocene/ferrocenium redox couple (internal standard) was 0.42 V under the above
conditions in anhydrous acetonitrile. The half cell potential for ferrocene/ferrocenium
redox couple was 0.52 V when anhydrous N,N-dimethylformamide (DMF) was used
instead of acetonitrile under the similar above conditions. The scan rate was 100
mV/sec and voltammograms were analyzed according to established procedures.
7.3. Quantum chemical calculation
Quantum chemical calculations were carried out with the aid of PC SPARTAN Pro
1.0.5 (2000) software package using semi-empirical method AM1 on an Intel Pentium
III ® computer where the operating system was Microsoft Windows® 2000.
Calculations were done on the molecule which has the lowest heat of formation and
no hydrogen bonding was used for the theoretical calculation. Geometry optimization
were done by semi-empirical AM1 method183.
7.4. Experimental details
Bis[3-(4'-bromophenyl)-4,6-dimethoxy-2-carbaldehyde-indol-7-yl]methane (75)
To a solution of 2,7-
dihydroxymethylindole 64 (1 g, 2.55
mmol) in tetrahydrofuran (10 mL) N-
bromosuccinimide (0.50 g) was added
and the mixture stirred under argon for
HN
OMe
NH
MeO
OO
OMeMeO
BrBrHH
Experimental 144
2 h at room temperature. The solvent was removed by evaporation, water was added,
and extracted with dichloromethane. The organic layer was washed with water, brine
and dried over magnesium sulfate. The title compound 7,7'-diindolylmethane-2,2'-
dicarbaldehyde 75 was purified by column chromatography using dichloromethane as
eluent, as light yellow crystals (0.19 g, 20%), m.p. 352 oC (dec.). (Found: C, 57.33; H,
4.00; N, 3.83. C35H28Br2N2O6 requires C, 57.40; H, 3.85; N, 3.82 %). HRMS (+ESI):
C35H28Br2N2O6 [M+Na]+ requires 755.0188, found 755.0196. max (KBr): 3316, 2940,
2829, 1647, 1616, 1586, 1526, 1484, 1437, 1367,1349, 1255, 1220, 1203, 1157, 1124,
1005, 991, 840, 789, 779 cm-1. max (MeOH): 208 nm ( 5,600 cm-1M-1), 263 (3,200),
325 (1,600). 1H NMR (300 MHz, CDCl3): 3.74 (s, 6H, OCH3), 4.32 (s, 6H, OCH3),
4.28 (s, 2H, CH2), 6.33 (s, 2H, aryl H5), 7.33 (d, J = 8.28 Hz, 4H, aryl H), 7.51 (d, J =
8.28 Hz, 4H, aryl H), 9.52 (s, 2H, CHO), 10.54 (br s, 2H, NH). 13C NMR (75 MHz,
CDCl3): 18.06 (CH2), 55.13, 56.96 (OCH3), 88.57, 130.43, 132.73 (aryl CH),
102.72, 112.27, 121.76, 128.54, 131.51, 131.81, 139.08, 155.29, 155.67 (aryl C),
181.37 (C=O). Mass Spectrum (+EI): m/z (%) 733 (M+1, 81Br, 100), 731 (79Br, 42),
503 (38), 439 (47), 385 (51), 335 (50), 296 (42), 162 (41), 122 (67).
Bis(3-phenyl-4,6-dimethoxy-2-carbaldehyde-indol-7-yl)methane (76)
This was prepared as described for the 7,7'-
diindolylmethane-2,2'-dicarbaldehyde 75 from 2,7-
dihydroxymethylindole 65 (50 mg, 0.16 mmol)
and N-bromosuccinimide (0.03 g) in
tetrahydrofuran (5 mL) under argon for 1.5 h at
room temperature to give the title compound 76 as a yellow solid (17 mg, 37%), m.p.
302-303 oC (lit.123 m.p. 302-304 oC). 1H NMR (300 MHz, CDCl3): 3.73 (s, 6H,
OCH3), 4.32 (s, 6H, OCH3), 4.30 (s, 2H, CH2), 6.33 (s, 2H, aryl H5), 7.36-7.47 (m,
10H, aryl H), 9.53 (s, 2H, CHO), 10.53 (br s, 2H, NH). 13C NMR (75 MHz, CDCl3):
18.63 (CH2), 55.68, 57.43 (OCH3), 89.07, 127.71, 127.80, 131.76 (aryl CH), 103.27,
113.02, 130.60, 132.45, 133.08, 139.67, 155.77, 156.33 (aryl C), 182.37 (C=O). Mass
Spectrum (+EI): m/z (%) 576 (M+1, 23), 575 (M, 44), 371 (26), 310 (49), 294 (100),
282 (86), 268 (23).
HN
OMe
NH
MeO
OO
OMeMeO
HH
Experimental 145
Bis[3-(4'-bromophenyl)-4,6-dimethoxy-2-hydroxymethyl-indol-7-yl]methane (82)
To a solution of 7,7'-diindolylmethane-
2,2'-dicarbaldehyde 75 (0.12 g, 0.16
mmol) in tetrahydrofuran/methanol (1:1,
50 mL), sodium borohydride (0.30 g)
was added and the mixture refluxed
overnight (18 h). The solution was
allowed to cool to room temperature, solvent was concentrated and treated with water.
The resulting precipitate was collected, washed with water and recrystallized from
ethanol to afford the dialcohol 82 as a white pad (0.10 g, 83%), m.p. 262-264 oC.
(Found: C, 56.80; H, 4.49; N, 3.74. C35H32Br2N2O6 requires C, 57.08; H, 4.38; N, 3.80
%). HRMS (+ESI): C35H32Br2N2O6 [M+Na]+ requires 759.0501, found 759.0500. max
(KBr): 3329, 2933, 2836, 1622, 1595, 1519, 1488, 1449, 1434, 1340, 1215, 1152,
1119, 1000, 838 cm-1. max (MeOH): 203 nm ( 72,700 cm-1M-1), 229 (75,400), 291
(28,900). 1H NMR (300 MHz, CDCl3): 3.70 (s, 6H, OCH3), 4.17 (s, 6H, OCH3),
4.30 (s, 2H, CH2), 4.74 (s, 4H, CH2OH) 6.33 (s, 2H, aryl H5), 7.21 (d, J = 8.28 Hz,
4H, aryl H), 7.44 (d, J = 8.28 Hz, 4H, aryl H), 10.18 (br s, 2H, NH). 13C NMR (75
MHz, CDCl3): 18.32, 57.12 (CH2), 55.25, 57.51 (OCH3), 88.94, 130.20, 132.75 (aryl
CH), 104.08, 119.76, 130.39, 132.22, 134.18, 137.12, 139.19, 151.49, 153.16 (aryl C).
Mass Spectrum (-EI): m/z (%) 735 (M-1, 81Br, 100), 733 (M-1, 79Br, 45), 379 (41).
Bis[3-phenyl-4,6-dimethoxy-2-hydroxymethyl-indol-7-yl]methane (83)
This was prepared as described for dialcohol 82
from 7,7'-diindolylmethane-2,2'-dicarbaldehyde 76
(30 mg, 0.052 mmol) and sodium borohydride
(0.20 g) in tetrahydrofuran/methanol (2:1, 20 mL)
under reflux for 6 h to give the title compound 83
as a white pad (26 mg, 87%), m.p. 291-293 oC.
(Found: C, 71.88; H, 6.04; N, 4.80. C35H34N2O6 0.3H2O requires C, 71.97; H, 5.97; N,
4.80 %). HRMS (+ESI): C35H34N2O6 [M+Na]+ requires 601.2309, found 601.2316.
max (KBr): 3334, 2934, 2837, 1620, 1600, 1519, 1450, 1434, 1338, 1200, 1151, 1118,
1003, 700. max (MeOH): 205 nm ( 63,900 cm-1M-1), 230 (75,600), 288 (29,100). 1H
HN
OMe
NH
MeO
HOOH
OMeMeO
BrBr
HN
OMe
NH
MeO
HOOH
OMeMeO
Experimental 146
NMR (300 MHz, DMSO-d6): 3.65 (s, 6H, OCH3), 4.09 (s, 6H, OCH3), 4.19 (s, 2H,
CH2), 4.54 (s, 4H, CH2OH), 5.42 (t, 2H, OH), 6.42 (s, 2H, aryl H5), 7.17-7.27 (m,
10H, aryl H), 10.11 (br s, 2H, NH). Mass Spectrum (+EI): m/z (%) 579 (M+1, 3), 578
(M, 5), 562 (22), 561 (70), 296 (37), 280 (27), 278 (100).
Bis[3-(4'-bromophenyl)-7-[(3-(4'-bromophenyl)-2-hydroxymethyl-4,6-
dimethoxyindol-7-yl)methyl]-4,6-dimethoxyindol-2-yl]methane polymer (85)
To a solution of
indole dialcohol 82
(50 mg, 0.068
mmol) in
anhydrous
tetrahydrofuran (5
mL), acetic acid (1
mL) was added and the mixture stirred at room temperature for 6 h. Ice water was
added to quench the reaction and the resulting white precipitate was filtered, washed
with water and dried to give the polymer 85 as a white solid (13 mg, 27%), m.p. 190 oC (dec.). max (KBr): 3342, 2934, 2838, 1736, 1620, 1594, 1521, 1488, 1449, 1340,
1218, 1155, 1118, 1000 cm-1. max (MeOH): 207 nm ( 69,700 cm-1M-1), 228 (71,000),
269 (34,300). Mass Spectrum (+EI): m/z (%) 1426 (M, 81Br, 3), 1424 (M, 79Br, 3), 720
(37), 719 (36), 718 (51), 716 (79), 714 (38), 702 (43), 700 (100), 698 (23).
4,12,24-Tri(4'-bromophenyl)-
6,8,14,16,20,22-hexamethoxy-25,28,30
triazaheptacyclo[17.5.2.23,9.211,27.05,29.013,27.023,26]triaconta-
1(24),3,5(29),6,8,11,13(27),14,16,19,21,23(26
)-dodecaene (86) Calix[3]indole
To a solution of indole 47 (4 mg, 0.0136
mmol) in acetic acid (1 mL) and
tetrahydrofuran (1 mL), a solution of dialcohol
82 (10 mg, 0.0136 mmol) in tetrahydrofuran
NH
OMe
HN
OMe
MeO
MeO
Br
Br
HN OMe
OMe
Br
NH
MeO
HN
OMe
HO
MeO
OMe
NH
MeO
HN
OMeOH MeO
OMe
Br
Br
Br
Br
Experimental 147
(1 mL) was added dropwise and the mixture stirred at room temperature for 1 h. Ice
water was added to quench the reaction and the resulting precipitate was collected,
washed with water, dried and recrystallized from dichloromethane/light petroleum to
afford the calix[3]indole 86 as a yellow powder (9 mg, 64%), m.p. 270-272 °C.
(Found: C, 56.81; H, 4.11; N, 3.74. C51H42Br3N3O6 0.7CH2Cl2 requires C, 56.86; H,
4.01; N, 3.85 %). max (KBr): 3328, 2932, 1620, 1594, 1488, 1449, 1340, 1217, 1155,
1120, 1000 cm-1. max (MeOH): 202 nm ( 1,02,800 cm-1M-1), 229 (1,05,200), 281
(42,800). 1H NMR (300 MHz, DMSO-d6): 3.72 (s, 9H, OCH3), 3.98 (s, 9H, OCH3),
4.12 (s, 6H, CH2), 6.29 (s, 3H, aryl H5), 7.26 (d, J = 8.28 Hz, 6H, aryl H), 7.49 (d, J =
8.28 Hz, 6H, aryl H), 9.23 (br s, 3H, NH). Mass Spectrum (MALDI): m/z (%) 1035
(M+3, 67), 1034 (M+2, 69), 1033 (M+1, 86), 1032 (M, 100), 1031 (86), 1030 (85),
1029 (78).
3-(4'-Bromophenyl)-7-(((3-(4'-bromophenyl)-4,6-dimethoxyindol-7-
yl)methoxy)methyl)-4,6-dimethoxyindole (99)
To a solution of 7-
hydroxymethylindole 26 (0.20 g, 0.55
mmol) in methanol (20 mL),
formaldehyde solution (37%, 0.5 mL)
was added dropwise and the mixture
stirred at room temperature for 24 h. The resulting white precipitate was filtered,
washed with water, dried and recrystallized from isopropanol to yield the
diindolylmethyl ether 99 as an off white solid (0.19 g, 96%), m.p. 160 oC (dec.).
HRMS (+ESI): C35H32Br2N2O5 [M+Na]+ requires 743.0554, found 743.0484. max
(KBr): 3422, 2931, 2834, 1621, 1594, 1518, 1486, 1463, 1450, 1431, 1334, 1258,
1202, 1143, 1111, 1071, 1009, 996, 814, 793 cm-1. max (MeOH): 229 nm ( 37,000
cm-1M-1), 283 (18,200). 1H NMR (300 MHz, CDCl3): 3.66 (s, 4H, CH2), 3.71 (s, 6H,
OCH3), 3.97 (s, 6H, OCH3), 6.10 (s, 2H, aryl H5), 7.36 (s, 2H, aryl H2), 7.50-7.53 (m,
8H, aryl H), 7.77 (s, 2H, NH). Mass Spectrum (+EI): m/z (%) 719 (M+1, 81Br, 100),
717 (M+1, 79Br, 12), 543 (81Br, 25), 541 (79Br, 15), 475 (62), 422 (66), 391 (22), 269
(52), 242 (61).
HN
OMe
MeO
BrNH
MeO
OMe
Br
O
Experimental 148
General procedure for the synthesis of 6-methoxyindole-4,7-diones
The indole-7-carbaldehyde was dissolved with warming in tetrahydrofuran/methanol
(1:1). Concentrated hydrochloric acid (few drops) was added to the solution and after
5 min stirring, excess 30% hydrogen peroxide solution was added slowly. The mixture
was stirred for another 2 h at room temperature before ice water was added to quench
the reaction. The resulting precipitate was collected, washed with water and
recrystallized from ethanol/methanol to afford the brightly colored indoloquinones.
6-Methoxy-2,3-dimethylindole-4,7-dione (117)
According to the general procedure, treatment of 2,3-
dimethylindole-7-carbaldehyde 59 (0.20 g, 0.85 mmol) in
tetrahydrofuran/methanol (20 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide
solution (5 mL) afforded the indoloquinone 117 as a dark brown powder (52 mg,
31%), m.p. 297 oC (dec.). (Found: C, 63.07; H, 5.50; N, 6.52. C11H11NO3 0.3CH3OH
requires C, 63.18; H, 5.72; N, 6.52 %). HRMS (+ESI): C11H11NO3 [M+Na]+ requires
228.0631, found 228.0630. max (KBr): 3427, 3189, 2923, 1666, 1633, 1594, 1563,
1494, 1456, 1336, 1249, 1116, 845 cm-1. max (MeOH): 205 nm ( 12,200 cm-1M-1),
228 (14,900), 283 (12,800), 353 (4,000), 467 (2,100). 1H NMR (300 MHz, DMSO-
d6): 2.10 (s, 3H, CH3), 2.14 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 5.63 (s, 1H, aryl H5),
12.35 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 9.71, 10.84 (CH3), 56.70
(OCH3), 107.09 (aryl CH), 117.89, 124.12, 127.41, 136.86, 160.19 (aryl C), 172.70,
184.98 (C=O). Mass Spectrum (+EI): m/z (%) 207 (M+2, 14), 306 (M+1, 100).
6-Methoxy-2,3-diphenylindole-4,7-dione (118)
According to the general procedure, treatment of 2,3-
diphenylindole-7-carbaldehyde 60 (1.10 g, 3.08 mmol) in
tetrahydrofuran/methanol (70 mL) with concentrated
hydrochloric acid (3 drops) and 30% hydrogen peroxide
solution (15 mL) afforded the indoloquinone 118 as a red
powder (0.58 g, 57%), m.p 325-326 oC (lit.104 m.p. 329 oC). 1H NMR (300 MHz,
DMSO-d6): 3.76 (s, 3H, OCH3), 5.74 (s, 1H, aryl H5), 7.17-7.25 (m, 10H, aryl H),
NH
O
MeOO
NH
O
MeOO
Me
Me
Experimental 149
13.07 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 56.84 (OCH3), 108.29,
127.47, 127.67, 128.16, 128.59, 128.97, 130.73 (aryl CH), 122.87, 126.35, 128.05,
129.81, 130.50, 133.36, 159.70 (aryl C), 171.25, 183.28 (C=O).
6-Methoxy-2-methyl-3-phenylindole-4,7-dione (119)
According to the general procedure, treatment of 2-methyl-3-
phenylindole-7-carbaldehyde 115 (0.20 g, 0.67 mmol) in
tetrahydrofuran/methanol (20 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide
solution (5 mL) afforded the indoloquinone 119 as a red
powder (0.10 g, 59%), m.p. 314 oC (dec.). (Found: C, 71.13; H, 4.95; N, 5.33.
C16H13NO3 0.1H2O requires C, 71.42; H, 4.94; N, 5.21 %). HRMS (+ESI): C16H13NO3
[M+Na]+ requires 290.0787, found 290.0785. max (KBr): 3410, 3190, 1665, 1635,
1598, 1492, 1454, 1338, 1253, 1117, 1033, 846, 703 cm-1. max (MeOH): 204 nm (
25,800 cm-1M-1), 225 (26,400), 285 (12,900), 364 (3,900), 471 (2,600). 1H NMR (300
MHz, DMSO-d6): 2.18 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 5.66 (s, 1H, aryl H5),
7.34-7.35 (m, 5H, aryl H), 12.71 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
11.90 (CH3), 56.74 (OCH3), 108.00, 127.20, 128.02, 130.22 (aryl CH), 122.52,
122.69, 128.52, 133.13, 136.66, 159.46 (aryl C), 170.70, 183.48 (C=O). Mass
Spectrum (+EI): m/z (%) 268 (M+1, 100), 267 (M, 18), 225 (37).
6-Methoxy-3-methylindole-4,7-dione (120)
According to the general procedure, treatment of 3-methylindole-
7-carbaldehyde 116 (1 g, 4.55 mmol) in tetrahydrofuran/methanol
(40 mL) with concentrated hydrochloric acid (3 drops) and 30%
hydrogen peroxide solution (10 mL) afforded the indoloquinone
120 as a dark brown powder (0.41 g, 47%), m.p. 180-182 oC. (lit.101 174-176 oC).
(Found: C, 62.75; H, 5.22; N, 6.90. C11H11NO3 0.2C2H5OH requires C, 62.33; H, 5.13;
N, 6.99 %). HRMS (+ESI): C10H9NO3 [M+Na]+ requires 214.0474, found 214.0475.
max (KBr): 3421, 2936, 1661, 1637, 1597, 1455, 1383, 1334, 1212, 1114, 1002, 791
cm-1. max (MeOH): 206 nm ( 11,600 cm-1M-1), 228 (14,200), 282 (7,600), 356
(2,700), 481 (1,300). 1H NMR (300 MHz, DMSO-d6): 2.07 (s, 3H, CH3), 3.71 (s,
NH
O
MeOO
Me
NH
O
MeOO
Me
Experimental 150
3H, OCH3), 5.67 (s, 1H, aryl H5), 6.34 (s, 1H, aryl H2), 12.23 (br s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6): 11.84 (CH3), 56.40 (OCH3), 106.42, 110.17 (aryl CH),
122.95, 125.61, 132.11, 160.32 (aryl C), 172.70, 184.91 (C=O). Mass Spectrum (+EI):
m/z (%) 192 (M+1, 100).
3-(4'-Bromophenyl)-6-methoxy-indole-4,7-dione (124)
According to the general procedure, treatment of 3-(4'-
bromophenyl)indole-7-carbaldehyde 57 (0.50 g, 1.38 mmol) in
tetrahydrofuran/methanol (50 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide solution
(5 mL) afforded the indoloquinone 124 as an orange powder
(0.25 g, 53%), m.p. 326 oC (dec.). (Found: C, 54.16; H, 3.21; N,
3.96. C15H10BrNO3 requires C, 54.24; H, 3.03; N, 4.22 %). max (KBr): 3341, 3124,
1665, 1628, 1605, 1540, 1481, 1454, 1374, 1335, 1310, 1258, 1087, 1023, 1010, 852,
798 cm-1. max (MeOH): 204 nm ( 36,700 cm-1M-1), 226 (29,300), 252 (19,800), 282
(17,600), 356 (5,100), 458 (3,100). 1H NMR (300 MHz, DMSO-d6): 3.75 (s, 3H,
OCH3), 5.80 (s, 1H, aryl H5), 7.51 (s, 1H, aryl H2), 7.54-7.71 (m, 4H, aryl H), 13.01
(br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 56.85 (OCH3), 108.92, 127.17,
130.76, 131.19 (aryl CH), 121.07, 124.65, 131.35, 131.39, 132.41, 159.26 (aryl C),
171.66, 183.50 (C=O). Mass Spectrum (+EI): m/z (%) 334 (M+2, 81Br, 65), 333 (M+1, 81Br, 20), 332 (M+2,79Br, 100), 331 (M+1,79Br, 68).
3-(4'-Cholrophenyl)-6-methoxy-indole-4,7-dione (125)
According to the general procedure, treatment of 3-(4'-
chlorophenyl)indole-7-carbaldehyde 58 (0.30 g, 0.95 mmol) in
tetrahydrofuran/methanol (30 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide solution
(6 mL) afforded the indoloquinone 125 as a brick red powder
(0.14 g, 52%), m.p. 320 oC (dec.). (Found: C, 61.64; H, 3.65; N,
4.64. C15H10ClNO3 0.3H2O requires C, 61.47; H, 3.65; N, 4.78 %). HRMS (+ESI):
C15H10ClNO3 [M+Na]+ requires 310.0241, found 310.0237. max (KBr): 3392, 3134,
1663, 1624, 1602, 1547, 1401, 1331, 1254, 1090, 1025, 848, 801 cm-1. max (MeOH):
NH
O
MeOO
Br
NH
O
MeOO
Cl
Experimental 151
203 nm ( 21,600 cm-1M-1), 228 (65,400), 252 (10,800), 283 (11,100), 365 (2,700),
457 (2,000). 1H NMR (300 MHz, DMSO-d6): 3.75 (s, 3H, OCH3), 5.80 (s, 1H, aryl
H5), 7.54 (s, 1H, aryl H2), 7.39 (d, J = 8.6 Hz, 2H, aryl H), 7.76 (d, J = 8.6 Hz, 2H,
aryl H), 13.01 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 56.85 (OCH3),
108.89, 127.98, 128.26, 130.43 (aryl CH), 121.08, 124.63, 131.30, 132.00, 132.11
159.25 (aryl C), 171.66, 183.52 (C=O). Mass Spectrum (-EI): m/z (%) 289 (M, 37Cl,
4), 288 (M-1, 37Cl, 30), 287 (M, 35Cl, 32), 286 (M-1, 35Cl, 71), 245 (37Cl, 30), 243
(35Cl, 100).
3-(4'-Methoxyphenyl)-6-methoxy-indole-4,7-dione (126)
According to the general procedure, treatment of 3-(4'-
methoxyphenyl)indole-7-carbaldehyde 121 (20 mg, 0.06
mmol) in tetrahydrofuran/methanol (5 mL) with concentrated
hydrochloric acid (1 drop) and 30% hydrogen peroxide
solution (1 mL) afforded the indoloquinone 126 as a light
strawberry powder (10 mg, 59%), m.p. 320 oC (dec). (Found:
C, 64.58; H, 4.80; N, 4.72. C16H13NO4 0.8H2O requires C, 64.55; H, 4.94; N, 4.71 %).
HRMS (+ESI): C16H13NO4 [M+Na]+ requires 306.0736, found 306.0725. max (KBr):
3419, 3124, 1665, 1634, 1602, 1547, 1489, 1403, 1336, 1254, 1090, 1021, 798 cm-1.
max (MeOH): 205 nm ( 36,400 cm-1M-1), 228 (30,100), 261 (15,500), 283 (18,600),
384 (3,100), 479 (4,500). 1H NMR (300 MHz, DMSO-d6): 3.75 (s, 3H, OCH3), 5.78
(s, 1H, aryl H5), 7.44 (s, 1H, aryl H2), 6.90 (d, J = 8.6 Hz, 2H, aryl H), 7.69 (d, J =
8.6 Hz, 2H, aryl H), 12.91 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 55.47,
56.79 (OCH3), 108.97, 113.74, 126.57, 129.95 (aryl CH), 120.88, 125.47, 126.07,
131.02, 158.98, 159.26 (aryl C) 171.49, 183.51 (C=O). Mass Spectrum (+EI): m/z (%)
285 (M+2, 28), 284 (M+1, 100), 256 (12).
3-(4'-Tert-Butylphenyl)-6-methoxy-indole-4,7-dione (127)
According to the general procedure, treatment of 3-(4'-tert-
butylphenyl)indole-7-carbaldehyde 122 (0.20 g, 0.59 mmol) in
tetrahydrofuran/methanol (20 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide
NH
O
MeOO
OMe
NH
O
MeOO
Experimental 152
solution (5 mL) afforded the indoloquinone 127 as a red powder (0.09 g, 50%), m.p.
120 oC. HRMS (+ESI): C19H19NO3 [M+Na]+ requires 332.1257, found 332.1262. max
(KBr): 3257, 2960, 2868, 1662, 1604, 1462, 1393, 1363, 1269, 1079, 841 cm-1. max
(MeOH): 204 nm ( 25,900 cm-1M-1), 227 (20,500), 284 (7,100), 359 (3,400). 1H
NMR (300 MHz, DMSO-d6): 1.28 (s, 9H, CH3), 3.75 (s, 3H, OCH3), 5.79 (s, 1H,
aryl H5), 7.56 (s, 1H, aryl H2), 7.34-7.65 (m, 4H, aryl H), 12.89 (br s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6): 31.46 (CH3), 34.62 (aliphatic C), 56.79 (OCH3),
108.90, 125.07, 128.45, 128.53 (aryl CH), 126.10, 126.87, 130.19, 131.08, 150.07,
159.27 (aryl C), 171.26, 183.51 (C=O). Mass Spectrum (+EI): m/z (%) 310 (M+1, 40),
308 (M-1, 34), 292 (66), 270 (66), 268 (54), 254 (100).
3-(4'-Phenylphenyl)-6-methoxy-indole-4,7-dione (128)
According to the general procedure, treatment of 3-(4'-
phenylphenyl)indole-7-carbaldehyde 123 (0.30 g, 0.84 mmol)
in tetrahydrofuran/methanol (30 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide
solution (5 mL) afforded the indoloquinone 128 as a brown
powder (0.18 g, 65%), m.p. 304 oC. (Found: C, 74.34; H, 4.98;
N, 3.90. C21H15NO3 0.6 CH3OH requires C, 74.43; H, 5.03; N,
4.02 %). HRMS (+ESI): C21H15NO3 [M+Na]+ requires 352.0944, found 352.0942.
max (KBr): 3413, 3130, 1664, 1631, 1605, 1482, 1337, 1311, 1255, 1091, 766 cm-1.
max (MeOH): 204 nm ( 25,300 cm-1M-1), 262 (12,900). 1H NMR (300 MHz, DMSO-
d6): 3.77 (s, 3H, OCH3), 5.83 (s, 1H, aryl H5), 7.58 (s, 1H, aryl H2), 7.32-7.86 (m,
9H, aryl H), 13.02 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 56.84 (OCH3),
109.01, 126.54, 126.87, 127.17, 127.78, 129.24, 129.32 (aryl CH), 125.62, 131.34,
132.33, 139.24, 140.19, 159.27 (aryl C), 172.80, 183.53 (C=O). Mass Spectrum (+EI):
m/z (%) 331 (M+2, 22), 330 (M+1, 100).
2-Methoxy-5,6,7,8-tetrahydrocarbazole-1,4-dione (131)
According to the general procedure, treatment of
indolecarbaldehyde 130 (1.50 g, 5.79 mmol) in
tetrahydrofuran/methanol (70 mL) with concentrated
NH
O
MeOO
NH
O
MeOO
Experimental 153
hydrochloric acid (3 drops) and 30% hydrogen peroxide solution (30 mL) afforded the
indoloquinone 131 as a dark brown powder (0.57 g, 50%), m.p. 179-180 oC. HRMS
(+ESI): C13H13NO3 [M+Na]+ requires 254.0787, found 254.0788. max (KBr): 3411,
3205, 2935, 2842, 1661, 1628, 1594, 1456, 1313, 1235, 1151, 1111, 1037 cm-1. max
(MeOH): 209 nm ( 16,300 cm-1M-1), 227 (17,400), 283 (9,400), 330 (3,000), 469
(1,100). 1H NMR (300 MHz, CDCl3): 1.74-1.79 (m, 4H, CH2), 2.61 (t, J = 5.84, 2H,
CH2), 2.74 (t, J = 5.84, 2H, CH2), 3.79 (s, 3H, OCH3), 5.62 (s, 1H, aryl H5), 9.24 (br
s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 22.17, 22.44, 22.84 (CH2), 56.35
(OCH3), 106.88 (aryl CH), 121.37, 123.93, 127.67, 138.46, 159.97 (aryl C), 170.38,
184.62 (C=O). Mass Spectrum (+EI): m/z (%) 232 (M+1, 77), 231 (M, 18), 230 (M-1,
100).
Bis[3-(4'-bromophenyl)-6-methoxy-4,7-dione-indol-2-yl]methane (133)
According to the general procedure, treatment
of 2,2'-bisindolyl-7,7'-dicarbaldehyde 132 (25
mg, 0.034 mmol) in tetrahydrofuran/methanol
(10 mL) with concentrated hydrochloric acid
(1 drop) and 30% hydrogen peroxide solution
(2 mL) for 4 h afforded the bisindolyl-4,7-
quinone 133 as an orange powder (13 mg, 57%), m.p. 280 -281 oC (dec). HRMS
(+ESI): C31H20Br2N2O6 [M+Na]+ requires 698.9573, found 698.9554. max (KBr):
3412, 2940, 2847, 1665, 1637, 1593, 1562, 1452, 1394, 1241, 1216, 1119, 991, 817
cm-1. max (MeOH): 202 nm ( 33,000 cm-1M-1), 228 (26,800), 361 (4,900). 1H NMR
(300 MHz, DMSO-d6): 3.73 (s, 6H, OCH3), 3.93 (s, 2H, CH2), 5.67 (s, 2H, aryl H5),
7.26-7.33 (m, 8H, aryl H), 12.66 (br s, 2H, NH). Mass Spectrum (+EI): m/z (%) 678
(M, 81Br, 15%), 676 (M, 79Br, 18), 589 (23), 579 (15), 578 (30), 574 (16), 374 (81Br,
100), 372 (79Br, 89), 346 (20), 344 (16), 293 (30).
4,6-Dimethoxy-2-phenylbenzimidazole (142)
The nitrobenzamide 156 (0.10 g, 0.33 mmol) was
dissolved in absolute ethanol (25 mL), stannous chloride
dihydrate ( 0.38 g, 0.84 mmol) and 5 M hydrochloric acid
NHMeO
O
NH OMe
O
O O
BrBr
NH
N
OMe
MeO
Experimental 154
(3 mL) was added and the mixture refluxed overnight. The reaction mixture was
allowed to cool to room temperature, water was added and the solution was basified
with 2 M sodium hydroxide solution. The mixture was extracted with ethyl acetate,
washed with water, brine and dried over magnesium sulfate. The residue was purified
by column chromatography on silica gel using dichloromethane/ethyl acetate (9:1) as
eluent, to afford the benzimidazole 142 as an off white solid (15 mg, 18%), m.p. 190-
191 °C (lit.117 188-190 °C). (Found: C, 70.92; H, 5.50; N, 10.97. C15H14N2O2 requires
C, 70.85; H, 5.55; N, 11.02 %). HRMS (+ESI): C15H14N2O2 [M+H]+ requires
255.1128, found 255.1127. max (KBr): 3200, 1628, 1604, 1508, 1454, 1363, 1223,
1202, 1153, 1047, 814, 690 cm-1. max (MeOH): 207 nm ( 35,800 cm-1M-1), 253,
16,800), 305 (19,000). 1H NMR (300 MHz, CDCl3): 3.77 (s, 3H, OCH3), 3.87 (s,
3H, OCH3), 6.35 (d, = 1.89, 1H, aryl H5), 6.67 (d, = 1.89, 1H, aryl H7), 7.37-7.41
(m, 3H, aryl H), 8.04-8.06 (m, 2H, aryl H), 10.31 (br s, 1H, NH). 13C NMR (75 MHz,
CDCl3): 55.48, 55.68 (OCH3), 89.14, 94.83, 126.33, 128.79, 129.40 (aryl CH),
124.61, 129.71, 139.24, 149.17, 149.85, 157.70 (aryl C). Mass Spectrum (+EI): m/z
(%) 256 (18%), 255 (M+1, 100%).
N-(3,5-Dimethoxy-phenyl)-4'-methoxybenzamide (154)
Anisoyl chloride (18 mL, 130.7 mmol) was
added dropwise to an ice cooled solution of 3,5-
dimethoxyaniline 39 (10 g, 65.35 mmol) in dry
dichloromethane (150 mL) containing
anhydrous potassium carbonate (5 g). The reaction was mixture stirred in an ice bath
for 2 h. Water was added to the reaction mixture and the organic phase was separated
and washed with water, brine and dried over magnesium sulfate. The solvent was
evaporated off and the benzamide 154 crystallized out from ethanol/water as colorless
needles (12.87 g, 69%), m.p. 110-112 °C. (Found: C, 66.70; H, 6.03; N, 4.78.
C16H17NO4 requires C, 66.89; H, 5.96; N, 4.88 %). max (KBr): 3313, 1686, 1642,
1600, 1536, 1508, 1456, 1429, 1314, 1289, 1258, 1201, 1177, 1106, 1065, 1028, 846,
763 cm-1. max (MeOH): 206 nm ( 47,200 cm-1M-1), 274 (20,800). 1H NMR (300
MHz, CDCl3): 3.77 (s, 6H, OCH3), 3.84 (s, 3H, OCH3), 6.25 (t, = 1.89 Hz, 1H,
aryl H4), 6.89 (d, = 1.99 Hz, 2H, aryl H2,6), 6.91-6.94 (m, 2H, aryl H), 7.79-7.83
(m, 2H, aryl H), 7.79 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55. 29, 55.34
MeO
OMe
NHCO OMe
Experimental 155
(OCH3), 96.83, 98.28, 113.87, 128.78 (aryl CH), 113.87, 127.02, 139.86 162.43,
165.21 (aryl C), 161.00 (C=O). Mass Spectrum (+EI): m/z (%) 289 (M+2, 20%), 288
(M+1, 100), 286 (7), 154(7).
N-(3,5-Dimethoxy-2-nitrophenyl)-4'-methoxybenzamide (157)
A previously cooled nitric acid (0.50 mL) in
acetic anhydride (10 mL) was added dropwise
over half an hour to an ice/salt cooled (-5 °C)
solution of benzamide 154 (1 g, 3.48 mmol) in
acetic anhydride (25 mL) with continuous stirring at such a rate that the temperature
stayed between 0-5°C. The solution was stirred for another half an hour before ice
water was added and the mixture stirred for another 24 h. The resulting precipitate was
filtered, washed with water and recrystallized from ethanol/water to yield the
nitrobenzamide 157 as yellow crystals (0.97 g, 83%), m.p. 180-182 °C. (Found: C,
57.75; H, 5.00; N, 8.38. C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43 %). max
(KBr): 3379, 1688, 1613, 1557, 1491, 1454, 1311, 1285, 1262, 1180, 1123, 1030, 838
cm-1. max (MeOH): 205 nm ( 35,800 cm-1M-1), 263 (20,300). 1H NMR (300 MHz,
CDCl3): 3.87 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6.28 (d, =
2.26 Hz, 1H, aryl H4), 6.96-6.99 (m, 2H, aryl H), 7.85-7.88 (m, 2H, aryl H), 7.97 (d,
= 2.64 Hz, 1H, aryl H6), 10.26 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.41,
55.86, 56.57 (OCH3), 95.58, 97.12, 114.12, 129.14 (aryl CH), 124.99, 126.01, 136.27,
155.82, 163.02, 163.76 (aryl C), 165.07 (C=O). Mass Spectrum (+EI): m/z (%) 333
(M+1, 21), 288 (M-NO2, 20), 286 (7), 200 (10), 199 (100), 183 (6), 153 (23).
N-(2-Amino-3,5-dimethoxyphenyl)acetamide (158)
To a refluxing solution of nitroacetamide 155 (1 g, 4.1
mmol) in absolute ethanol (50 mL), 10% Pd/C (0.10 g) was
added under argon followed by hydrazine monohydrate (2
mL) dropwise over 15 min, and reflux continued for another 2 h. The solution was
filtered and solvent was removed under reduced pressure. The residue was dissolved
in dichloromethane, washed with brine, and dried over magnesium sulfate. The
organic solvent was removed under reduced pressure to yield the aminoacetamide 158
as a brown solid (0.77 g, 90%), m.p. 86-88 °C. HRMS (+ESI): C10H14N2O3 [M+H]+
MeO
OMe
NHCOCH3
NH2
MeO
OMe
NHCO OMe
NO2
Experimental 156
requires 211.1077, found 211.1028. max (KBr): 3459, 3424, 3321, 3226, 1652, 1601,
1544, 1459, 1371, 1276, 1205, 1150, 1051, 800 cm-1. max (MeOH): 211 nm ( 52,400
cm-1M-1), 299 (7,700). 1H NMR (300 MHz, CDCl3): 2.07 (s, 3H, CH3), 3.67 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 3.83 (s, 2H, NH2), 6.28 (d, = 1.89, 1H, aryl H4), 6.57
(d, = 1.89, 1H, aryl H6), 8.02 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 23.55
(CH3), 55.51, 55.65 (OCH3), 96.66, 100.19 (aryl CH), 122.57, 126.15, 150.06, 153.16
(aryl C), 168.85 (C=O). Mass Spectrum (+EI): m/z (%) 211 (M+1, 20), 193 (100).
N-(2-Amino-3,5-dimethoxyphenyl)- 4'-methoxybenzamide (160)
This was prepared as described for the
aminoacetamide 158 from a refluxing solution of
nitrobenzamide 157 (1.40 g, 4.2 mmol) in
absolute ethanol (25 mL),10% Pd/C (0.14 g) and
hydrazine monohydrate (2 mL, 42 mmol, 10 eq.) under reflux for 1 h to yield the
aminobenzamide 160 as a white solid (1.24 g, 98%), m.p. 154-156 °C. (Found: C,
63.39; H, 6.17; N, 9.15. C16H18N2O4 requires C, 63.56; H, 6.00; N, 9.27 %). HRMS
(+ESI): C16H18N2O4 [M+Na]+ requires 325.1158, found 325.1150. max (KBr): 3406,
3287, 1639, 1606, 1532, 1510, 1495, 1464, 1296, 1254, 1202, 1187, 1157, 1058,
1029, 852 cm-1. max (MeOH): 207 nm ( 47,400 cm-1M-1), 255 (20,600), 305 (3,200). 1H NMR (300 MHz, CDCl3): 3.72 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.39 (s, 2H, NH2), 6.29 (d, = 1.88 Hz, 1H, aryl H4), 6.89 (d, = 1.88 Hz,
1H, aryl H6), 6.91 (d, = 8.66 Hz, 2H, aryl H), 7.83 (d, = 8.66 Hz, 2H, aryl H), 8.39
(br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.31, 55.53, 55.64 (OCH3), 96.31,
99.22, 113.76, 129.03 (aryl CH), 121.23, 126.60, 127.97, 150.78, 153.92, 162.35 (aryl
C), 164.97 (C=O). Mass Spectrum (+EI): m/z (%) 303 (M+1, 30), 286 (17), 285 (100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-benzimidazole (161)
To a solution of aminobenzamide 160 (1.24 g, 4.10
mmol) in absolute ethanol (50 mL) was added few
drops of 5 M hydrochloric acid to make the mixture
slightly acidic. The solution was then refluxed under argon for 8 h, cooled to room
temperature and then made basic using 2 M sodium hydroxide solution. The resulting
NH
N
OMe
MeOOMe
MeO
OMe
NHCO OMe
NH2
Experimental 157
precipitate was filtered, washed with water and recrystallized from ethanol/water to
yield the benzimidazole 161 as an off white solid (0.92 g, 80%), m.p. 202-204 °C.
(Found: C, 67.51; H, 5.74; N, 9.72. C16H16N2O3 requires C, 67.59; H, 5.67; N, 9.85
%). max (KBr): 3380, 1643, 1612, 1579, 1504, 1469, 1361, 1302, 1268, 1224, 1202,
1190, 1151, 1024, 837, 825 cm-1. max (MeOH): 208 nm ( 30,200 cm-1M-1), 256
(15,700), 307 (18,200). 1H NMR (300 MHz, CDCl3): 3.72 (s, 3H, OCH3), 3.78 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 6.32 (d, = 1.88 Hz, 1H, aryl H5), 6.58 (d, = 1.88
Hz, 1H, aryl H7), 6.86 (d, = 8.67 Hz, 2H, aryl H), 7.98 (d, = 8.67 Hz, 2H, aryl H),
10.28 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.20, 55.39, 55.63 (OCH3),
88.98, 94.29, 114.14, 127.88 (aryl CH), 122.48, 125.20, 139.26, 149.27, 150.34,
157.32, 160.70 (aryl C). Mass Spectrum (+EI): m/z (%) 286 (M+2, 21), 285 (M+1,
100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)benzimidazole-7-carbaldehyde (165)
Phosphoryl chloride (0.33 mL, 3.52 mmol, 2 eq.)
was added dropwise to an ice cooled anhydrous
N,N-dimethylformamide (2 mL), and this cooled
solution of Vilsmeier reagent was added dropwise
to a previously ice cooled stirred solution of benzimidazole 161 (0.5 g, 1.76 mmol) in
anhydrous N,N-dimethylformamide (3 mL) at 0°C. After the addition the reaction
mixture was allowed to come to room temperature, stirred for 2 h and was heated in an
oil bath at 70°C overnight. The reaction was quenched with ice water followed by
20% sodium hydroxide solution to make the mixture strongly basic, which was stirred
vigorously for 2 h. The resulting precipitate was filtered, thoroughly washed with
water and recrystallized from ethanol/water to afford the 7-formylbenzimidazole 165
as an off white solid (0.44 g, 80%), m.p. 205 °C. (Found: C, 65.20; H, 5.15; N, 8.80.
C17H16N2O4 requires C, 65.38; H, 5.16; N, 8.97 %). max (KBr): 3294, 1631, 1604,
1512, 1489, 1466, 1428, 1397, 1370, 1344, 1312, 1260, 1209, 1176, 1125, 1036, 986,
831, 795, 775 cm-1. max (MeOH): 208 nm ( 21,100 cm-1M-1), 296 (23,800), 347
(14,200). 1H NMR (300 MHz, CDCl3): 3.87 (s, 3H, OCH3), 4.01 (s, 3H, OCH3),
4.18 (s, 3H, OCH3), 6.33 (s, 1H, aryl H5), 7.02 (d, J = 8.64 Hz, 2H, aryl H), 8.13 (d, J
= 8.64 Hz, 2H, aryl H), 10.31 (s, 1H, CHO), 11.04 (br s, 1H, NH). 13C NMR (75
NH
N
OMe
MeOOMe
OH
Experimental 158
MHz, CDCl3): 55.29, 56.37, 56.51 (OCH3), 89.34, 114.26, 127.94 (aryl CH),
104.65, 121.76, 128.51, 136.01, 150.76, 157.49, 161.14, 161.98 (aryl C), 187.82
(C=O). Mass Spectrum (+EI): m/z (%) 314 (M+2, 19), 313 (M+1, 100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-7-hydroxymethylbenzimidazole (167)
To a solution of 7-formylbenzimidazole 165 (0.20
g, 0.64 mmol) in anhydrous methanol (20 mL)
sodium borohydride (0.2 g) was added portionwise
and the mixture was refluxed for 2 h. The solvent
was concentrated and cooled before ice water was added The resulting precipitate was
filtered, washed with water and dried to yield the 7-hydroxymethylbenzimidazole 167
as a white solid (0.187 g, 93%), m.p. 116-118 °C. (Found: C, 64.33; H, 5.87; N; 8.69.
C17H18N2O4 requires C, 64.96; H, 5.77; N, 8.91 %). max (KBr): 3136, 1612, 1579,
1520, 1489, 1436, 1342, 1309, 1292, 1249, 1211, 1179, 1154, 1128, 1031, 1007, 840,
790, 736 cm-1. max (MeOH): 210 nm ( 35,300 cm-1M-1), 257 (24,200), 307 (23,100). 1H NMR (300 MHz, CDCl3): 3.73 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 5.02 (s, 2H, CH2), 5.76 (br s, 1H, OH), 6.21 (s, 1H, aryl H5), 6.75 (d, J = 8.64
Hz, 2H, aryl H), 7.86 (d, J = 8.64 Hz, 2H, aryl H), 11.04 (br s, 1H, NH). 13C NMR (75
MHz, CDCl3): 55.14, 55.57, 56.83 (OCH3), 56.74 (CH2), 90.69, 113.94, 127.88 (aryl
CH), 105.65, 121.88, 126.43, 137.04 148.94, 150.45, 153.43, 160.70 (aryl C). Mass
Spectrum (+EI): m/z (%) 316 (M+2, 15), 315 (M+1, 100).
Bis(4,6-dimethoxybenzimidazol-7-yl)methane (168)
To a warm (70°C) solution of benzimidazole 10 (0.20 g, mmol) in
glacial acetic acid (5 mL), formaldehyde solution (1 mL, 37%)
was added followed by concentrated hydrochloric acid ( 5 drops).
The mixture was heated at 100°C overnight and cooled to room
temperature before ice water and 20% sodium hydroxide solution
were added. The resulting precipitate was filtered, washed with water and
recrystallized from ethanol to afford the 7,7'-dibenzimidazolylmethane 168 as a white
solid (0.18 g, 87%), m.p. 118-120 °C. (Found: C, 61.32; H, 5.44; N, 14.77.
C19H20N4O4 0.2CH3OH requires C, 61.53; H, 5.59; N, 14.95 %). max (KBr): 3350,
NH
N
OMe
MeOOMe
OH
NH
N
OMe
MeO
HN
N
OMe
MeO
Experimental 159
2937, 2837, 1611, 1523, 1497, 1453, 1394, 1336, 1255, 1147, 1116, 991, 804 cm-1.
max (MeOH): 214 nm ( 47,400 cm-1M-1), 262 (12,200), 285 (8,100). 1H NMR (300
MHz, DMSO-d6): 3.73 (s, 6H, OCH3), 3.90 (s, 6H, OCH3), 4.24 (s, 2H, CH2), 6.47
(s, 2H, aryl H5), 8.07 (s, 2H, aryl H2), 12.64 (br s, 2H, NH). 13C NMR (75 MHz,
DMSO-d6): 19.73 (CH2), 56.18, 57.53 (OCH3), 92.22, 142.93 (aryl CH), 102.10,
128.14, 139.67, 151.66, 156.32 (aryl C). Mass Spectrum (+EI): m/z (%) 370 (M+2,
21), 369 (M+1, 100).
Bis(4,6-dimethoxy-2-methylbenzimidazol-7-yl)methane (169)
This was prepared as described for the compound 168 from a
solution of benzimidazole 141 (0.10 g, mmol) in glacial
acetic acid (2 mL), formaldehyde solution (1 mL, 37%) and
concentrated hydrochloric acid (0.5 mL) under overnight heat
to afford the 7,7'-dibenzimidazolylmethane 169 as an off
white solid (51 mg, 50%), m.p. 150-152 °C. (Found: C,
60.31; H, 5.92; N, 13.10. C21H24N4O4 0.3CH2Cl2 requires C,
60.63; H, 5.88; N, 13.28 %). HRMS (+ESI): C21H24N4O4 [M+H]+ requires 397.1870,
found 397.1876. max (KBr): 3340, 2934, 2836, 1613, 1538, 1517, 1454, 1409, 1340,
1212, 1147, 1120 998 cm-1. max (MeOH): 213 nm ( 58,200 cm-1M-1), 259 (14,700). 1H NMR (300 MHz, DMSO-d6): 2.38 (s, 6H, CH3), 3.75 (s, 6H, OCH3), 3.87 (s, 6H,
OCH3), 4.11 (s, 2H, CH2), 6.42 (s, 2H, aryl H5), 12.23 (br s, 2H, NH). 13C NMR (75
MHz, DMSO-d6): 14.87 (CH3), 19.91 (CH2), 56.21, 57.56 (OCH3), 92.65 (aryl CH),
105.91, 127.00, 136.80, 148.21, 150.85, 153.05 (aryl C). Mass Spectrum (+EI): m/z
(%) 398 (M+2, 25), 397 (M+1, 100).
Bis(4,6-dimethoxy-2-phenylbenzimidazol-7-yl)methane (170)
This was prepared as described for the compound 168
from a solution of benzimidazole 142 (0.10 g, mmol) in
glacial acetic acid (5 mL), formaldehyde solution (1 mL,
37%) and concentrated hydrochloric acid (5 drops) under
overnight heat to afford the 7,7'-dibenzimidazolylmethane
170 as a white solid (0.09 g, 89%), m.p. 218-220 °C
NH
N
OMe
MeO
HN
N
OMe
MeO
Me
Me
NH
N
OMe
MeO
HN
N
OMe
MeO
Experimental 160
(lit.118 181-184 °C). (Found: C, 69.67; H, 5.51; N, 10.56. C31H28N4O4 0.7H2O requires
C, 69.83; H, 5.56; N, 10.51 %). HRMS (+ESI): C31H28N4O4 [M+H]+ requires
521.2183, found 521.2194. max (KBr): 3427, 2936, 2838, 1617, 1455, 1399, 1345,
1301, 1210, 1140, 1051, 998, 694 cm-1. max (MeOH): 206 nm ( 83,100 cm-1M-1),
252 (49,200), 303 (41,800). 1H NMR (300 MHz, DMSO-d6): 3.82 (s, 6H, OCH3),
3.89 (s, 6H, OCH3), 4.36 (s, 2H, CH2), 6.54 (s, 2H, aryl H5), 7.64-7.66 (m, 6H, aryl
H), 8.32-8.35 (m, 4H, aryl H), 12.24 (br s, 2H, NH). 13C NMR (75 MHz, DMSO-d6):
19.31 (CH2), 55.06, 57.60 (OCH3), 110.38, 125.81, 126.95, 128.71 (aryl CH),
128.90, 129.41, 129.93, 132.63, 138.71, 151.37, 159.77 (aryl C). Mass Spectrum (-
EI): m/z (%) 520 (M, 41), 519 (M-1, 100), 253 (50).
Bis[4,6-dimethoxy-2-(4'-methoxyphenyl)benzimidazol-7-yl]methane (171)
Method A: This was prepared as described for the
compound 168 from a solution of benzimidazole
161 (0.1 g, mmol) in glacial acetic acid (2 mL),
formaldehyde solution (1 mL, 37%) and
concentrated hydrochloric acid (0.5 mL) under
overnight heat to afford the 7,7'-
dibenzimidazolylmethane 171 as a white solid (0.08 g, 60%), m.p. 288-290 °C.
Method B: To a solution of 7-hydroxymethylbenzimidazole 167 (0.10 g, 0.32 mmol)
in dry tetrahydrofuran (5 mL), a few drops of glacial acetic acid were added and the
solution was heated at 100°C overnight. The mixture was cooled to room temperature,
ice water was added to quench the reaction followed by addition of 10% sodium
bicarbonate solution to neutralize the solution. The resulting precipitate was filtered,
washed with water, recrystallized from ethanol and dried to give the 7,7'-
dibenzimidazolylmethane 171 as an off white powder (56 mg, 60%). (Found: C,
59.02; H, 5.01; N, 8.07. C33H32N4O6 1.4CH2Cl2 requires C, 59.06; H, 5.01; N, 8.01
%). HRMS (+ESI): C33H32N4O6 [M+H]+ requires 581.2394, found 581.2380. max
(KBr): 3406, 2935, 2840, 1636, 1611, 1534, 1507, 1462, 1304, 1265, 1220, 1193,
1130, 1023, 990, 838 cm-1. max (MeOH): 208 nm ( 71,800 cm-1M-1), 259 (47,400),
306 (19,100). 1H NMR (300 MHz, DMSO-d6): 3.60 (s, 6H, OCH3), 3.88 (s, 6H,
OCH3), 3.98 (s, 6H, OCH3), 4.51 (s, 2H, CH2), 6.73 (s, 2H, aryl H5), 7.21 (d, J = 6.12
NH
N
OMe
MeO
HN
N
OMe
MeO
OMe
OMe
Experimental 161
Hz, 4H, aryl H), 8.30 (d, J = 6.12 Hz, 4H, aryl H), 14.40 (br s, 2H, NH). 13C NMR (75
MHz, DMSO-d6): 26.98 (CH2), 56.23, 56.68, 57.19 (OCH3), 99.16, 116.42, 127.24
(aryl CH), 102.97, 122.79, 130.67, 143.82, 145.94, 149.33, 154.63, 163.26 (aryl C).
Mass Spectrum (+EI): m/z (%) 582 (M+2, 40), 581 (M+1, 100), 313 (23), 285 (28).
4,6-Dimethoxy-2-phenyl-7-acetylbenzimidazole (172)
To an ice cooled solution of benzimidazole 142 (0.5 g, 1.9
mmol) and acetyl chloride (0.6 mL, 7.6 mmol) in dry
dichloromethane (20 mL), antimony pentachloride (1 mL,
7.6 mmol) was added dropwise under argon and the
mixture stirred for 2 h at room temperature. The resulting precipitate was filtered,
washed with water, dried and purified by column chromatography using
dichloromethane/methanol (95:5) as eluent to yield the 7-acetylbenzimidazole 172 as
a yellow powder (0.39 g, 70%). m.p. 151-153°C. (lit.119 148-150°C). (Found: C,
68.39; H, 5.37; N, 9.31. C17H16 N2O3, requires C, 68.91; H, 5.44; N, 9.45 %). max
(KBr): 3346, 1635, 1566, 1474, 1423, 1382, 1362, 1349, 1284, 1249, 1221, 1179,
1103, 981, 702 cm-1. max (MeOH): 208 nm ( 19,600 cm-1M-1), 241 (13,500), 289
(16,511), 330 (14,100). 1H NMR (300 MHz, CDCl3): 2.68 (s, 3H, CH3C=O), 4.02
(s, 3H, OCH3), 4.15 (s, 3H, OCH3), 6.36 (s, 1H, aryl H5), 7.43-7.51 (m, 3H, aryl H),
8.07-8.10 (m, 2H, aryl H), 11.57 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 32.57
(CH3CO), 56.47, 56.54 (OCH3), 90.92, 127.17, 129.16, 131.25 (aryl CH), 104.68,
126.40, 136.07, 149.61, 155.30, 161.08, 188.75 (aryl C), 198.07 (C=O). Mass
Spectrum (+EI): m/z (%) 298 (M+2, 22), 297 (M+1, 100).
4,6-Dimethoxy-2-methyl-7-acetylbenzimidazole (173)
This was prepared as described for the compound 172 from an
ice cooled solution of benzimidazole 141 (1 g, 5.2 mmol),
acetyl chloride (1.5 mL, 20.8 mmol) and antimony
pentachloride (2.5 mL, 20.8 mmol) in anhydrous chloroform
(20 mL) and stirring under argon for 2 h at room temperature. The resulting precipitate
was filtered, washed with water and recrystallized from ethanol to yield the title 7-
acetylbenzimidazole 173 as a yellow powder (1.15 g, 95%), m.p. 184-185 °C. HRMS
NH
N
OMe
MeOMe
Me O
NH
N
OMe
MeO
Me O
Experimental 162
(+ESI): C12H14N2O3 [M+Na]+ requires 257.0896, found 257.0897. max (KBr): 3345,
1637, 1562, 1471, 1424, 1273, 1224, 1208, 1177, 1017, 980 cm-1. max (MeOH): 206
nm ( 6,900 cm-1M-1), 230 (5,800), 291 (5,100). 1H NMR (300 MHz, Acetone-d6):
2.63 (s, 3H, CH3), 3.01 (s, 3H, CH3C=O), 4.17 (s, 3H, OCH3), 4.21 (s, 3H, OCH3),
7.05 (s, 1H, aryl H5), 13.37 (br s, 1H, NH). 13C NMR (75 MHz, Acetone-d6): 11.61
(CH3), 31.83 (CH3C=O), 56.64, 56.82 (OCH3), 93.75 (aryl CH), 105.54, 116.03,
129.87, 151.59, 161.42, 161.96 (aryl C), 196.29 (C=O). Mass Spectrum (+EI): m/z
(%) 235 (M+2, 18), 235 (M+1, 100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-7-acetylbenzimidazole (174)
This was prepared as described for the compound
172 from an ice cooled solution of benzimidazole
161 (0.25 g, 0.88 mmol), acetyl chloride (0.25 mL,
3.52 mmol) and antimony pentachloride (0.45 mL,
3.52 mmol) in anhydrous chloroform (10 mL) stirring under argon for 2 h. Column
chromatography using dichloromethane/methanol (98:02) as eluent afforded the 7-
acetylbenzimidazole 174 as a light brown powder (0.18 g, 61%), m.p. 126-128 °C.
HRMS (+ESI): C18H18N2O4 [M+Na]+ requires 349.1158, found 349.1167. max (KBr):
3403, 1625, 1592, 1468, 1429, 1384, 1345, 1288, 1253, 1214, 1177, 1147, 1029, 995,
847 cm-1. max (MeOH): 208 nm ( 15,800 cm-1M-1), 292 (16,200), 339 (12,300). 1H
NMR (300 MHz, Acetone-d6): 2.59 (s, 3H, CH3C=O), 3.87 (s, 3H, OCH3), 4.05 (s,
3H, OCH3), 4.18(s, 3H, OCH3), 6.58 (s, 1H, aryl H5), 7.07 (d, J = 8.37 Hz, 2H, aryl
H), 8.14 (d, J = 9.03 Hz, 2H, aryl H). 13C NMR (75 MHz, Acetone-d6): 31.73
(COCH3), 54.79, 56.03, 56.25 (OCH3), 91.10, 114.92, 127.97 (aryl CH), 104.92,
122.19, 137.58, 150.00, 155.91, 160.05, 161.11 (aryl C), 196.47 (C=O). Mass
Spectrum (+EI): m/z (%) 328 (M+2, 18), 327 (M+1, 100).
4,6-Dimethoxy-2-phenyl-7-trifluoroacetylbenzimidazole (175)
To a solution of benzimidazole 142 (0.50 g, 1.96 mmol)
in tetrahydrofuran (20 mL), trifluoroacetic anhydride (2.8
mL) was added and the mixture refluxed for 7 days. The
solution was allowed to cool to room temperature and ice
NH
N
OMe
MeO
F3C O
N
NH
OMe
MeOOMe
OMe
Experimental 163
water was added. The product was extracted with ethyl acetate, washed with water,
dried over magnesium sulfate and recrystallized from ethyl acetate to afford 7-
trifluoroacetylbenzimidazole 175 as yellow needles (0.55 g, 80%), m.p. 200-202 °C.
(Found: C, 58.27 ; H, 3.91; N, 7.95. C17H13F3N2O3 requires C, 58.29; H, 3.74; N, 8.00
%). max (KBr): 3436, 3058, 1636, 1597, 1470, 1453, 1383, 1355, 1326, 1264, 1239,
1225, 1203, 1155, 1068, 990, 956, 849, 802, 777, 765, 740, 693 cm-1. max (MeOH):
207 nm ( 25,600 cm-1M-1), 245 (13,200), 306 (17,600), 358 (7,200). 1H NMR (300
MHz, CDCl3): 4.00 (s, 3H, OCH3), 4.21 (s, 3H, OCH3), 6.31 (s, 1H, aryl H5), 7.45-
7.51 (m, 3H, aryl H), 8.03-8.06 (m, 2H, aryl H), 11.16 (br s, 1H, NH). 13C NMR (75
MHz, CDCl3): 56.62, 56.82 (OCH3), 100.08 (CF3), 90.33, 126.29, 128.91, 130.17
(aryl CH), 115.13, 118.93, 128.87, 129.02, 138.70, 150.52, 159.12 (aryl C), 161.52
(C=O). Mass Spectrum (+EI): m/z (%) 352 (M+2, 20), 351(M+1, 100), 256 (8),
255(M-COCF3).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-7-trifluoroacetylbenzimidazole (176)
Method A: To a solution of benzimidazole 161
(0.10 g, 0.35 mmol) in tetrahydrofuran (10 mL),
trifluoroacetic anhydride (1 mL) was added and the
mixture refluxed for 5 days. The solution was
allowed to cool to room temperature and ice water
was added. The resulting precipitate was collected, washed with water and
recrystallized from ethanol/water to afford the 7-trifluoroacetylbenzimidazole 176 as
yellow crystals (0.11 g, 83%).
Method B: To a solution of potassium hydroxide (2.50 g) in methanol (25 mL),
benzimidazole 178 (1 g, 2.10 mmol) was added and the mixture stirred at room
temperature for overnight. The solvent was concentrated and water added to give a
precipitate, which was collected, washed with water and recrystallized from
ethanol/water to give the title 7-trifluoroacetylbenzimidazole 176 as yellow needles
(0.62 g, 78 %), m.p. 168-170 °C. (Found: C, 57.01; H, 4.02; N, 7.32. C18H15F3N2O4
requires C, 56.85; H, 3.98; N, 7.37 %). max (KBr): 3426, 1620, 1594, 1495, 1471,
1432, 1373, 1328, 1260, 1216, 1158, 933 cm-1. max (MeOH): 207 nm ( 30,500 cm-
1M-1), 302 (21,200), 365 (7,600). 1H NMR (300 MHz, CDCl3): 3.87 (s, 3H, OCH3),
NH
N
OMe
MeO
F3C O
OMe
Experimental 164
4.00 (s, 3H, OCH3), 4.21 (s, 3H, OCH3), 6.31 (s, 1H, aryl H5), 7.01 (d, J = 8.67 Hz,
2H, aryl H), 8.01 (d, J = 8.67 Hz, 2H, aryl H), 11.09 (br s, 1H, NH). 13C NMR (75
MHz, CDCl3): 55.35, 56.66, 56.75 (OCH3), 90.23, 114.42, 128.05 (aryl CH), 100.04
(CF3), 117.69, 118.06, 121.02, 127.95, 138.43, 150.58, 158.66, 161.35 (aryl C),
161.47 (C=O). Mass Spectrum (+EI): m/z (%) 382 (M+2, 18), 381 (M+1, 100), 285
(35).
4,6-Dimethoxy-2-phenyl-1,7-ditrifluoroacetyl-benzimidazole (177)
To a solution of benzimidazole 142 (0.50 g, 1.96 mmol)
in tetrahydrofuran (20 mL), trifluoroacetic anhydride (2.8
mL) was added and the mixture refluxed for 10 days. The
solvent was concentrated and water added to give a
precipitate, which was collected, washed with water and recrystallized from
ethanol/water to give the title 1,7-ditrifluoroacetylbenzimidazole 177 as a white coarse
powder (0.61 g, 70 %), m.p. >350 °C. max (KBr): 3416, 2925, 1638, 1618, 1505,
1463, 1361, 1303, 1269, 1225, 1190, 1157, 1026 cm-1. max (MeOH): 213 nm ( 1,000
cm-1M-1), 247 (900). 1H NMR (300 MHz, CDCl3) 4.07 (s, 3H, OCH3), 4.20 (s, 3H,
OCH3), 6.42 (s, 1H, aryl H5), 7.47-7.52 (m, 3H, aryl H), 8.12-8.14 (m, 2H, aryl H).
Mass Spectrum (+EI): m/z (%) 448 (M+2, 70), 447 (M+1,100), 445(14), 350(17),
289(12).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-1,7-ditrifluoroacetyl-benzimidazole (178)
To a solution of benzimidazole 161 (1 g, 3.52
mmol) in tetrahydrofuran (50 mL), trifluoroacetic
anhydride (5 mL) was added and the mixture
refluxed for 10 days. The solution was allowed to
cool to room temperature and ice water was added.
The resulting precipitate was collected, washed with water and recrystallized from
ethanol/water to afford the 1,7-ditrifluoroacetylbenzimidazole 178 as an off white
powder (1.29 g, 77 %), m.p. 238-240 °C. (Found: C, 48.73; H, 3.32; N, 5.62.
C20H14F6N2O5 1.0H2O requires C, 48.59; H, 3.26; N, 5.67 %). max (KBr): 1689, 1611,
1578, 1509, 1471, 1427, 1352, 1309, 1268, 1186, 1162, 1071, 1017, 841, 714 cm-1.
N
N
OMe
MeO
F3C OO
F3C
OMe
N
N
OMe
MeO
F3C OO
F3C
Experimental 165
max (MeOH): 208 nm ( 37,200 cm-1M-1), 306 (28,900), 358 (9,500). 1H NMR (300
MHz, CDCl3): 3.91 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 4.20 (s, 3H, OCH3), 6.45 (s,
1H, aryl H5), 7.12 (d, J = 7.92 Hz, 2H, aryl H), 8.31 (d, J = 7.92 Hz, 2H, aryl H). 13C
NMR (75 MHz, DMSO-d6): 55.74, 57.18, 57.59 (OCH3), 92.14, 114.49, 129.71
(aryl CH), 100.80 (CF3), 118.79, 120.36, 125.22, 137.61, 151.58, 156.35, 158.44,
158.93 (aryl C), 160.73, 161.64 (C=O). Mass Spectrum (+EI): m/z (%) 477 (M+1, 1),
381 (100), 285 (32).
4,6-Dimethoxy-2-phenylbenzimidazole-7-carboxylic acid (180)
A mixture of benzimidazole 175 (0.50 g, 1.42 mmol),
crushed potassium hydroxide (1.0 g) in ethanol/water
(3 :1) was heated under reflux for 4 h. The reaction was
allowed to come to room temperature and concentrated
hydrochloric acid was added to acidify the mixture, which was stirred for half an hour.
The insoluble materials was filtered off and the filtrate was neutralized with 10%
sodium bicarbonate solution. The resulting precipitate was filtered, washed with water
and dried to give the product 180 as a white solid (0.33 g, 77%), m.p. 221-222 °C.
(Found: C, 64.57 ; H, 4.86 ; N, 9.34. C16H14N2O4 requires C, 64.42; H, 4.73; N, 9.39
%). max (KBr): 3611, 3387, 3283, 1701, 1604, 1466, 1455, 1386, 1337, 1255, 1215,
1182, 1149, 990, 800, 699 cm-1. max (MeOH): 211 nm ( 27,600 cm-1M-1), 241
(20,200), 262 (15,100), 318 (21,900). 1H NMR (300 MHz, CDCl3): 4.15 (s, 3H,
OCH3), 4.18 (s, 3H, OCH3), 6.41 (s, 1H, aryl H5), 7.44-7.53 (m, 3H, aryl H), 8.09-
8.12 (m, 2H, aryl H), 11.12 (br s, 2H, NH+OH). 13C NMR (75 MHz, CDCl3): 56.75,
57.52 (OCH3), 90.01, 126.61, 128.91, 130.35 (aryl CH), 94.63, 101.35, 128.68,
137.84, 151.03, 155.90, 157.34 (aryl C), 165.94 (C=O). Mass Spectrum (+EI): m/z
(%) 299 (M+1, 96), 256 (19), 255 (100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)benzimidazole-7-carboxylic acid (181)
This was prepared according to the method
described for the compound 180 from
benzimidazole 176 (0.50 g, 1.31 mmol), crushed
potassium hydroxide (1.0 g) in ethanol/water (30
NH
N
OMe
MeO
OHO
NH
N
OMe
MeO
OHO
OMe
Experimental 166
mL, 3 :1) under reflux for 4 h to give the product 181 as a white solid (0.40 g, 93%),
m.p. 260-262 °C. (Found: C, 51.36; H, 4.51; N, 6.74. C17H16N2O5 1.1CH2Cl2 requires
C, 51.55; H, 4.35; N, 6.64 %). max (KBr): 3383, 1700, 1613, 1567, 1479, 1430, 1390,
1321, 1257, 1213, 1176, 1148, 1106, 992, 829 cm-1. max (MeOH): 211 nm ( 23,100
cm-1M-1), 260 (15,300), 318 (18,300). 1H NMR (300 MHz, DMSO-d6): 3.77 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6.27 (s, 1H, aryl H5), 6.90 (d, J =
9.06 Hz, 2H, aryl H), 7.96 (d, J = 9.06 Hz, 2H, aryl H), 13.31 ( br s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6): 55.58, 56.05, 57.99 (OCH3), 93.62, 114.48, 127.94
(aryl CH), 123.56, 128.71, 138.06, 149.27, 150.49, 155.27, 155.98, 160.32 (aryl C),
168.51 (C=O). Mass Spectrum (+EI): m/z (%) 330 (M+2, 23), 329 (M+1, 100).
Methyl-4,6-dimethoxy-1-methyl-2-phenylbenzimidazole-7-carboxylate (182)
To a solution of benzimidazole 180 (0.10 g, 0.33 mmol)
in acetone (20 mL) containing anhydrous potassium
carbonate (0.05 g), a solution of dimethylsulfate (9.20
mg, 0.73 mmol) in acetone (2 mL) was added dropwise
with stirring. The mixture was refluxed overnight and allowed to come to room
temperature before water was added and the resulting solid was filtered, washed with
water, recrystallized from ethanol and dried to yield the 1-methyl-7-carboxylate 182
as a white solid (78 mg, 73%), m.p. 126-128 °C. (Found: C, 66.32; H, 5.77; N, 8.36.
C18H18N2O4 requires C, 66.25; H, 5.56; N, 8.58 %). max (KBr): 2957, 1700, 1615,
1471, 1250, 1204, 1121, 1083, 983, 713 cm-1. max (MeOH): 208 nm ( 30,500 cm-1M-
1), 238 (25,700), 288 (13,000). 1H NMR (300 MHz, CDCl3): 3.94 (s, 3H, CH3), 3.99
(s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 6.48 (s, 1H, aryl H5), 7.48-
7.50 (m, 3H, aryl H), 7.71-7.75 (m, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 34.37
(CH3), 52.16, 55.82, 58.06 (OCH3), 92.69, 128.46, 129.94, 129.98 (aryl CH), 105.06,
120.94, 128.89, 142.30, 149.42, 154.92, 156.22 (aryl C), 165.98 (C=O). Mass
Spectrum (+EI): m/z (%) 328 (M+2, 19), 327 (M+1, 100), 269 (22).
N
N
OMe
MeO
OMeOMe
Experimental 167
Methyl-4,6-dimethoxy-2-(4'-methoxyphenyl)-1-methylbenzimidazole-7-
carboxylate (183)
This compound was prepared according to the
method of preparation of the compound 182 from a
solution of benzimidazole 181 (0.10 g, 0.30 mmol)
in acetone (20 mL), anhydrous potassium carbonate (0.04 g) and a solution of
dimethylsulfate (8.3 mg, 0.66 mmol) in acetone (2 mL) under reflux overnight to yield
the 1-methyl-7-carboxylate 183 as an off white solid (78 mg, 73%), m.p. 124-126 °C.
(Found: C, 63.23; H, 5.79; N, 7.65. C19H20N2O5 0.2H2O requires C, 63.39; H, 5.71; N,
7.78 %). max (KBr): 2944, 2843, 1710, 1614, 1468, 1376, 1252, 1211, 1177, 1140,
1097, 1026, 843 cm-1. max (MeOH): 211 nm ( 30,600 cm-1M-1), 250 (23,600), 293
(15,500). 1H NMR (300 MHz, CDCl3): 3.86 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 4.01
(s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.49 (s, 1H, aryl H5), 7.02 (d, J = 8.64 Hz, 2H,
aryl H), 7.72 (d, J = 8.64 Hz, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 34.34 (CH3),
52.09, 55.29, 55.73, 58.02 (OCH3), 92.35, 113.90, 131.31 (aryl CH), 105.13, 121.04,
121.48, 142.70, 149.24, 155.11, 155.98, 160.85 (aryl C), 166.17 (C=O). Mass
Spectrum (+EI): m/z (%) 358 (M+2, 22), 357 (M+1, 100), 299 (36).
4,6-Dimethoxy-7-nitro-2-phenylbenzimidazole (185)
To an ice cooled solution of benzimidazole 142 (0.50 g,
1.96 mmol) in acetic anhydride (20 mL), a previously
cooled solution of nitric acid (0.15 g, mmol) in acetic
anhydride (2 mL) was added dropwise over 10 min. The
mixture was stirred at 0°C for a further 2 h before ice water was added and stirred for
another 2 h. The mixture was made neutral by 2 M sodium hydroxide solution and the
resulting precipitate was filtered, washed with water, recrystallized from ethanol/water
and dried to afford the 7-nitrobenzimidazole 185 as a yellow solid (0.41 g, 70%), m.p.
207-208 °C. (Found: C, 60.22; H, 4.47; N, 14.07. C15H13N3O4 requires C, 60.20; H,
4.38; N, 14.04 %). max (KBr): 3356, 1621, 1597, 1479, 1448, 1318, 1251, 1118, 980
cm-1. max (MeOH): 204 nm ( 25,300 cm-1M-1), 290 (12,800). 1H NMR (300 MHz,
CDCl3): 4.09 (s, 3H, OCH3), 4.22 (s, 3H, OCH3), 6.40 (s, 1H, aryl H5), 7.50-7.52
N
N
OMe
MeOOMe
OMeO Me
NH
N
OMe
MeONO2
Experimental 168
(m, 3H, aryl H), 8.06-8.09 (m, 2H, aryl H), 10.88 (br s, 1H, NH). 13C NMR (75 MHz,
CDCl3): 56.96, 57.27 (OCH3), 90.88, 126.48, 128.49, 130.48 (aryl CH), 118.32,
128.72, 128.98, 132.84, 150.74, 156.20, 157.30 (aryl C). Mass Spectrum (+EI): m/z
(%) 301 (M+2, 18), 300 (M+1, 100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-7-nitrobenzimidazole (186)
This compound was prepared as described for the
preparation of 7-nitrobenzimidazole 185 from a
solution of benzimidazole 161 (0.25 g, 0.88 mmol)
in acetic anhydride (10 mL) and a previously
cooled solution of nitric acid (0.15 g, mmol) in acetic anhydride (2 mL) under stirring
at 0°C for 2 h to afford the 7-nitrobenzimidazole 186 as a yellow solid (0.23 g, 78%),
m.p. 208-209 °C. (Found: C, 58.66; H, 4.75; N, 12.85. C16H15N3O5 requires C, 58.36;
H, 4.59; N, 12.76 %). max (KBr): 3454, 1621, 1592, 1477, 1428, 1306, 1250, 1232,
1179, 1024, 982, 567 cm-1. max (MeOH): 206 nm ( 38,800 cm-1M-1), 235 (16,737),
293 (24,300). 1H NMR (300 MHz, CDCl3): 3.86 (s, 3H, OCH3), 4.06 (s, 3H, OCH3),
4.18 (s, 3H, OCH3), 6.35 (s, 1H, aryl H5), 6.99 (d, J = 9.03 Hz, 2H, aryl H), 7.98 (d, J
= 9.03 Hz, 2H, aryl H), 10.74 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.33,
56.82, 57.21 (OCH3), 90.66, 114.36, 128.02 (aryl CH), 118.31, 121.17, 128.80,
132.84, 150.87, 155.81, 156.99, 161.41 (aryl C). Mass Spectrum (+EI): m/z (%) 331
(M+2, 20), 330 (M+1, 100).
4,6-Dimethoxy-2-phenylbenzimidazol-7-yl)phenylmethanone (187)
To an ice cooled solution of benzimidazole 142 (0.10 g,
0.39 mmol) in dry dichloromethane (20 mL), benzoyl
chloride (0.14 mL, 1.17 mmol) was added followed by
antimony pentachloride (0.15 mL, 1.17 mmol) and stirred
at room temperature under argon for 3 days. Water was
added to this solution and extracted with dichloromethane. The organic solvent was
washed with water, dried over magnesium sulfate and the solvent was evaporated off.
The crude solid was purified by column chromatography using
dichloromethane/methanol (95 :05) as eluent to yield the product 187 as light yellow
crystals (40 mg, 29%), m.p. 157-158 °C. (Found: C, 73.86 ; H, 5.09 ; 7.89.
NH
N
OMe
MeONO2
OMe
NH
N
OMe
MeO
O
Experimental 169
C22H18N2O3 requires C, 73.73; H, 5.06; N, 7.82 %). max (KBr): 3406, 1619, 1584,
1401, 1461, 1384, 1298, 1283, 1252, 1213, 1177, 1149, 1120, 931, 774, 744, 691 cm-
1. max (MeOH): 206 nm ( 47,800 cm-1M-1), 249 (31,100), 307 (25,300). 1H NMR
(300 MHz, CDCl3): 3.61 (s, 3H, OCH3), 4.15 (s, 3H, OCH3), 6.32 (s, 1H, aryl H5),
7.36-7.49 (m, 6H, aryl H), 7.61-7.65 (m, 2H, aryl H), 8.06-8.09 (m, 2H, aryl H), 10.93
(br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 56.22, 56.34 (OCH3), 90.57, 126.39,
127.53, 128.20, 128.78, 129.87, 131.03 (aryl CH), 104.31, 129,06, 129.27, 137.90,
141.30, 150.47, 156.12, 159.16 (aryl C), 195.28 (C=O). Mass Spectrum (+EI): m/z
(%) 360 (M+2, 24), 359 (M+1, 100).
(4,6-Dimethoxy-2-phenylbenzimidazol-1-yl)phenylmethanone (188)
Method A: To a solution of benzimidazole 142 (0.10 g,
0.39 mmol) in dry dichloromethane (20 mL), benzoyl
chloride (0.14 mL, 1.17 mmol) followed by graphite (0.2
g) was added and the mixture refluxed for 3 days. The
graphite was filtered off and washed with
dichloromethane. The combined dichloromethane was washed with water and dried
over magnesium sulfate. The solvent was evaporated off and the solid was
chromatographed using dichloromethane/methanol (95/05) to yield the benzimidazole
188 as a yellow solid (24 mg, 17 %).
Method B: To a solution of benzimidazole 142 (0.10 g, 0.39 mmol) in dry
dichloromethane (20 mL), benzoyl chloride (0.14 mL, 1.17 mmol) followed by
activated carbon granules (0.2 g) was added and the mixture refluxed for 1 d under
argon. The mixture was allowed to cool to room temperature and the carbon granules
were filtered off. The organic solvent was evaporated off and the resulting crude solid
was purified by column chromatography using dichloromethane/ethyl acetate (90/10)
to yield the title benzimidazole 188 as a yellow solid (56 mg, 40 %).
Method C: To a solution of benzimidazole 142 (0.10 g, 0.39 mmol) in dry
dichloromethane (20 mL), benzoyl chloride (0.14 mL, 1.17 mmol) followed by carbon
fiber (0.2 g) was added and the mixture refluxed for 3 days under argon. The mixture
was allowed to cool to room temperature and the carbon fibers were filtered off. The
organic solvent was evaporated off and the resulting crude solid was purified by
column chromatography using dichloromethane/ethyl acetate (90/10) to yield the titled
N
N
OMe
MeOO
Experimental 170
benzimidazole 188 as a yellow solid (28 mg, 20%), m.p. 158-159 °C. (Found: C,
73.52; H, 5.20 ; N, 7.64. C22H18N2O3 requires C, 73.73; H, 5.06; N, 7.82 %). max
(KBr): 3443, 1687, 1613, 1600, 1497, 1447, 1325, 1295, 1285, 1255, 1226, 1178,
1151, 922, 800, 695 cm-1. max (MeOH): 205 nm ( 34,700 cm-1M-1), 237 (20,700),
290 (13,700). 1H NMR (300 MHz, CDCl3): 3.78 (s, 3H, OCH3), 4.03 (s, 3H, OCH3),
6.48 (d, J = 1.86 Hz, 1H, aryl H5), 6.70 (d, J = 1.86 Hz, 1H, aryl H7), 7.17-7.24 (m,
3H, aryl H), 7.27-7.29 (m, 2H, aryl H), 7.40-7.45 (m, 1H, aryl H), 7.54-7.62 (m, 4H,
aryl H). 13C NMR (75 MHz, CDCl3): 55.71, 55.87 (OCH3), 88.64, 96.07, 127.98,
128.45, 129.08, 129.14, 130.40, 133.73 (aryl CH), 127.77, 130.52, 133.16, 136.54,
151.15, 151.78, 158.90 (aryl C), 169.49 (C=O). Mass Spectrum (+EI): m/z (%) 360
(M+2, 25), 359 (M+1, 100), 256 (8), 255 (48).
Dimethyl 3,5-dimethoxy-1-phenyl-imidazo[4,5,1-ij]quinoline-7,8-dicarboxylate
(190)
To a partially dissolved ice cooled solution of
benzimidazole 164 (0.30 g, 1.06 mmol) in dry
dichloromethane (20 mL), triphenylphosphine (0.31 g)
followed by dimethyl acetylene dicarboxylate (0.17 g,
1.20 mmol) in dry dichloromethane (5 mL) over 10 min.
The resulting clear red solution was stirred at room temperature for 5 days under
argon and the solvent was evaporated off. The crude product was chromatographed
using dichloromethane/ethyl acetate (90/10) as eluent to yield the quinoline compound
190 as a yellow powder (0.31 g, 72%), m.p. 180-182 °C (lit.119 187-189 °C). (Found:
C, 63.82; H, 5.41; N, 6.21. C22H20N2O6 0.50 EtOAc requires C, 63.71; H, 5.35; N,
6.19 %). max (KBr): 2945, 1748, 1697, 1613, 1523, 1452, 1432, 1261, 1243, 1149,
1067, 775 cm-1. max (MeOH): 206 nm ( 26,900 cm-1M-1), 231 (21,500), 364
(15,600). 1H NMR (300 MHz, CDCl3): 3.44 (s, 3H, OCH3), 3.85 (s, 3H, OCH3),
3.93 (s, 3H, OCH3), 4.18 (s, 3H, OCH3), 6.25 (s, 1H, aryl H8), 6.46 (s, 1H, aryl H4),
7.46-7.48 (m, 3H, aryl H), 7.76- 7.80 (m, 2H, aryl H), 8.06 (s, 1H, aryl H6). 13C NMR
(75 MHz, CDCl3): 52.02, 52.76, 56.44, 57.00 (OCH3), 56.35 (aliph. CH), 91.70,
128.39, 128.71, 129.67, 130.54 (aryl CH), 98.99, 115.99, 125.21, 129.75, 136.58,
N
N
OMe
MeO
COOMeCOOMe
Experimental 171
152.03, 155.44, 155.47 (aryl C), 165.86, 168.44 (C=O). Mass Spectrum (+EI): m/z
(%) 410 (M+2, 26%), 409 (M+1, 100), 351 (5).
Dimethyl 7,9-dimethoxy-2-(4'-methoxyphenyl)-4H-imidazo[3,2,1-ij]quinoline-4,5-
dicarboxylate (191)
This compound was prepared from an ice cooled
solution of benzimidazole 165 (0.50 g, 1.60 mmol)
in dry dichloromethane (25 mL),
triphenylphosphine (0.46 g) and dimethyl acetylene
dicarboxylate (0.25 g) with stirring under argon for 5 days. The product 191 was
purified by column chromatography using dichloromethane/ethyl acetate (90/10) as
eluent as a yellow powder (0.53 g, 76%), m.p. 159-160 °C. (Found: C, 58.83; H, 4.88;
N, 5.76. C23H22N2O7 0.5CH2Cl2 requires C, 58.69; H, 4.82; N, 5.83 %). max (KBr):
2951, 2841, 1739, 1706, 1608, 1571, 1520, 1463, 1435, 1298, 1268, 1175, 1145,
1072, 987 cm-1. max (MeOH): 203 nm ( 40,500 cm-1M-1), 233 (31,300), 267
(20,600), 361 (22,800). 1H NMR (300 MHz, CDCl3): 3.45 (s, 3H, OCH3), 3.79 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.16 (s, 3H, OCH3), 6.23 (s, 1H,
aryl H8), 6.44 (s, 1H, aryl H4), 6.99 (d, J = 8.28 Hz, 2H, aryl H), 7.73 (d, J = 8.28 Hz,
2H, aryl H), 8.03 (s, 1H, aryl H6). 13C NMR (75 MHz, CDCl3): 52.03, 52.82, 56.38,
56.47, 56.92 (OCH3), 55.27 (aliph. CH), 91.47, 114.18, 129.83, 130.59 (aryl CH),
98.92, 115.90, 122.09, 125.03, 136.48, 151.99, 155.20, 155.28, 160.72 (aryl C),
165.86, 168.46 (C=O). Mass Spectrum (+EI): m/z (%) 439 (M+2, 27), 439 (M+1,
100).
7-(Benzimidazol-2-yl)-4,6-dimethoxy-2-methylbenzimidazole (193)
To a solution of 7-formylbenzimidazole 163 (0.10 g, 0.45
mmol) in anhydrous N,N-dimethylformamide (5 mL) 1,2-
diaminobenzene (0.05 g, 0.50 mmol) was added and the
mixture heated at 110°C for 24 h. The reaction mixture was
allowed to cool to room temperature before ice water was
added, the resulting precipitate was filtered and washed with
water. The crude solid was recrystallized from ethanol/water to afford the
bisbenzimidazole 193 as light brown solids (70 g, 52%), m.p.>350 °C. HRMS (+ESI):
N
N
OMe
MeO
COOMeCOOMe
OMe
NH
N
OMe
MeOMe
HN N
Experimental 172
C17H16N4O2 [M+H]+ requires 309.1346, found 309.1349. max (KBr): 3395, 2921,
2848, 1644, 1605, 1570, 1452, 1388, 1331, 1213, 1141 cm-1. max (MeOH): 222 nm (
11,000 cm-1M-1), 260 (10,200), 336 (12,300). 1H NMR (300 MHz, CDCl3): 2.69 (s,
3H, CH3), 4.09 (s, 3H, OCH3), 4.12 (s, 3H, OCH3), 6.41 (s, 1H, aryl H5), 7.26-7.28
(m, 2H, aryl H), 7.66-7.69 (m, 2H, aryl H), 9.47 (br s, 1H, NH). Mass Spectrum (+EI):
m/z (%) 308 (M+2, 25), 309 (M+1, 100).
7-(Benzimidazol-2-yl)-4,6-dimethoxy-2-phenylbenzimidazole (194)
This compound was prepared as described for the
preparation of bisbenzimidazole 193 from a solution of 7-
formylbenzimidazole 164 (1.95 g, 6.91 mmol) in
anhydrous N,N-dimethylformamide (5 mL) and 1,2-
diaminobenzene (0.82 g, 7.6 mmol) at 110 °C for 48 h to
yield the bisbenzimidazole 194 as a light brown powder
(1.76 g, 69 %), m.p. 216-217 °C. (lit.118 201-202°C) (Found: C, 68.29; H, 5.26; N,
14.51. C22H18N4O2 0.9H2O requires C, 68.35; H, 5.16; N, 14.49 %). max (KBr): 3655,
3300, 1620, 1492, 1465, 1450, 1433, 1391, 1335, 1311, 1278, 1237, 1216, 1151,
1102, 994, 791, 742, 692 cm-1. max (MeOH): 209 nm ( 10,200 cm-1M-1), 253 (9,000),
323 (11,400). 1H NMR (300 MHz, CDCl3): 4.13 (s, 3H, OCH3), 4.14 (s, 3H, OCH3),
6.45 (s, 1H, aryl H5), 7.26-7.29 (m, 2H, aryl H), 7.43-7.55 (m, 3H, aryl H), 7.67 (s br,
2H, aryl H), 7.90 (br s, 1H, NH), 8.18-8.21 (m, 2H, aryl H), 10.51 (br s, 1H, NH). 13C
NMR (75 MHz, CDCl3): 56.20, 56.72 (OCH3), 89.94, 93.55, 122.37, 126.51,
128.74, 129.69 (aryl CH), 94.48, 117.47, 123.44, 129.76, 136.37, 149.47, 150.56,
152.89, 155.11, 173.09, 174.59 (aryl C). Mass Spectrum (+EI): m/z (%) 372 (M+2,
47%), 371 (M+1, 100).
7-(Benzimidazol-2-yl)-4,6-dimethoxy-2-(4'-
methoxyphenyl)benzimidazole (195)
This compound was prepared as described for the
bisbenzimidazole 193 from a solution of 7-
formylbenzimidazole 165 (0.20 g, 0.64 mmol) in
anhydrous N,N-dimethylformamide (3 mL) and
NH
N
OMe
MeO
HN N
OMe
NH
N
OMe
MeO
HN N
Experimental 173
1,2-diaminobenzene (76 mg, 0.70 mmol) at 110 °C for 48 h to yield the
bisbenzimidazole 195 as a brown solid (0.14 g, 56%), m.p. 150-152 °C. (Found: C,
66.42; H, 5.21; N, 12.88. C23H20N4O3 0.9MeOH requires C,66.87; H, 5.54; N, 13.05
%). max (KBr): 3348, 1618, 1488, 1453, 1422, 1384, 1333, 1253, 1213, 1176, 1028,
837, 744 cm-1. max (MeOH): 206 nm ( 51,500 cm-1M-1), 258 (31,600), 327 (43,400). 1H NMR (300 MHz, CDCl3): 3.88 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.10 (s, 3H,
OCH3), 6.26 (s, 1H, aryl H5), 6.98-7.01 (m, 2H, aryl H), 7.28-7.31 (m, 2H, aryl H),
7.75 (d, J = 8.67 Hz, 2H, aryl H), 8.15 (d, J = Hz, 2H, aryl H). 13C NMR (75 MHz,
CDCl3): 55.29, 56.69, 57.13 (OCH3), 94.12, 114.16, 115.36, 123.57, 128.23 (aryl
CH), 102.34, 123.47, 126.78, 138.56, 141.82, 150.1, 153.23, 155.02, 155.82, 160.56
(aryl C). Mass Spectrum (+EI): m/z (%) 402 (M+2, 26), 401 (M+1, 100).
Reaction of allyl bromide with 7-(benzimidazol-2-yl)-4,6-dimethoxy-2-
phenylbenzimidazole (194)
A solution of benzimidazole 194 (0.20 g, 0.54 mmol) in anhydrous dimethyl sulfoxide
(5 mL) was stirred at room temperature with potassium hydroxide (0.06 g, 1.08 mmol)
for 1 h. Allyl bromide (0.06 g, 0.54 mmol) in dimethyl sulfoxide (2 mL) and sodium
iodide (0.16 g, 1.08 mmol) were added and the mixture stirred for 3 days at room
temperature. The mixture was then diluted with iced water and extracted with
dichloromethane. The organic solvent was washed with water, brine, dried over
magnesium sulfate and the solvent evaporated in vacuo to give a mixture of the title
compounds as a yellow syrup, which partially solidified after long standing (0.13 g),
m.p. 178-180°C. max (KBr): 1619, 1460, 1414, 1384, 1336, 1217, 1147, 1098, 986,
745, 700 cm-1. max (MeOH): 206 nm ( 31,000 cm-1M-1), 248 (15,700), 313 (14,400).
HRMS (+ESI): C28H26N4O2 [M+H]+ requires, 451.2129 found 451.2142, represents
compounds 199 and 200. HRMS (+ESI): C25H22N4O2 [M+H]+ requires, 411.1816
found 411.1828, represents compounds 201-204.
Experimental 174
1-Allyl-7-(1-allylbenzimidazol-2-yl)-4,6-dimethoxy-2-
phenylbenzimidazole (199)
.
1-Allyl-4-(1-allylbenzimidazol-2-yl)-5,7-dimethoxy-2-
phenylbenzimidazole (200)
4-(1-Allylbenzimidazol-2-yl)-5,7-dimethoxy-2-
phenylbenzimidazole (201)
7-(1-Allylbenzimidazol-2-yl)-4,6-dimethoxy-2-
phenylbenzimidazole (202)
1-Allyl-7-(benzimidazol-2-yl)-4,6-dimethoxy-2-
phenylbenzimidazole (203)
N
N
OMe
MeO
N N
NH
N
OMe
MeO
N N
N
N
OMe
MeO
HN N
N
N
OMe
MeO
N N
N
HN
OMe
MeO
N N
Experimental 175
1-Allyl-4-(1H-benzo[d]imidazol-2-yl)-5,7-dimethoxy-2-
phenyl-1H-benzo[d]imidazole (204)
Bis[7-(benzimidazol-2-yl)-4,6-dimethoxy-2-phenylbenzimidazol-1-yl]nickel(II)
(205)
To a solution of bisbenzimidazole 194 (0.10 g,
0.27 mmol) in anhydrous methanol (20 mL)
nickel(II) acetate tetrahydrate (34 mg, 0.14
mmol) was added and the solution was refluxed
overnight. The solvent was evaporated off and
the mixture recrystallized from acetonitrile to
afford the title complex 205 as an orange powder (44 mg, 40%), m.p. >350°C. max
(KBr): 3421, 1614, 1588, 1453, 1430, 1319, 1281, 1213, 1151, 1105, 745 cm-1. max
(MeOH): 208 nm ( 93,300 cm-1M-1), 236 (65,600), 327 (80,300), 339 (83,500), 355
(61,100). 1H NMR (300 MHz, CDCl3): 4.18 (s, 6H, OCH3), 4.20 (s, 6H, OCH3),
6.51 (s, 2H, aryl H5), 7.47-7.86 (m, 12H, aryl H), 8.21-8.24 (m, 6H, aryl H). Mass
Spectrum (+ESI): m/z 857.20 [M+Na]+.
Bis[7-(benzimidazol-2-yl)-4,6-dimethoxy-2-phenylbenzimidazol-1-yl]cobalt(II)
(206)
This complex was prepared as described for the
complex 205 from a solution of
bisbenzimidazole 194 (50 mg, 0.135 mmol) in
anhydrous methanol (10 mL) and cobalt(II)
acetate tetrahydrate (17 mg, 0.068 mmol) under
reflux overnight to afford the complex 206 as a
pink powder (40 mg, 73%), m.p. >350 °C. Correct microanalysis for C45H37CoN8O4
could not be obtained. max (KBr): 3402, 1598, 1454, 1432, 1323, 1285, 1215, 1143,
N
N
OMe
MeOPh
NHN
N
N
OMe
OMePh
N NHNi
N
N
OMe
MeOPh
NHN
N
N
OMe
OMePh
N NHCo
N
N
OMe
MeO
HN N
Experimental 176
1106, 1004, 745 cm-1. max (MeOH): 204 nm ( 87,700 cm-1M-1), 337 (67,200). Mass
Spectrum (+EI): m/z (%) 813 (M+1, 7), 812 (M, 12), 799 (52), 798 (100).
Bis[7-(benzimidazol-2-yl)-4,6-dimethoxy-2-phenylbenzimidazol-1-yl]copper(II)
(207)
This complex was prepared as described for the
complex 205 from a solution of
bisbenzimidazole 194 (50 mg, 0.135 mmol) in
anhydrous methanol (10 mL) and copper(II)
acetate monohydrate (14 mg, 0.068 mmol)
under reflux overnight to afford the complex
207 as a blue powder (20 mg, 36%), m.p. 282-284 °C. (Found: C, 64.21; H, 4.70; N,
13.42. C45H37CuN8O4 1.2H2O requires C, 64.42; H, 4.73; N, 13.36 %). max (KBr):
3394, 1612, 1587, 1454, 1429, 1318, 1281, 1212, 1152, 1106 cm-1. max (MeOH): 203
nm ( 75,000 cm-1M-1), 342 (65,100), 358 (52,600). Mass Spectrum (+EI): m/z (%)
817 (M, 1), 802 (24), 372 (25), 371 (100).
4,6-Dimethoxy-2-phenylbenzimidazole-7-carbaldehyde oxime (209)
To a warm solution of 7-formylbenzimidazole 164 (0.35
g, 1.24 mmol) in ethanol (50 mL) crushed potassium
hydroxide (1.40 g) and hydroxylamine hydrochloride
(0.86g, 12.4 mmol) were added and the mixture refluxed
for 8 h. The precipitate was filtered off and the filtrate was concentrated and diluted
with water to yield a fluffy precipitate, which was filtered, washed with water and
dried to yield the aldoxime 209 as a white pad (0.25 g, 68%), m.p. 210-211 °C.
(Found: C 64.86, ; H, 5.17; N, 14.04. C16H15N3O3 requires C, 64.64; H, 5.09; N, 14.13
%). max (KBr): 3399, 3358, 3161, 1631, 1612, 1452, 1387, 1346, 1252, 1208, 1155,
1118, 998, 793, 687 cm-1. max (MeOH): 203 nm ( 25,600 cm-1M-1), 217 (24,800),
251 (22,000), 290 (24,800), 321 (25,700). 1H NMR (300 MHz, Acetone-d6): 3.95 (s,
3H, OCH3), 4.13 (s, 3H, OCH3), 6.58 (s, 1H, aryl H5), 7.47-7.50 (m, 3H, aryl H),
8.07-8.09 (m, 2H, aryl H), 8.54 (s, 1H, NCH), 10.16 (br s, 1H, NH), 10.26 (br s, 1H,
OH). 13C NMR (75 MHz, Acetone-d6): 56.05, 56.29 (OCH3), 91.55, 126.04, 128.71,
N
N
OMe
MeOPh
NHN
N
N
OMe
OMePh
N NHCu
NH
N
OMe
MeO
NOHH
Experimental 177
129.42 (aryl CH), 97.96, 128.94, 130.11, 134.21, 149.30, 153.36, 155.95 (aryl C),
143.99 (C=N). Mass Spectrum (+EI): m/z (%) 299 (M+2, 21), 298 (M+1, 100), 281
(18), 280 (83).
4,6-Dimethoxy-2-(4'-methoxyphenyl)-benzimidazole-7-carbaldehyde oxime (210)
This compound was prepared as described for the
oxime 209 from a solution of 7-
formylbenzimidazole 165 (0.10 g, 0.32 mmol) in
ethanol (25 mL), crushed potassium hydroxide
(0.35 g) and hydroxylamine hydrochloride (0.22 g, 3.2 mmol) under reflux for 8 h to
give the aldoxime 210 as a white solid (87 mg, 83%), m.p. 242-244 °C. (Found: C,
62.57; H, 5.46; N, 12.53. C17H17N3O4 requires C, 62.38; H, 5.23; N, 12.84 %). max
(KBr): 3388, 3150, 1631, 1611, 1483, 1643, 1340, 1272, 1256, 1179, 1153, 995, 829
cm-1. max (MeOH): 203 nm ( 21,100 cm-1M-1), 218 (20,300), 262 (17,100), 292
(19,400), 324 (20,500). 1H NMR (300 MHz, Acetone-d6): 3.86 (s, 3H, OCH3), 3.93
(s, 3H, OCH3), 4.12 (s, 3H, OCH3), 6.54 (s, 1H, aryl H5), 7.07 (d, J = 8.64 Hz, 2H,
aryl H), 8.02 (d, J = 8.64 Hz, 2H, aryl H), 8.52 (s, 1H, NCH), 10.91 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 55.69, 56.39, 57.30 (OCH3), 91.71, 114.60, 128.27
(aryl CH), 97.80, 128.88, 130.56, 135.47, 140.14, 152.86, 155.37, 160.79 (aryl C),
143.73 (C=N). Mass Spectrum (+EI): m/z (%) 329 (M+2, 14), 328 (M+1, 70), 310
(100).
1-(4,6-Dimethoxy-2-phenylbenzimidazol-7-yl)ethanone
oxime (211)
This compound was prepared as described for the oxime
209 from a solution of 7-acetylbenzimidazole 172 (0.50
g, 1.69 mmol) in ethanol (50 mL), crushed potassium
hydroxide (2.84 g) and hydroxylamine hydrochloride (2.35 g, 33.78 mmol) under
reflux for 48 h to afford the ketoxime 211 as a white solid (0.36 g, 69%), m.p. 128-
130 °C. (Found: C, 63.34; H, 5.59; N, 12.94. C17H17N3O3 0.6H2O requires C, 63.38;
H, 5.69; N, 13.04 %). HRMS (+ESI): C17H17N3O3 [M+H]+ requires 312.1342, found
312.1340. max (KBr): 3397, 2937, 1610, 1452, 1376, 1341, 1209, 1146, 1002, 690
NH
N
OMe
MeO
NOHH
OMe
NH
N
OMe
MeO
NOHMe
Experimental 178
cm-1. max (MeOH): 204 nm ( 28,700 cm-1M-1), 251 (23,200), 308 (18,800). 1H NMR
(300 MHz, CDCl3): 2.33 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 6.58
(s, 1H, aryl H5), 7.45-7.48 (m, 3H, aryl H), 8.11-8.13 (m, 2H, aryl H), 10.07 (br s, 1H,
OH), 11.48 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 16.11 (CH3), 56.22,
57.38 (OCH3), 92.46, 126.85, 129.01, 129.74 (aryl CH), 104.56, 127.49, 128.69,
130.56, 130.69, 135.49, 150.19, 154.62 (aryl C), 151.59 (C=N). Mass Spectrum (+EI):
m/z (%) 313 (M+2, 20), 312 (M+1, 100), 296 (21), 280 (30).
1-(4,6-Dimethoxy-2-methylbenzimidazol-7-yl)ethanone oxime (212)
This compound was prepared as described for the oxime 209
from a solution of 7-acetylbenzimidazole 173 (1.80 g, 7.69
mmol) in ethanol (100 mL), crushed potassium hydroxide
(7.10 g) and hydroxylamine hydrochloride (4 g, 57.55 mmol)
under reflux for 48 h to yield the ketoxime 212 as a white pad (1.21 g, 64%), m.p.
204-206 °C. (Found: C, 57.83; H, 6.20; N, 16.77. C12H15N3O3 requires C, 57.82; H,
6.07; N, 16.86 %). HRMS (+ESI): C12H15N3O3 [M+Na]+ requires 272.1006, found
272.1001. max (KBr): 3410, 3258, 1613, 1456, 1400, 1336, 1306, 1244, 1211, 1139,
1103, 1023, 991, 899, 786 cm-1. max (MeOH): 212 nm ( 19,400 cm-1M-1), 275
(7,800). 1H NMR (300 MHz, CDCl3): 2.37 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.85 (s,
3H, OCH3), 3.95 (s, 3H, OCH3), 6.33 (s, 1H, aryl H5), 8.88 (br s, 2H, NH+OH). 13C
NMR (75 MHz, CDCl3): 14.26, 14.61 (CH3), 55.91, 57.00 (OCH3), 91.63 (aryl CH),
102.68, 126.68, 134.36, 149.43, 150.81, 156.14 (aryl C), 155.65 (C=N). Mass
Spectrum (+EI): m/z (%) 252 (M+2, 16), 250 (M+1, 100).
Bis[1-(4,6-dimethoxy-2-methylbenzimidazol-4-
yl)ethanoneoxime-O-yl]nickel(II) (213)
To a solution of ketoxime 212 (50 mg, 0.20 mmol)
in anhydrous methanol (3 mL), nickel (II) acetate
tetrahydrate (50 mg, 0.20 mmol) was added and the
mixture refluxed overnight. The solvent was
evaporated off and the crude solid was
recrystallized from acetonitrile to afford the
NH
N
OMe
MeOMe
NOHMe
N
HN
OMe
MeOMe
N
N
NH
OMe
OMeMe
NOOMe
MeNi
Experimental 179
complex 213 as a light green solid (21 mg, 38%), m.p. 245-246 °C. max (KBr): 3354,
3302, 3258, 1627, 1608, 1541, 1419, 1156, 635 cm-1. max (MeOH): 207 nm ( 9,200
cm-1M-1). Mass Spectrum (MALDI): m/z (%) 555 (M+1, 15), 554 (M, 23), 497(57),
496 (39), 495 (M-Ni, 100).
Bis[1-(4,6-dimethoxy-2-methylbenzimidazol-7-
yl)ethanone oxime-O-yl]cobalt(II) (214)
This complex was prepared as described for the
complex 213 from ketoxime 212 (50 mg, 0.20
mmol) in anhydrous methanol (3 mL), cobalt(II)
acetate tetrahydrate (50 mg, 0.20 mmol) under
reflux overnight to yield the complex 214 as a
brown solid (50 mg, 90%), m.p. >350 °C. max
(KBr): 3406, 1625, 1611, 1557, 1409, 1333, 1212, 1117, 1054 cm-1. max (MeOH):
208 nm ( 20,200 cm-1M-1), 339 (9,400). Mass Spectrum (MALDI): m/z (%) 557
(M+2, 29), 556 (M+1, 85), 555 (M, 55), 496 (M-Co, 100).
Reaction of 2-phenyl-4,6-dimethoxybenzimidazole 142 with excess methyl iodide
To a solution of benzimidazole 142 (0.50 g, 1.97 mmol) in dry dimethylsulfoxide (10
mL) crushed potassium hydroxide (0.50 g) was added and the mixture stirred for 1 h.
Methyl iodide (0.25 mL, 3.94 mmol) was then added and the solution was heated for 3
h at 110 °C. The solution was allowed to cool to room temperature and water was
added. The resulting precipitate was filtered, washed with water and dried. The crude
product was column chromatographed using dichloromethane/methanol (95:5) as
eluent to yield the following three products.
(i) N-Methyl-N-(2,4,6-trimethoxyphenyl)benzamide (222)
was obtained as colorless crystals (0.40 g, 67%), m.p. 186-
188 °C. (Found: C, 67.83; H, 6.42; N, 4.58. C17H19NO4
requires C, 67.76; H, 6.36; N, 4.65 %). max (KBr): 3360,
1635, 1525, 1483, 1451, 1420, 1381, 1350, 1240, 1204, 1188, 1157, 1058, 802, 721,
701 cm-1. max (MeOH): 217 nm ( 40,600 cm-1M-1), 291 (3,200). 1H NMR (300 MHz,
CDCl3): 2.89 (s, 3H, N-CH3), 3.16 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.71 (s, 3H,
O
N
OMeMeO
OMe Me
N
HN
OMe
MeOMe
N
N
NH
OMe
OMeMe
NOOMe
MeCo
Experimental 180
OCH3), 5.62 (d, J = 2.64 , 1H, aryl H4), 5.74 (d, J = 2.64 , 1H, aryl H6), 7.11-7.33 (m,
5H, aryl H). 13C NMR (75 MHz, CDCl3): 30.23 (CH3), 35.02, 55.02, 55.11 (OCH3),
86.86, 88.57, 126.56, 127.08, 129.37 (aryl CH), 112.43, 136.16, 146.11, 155.90,
160.72 (aryl C), 174.06 (C=O). Mass Spectrum (+EI): m/z (%) 302 (M+1, 12), 301
(M, 58), 283 (10), 270 (18), 269 (100).
(ii) 4,6-Dimethoxy-1-methyl-2-phenylbenzimidazole (220)
was obtained as a light brown solid after long standing (60
mg, 11%), m.p. 73-74 °C. (Found: C, 71.49; H, 6.21; N,
10.27. C16H16N2O2 requires C, 71.62; H, 6.01; N, 10.44
%). max (KBr): 2936, 1615, 1593, 1503, 1470, 1450,
1385, 1353, 1337, 1245, 1207, 1152, 1143, 1071, 818, 781, 707 cm-1. max (MeOH):
208 nm ( 33,500 cm-1M-1), 234 (15,500), 295 (13,600). 1H NMR (300 MHz, CDCl3):
3.74 (s, 3H, N-CH3), 3.85 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.37-6.39 (m, 2H, aryl
H5,7), 7.42-7.44 (m, 3H, aryl H), 7.71-7.74 (m, 2H, aryl H). 13C NMR (75 MHz,
CDCl3): 31.81 (CH3), 55.65, 55.75 (OCH3), 85.12, 94.10, 128.31, 129.13, 129.28
(aryl CH), 127.89, 130.19, 137.93, 151.35, 151.78, 157.70 (aryl C). Mass Spectrum
(+EI): m/z (%) 270 (M+2, 18), 269 (M+1, 100).
(iii) 5,7-Dimethoxy-1-methyl-2-phenylbenzimidazole (221)
was obtained as a light brown solid after long standing (66
mg, 13 %), m.p. 73-74 °C. (Found: C, 71.55; H, 6.17; N,
10.20. C16H16N2O2 requires C, 71.62; H, 6.01; N, 10.44
%). max (KBr): 2962, 1625, 1608, 1504, 1470, 1438, 1415, 1304, 1201, 1148, 1113,
1041, 936, 776, 706 cm-1. max (MeOH): 208 nm ( 34,200 cm-1M-1), 247 (13,900),
285 (9,300). 1H NMR (300 MHz, CDCl3): 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
3.98 (s, 3H, N-CH3), 6.36 (d, J = 1.89 Hz, 1H, aryl H6), 6.84 (d, J = 1.89 Hz, 1H, aryl
H4), 7.44-7.47 (m, 3H, aryl H), 7.66-7.69 (m, 2H, aryl H). 13C NMR (75 MHz,
CDCl3): 34.11 (CH3), 55.49, 55.61 (OCH3), 93.49, 95.43, 128.43, 129.35, 129.38
(aryl CH), 120.84, 130.08, 144.65, 147.52, 153.66, 156.70 (aryl C). Mass Spectrum
(+EI): m/z (%) 270 (M+2, 19), 269 (M+1, 100).
N
N
OMe
MeO
Me
N
N
OMe
MeOMe
Experimental 181
4,6-Dimethoxy-1-tosylbenzimidazole (226)
To a partially dissolved solution of benzimidazole 10 (1 g,
5.61mmol) in chloroform (25 mL) triethylamine (2.34 mL, 16.83
mmol) was added and the mixture stirred for an hour. Tosyl
chloride (3.2 g, 16.83 mmol) was then added and the mixture
was refluxed for 2 h. The solution was allowed to cool, water and
dichloromethane were added to the mixture. The organic phase
was separated, washed with water and dried over magnesium sulfate. The title N-
tosylbenzimidazole 226 was obtained by recrystallization from dichloromethane/light
petroleum as off colorless crystals (1.68 g, 87%), m.p. 140-142 °C. (Found: C, 57.85;
H, 4.86; N, 8.50. C16H16N2O4S requires C, 57.82; H, 4.85; N, 8.43 %). max (KBr):
3118, 1609, 1501, 1459, 1436, 1419, 1375, 1358, 1189, 1163, 1128, 1087, 935, 804,
675 cm-1. max (MeOH): 203 nm ( 34,400 cm-1M-1). 1H NMR (300 MHz, CDCl3):
2.36 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 6.39 (d, J = 2.26 Hz, 1H,
aryl H5), 6.91 (d, J = 2.26 Hz, 1H, aryl H7), 7.27 (d, J = 8.67 Hz, 2H, aryl H), 7.81 (d,
J = 8.67 Hz, 2H, aryl H), 8.15 (s, 1H, aryl H2). 13C NMR (75 MHz, CDCl3): 21.52
(CH3), 55.87, 55.94 (OCH3), 88.18, 96.30, 127.02, 130.16, 138.44 (aryl CH), 128.55,
132.59, 134.54, 146.000, 151.97, 159.51 (aryl C). Mass Spectrum (+EI): m/z (%) 334
(M+2, 10), 333 (M+1, 100).
4,6-Dimethoxy-2-methyl-1-tosyl-benzimidazole (227)
To a solution of benzimidazole 141 (5 g, 26 mmol) in
chloroform (50 mL) triethylamine (10.8 mL, 78 mmol) was
added and the mixture stirred for 1 h. Tosyl chloride (15 g, 78
mmol) was added and the mixture was refluxed for 1.5 h. The
solution was allowed to cool to room temperature before
water and dichloromethane were added. The organic phase was separated, washed
with water, dried over magnesium sulfate and concentrated to yield an oil. The crude
material was purified by a short column and the title N-tosylbenzimidazole 227 was
crystallized from dichloromethane/light petroleum as colorless crystals (7.12 g, 79%),
m.p. 140-142 °C. (Found: C, 59.00; H, 5.27; N, 8.15. C17H18N2O4S requires C, 58.94;
H, 5.24; N, 8.09 %). max (KBr): 3415, 1598, 1496, 1450, 1426, 1366, 1267, 1253,
1225, 1201, 1151, 1122, 1088, 1053, 1003, 937, 814, 669 cm-1. max (MeOH): 203 nm
N
N
OMe
MeOS OO
Me
N
N
OMe
MeOMe
S OO
Me
Experimental 182
( 30,500 cm-1M-1), 211 (27,300), 249 (12,400). 1H NMR (300 MHz, CDCl3): 2.39
(s, 3H, CH3), 2.74 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.40 (d, J =
1.86, 1H, aryl H5), 7.14 (d, J = 1.86, 1H, aryl H7), 7.27 (d, J = 8.91 , 2H, aryl H), 7.76
(d, J = 8.91, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 16.68, 21.50 (CH3), 55.72,
55.88 (OCH3), 89.64, 95.94, 126.56, 130.08 (aryl CH), 126.26, 134.76, 135.45,
145.78, 148.58, 150.98, 158.70 (aryl C). Mass Spectrum (+EI): m/z (%) 348 (M+2,
25%), 347 (M+1, 100).
Reaction of N-tosylbenzimidazole 227 with phosphoryl chloride and N,N-
dimethylformamide
Previously ice cooled phosphoryl chloride (0.28 mL, 3 mmol) in anhydrous N,N-
dimethylformamide (2 mL) was slowly added to an ice cooled solution of N-
tosylbenzimidazole 227 (0.5 g, 1.50 mmol) in anhydrous N,N-dimethylformamide (3
mL) and the mixture was stirred at room temperature for 4 h. Ice water was added to
this solution followed by 2 M sodium hydroxide solution and the mixture stirred
vigorously for 2 h. The resulting precipitate was filtered, washed with water and dried
to yield the compound 228. The filtrate was extracted with dichloromethane, washed
with water and dried over magnesium sulfate. The solvent was evaporated off and
purification by column chromatography (dichloromethane/methanol 95:05) yielded
two products.
(i) N,N,4-Trimethylbenzenesulfonamide (228) was obtained as an off
white solid (0.11 g, 38%), m.p. 76-78 °C. (Found: C, 54.45 ; H, 6.71; N,
6.97. C9H13NO2S requires C, 54.25; H, 6.58; N, 7.03 %). max (KBr):
3036, 2905, 1596, 1455, 1380, 1332, 1188, 1159, 1090, 955, 824, 815,
800, 722, 701 cm-1. max (MeOH): 202 nm ( 11,500 cm-1M-1), 227
(12,200). 1H NMR (300 MHz, CDCl3): 2.43 (s, 3H, CH3), 2.68 (s, 3H, OCH3), 7.32
(d, J = 8.28 Hz, 2H, aryl H), 7.65 (d, J = 8.28 Hz, 2H, aryl H). 13C NMR (75 MHz,
CDCl3): 21.37, 37.81(CH3), 127.68, 129.49 (aryl CH), 132.49, 143.34 (aryl C).
Mass Spectrum (+EI): m/z (%) 202 (M+3, 5), 201 (M+2, 12), 200 (M+1, 100).
(ii) 4,6-Dimethoxy-2-methylbenzimidazole (141) was
obtained as a light brown solid (0.27 g, 37%), m.p. 200-201
°C (lit.117 200-202 °C). (Found: C, 62.66; H, 6.28; N, 14.62. NH
N
OMe
MeOMe
S OON
Me
Me Me
Experimental 183
C10H12N2O2 requires C, 62.49; H, 6.29; N, 14.57 %). 1H NMR (300 MHz, CDCl3):
2.56 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.33 (d, = 1.86 Hz, 1H,
aryl H5), 6.61 (d, = 1.86 Hz, 1H, aryl H7), 9.00 (br s, 1H, NH). 13C NMR (75 MHz,
CDCl3): 14.56 (CH3), 55.42, 55.71 (OCH3), 88.93, 93.79 (aryl CH), 124.53, 138.84,
148.90, 149.38, 156.90 (aryl C). Mass Spectrum (+EI): m/z (%) 194 (M+2, 10), 193
(M+1, 100).
This compound 141 was also prepared according to the method described by
Martinovic117 from nitroacetanilide 155 (13 g, 54.39 mmol), 30% Pd/C (1.30 g) and
hydrazine monohydrate (26 mL, 543.9 mmol, 10 eq.) in absolute ethanol (150 mL)
under reflux for 3 h followed by acid treatment to give light brown crystals (7.78 g,
75%) m.p. 200-201°C (lit.117 200-202°C).
6-Hydroxy-4-methoxy-2-phenylbenzimidazole-7-carbaldehyde (229)
To a partially dissolved solution of benzimidazole 164
(0.20 g, 0.71 mmol) in acetonitrile (20 mL) sodium iodide
(0.26 g, 1.73 mmol) was added followed by ceric chloride
(0.68 g, 1.80 mmol). The mixture was refluxed for 48 h
before it was allowed to cool to room temperature. The resulting precipitate was
filtered and washed with water. The crude solid was chromatographed with
dichloromethane/methanol (98:2) as eluent to yield the title product 229 as a brown
solid m.p. >350 °C. max (KBr): 3391, 3296, 1623, 1604, 1451, 1278, 1209, 1171,
1113, 1055 cm-1. max (MeOH): 207 nm ( 18,200 cm-1M-1), 249 (10,900), 304
(11,400). 1H NMR (300 MHz, CDCl3): 3.96 (s, 3H, OCH3), 6.42 (s, 1H, aryl H5),
7.51-7.53 (m, 3H, aryl H), 7.94-7.95 (m, 2H, aryl H), 10.29 (s, 1H, CHO), 11.09 (br s,
1H, NH). Mass Spectrum (+ESI): m/z (%) 270 (M+2, 23), 269 (M+1, 100), 268 (M,
12).
4,6-Dimethoxy-2-hydroxymethylbenzimidazole (231)
To a solution of 2-formylbenzimidazole 234 (0.20 g, 0.97
mmol) in anhydrous methanol (20 mL), sodium borohydride
(0.40 g) was added portionwise and the mixture was refluxed
for 6 h. The solvent was concentrated and cooled before ice water was added. The
resulting precipitate was filtered, washed with water, and recrystallized from ethanol
NH
N
OMe
HO
OH
N
NH
OMe
MeO OH
Experimental 184
to yield the 2-hydroxymethylbenzimidazole 231 as light brown powder (0.121 g, 60
%), m.p. 212-213 °C. (Found: C, 57.87; H, 6.06; N, 13.25. C10H12N2O3 requires C,
57.68; H, 5.81; N, 13.45 %). max (KBr): 3117, 1605, 1454, 1433, 1148, 1130, 1046
cm-1. max (MeOH): 205 nm ( 21,200 cm-1M-1), 244 (4,200). 1H NMR (300 MHz,
DMSO-d6): 3.72 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.56 (s, 2H, CH2), 5.50 (br s,
1H, OH), 6.27 (s, 1H, aryl H5), 6.54 (s, 1H, aryl H7), 12.13 (br s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): 55.47, 55.71 (OCH3), 57.67 (CH2), 87.51, 94.66 (aryl CH),
119.09, 136.20, 145.01, 146.41, 156.11, (aryl C). Mass Spectrum (+EI): m/z (%) 210
(M+2, 17), 209 (M+1, 100).
4,6-Dimethoxybenzimidazole-2-carbaldehyde (234)
The 2-styrylbenzimidazole 236 (0.42 g, 1.5 mmol) was
dissolved in warm dioxan/water (50 mL, 3:1) and later cooled
in an ice bath. Osmium tetroxide (0.038 g,, 0.15 mmol) was
then added and the mixture stirred for 5 min. Sodium periodate (1.2 g, 5.61 mmol)
was added to this mixture in portions and the mixture stirring was continued at room
temperature for 48 h. The product was extracted with ethyl acetate, washed with
sodium thiosulfate solution (1 M), water and dried over magnesium sulfate. The
solution was concentrated and the resulting precipitate was collected and dried to yield
the 2-formylbenzimidazole 234 as a light brown solid (0.23 g, 74%), m.p. 190-192 °C.
(Found: C, 57.75; H, 5.00; N, 13.35. C10H10N2O3 0.1H2O requires C, 57.74; H, 4.94;
N, 13.47 %). HRMS (+ESI): C10H10N2O3 [M+Na]+ requires 229.0583, found
229.0585. max (KBr): 3484, 3159, 1619, 1521, 1508, 1455, 1437, 1409, 1282, 1234,
1217, 1202, 1159, 1120, 1049, 908, 864, 830, 785 cm-1. max (MeOH): 211 nm (
21,200 cm-1M-1), 252 (6,100), 329 (2,900). 1H NMR (300 MHz, CDCl3): 3.85 (s,
3H, OCH3), 3.99 (s, 3H, OCH3), 6.40 (d, J = 1.88 Hz, 1H, aryl H5), 6.56 (s, J = 1.88
Hz, 1H, aryl H7), 9.89 (s, 1H, CHO), 10.53 (br s, 1H, NH). 1H NMR (300 MHz,
DMSO-d6): 3.79 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6.41 (d, J = 1.86 Hz, 1H, aryl
H5), 6.52 (d, J = 1.86 Hz, 1H, aryl H7), 9.77 (s, 1H, CHO), 13.30 (br s, 1H, NH). 13C
NMR (75 MHz, CDCl3): 55.74, 55.79 (OCH3), 92.83, 96.34 (aryl CH), 129.66,
136.40, 146.21, 153.46, 160.97 (aryl C), 182.71 (C=O). Mass Spectrum (-EI): m/z (%)
205 (M-1, 100), 113 (21).
N
NH
OMe
MeO O
H
Experimental 185
4,6-Dimethoxy-2-styrylbenzimidazole (236)
To a solution of nitrocinnamide 252 (1 g, 3.08
mmol) in dry ethanol (25 mL), Pd/C (0.05 g,
10%) was added followed by hydrazine
monohydrate (3 mL) dropwise over 15 min with
stirring under argon at room temperature. The mixture was further stirred under argon
at room temperature for 4 h, and filtered through Celite. The filtrate was concentrated
under reduced pressure to give a yellow residue, and was dissolved in
dichloromethane, washed with brine and dried over magnesium sulfate. The organic
solvent was evaporated under reduced pressure and the residue dissolved in glacial
acetic acid (2 mL). The solution was heated at 65 °C for 3 h under argon before being
allowed to come to room temperature and made basic using 2 M sodium hydroxide
solution. The resulting precipitate was collected, washed with water and recrystallized
from isopropanol to give the 2-styrylbenzimidazole 236 as a tan colored powder (0.35
g, 1.25 mmol, 41%), m.p. 218-219 °C. (Found: C, 72.80; H, 5.86; N, 9.98.
C17H16N2O2 requires C, 72.84; H, 5.75; N, 9.99 %). HRMS (+ESI): C17H16N2O2
[M+H]+ requires 281.1285, found 281.1288. max (KBr): 3370, 2992, 1624, 1605,
1451, 1424, 1311, 1223, 1203, 1150, 1042, 961, 815, 749 cm-1. max (MeOH): 208 nm
( 28,600 cm-1M-1), 266 (13,400), 337 (23,300). 1H NMR (300 MHz, CDCl3): 3.79
(s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.33 (d, J = 1.89 Hz, 1H, aryl H5), 6.65 (d, J =
1.89 Hz, 1H, aryl H7), 7.08 (d, J = 16.2 Hz, 1H, =CH), 7.26-7.32 (m, 3H, aryl H),
7.42-7.45 (m, 2H, aryl H), 7.60 (d, J = 16.2 Hz, 1H, CH=), 8.96 ( 1H, NH). 13C NMR
(75 MHz, CDCl3): 55.46, 55.68 (OCH3), 88.51, 94.94, 126.88, 128.65, 128.77 (aryl
CH), 115.62, 135.02 (CH=CH), 127.25, 135.58, 138.29, 148.99, 149.20, 158.02 (aryl
C). Mass Spectrum (+EI): m/z (%) 283 (M+3, 9), 282 (M+1, 19), 281 (M, 100).
Bis(4,6-dimethoxy-2-methylbenzimidazol-7-yl)selane (239)
To a solution of benzimidazole 141 (0.10 g, 0.52 mmol) in
dioxan (30 mL) selenium dioxide (0.29 g, 1.56 mmol) was
added and the mixture refluxed at 120°C for 3 days. The
resulting precipitate was filtered off and the filtrate was
concentrated under reduced pressure and chromatographed
NH
N
OMe
MeOSe
Me
N
HN
OMe
MeOMe
NH
N
OMe
MeOCH=CH
Experimental 186
(dichloromethane/methanol 95:05) as eluent to yield the selenide 239 as a red solid
(0.04 g, 36%), m.p. >320 °C. max (KBr): 2410, 1626, 1460, 1416, 1340, 1217, 1090,
982, 731, 517 cm-1. max (MeOH): 213 nm ( 50,200 cm-1M-1). 1H NMR (300 MHz,
DMSO-d6): 2.38 (s, 6H, CH3), 3.46 (s, 6H, OCH3), 3.90 (s, 6H, OCH3), 6.41 (s, 2H,
aryl H5), 10.96 (br s, 2H, NH). 13C NMR (75 MHz, DMSO-d6): 14.88 (CH3), 56.35,
57.89 (OCH3), 92.77 (aryl CH), 94.21, 126.30, 150.21, 156.95, 159.60, 172.84 (aryl
C). Mass Spectrum (MALDI): m/z (%) 465 (M+4, 42), 464 (M+3, 55), 463 (M+2,
100), 462 (M+1, 60), 461 (M, 92 ), 460 (78), 459 (54).
4,6-Dimethoxybenzimidazole-2,7-dicarbaldehyde (242)
To a solution of 7-formylbenzimidazole 163 (0.20 g, 0.9
mmol) in dioxan (15 mL) selenium dioxide (0.5 g, 4.5 mmol)
was added and the mixture was refluxed for 3 days. The
resulting precipitate was filtered off, the filtrate was concentrated and extracted with
ethyl acetate. The ethyl acetate was washed with water, dried over magnesium sulfate
and concentrated. The residue was chromatographed using dichloromethane/methanol
(95:05) as eluent to yield the 2,7-dialdehyde 242 as a yellow powder (0.143 g, 68%),
m.p. 184-186 °C. (Found: C, 56.65; H, 4.24; N, 11.94. C11H10N2O4 requires C, 56.41;
H, 4.30; N, 11.96 %). max (KBr): 3440, 1664, 1649, 1596, 1491, 1458, 1358, 1279,
1220, 1153, 992, 882, 797 cm-1. max (MeOH): 207 nm ( 19,500 cm-1M-1), 231
(16,300), 302 (16,400), 327 (11,700). 1H NMR (300 MHz, CDCl3): 4.04 (s, 3H,
OCH3), 4.20 (s, 3H, OCH3), 6.39 (s, 1H, aryl H5), 9.92 (s, 1H, CHO), 10.31 (s, 1H,
CHO), 11.40 (s br, 1H, NH). 13C NMR (75 MHz, CDCl3): 56.57, 56.83 (OCH3),
90.58 (aryl CH), 104.58, 129.47, 135.21, 147.34, 159.76, 164.98 (aryl C), 182.10,
187.16 (C=O). Mass Spectrum (+EI): m/z (%) 237 (M+3, 12), 236 (M+2,18), 235
(M+1,100), 221(4), 207(22).
4,6-Dimethoxy-2,7-dihydroxymethylbenzimidazole (243)
To a solution of 2,7-diformylbenzimidazole 242 (0.10 g,
0.427 mmol) in anhydrous methanol (20 mL), sodium
borohydride (0.2 g) was added portionwise and the mixture
was refluxed for 4 h. The solvent was concentrated and cooled before ice water was
NH
N
OMe
MeO
O
O
H
H
NH
N
OMe
MeO
OH
OH
Experimental 187
added. The resulting precipitate was filtered, washed with water, and recrystallized
from ethanol to yield the 2,7-dihydroxymethylbenzimidazole 243 (69 mg, 69%), m.p.
208-210 °C. HRMS (+ESI): C11H14N2O4 [M+Na]+ requires 261.0845, found 261.0845.
max (KBr): 3249, 2932, 1619, 1451, 1338, 1215, 1154, 1004, 787 cm-1. max (MeOH):
216 nm ( 29,600 cm-1M-1), 259 (7,500). 1H NMR (300 MHz, CDCl3): 3.78 (s, 3H,
OCH3), 3.92 (s, 3H, OCH3), 4.56 (s, 2H, CH2), 4.57 (s, 1H, OH), 4.67 (s, 2H, CH2),
4.75 (s, 1H, OH), 6.42 (s, 1H, aryl H5), 11.76 (br s, 1H, NH). Mass Spectrum (+EI):
m/z (%) 239 (M+1, 100), 237 (13), 221 ( 85).
Bis(4,6-dimethoxybenzimidazol-2-yl)methane (246)
To a solution of nitroaniline 279 (2.5 g, 5.38
mmol) in absolute ethanol/tetrahydrofuran (70
mL, 2:1), 10% Pd/C (0.5 g) was added and
the mixture refluxed under argon. Hydrazine monohydrate (5.2 mL, 107 mmol) was
added dropwise to this refluxing solution and the mixture refluxed overnight. The
solution was filtered hot and the filtrate was evaporated off. The solid residue was
redissolved in absolute ethanol (100 mL), made acidic by 5M hydrochloric acid and
refluxed for a further 22 h. The reaction mixture was concentrated and made basic by
20% sodium hydroxide solution. The resulting solid was filtered, washed with water
and recrystallized from ethanol/water as a yellow solid 246 (1.21 g, 61 %), m.p. 278-
280 °C (lit.120 >310 °C as dihydrochloride salt). (Found: C, 59.20 ; H, 5.64 ; N, 14.52
C19H20N4O4 0.9H2O requires C, 59.34; H, 5.71; N, 14.57 %). max (MeOH): 209 nm (
38,700 cm-1M-1), 253 (9,100), 283 (7,100), 406 (2,600). 1H NMR (300 MHz, CDCl3):
3.77 (s, 6H, OCH3), 3.88 (s, 6H, OCH3), 4.68 (s, 2H, CH2), 6.49 (d, J = 1.88 Hz, 2H,
aryl H5), 6.67 (d, J = 1.88 Hz, 2H, aryl H7), 7.74 (br s, 2H, NH). 13C NMR (75 MHz,
CDCl3): 27.11 (CH2), 56.13, 56.22 (OCH3), 88.98, 96.03 (aryl CH), 121.00, 136.36,
147.08, 148.60, 158.20 (aryl C). Mass Spectrum (+EI): m/z (%) 370 (M+2, 25%), 369
(M+1, 100).
N
NHMeO
OMe
N
NH OMe
OMe
Experimental 188
7-Bromo-4,6-dimethoxy-2-methylbenzimidazole (248) and
5,7-Dibromo-4,6-dimethoxy-2-methylbenzimidazole (249)
To a solution of benzimidazole 141 (0.10 g, 0.52 mmol) in absolute ethanol (10 mL)
N-bromosuccinimide was added and the mixture stirred at room temperature for 1 h.
The solvent was concentrated in vacuo and water added to the mixture, the resulting
precipitate was collected, washed with water and dried. The solid was then
chromatographed by preparative thin layer chromatography using
dichloromethane/ethyl acetate (9:1) as eluent to give two products.
(i) 7-Bromo-4,6-dimethoxy-2-methylbenzimidazole (248)
was obtained as an off white powder (79 mg, 56 %), m.p.
234-235 °C. (Found: C, 40.92; H, 3.64; N, 9.00.
C10H11BrN2O2 0.5CH2Cl2 requires C, 40.22; H, 3.86; N, 8.93
%). max (KBr): 3150, 3081, 1772, 1697, 1635, 1594, 1537, 1456, 1403, 1338, 1295,
1192, 1142, 1095, 1080, 994, 895, 849, 822 cm-1. max (MeOH): 216 nm ( 31,000 cm-
1M-1), 256 (6,800), 286 (3,200). 1H NMR (300 MHz, CDCl3): 2.59 (s, 3H, CH3),
3.93 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.43 (s, 1H, aryl H5), 8.67 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 14.78 (CH3), 56.01, 57.68 (OCH3), 92.38 (aryl CH),
148.65, 149.48, 152.66, 161.43, 165.06, 174.78 (aryl C). Mass Spectrum (+EI): m/z
(%) 274 (M+1, 81Br,11), 273 (M, 81Br,100), 272 (M+1, 79Br, 13), 271 (M, 79Br, 88),
215 (10), 194 (15), 193 (98).
(ii) 5,7-Dibromo-4,6-dimethoxy-2-methylbenzimidazole (249)
was obtained as an off white powder (43 mg, 23 %), m.p.
177-179 °C. (Found: C, 34.16; H, 2.78; N, 7.89.
C10H10Br2N2O2 requires C, 34.32; H, 2.88; N, 8.00 %). max
(KBr): 2935, 2837, 1537, 1455, 1391, 1342, 1229, 1115,
1079, 984, 967, 659 cm-1. max (MeOH): 216 nm ( 38,100 cm-1M-1), 253 (6,900), 290
(3,100). 1H NMR (300 MHz, CDCl3): 2.65 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 4.18
(s, 3H, OCH3), 6.91 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 14.68 (CH3),
61.12, 61.41 (OCH3), 105.08, 129.18, 136.13, 146.03, 148.69, 150.38, 150.97 (aryl
C). Mass Spectrum (+EI): m/z (%) 354 (M, 81/81Br, 4), 353 (M+1, 79/81Br, 41), 351
(M+1, 79/79Br, 100), 350 (M, 79/79Br, 3), 349 (51), 273 (15), 271(14), 193 (28), 179 (5).
NH
N
OMe
MeOMe
Br
NH
N
OMe
MeOMe
Br
Br
Experimental 189
This compound 249 was also prepared from a solution of benzimidazole 141 (0.10 g,
0.52 mmol) in dichloromethane (10 mL), triethylamine (0.1 mL), followed by slow
addition of bromine (0.05 mL, 0.97 mmol). The clear yellow solution turned to a
fluffy yellow suspension which was stirred for 15 min. Water was added to the
mixture and the organic layer was washed with water, and dried over magnesium
sulfate. The solvent was evaporated off and the residue dried as an off white solid to
afford the dibromobenzimidazole 249 (0.16 g, 88 %), m.p. 177-179 °C.
5,7-Dibromo-4,6-dimethoxy-2-methyl-1-tosylbenzimidazole (250)
To a solution of benzimidazole 227 (0.10 g, 0.28 mmol) in
carbon tetrachloride (10 mL), AIBN (4 mg) was added
followed by N-bromosuccinimide (0.12 g, 0.70 mmol) and the
mixture heated under reflux overnight. The reaction was
allowed to cool to room temperature, water was added and the
mixture extracted with dichloromethane. The organic extract
was washed with water, dried over magnesium sulfate and
evaporated off. The resulting solid was chromatographed to yield the 5,7-
dibromobenzimidazole 250 as an off white solid (68 mg, 49%), m.p. 138-140 °C. max
(KBr): 3435, 2923, 1623, 1452, 1414, 1341, 1236, 1217, 1160, 1123, 1079, 1034,
1010, 816, 681, 568 cm-1. max (MeOH): 217 nm ( 43,100 cm-1M-1). 1H NMR (300
MHz, CDCl3): 2.44 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.26 (s,
3H, OCH3), 7.30-7.34 (m, 2H, aryl H), 7.76-7.78 (m, 2H, aryl H). Mass Spectrum
(+EI): m/z (%) 507 (M+1, 81/81Br, 6), 506 (M, 81/81Br, 13), 505 (M+1, 79/81Br, 20), 503
(M+1, 79/79Br, 11), 351 (79/81Br, 100), 349 (79/79Br, 52), 289 (79/81Br, 21), 287 (79/79Br,
25).
N-(3,5-Dimethoxy-2-aminophenyl)cinnamide (253)
To a solution of nitrocinnamide 252 (1 g, 3.08 mmol)
in dry ethanol (25 mL), Pd/C (0.05 g, 10%) was added
followed by hydrazine monohydrate (3 mL) dropwise
over 15 min with stirring under argon at room temperature. The mixture was further
stirred under argon at room temperature for 4 h, and filtered through Celite. The
filtrate was concentrated under reduced pressure to give a yellow residue, and was
N
N
OMe
MeOS OO
Me
Me
Br
Br
OMe
NHCOCH=CHPhMeO
NH2
Experimental 190
dissolved in dichloromethane, washed with brine, and dried over magnesium sulfate.
The resulting solvent was evaporated off and the residue dried to yield the
aminocinnamide 253 as a yellow solid (0.52 g, 57%), m.p. 168-170 °C. (Found: C,
68.29; H, 6.25; N, 9.33. C17H18N2O3 requires C, 68.44; H, 6.08; N, 9.39 %). max
(KBr): 3375, 3000, 2938, 1661, 1610, 1530, 1498, 1450, 1336, 1220, 1202, 1167,
1151, 1053, 982, 835, 766 cm-1. max (MeOH): 208 nm ( 40,500 cm-1M-1), 282
(27,800). 1H NMR (300 MHz, CDCl3): 3.32 (s, 2H, NH2), 3.74 (s, 3H, OCH3), 3.81
(s, 3H, OCH3), 6.30 (s, 1H, aryl H4), 6.56 (d, = 16.15, 1H, =CH), ), 6.92 (s, 1H, aryl
H6), 7.34-7.36 (m, 3H, aryl H), 7.48-7.50 (m, 2H, aryl H), 7.73 (d, = 16.15, 1H,
CH=), 8.10 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.56, 55.68 (OCH3),
96.52, 99.16 (aryl CH), 120.48, 142.12 (CH=CH), 127.88, 128.72, 129.80 (aryl CH),
125.78, 127.78, 134.61, 150.74, 154.03 (aryl C), 163.99 (C=O). Mass Spectrum (+EI):
m/z 300 (M+2, 20), 299 (M+1, 100), 295 (4).
2-[(4,6-Dimethoxybenzimidazol-2-yl)methoxy)methyl]-4,6-methoxybenzimidazole
(254)
To a partially dissolved solution of 7-
hydroxymethylbenzimidazole 231 (50 mg,
0.24 mmol) in isopropanol (2 mL), a few
crystals of p-toluene sulfonic acid were added and the mixture heated to dissolve. The
stirring continued at 120°C for 4 h before cooling to room temperature. The resulting
precipitate was filtered, washed with cold isopropanol and dried to give the
benzimidazole 254 as a white solid (42 mg, 88%), m.p. 212-213 °C. (Found: C, 57.75;
H, 5.91; N, 13.27. C20H22N4O5 1.1H2O requires C, 57.44; H, 5.83; N, 13.40 %). max
(KBr): 3119, 2833, 2653, 1606, 1504, 1454, 1433, 1299, 1223, 1200, 1148, 1130,
1046, 818 cm-1. max (MeOH): 212 nm ( 37,300 cm-1M-1), 253 (8,500). 1H NMR (300
MHz, DMSO-d6): 3.76 (s, 6H, OCH3), 3.90 (s, 6H, OCH3), 4.68 (s, 4H, CH2), 6.45
(d, J = 1.89 Hz, 2H, aryl H5), 6.60 (d, J = 1.89 Hz, 2H, aryl H), 12.11 (br s, 2H, NH). 13C NMR (75 MHz, DMSO-d6): 55.76, 56.02 (OCH3), 58.04 (CH2), 87.23, 94.07
(aryl CH), 128.06, 136.20, 151.23, 152.39, 156.71 (aryl C). Mass Spectrum (+EI): m/z
(%) 399 (M+1, 17), 281 (24), 223 (17), 209 (100).
N
NHMeO
OMe
N
NH OMe
OMe
O
Experimental 191
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]benzenato
(2-)nickel(II) (255)
A mixture of benzimidazole 164 (0.20 g,
0.71 mmol), 1,2-diaminobenzene (39 mg,
0.365 mmol) and nickel(II) acetate
tetrahydrate (92 mg, 0.37 mmol) in
anhydrous methanol (30 mL) was refluxed
for 2 h under argon. The reaction mixture
was allowed to come to room temperature
and the resulting precipitate was filtered and washed with a little cold methanol to
give the metal complex 255 as a dark brown powder (0.23 g, 46%), m.p. 304-306 °C.
(Found: C, 58.67; H, 4.28; N, 10.65. C38H30N6NiO4 1.4CH2Cl2, requires C, 58.26; H,
4.07; N, 10.35 %). max (KBr): 3427, 1597, 1535, 1504, 1460, 1382, 1317, 1268,
1199, 1135, 1011 cm-1. max (MeOH): 206 nm ( 47,400 cm-1M-1), 272 (24,300), 309
(17,500), 458 (20,800). 1H NMR (300 MHz, CDCl3): 4.01 (s, 6H, OCH3), 4.17 (s,
6H, OCH3), 6.13 (s, 2H, aryl H5), 6.96-6.97 (m, 6H, aryl H), 7.29-7.31 (m, 2H, aryl
H), 7.70-7.72 (m, 2H, aryl H), 8.45-8.47 (m, 4 H, aryl H), 8.80 (br s, 2H, N=CH). 13C
NMR (75 MHz, CDCl3): 56.26, 58.04 (OCH3), 128.36, 127.18, 126.94, 126.63,
115.98 (aryl CH), 104.54, 131.74, 142.94, 143.76, 147.86, 157.90, 160.16 (aryl C),
173.12 (C=N). Mass Spectrum (+EI): m/z (%) 695 (M+2, 48), 694 (M+1, 49), 693 (M,
100).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]benzenato
(2-)cobalt(II) (256)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminobenzene (20 mg,
0.18 mmol) and cobalt(II) acetate
tetrahydrate (47 mg, 0.19 mmol) in
anhydrous methanol (20 mL) was refluxed
for 5 h under argon. The solvent was
evaporated off and the title metal complex
256 was recrystallized from acetonitrile as a dark brown powder (0.123 g, 85%), m.p.
>360 °C. Correct microanalysis for C38H30CoN6O4 could not be obtained. max (KBr):
N
NMeO
MeO N N
N
N OMe
OMe
Ni
N
NMeO
MeO N N
N
N OMe
OMe
Co
Experimental 192
3402, 1597, 1560, 1460, 1410, 1376, 1332, 1278, 1237, 1213, 1175, 1120, 995, 718
cm-1. max (MeOH): 208 nm ( 36,800 cm-1M-1), 248 (25,500), 371 (23,700). Mass
Spectrum (+EI): m/z (%) 695 (M+2, 50), 694 (M+1, 100).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]benzenato
(2-)copper(II) (257)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminobenzene (20 mg,
0.18 mmol) and copper (II) acetate
monohydrate (37 mg, 0.19 mmol) in
anhydrous methanol (15 mL) was refluxed
for 2 h under argon. The solvent was
evaporated off and the title metal complex 257 was recrystallized from acetonitrile as
a dark blue powder (52 mg, 40 %), m.p. >350 °C. (Found: C, 62.65; H, 4.53; N, 12.35.
C38H30CuN6O4 1.6H2O requires C, 62.77; H, 4.60; N, 11.56 %). max (KBr): 3399,
1596, 1540, 1454, 1380, 1321, 1275, 1217, 1129, 1005, 694 cm-1. max (MeOH): 205
nm ( 59,570 cm-1M-1), 254 (34,900), 361 (23,900). Mass Spectrum (+EI): m/z (%)
700 (M+2, 54), 699 (M+1, 42), 698 (M, 88), 399 (35), 385 (50), 371 (100).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]benzenato
(2-)zinc(II) (258)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminobenzene (20 mg,
0.18 mmol) and zinc(II) acetate dihydrate
(42 mg, 0.19 mmol) in anhydrous
methanol (20 mL) was refluxed for 6 h
under argon. The solvent was evaporated
off and the title metal complex 258 was recrystallized from acetonitrile as an orange
red powder (98 mg, 79%), m.p. >360 °C. (Found: C, 61.87; H, 5.20; N, 12.28.
C38H30N6O4Zn 1.2 H2O requires C, 61.73; H, 5.09; N, 12.34 %). max (KBr): 3417,
1590, 1551, 1511, 1460, 1409, 1380, 1331, 1300, 1279, 1213, 1121, 995 cm-1. max
(MeOH): 208 nm ( 22,100 cm-1M-1), 254 (17,400), 364 (20,300). 1H NMR (300
N
NMeO
MeO N N
N
N OMe
OMe
Cu
N
NMeO
MeO N N
N
N OMe
OMe
Zn
Experimental 193
MHz, CDCl3): 4.08 (s, 6H, OCH3), 4.14 (s, 6H, OCH3), 6.62 (s, 2H, aryl H5), 6.75-
6.80 (m, 6H, aryl H), 7.02-7.04 (m, 2H, aryl H), 7.43-7.44 (m, 2H, aryl H), 7.89-7.92
(m, 4 H, aryl H), 9.53 (br s, 2H, N=CH). Mass Spectrum (+EI): m/z (%) 703 (M+3,
61), 702 (M+2, 52), 701 (M+1, 100), 700 (M, 44), 699 (M-1, 98), 295 (43), 145 (22).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]benzenato
(2-)palladium(II) (259)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminobenzene (20 mg,
0.18 mmol) and palladium(II) acetate
(42.6 mg, 0.19 mmol) in anhydrous
methanol (15 mL) was refluxed for 2 h
under argon. The reaction was allowed to
come to room temperature, the resulting
precipitate was filtered and washed with a little cold methanol to give the metal
complex 259 as an orange powder (79 mg, 60%), m.p. 280-282 °C. (Found: C, 60.73;
H, 4.37; N, 11.21. C38H30N6O4Pd 0.6CH3OH requires C, 60.98; H, 4.30; N, 11.05 %).
max (KBr): 3417, 1595, 1537, 1502, 1457, 1380, 1318, 1269, 1196, 1129, 1009 cm-1.
max (MeOH): 205 nm ( 30,100 cm-1M-1), 258 (15,100), 306 (9,300). 1H NMR (300
MHz, DMSO-d6): 4.05 (s, 6H, OCH3), 4.15 (s, 6H, OCH3), 6.39 (s, 2H, aryl H5),
6.76-6.81 (m, 4H, aryl H), 6.91-6.94 (m, 2H, aryl H), 7.40-7.43 (m, 2H, aryl H), 7.62-
7.65 (m, 4H, aryl H), 8.05-8.08 (m, 2H, aryl H), 9.03 (s, 2H, N=CH). Mass Spectrum
(+EI): m/z (%) 746 (M+5, 17), 745 (M+4, 42), 744 (M+3, 48), 743 (M+2, 88), 742
(M+1, 48), 741 (M, 100), 740 (71), 739 (28).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]benzenato
(2-)manganese(II) (260)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminobenzene (20 mg,
0.18 mmol) and manganese(II) acetate
tetrahydrate (46 mg, 0.19 mmol) in
anhydrous methanol (15 mL) was refluxed
N
NMeO
MeO N N
N
N OMe
OMe
Mn
N
NMeO
MeO N N
N
N OMe
OMe
Pd
Experimental 194
for 2 h under argon. The reaction was allowed to come to room temperature, the
resulting precipitate was filtered and washed with a little cold methanol to give the
metal complex 260 as a yellow solid (0.11 g, 90%), m.p. >350 °C. (Found: C, 63.44;
H, 4.71; N, 11.78. C38H30MnN6O4 1.5H2O requires C, 63.69; H, 4.64; N, 11.73 %).
max (KBr): 3435, 1593, 1561, 1328, 1278, 1212, 1173, 1118, 992 cm-1. max (MeOH):
204 nm ( 94,600 cm-1M-1), 239 (57,400), 355 (56,300). Mass Spectrum (+EI): m/z
(%) 691 (M+2, 3), 690 (M+1, 3), 689 (M, 2), 373 (15), 283 (100).
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]benzenato(2-)nickel(II) (261)
A mixture of benzimidazole 165 (0.10
g, 0.32 mmol), 1,2-diaminobenzene (17
mg, 0.16 mmol) and nickel(II) acetate
tetrahydrate (42 mg, 0.17 mmol) in
anhydrous methanol (20 mL) was
refluxed for 16 h under argon. The
solvent was evaporated off and the title
metal complex 261 was recrystallized
from acetonitrile as a dark brown powder (85 mg, 70%), m.p. 272-274 °C. (Found: C,
62.96; H, 4.68; N, 10.85. C40H34N6NiO6 0.5H2O requires C, 63.01; H, 4.63; N, 11.02
%). max (KBr): 3421, 1603, 1536, 1501, 1465, 1382, 1313, 1260, 1200, 1183, 1135,
1032, 830, 744 cm-1. max (MeOH): 204 nm ( 57,200 cm-1M-1), 275 (29,800), 430
(20,000). 1H NMR (300 MHz, CDCl3): 3.69 (s, 6H, OCH3), 4.01 (s, 6H, OCH3),
4.17 (s, 6H, OCH3), 6.09 (s, 2H, aryl H5), 6.46 (d, J = 8.64 Hz, 4H, aryl H), 7.25-7.27
(m, 2H, aryl H), 7.67-7.70 (m, 2H, aryl H), 8.38 (d, J = 8.64 Hz, 4H, aryl H), 8.79 ( s,
2H, N=CH). 13C NMR (75 MHz, CDCl3): 55.01, 56.29, 57.91 (OCH3), 89.91,
112.18, 115.98, 126.93, 129.79 (aryl CH), 104.51, 124.56, 128.21, 143.04, 143.70,
147.92, 157.41, 159.14, 159.91 (aryl C), 172.70 (C=N). Mass Spectrum (+EI): m/z
(%) 756 (M+3, 20), 754 (M+1, 41), 753 (M, 100).
NN
MeO
MeON N
NN
OMe
OMe
Ni
MeOOMe
Experimental 195
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]benzenato(2-)cobalt(II) (262)
A mixture of benzimidazole 165 (0.10
g, 0.32 mmol), 1,2-diaminobenzene (17
mg, 0.16 mmol) and cobalt(II) acetate
tetrahydrate (42 mg, 0.17 mmol) in
anhydrous methanol (20 mL) was
refluxed for 2 h under argon. The
solvent was evaporated off and the title
metal complex 262 was recrystallized
from acetonitrile as a red powder (0.10 g, 83%), m.p. >350 °C. Correct microanalysis
for C40H34CoN6O6 could not be obtained. max (KBr): 3415, 1610, 1558, 1410, 1333,
1280, 1177, 1119 cm-1. max (MeOH): 203 nm ( 76,400 cm-1M-1), 239 (45,600), 277
(42,200), 371 (47,000). Mass Spectrum (+EI): m/z (%) 755 (M+2, 47), 754 (M+1,
100).
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]benzenato(2-)copper(II) (263)
A mixture of benzimidazole 165 (0.10 g,
0.32 mmol), 1,2-diaminobenzene (17 mg,
0.16 mmol) and copper(II) acetate
monohydrate (34 mg, 0.17 mmol) in
anhydrous methanol (20 mL) was refluxed
for 2 h under argon. The solvent was
evaporated off and the title metal complex
263 was recrystallized from chloroform and
ether as a dark brown solid (0.11 g, 92%), m.p. 234-235 °C. (Found: C, 61.59; H,
4.45; N, 11.00. C40H34CuN6O6 0.2CHCl3 requires C, 61.73; H, 4.41; N, 10.74 %). max
(KBr): 3418, 1608, 1538, 1458, 1378, 1313, 1272, 1176, 1129 cm-1. max (MeOH):
204 nm ( 76,400 cm-1M-1), 249 (34,300), 359 (31,400). Mass Spectrum (+EI): m/z
(%) 761 (M+3, 24), 760 (M+2, 54), 759 (M+1, 47), 758 (M, 100), 313 (39).
NN
MeO
MeON N
NN
OMe
OMe
Co
MeOOMe
NN
MeO
MeON N
NN
OMe
OMe
Cu
MeOOMe
Experimental 196
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]benzenato(2-)zinc(II) (264)
A mixture of benzimidazole 165 (0.10 g,
0.32 mmol), 1,2-diaminobenzene (17
mg, 0.16 mmol) and zinc(II) acetate
dihydrate (37 mg, 0.17 mmol) in
anhydrous methanol (20 mL) was
refluxed for 2 h under argon. The
solvent was evaporated off and the title
metal complex 264 was recrystallized
from acetonitrile as an orange powder (0.11 g, 97 %), m.p. >350 °C. (Found: C, 58.74;
H, 4.45; N, 10.04. C40H34N6O6Zn 0.9CH2Cl2 requires C, 58.72; H, 4.31; N, 10.05 %).
max (KBr): 3432, 1610, 1561, 1410, 1332, 1178, 1117, 838 cm-1. max (MeOH): 203
nm ( 60,400 cm-1M-1), 260 (35,000), 365 (47,900). 1H NMR (300 MHz, DMSO-d6):
3.58 (s, 6H, OCH3), 4.04 (s, 6H, OCH3), 4.14 (s, 6H, OCH3), 6.17 (d, J = 8.64 Hz,
4H, aryl H), 6.42 (s, 2H, aryl H5), 7.12 (d, J = 8.64 Hz, 4H, aryl H), 7.35-7.38 (m, 2H,
aryl H), 7.83-7.85 (m, 2H, aryl H), 9.49 (s, 2H, N=CH). 13C NMR (75 MHz, DMSO-
d6): 54.97, 57.11, 57.21 (OCH3), 89.72, 112.18, 116.64, 127.66, 128.77 (aryl CH),
103.80, 125.78, 140.33, 146.08, 153.23, 156.58, 158.77, 159.80, 160.09 (aryl C).
Mass Spectrum (+EI): m/z (%) 760 (M, 4), 759 (3), 758 (5), 403 (16), 313 (100).
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]benzenato(2-)palladium(II) (265)
A mixture of benzimidazole 165 (0.10
g, 0.32 mmol), 1,2-diaminobenzene (17
mg, 0.16 mmol) and palladium(II)
acetate (38 mg, 0.17 mmol) in
anhydrous methanol (20 mL) was
refluxed for 4 h under argon. The
reaction was allowed to come to room
temperature, the resulting precipitate
was filtered and washed with a little cold methanol to give the metal complex 265 as a
brown powder (81 mg, 63%), m.p. 205-206 °C. Correct microanalysis for
NN
MeO
MeON N
NN
OMe
OMe
Zn
MeOOMe
NN
MeO
MeON N
NN
OMe
OMe
Pd
MeOOMe
Experimental 197
C40H34N6O6Pd could not be obtained. max (KBr): 3443, 1632, 1608, 1490, 1345,
1260, 1213, 1125, 987 cm-1. max (MeOH): 203 nm ( 1,21,700 cm-1M-1), 296
(1,15,800), 347 (70,100). 1H NMR (300 MHz, CDCl3): 3.89 (s, 6H, OCH3), 4.05 (s,
6H, OCH3), 4.18 (s, 6H, OCH3), 6.41 (s, 2H, aryl H5), 7.07 (d, J = 9.03 Hz, 2H, aryl
H), 7.10 (d, J = 8.67 Hz, 4H, aryl H), 7.99 (d, J = 9.03 Hz, 2H, aryl H), 8.35 (d, J =
8.67 Hz, 4H, aryl H), 8.99 (s, 2H, N=CH). Mass Spectrum (MALDI): m/z (%) 807
(15), 806 (31), 805 (62), 804 (64), 803 (83), 802 (75), 801 (100), 800 (68), 799 (27).
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]benzenato(2-)manganese(II) (266)
A mixture of benzimidazole 165 (0.10
g, 0.32 mmol), 1,2-diaminobenzene (17
mg, 0.16 mmol) and manganese(II)
acetate tetrahydrate (42 mg, 0.17 mmol)
in anhydrous methanol (20 mL) was
refluxed for 2 h under argon. The
solvent was evaporated off and the title
metal complex 266 was recrystallized
from acetonitrile as a yellow solid (0.11 g, 91%), m.p. >350°C. Correct microanalysis
for C40H34MnN6O6 could not be obtained. max (KBr): 3421, 1609, 1562, 1410, 1329,
1171, 1115 cm-1. max (MeOH): 203 nm ( 46,500 cm-1M-1), 239 (28,000), 274
(24,000), 357 (27,600). Mass Spectrum (+EI): m/z (%) 752 (M+3, 20), 751 (M+2, 51),
750 (M+1, 78), 698 (25), 697 (50), 401 (20), 313 (100).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]ethanato(2-)
nickel(II) (267)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminoethane (11 mg,
0.18 mmol) and nickel(II) acetate
tetrahydrate (47 mg, 0.19 mmol) in
anhydrous methanol (20 mL) was refluxed
for 16 h under argon. The reaction mixture was concentrated and the resulting
precipitate was filtered and washed with a little cold methanol to give the title metal
NN
MeO
MeON N
NN
OMe
OMe
Ni
NN
MeO
MeON N
NN
OMe
OMe
Mn
MeOOMe
Experimental 198
complex 267 as a dark brown solid (47 mg, 41%), m.p. 180-182 °C. Correct
microanalysis for C34H30N6NiO4 could not be obtained. max (KBr): 3407, 2941, 1627,
1595, 1455, 1407, 1320, 1212, 1169, 1132 cm-1. max (MeOH): 205 nm ( 39,100 cm-
1M-1), 241 (30,300, 339 (24,900). 1H NMR (300 MHz, CDCl3): 3.68 (s, 4H, CH2),
3.98 (s, 6H, OCH3), 4.10 (s, 6H, OCH3), 6.09 (s, 2H, aryl H5), 6.90-6.92 (m, 6H, aryl
H), 8.16 (s, 2H, N=CH), 8.31-8.32 (m, 4H, aryl H). Mass Spectrum (MALDI): m/z
(%) 648 (M+3, 33), 647 (M+2, 61), 646 (M+1, 76), 645 (M, 100 ).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]ethanato(2-)
cobalt(II) (268)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminoethane (11 mg,
0.18 mmol) and cobalt(II) acetate
tetrahydrate (47 mg, 0.19 mmol) in
anhydrous methanol (20 mL) was refluxed for 2 h under argon. The solvent was
evaporated off and the title metal complex 268 was recrystallized from acetonitrile as
a dark brown powder (31 mg, 27%), m.p. >350 °C. Correct microanalysis for
C34H30CoN6O4 could not be obtained. max (KBr): 3417, 1595, 1565, 1460, 1412,
1315, 1222, 1171, 1127 cm-1. max (MeOH): 204 nm ( 44,500 cm-1M-1), 223 (35,700),
249 (28,200), 343 (26,500). Mass Spectrum (+EI): m/z (%) 647 (M+2, 37), 646 (M+1,
100).
1,2-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]ethanato(2-)
palladium(II) (269)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,2-diaminoethane (11 mg,
0.18 mmol) and palladium(II) acetate (42
mg, 0.19 mmol) in anhydrous methanol (20
mL) was refluxed for 2 h under argon. The
solvent was evaporated off and the title metal complex 269 was obtained from
acetonitrile as a light green cream solid (42 mg, 34%), m.p. 60°C. Correct
microanalysis for C34H30N6O4Pd could not be obtained. max (KBr): 3418, 3071, 1595,
NN
MeO
MeON N
NN
OMe
OMe
Co
NN
MeO
MeON N
NN
OMe
OMe
Pd
Experimental 199
1572, 1453, 1409, 1319, 1230, 1179, 1136 cm-1. max (MeOH): 204 nm ( 46,200 cm-
1M-1), 224 (37,400), 243 (28,600), 349 (27,900). ). Sample too insoluble for 1H NMR
measurement. Mass Spectrum (+EI): m/z (%) 698 (M+5, 14), 697 (M+4, 39), 696
(M+3, 28), 695 (M+2, 81), 694 (M+1, 38), 693 (M, 100), 692 (69), 691 (34), 431 (24),
429 (28), 427 (20), 283 (25), 280 (13).
1,2-Bis[2-(4'-methoxyphenyl)-4,6-dimethoxybenzimidazol-7-
ylidenamino]ethanato(2-)nickel(II) (270)
A mixture of benzimidazole 165 (0.10
g, 0.32 mmol), 1,2-diaminoethane (10
mg, 0.16 mmol) and nickel(II) acetate
tetrahydrate (42 mg, 0.17 mmol) in
anhydrous methanol (30 mL) was
refluxed for 2 h under argon. The
solvent was evaporated off and the title metal complex 270 was recrystallized from
ether as a brown powder (0.10 g, 89%), m.p. 212-214 °C. Correct microanalysis for
C36H34N6NiO6 could not be obtained. max (KBr): 3413, 2939, 2840, 1608, 1573, 1451,
1407, 1313, 1246, 1222, 1174, 1117, 1029, 994, 837 cm-1. max (MeOH): 203 nm (
64,900 cm-1M-1), 227 (54,000), 258 (37,900), 338 (42,300). 1H NMR (300 MHz,
CDCl3): 3.58 (s, 4H, CH2), 3.73 (s, 6H, OCH3), 3.94 (s, 6H, OCH3), 4.02 (s, 6H,
OCH3), 6.24 (s, 2H, aryl H5), 6.32 (d, J = 8.67 Hz, 4H, aryl H), 8.02 (d, J = 8.67 Hz,
4H, aryl H), 8.27 (s, 2H, NCH). Mass Spectrum (+EI): m/z (%) 707 (M+2, 6), 706
(M+1, 6), 705 (M, 9), 411 (60), 355 (100), 313 (53).
1,3-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]propanato(2-)
nickel(II) (271)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,3-diaminopropane (13 mg,
0.18 mmol) and nickel(II) acetate
tetrahydrate (47 mg, 0.19 mmol) in
anhydrous methanol (20 mL) was refluxed
for 16 h under argon. The solvent was
evaporated off and the title metal complex 271 was recrystallized from acetonitrile as
NN
MeO
MeON N
NN
OMe
OMe
Ni
NN
MeO
MeON N
NN
OMe
OMe
Ni
MeOOMe
Experimental 200
a brown solid (0.10 g, 90%), m.p. 270-272 °C. Correct microanalysis for
C35H32N6NiO4 could not be obtained. max (KBr): 3407, 2936, 1595, 1569, 1456,
1387, 1317, 1276, 1230, 1210, 1174, 1134 cm-1. max (MeOH): 206 nm ( 52,100 cm-
1M-1), 224 (44,600), 247 (37,500), 348 (37,300). 1H NMR (300 MHz, CDCl3): 2.90
(s, 2H, CH2), 3.56 (s, 4H, CH2), 3.90 (s, 6H, OCH3), 4.11 (s, 6H, OCH3), 6.32 (s, 2H,
aryl H5), 7.39-7.47 (m, 6H, aryl H), 8.06-8.08 (m, 4H, aryl H), 8.86 (s, 2H, N=CH).
Mass Spectrum (+EI): m/z (%) 662 (M+3, 21), 661 (M+2, 42), 660 (M+1, 31), 659
(M, 100).
1,4-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]butanato(2-)
nickel(II) (272)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,4-diaminobutane (16 mg,
0.18 mmol) and nickel(II) acetate
tetrahydrate (47 mg, 0.19 mmol) in
anhydrous methanol (20 mL) was refluxed
for 2 h under argon. The solvent was evaporated off and the title metal complex
272was recrystallized from ether as a dark brown powder (0.11 g, 92%), m.p. 140-142
°C. (Found: C, 62.23; H, 5.24; N, 11.93. C36H34N6NiO4 1.2H2O C, 62.21; H, 5.28; N,
12.09 %). max (KBr): 3390, 2935, 1595, 1564, 1455, 1389, 1317, 1237, 1229, 1172,
1132, 1009, 719 cm-1. max (MeOH): 203 nm ( 55,100 cm-1M-1), 262 (30,700), 386
(25,900). Sample too insoluble for 1H NMR. .Mass Spectrum (+EI): m/z (%) 677
(M+4, 11), 676 (M+3, 19), 675 M+2, 47), 674 (M+1, 42), 673 (M, 100).
1,4-Bis[2-phenyl-4,6-dimethoxybenzimidazol-7-ylidenamino]butanato(2-)
cobalt(II) (273)
A mixture of benzimidazole 164 (0.10 g,
0.35 mmol), 1,4-diaminobutane (16 mg,
0.18 mmol) and cobalt(II) acetate
tetrahydrate (47 mg, 0.19 mmol) in
anhydrous methanol (20 mL) was refluxed
for 2 h under argon. The solvent was evaporated off and the title metal complex 273 as
recrystallized from ether as a dark brown powder (0.11 g, 92%), m.p. 198-200 °C.
NN
MeO
MeON N
NN
OMe
OMe
Ni
NN
MeO
MeON N
NN
OMe
OMe
Co
Experimental 201
Correct microanalysis for C36H34CoN6O4 could not be obtained. max (KBr): 3410,
2938, 1596, 1563, 1456, 1390, 1318, 1276, 1230, 1211, 1174, 1127, 1009 cm-1. max
(MeOH): 204 nm ( 78,000 cm-1M-1), 293 (26,200), 355 (42,400). Mass Spectrum
(+EI): m/z (%) 676 (M+3, 11), 675 (M+2, 45), 674 (M+1, 100).
Bis(7-carbaldehyde-4,6-dimethoxy-2-phenylbenzimidazol-1-yl)cobalt(II) (274)
A mixture of benzimidazole 164 (0.10 g, 0.35 mmol)
and copper(II) acetate monohydrate (37 mg, 0.19
mmol) in anhydrous methanol (15 mL) was refluxed
for 2 h under argon. The solvent was evaporated off
and the title metal complex 274 as recrystallized
from acetonitrile as a brown powder (53 mg, 48%),
m.p. 328-330 °C. (Found: C, 55.74; H, 3.93; N, 7.97.
C32H26CuN4O6 CH2Cl2 requires C, 55.74; H, 3.97;
N, 7.88 %). max (KBr): 3422, 1609, 1572, 1453, 1393, 1326, 1215, 1172, 1119 cm-1.
max (MeOH): 206 nm ( 21,600 cm-1M-1). Mass Spectrum (+EI): m/z (%) 630 (M+4,
12), 629 (M+3, 36), 628 (M+2, 16), 627 (M+1, 82), 386 (100).
Bis(7-carbaldehyde-4,6-dimethoxy-2-phenylbenzimidazol-1-yl)palladium(II)
(275)
A mixture of benzimidazole 164 (0.10 g, 0.35
mmol) and palladium(II) acetate (42 mg, 0.19
mmol) in anhydrous methanol (15 mL) was
refluxed for 6 h under argon. The reaction was
allowed to come to room temperature, the resulting
precipitate was filtered and washed with a little cold
methanol to give the metal complex 275 s a yellow
powder (28 mg, 24%), m.p. 206-208 °C. Correct microanalysis for C32H26N4O6Pd
could not be obtained. max (KBr): 3279, 1602, 1450, 1376, 1264, 1211, 1160, 1118,
780, 693 cm-1. max (MeOH): 207 nm ( 75,400 cm-1M-1), 242 (46,400), 296 (65,700),
343 (47,100). 1H NMR (300 MHz, CDCl3): 4.02 (s, 6H, OCH3), 4.19 (s, 6H, OCH3),
6.35 (s, 2H, aryl H5), 7.50-7.53 (m, 6H, aryl H), 8.16-8.19 (m, 4H, aryl H), 10.31 (s,
N
N
OMe
MeO
OH
N
N
OMe
OMe
O HCu
N
N
OMe
MeO
OH
N
N
OMe
OMe
O HPd
Experimental 202
2H, CHO). Mass Spectrum (MALDI): m/z (%) 675 (15), 674 (28), 673 (52), 672 (82),
671 (77), 670 (80), 669 (M, 100), 668 (69), 667 (38), 666 (18).
Bis(7-carbaldehyde-4,6-dimethoxy-2-phenylbenzimidazol-1-yl)manganese(II)
(276)
A mixture of benzimidazole 164 (0.10 g, 0.35
mmol) and manganese(II) acetate tetrahydrate (46
mg, 0.19 mmol) in anhydrous methanol (15 mL)
was refluxed for 2 h under argon. The solvent was
evaporated off and the title metal complex 276 was
recrystallized from acetonitrile as a brown powder
(87 mg, 80%), m.p. 208-210 °C. Correct
microanalysis for C32H26MnN4O6 could not be obtained. max (KBr): 3430, 1599,
1451, 1385, 1347, 1274, 1211, 1168, 1122, 990 cm-1. max (MeOH): 205 nm ( 50,400
cm-1M-1), 243 (30,400), 293 (43,500), 343 (31,400). Mass Spectrum (+ESI): m/z (%)
622 (M+5, 46), 621 (M+4, 32), 620 (M+3, 48), 619 (M+2, 100), 618 (M+1, 27), 617
(M, 15).
Bis[7-carbaldehyde-4,6-dimethoxy-2-(4'-methoxyphenyl)benzimidazol-1-
yl]copper(II) (277)
A mixture of benzimidazole 165 (0.10 g, 0.32
mmol) and copper(II) acetate monohydrate (42
mg, 0.17 mmol) in anhydrous methanol (20 mL)
was refluxed for 2 h under argon. The reaction was
allowed to come to room temperature, the resulting
precipitate was filtered and washed with a little
cold methanol to give the metal complex 277 as a
green solid (52 mg, 47 %), m.p. >350 °C. Correct microanalysis for C34H30CuN4O8
could not be obtained. max (KBr): 3431, 1609, 1564, 1455, 1328, 1249, 1218, 1177,
1130, 1028 cm-1. max (MeOH): 209 nm ( 20,900 cm-1M-1), 295 (16,000), 347
(12,400). Mass Spectrum (+EI): m/z (%) 689 (M+3, 3), 688 (M+2, 5), 687 (M+1, 5),
686 (M, 8), 313 (100).
N
N
OMe
MeO
OH
N
N
OMe
OMe
O HMn
N
N
OMe
MeO
OH
N
N
OMe
OMe
O HCu
OMe
MeO
Experimental 203
Bis[7-carbaldehyde-4,6-dimethoxy-2-(4'-methoxyphenyl)benzimidazol-1-
yl]palladium(II) (278)
A mixture of benzimidazole 165 (0.10 g, 0.32
mmol) and palladium(II) acetate (42 mg, 0.17
mmol) in anhydrous methanol (20 mL) was
refluxed for 6 h under argon. The reaction mixture
was allowed to come to room temperature, the
resulting precipitate was filtered and washed with
a little cold methanol to give the metal complex
278 as a dark brown powder (59 mg, 50 %), m.p. 200-202 °C. (Found: C, 49.78; H,
4.00; N, 6.44. C34H30N4O8Pd 1.5CH2Cl2 requires C, 49.78; H, 3.88; N, 6.54 %). max
(KBr): 3295, 1605, 1464, 1258, 1213, 1176, 1125, 986 cm-1. max (MeOH): 206 nm (
49,300 cm-1M-1), 297 (43,600), 347 (26,700). ). 1H NMR (300 MHz, DMSO-d6):
3.81 (s, 6H, OCH3), 3.98 (s, 6H, OCH3), 4.10 (s, 6H, OCH3), 6.56 (s, 2H, aryl H5),
7.02 (d, J = 8.64 Hz, 4H, aryl H), 8.18 (d, J = 8.64 Hz, 4H, aryl H), 10.27 (s, 2H,
CHO). Mass Spectrum (+EI): m/z (%) 731 (M+2, 20), 730 (M+1, 10), 729 (M, 27),
728 (11), 727 (9), 313 (100).
N1,N3-Bis(3,5-dimethoxy-2-nitrophenyl)isophthalamide (280)
To a solution of nitroaniline 150 (5
g, 25.25 mmol) in dry
tetrahydrofuran (100 mL)
containing anhydrous potassium carbonate (5 g) isophthaloyl chloride (5.2 g, 25.25
mmol) was added portionwise to this solution. The mixture was stirred under argon
for 3 days, followed by addition of water. The resulting precipitate was filtered,
washed with water and recrystallized from ethanol to afford the isophthalamide 280 as
a yellow powder (3.11 g, 47%), m.p. 227-228 C. (Found: C, 54.81; H, 4.28 ; N, 10.49.
C24H22N4O10 requires C, 54.75; H, 4.21; N, 10.64 %). max (KBr): 3328, 3164, 1661,
1627, 1558, 1456, 1420, 1326, 1203, 1158, 1061, 973, 831, 745, 676 cm-1. max
(MeOH): 208 nm ( 87,200 cm-1M-1), 225 (53,000), 316 (26,800). 1H NMR (300
MHz, CDCl3): 3.92 (s, 6H, OCH3), 3.93 (s, 6H, OCH3), 6.35 (d, J = 2.64 Hz, 2H,
aryl H4), 7.64-7.69 (m, 1H, aryl H), 7.94 (d, J = 2.64 Hz, 2H, aryl H6), 8.06-8.09 (m,
N
N
OMe
MeO
OH
N
N
OMe
OMe
O HPd
OMe
MeO
OMe
NHCO
OMe
OMe
NO2 O2N
OCHNMeO
Experimental 204
2H, aryl H), 8.51 (s, 1H, aryl H), 10.42 ( s, 2H, NH). 13C NMR (75 MHz, CDCl3):
55.96, 56.64 (OCH3), 96.10, 97.58, 126.60, 129.63, 130.58 (aryl CH), 125.17, 134.92,
135.66, 155.93, 163.82 (aryl C), 164.35 (C=O). Mass Spectrum (+EI): m/z (%) 528
(M+2, 30), 527 (M+1, 100), 497 (22), 496 (18), 483(14), 482 (20), 481 (54).
N1,N4-Bis(3,5-dimethoxy-2-nitrophenyl)terephthalamide (281)
This terephthalamide 281 was
prepared as described for the
compound 280 from a solution of
nitroaniline 150 (5 g, 25.25
mmol) in dry tetrahydrofuran (120 mL), anhydrous potassium carbonate (5 g) and
terephthaloyl chloride (3.07 g, 15.15 mmol) for 5 days as a yellow solid (3.39 g,
51%), m.p. 287 °C. (Found: C, 54.71; H, 4.25; N, 10.37. C24H22N4O10 requires C,
54.75; H, 4.21; N, 10.64 %). max (KBr): 3362, 2945, 1722, 1695, 1605, 1556, 1493,
1454, 1419, 1280, 1206, 1119, 1069, 939, 838, 719 cm-1. max (MeOH): 205 nm (
64,600 cm-1M-1). 1H NMR (300 MHz, DMSO-d6): 3.31(s, 6H, OCH3), 3.87 (s, 6H,
OCH3), 6.72 (s, 2H, aryl H4,6), 7.89-8.01 (m, 4H, aryl H), 10.54 (br s, 2H, NH). 13C
NMR (75 MHz, DMSO-d6): 56.41, 57.30 (OCH3), 97.59, 103.79, 128.30 (aryl CH),
130.84, 133.19, 136.83, 153.88, 161.88 (aryl C), 165.28 (C=O). Mass Spectrum (-EI):
m/z (%) 526 (M, 22), 525 (M-1, 100), 373 (15), 345 (6), 285 (10), 253 (12), 235 (9).
N1,N3-Bis(3,5-dimethoxy-2-aminophenyl)malonamide (282)
To a refluxing solution of nitroamide
279 (2.50 g, 5.38 mmol) in absolute
ethanol and tetrahydrofuran (100 mL,
3:2), 10% Pd/C (0.50 g) was added under argon followed by hydrazine monohydrate
(5.2 mL) dropwise over 15 min and reflux continued for another 20 h. The solution
was filtered and solvent was removed under reduced pressure and the residue was
dissolved in dichloromethane, washed with brine, and dried over magnesium sulfate.
The organic solvent was removed under reduced pressure to yield the aminoamide 282
as a light yellow solid (1.80 g, 84 %), m.p. 238-240 °C. max (KBr): 3112, 3000, 2985,
2831, 1634, 1603, 1496, 1450, 1357, 1311, 1223, 1192, 1043, 1027, 993, 931 cm-1.
MeO
OMe
NHCO
NO2
OMe
OMe
O2N
OCHN
OMe
NHCOCH2COHN
OMe
OMe
NH2 H2N
MeO
Experimental 205
max (MeOH): 210 nm ( 63,900 cm-1M-1), 252 (15,900), 284 (12,600).1H NMR (300
MHz, CDCl3): 3.72 (s, 6H, OCH3), 3.76 (s, 6H, OCH3), 4.69 (s, 2H, CH2), 6.26 (d, J
= 1.80 Hz, 2H, aryl H4), 6.49 (d, J = 1.80 Hz, 2H, aryl H6), 9.74 (br s, 2H, NH). 13C
NMR (75 MHz, CDCl3): 24.92 (CH2), 55.33, 55.64 (OCH3), 87.89, 94.41 (aryl CH),
124.92, 136.66, 147.41, 149.60 (aryl C), 157.60 (C=O). Mass Spectrum (+ESI): m/z
405.
N1,N3-Bis(2-amino-3,5-dimethoxyphenyl)isophthalamide (283)
To a refluxing solution of
nitroamide 280 (1 g, 1.90 mmol) in
anhydrous N,N-
dimethylformamide (20 mL), 30% Pd/C (0.10 g) was added under argon followed by
hydrazine monohydrate (1.80 mL) dropwise over 15 min and reflux continued for
another 3 h. The solution was filtered and the filtrate was concentrated under reduced
pressure. Water was added to the mixture and the resulting precipitate was filtered,
washed with water and dried to yield the diamine 283 as a light yellow solid (0.73 g,
82%), m.p. 206-207 °C. HRMS (+ESI): C24H26N4O6 [M+Na]+ requires 489.1744,
found 489.1751. max (KBr): 3381, 3195, 1634, 1606, 1536, 1452, 1418, 1363, 1222,
1201, 1151, 1042, 993, 812, 698 cm-1. max (MeOH): 207 nm ( 45,100 cm-1M-1), 249
(21,900), 312 (23,200). 1H NMR (300 MHz, DMSO-d6): 3.78 (s, 6H, OCH3), 3.92
(s, 6H, OCH3), 6.37 (s, 2H, aryl H4), 6.64 (s, 2H, aryl H6), 7.60-7.65 (m, 1H, aryl H),
8.13-8.92 (m, 3H, aryl H), 12.89 (s, 2H, NH). 13C NMR (75 MHz, DMSO-d6):
55.37, 55.80 (OCH3), 96.99, 102.35, 127.29, 128.53, 130.68 (aryl CH), 123.97,
134.65, 138.00, 148.56, 150.71(aryl C), 164.57 (C=O). Mass Spectrum (+EI): m/z (%)
467 (M+1, 8), 466 (M, 26), 254 (10), 167 (100), 140 (23), 76 (20).
N1,N4-Bis(2-amino-3,5-dimethoxyphenyl)terephthalamide (284)
To a refluxing solution of
nitroamide 281 (0.50 g, 0.95
mmol) in absolute
ethanol/tetrahydrofuran (50 mL,
1:1), 10% Pd/C (0.05 g) was added under argon followed by hydrazine monohydrate
MeO
OMe
NHCO
NH2
OMe
OMe
H2N
OCHN
OMe
NHCO
OMe
OMe
NH2 H2N
OCHNMeO
Experimental 206
(0.90 mL) dropwise over 5 min and reflux continued overnight. The solution was
filtered hot and the filtrate was concentrated under reduced pressure to give a
precipitate which was filtered, washed with water and dried to yield the diamine 284
as a light yellow solid (0.32 g, 72%), m.p. >360 °C. HRMS (+ESI): C24H26N4O6
[M+Na]+ requires 489.1745, found 489.1750. max (KBr): 3409, 3271, 1635, 1595,
1531, 1492, 1460, 1421, 1375, 1318, 1282, 1202, 1154, 1058, 895, 822, 678 cm-1. max
(MeOH): 211 nm ( 3,900 cm-1M-1). 1H NMR (300 MHz, DMSO-d6): 3.66 (s, 6H,
OCH3), 3.79 (s, 6H, OCH3), 4.23 (br s, 4H, NH2), 6.45 (s, 2H, aryl H4), 6.55 (s, 2H,
aryl H6), 8.00-8.07 (m, 4H, aryl H), 9.88 (br s, 2H, NH). 13C NMR (75 MHz, DMSO-
d6): 55.75, 56.18 (OCH3), 97.48, 102.78, 128.13 (aryl CH), 124.32, 125.92, 137.26,
148.89, 151.14 (aryl C), 164.69 (C=O). Mass Spectrum (+EI): m/z (%) 468 (M+2, 46),
467 (100), 438 (12), 431 (15), 331 (11), 255 (18), 114 (11).
2-[3-(4,6-Dimethoxybenzimidazol-2-yl)phenyl]-4,6-dimethoxybenzimidazole (285) and 2-
[3-(5,7-Dimethoxybenzimidazol-2-yl)phenyl]-5,7-dimethoxybenzimidazole (287)
To a solution of diamine 283 (0.50 g, 1.07 mmol) in absolute ethanol (50 mL) a few
drops of concentrated hydrochloric acid were added and the mixture refluxed
overnight. The reaction mixture was allowed to come to room temperature before
water was added and made basic with 2 M sodium hydroxide solution. The resulting
precipitate was filtered, washed with water and recrystallized from ethanol to yield the
bisbenzimidazole 285 and 287 as a tautomeric mixture (1:0.38) as a brown powder
(0.31 g, 67%), m.p. 210-212 °C. HRMS (+ESI): C24H22N4O4 [M+H]+ requires
431.1714, found 431.1718. max (KBr): 3380, 1629, 1606, 1506, 1451, 1418, 1361,
1221, 1200, 1149, 1042, 811, 700 cm-1. max (MeOH): 207 nm ( 49,300 cm-1M-1),
239 (25,200), 249 (25,000), 314 (29,500). 13C NMR (75 MHz, DMSO-d6): 55.75,
55.88 (OCH3), 87.85, 95.97, 96.10, 125.83, 127.53, 128.88 (aryl CH), 121.90, 136.02,
147.13, 147.37, 148.80, 158.37 (aryl C). Mass Spectrum (+EI): m/z (%) 432 (M+2,
26), 431 (M+1, 100).
(i) 2-[3-(4,6-Dimethoxybenzimidazol-2-yl)phenyl]-4,6-dimethoxybenzimidazole (285) 1H NMR (300 MHz, DMSO-d6): 3.79
(s, 6H, OCH3), 3.91 (s, 6H, OCH3), 6.33
(s, 2H, aryl H5), 6.58 (s, 2H, aryl H7),
N
NHMeO
OMe
N
NH OMe
OMe
Experimental 207
7.61-7.63 (m, 2H, aryl H), 8.08-8.10 (m, 2H, aryl H), 12.89 (br s, 2H, NH).
(ii) 2-[3-(5,7-Dimethoxybenzimidazol-2-yl)phenyl]-5,7-dimethoxybenzimidazole (287) 1H NMR (300 MHz, DMSO-d6): 3.79
(s, 6H, OCH3), 3.91 (s, 6H, OCH3), 6.45
(s, 2H, aryl H6), 6.78 (s, 2H, aryl H4),
8.21-8.23 (m, 2H, aryl H), 8.84-8.94 (m, 2H, aryl H), 13.03 (br s, 2H, NH).
2-[4-(4,6-Dimethoxybenzimidazol-2-yl)phenyl]-4,6-dimethoxybenzimidazole (286) and 2-
[4-(5,7-Dimethoxybenzimidazol-2-yl)phenyl]-5,7-dimethoxybenzimidazole (288)
To a solution of diamine 284 (0.50 g, 1.07 mmol) in absolute ethanol (50 mL) a few
drops of concentrated hydrochloric acid were added and the mixture refluxed
overnight. The reaction mixture was allowed to come to room temperature before
water was added and made basic by 2 M sodium hydroxide solution. The resulting
precipitate was filtered, washed with water and recrystallized from ethanol to yield the
benzimidazole 286 and 288 as a tautomeric mixture (1:0.38) as a brown powder (0.29
g, 63%), m.p. >360 °C. (Found: C, 66.72 ; H, 5.31 ; N, 13.05. C24H22N4O4 requires C,
66.97; H, 5.15; N, 13.02 %). max (KBr): 3506, 3118, 2920, 2892, 1635, 1601, 1453,
1360, 1303, 1203, 1154, 1041, 995 cm-1. max (MeOH): 208 nm ( 11,800 cm-1M-1),
260 (3,600), 354 (5,400). 13C NMR (75 MHz, DMSO-d6): 55.86, 55.91(OCH3),
87.02, 94.56, 126.61 (aryl CH), 129.28, 131.00, 136.94, 148.56, 151.63, 157.69 (aryl
C). Mass Spectrum (+EI): m/z (%) 432 (M+2, 16), 431 (M+1, 100).
Tautomeric ratio (1: 0.34)
(i) 2-[4-(4,6-Dimethoxybenzimidazol-2-yl)phenyl]-4,6-dimethoxybenzimidazole (286)1H NMR (300 MHz, DMSO-d6):
3.79 (s, 6H, OCH3), 3.92 (s, 6H,
OCH3), 6.33 (d, J = 1.86 Hz, 2H, aryl
H5), 6.58 (d, J = 1.86 Hz, 2H, aryl H7), 8.20-8.32 (m, 4H, aryl H), 12.76 (br s, 2H,
NH).
(ii) 2-[4-(5,7-Dimethoxybenzimidazol-2-yl)phenyl]-5,7-dimethoxybenzimidazole (288)1H NMR (300 MHz, DMSO-d6): 3.78 (s, 6H,
OCH3), 3.93 (s, 6H, OCH3), 6.44 (s, 2H, aryl
H6), 6.78 (s, 2H, aryl H4), 8.20-8.32
(m, 4H, aryl H), 12.91 (br s, 2H, NH).
HN
NMeO
OMeHN
N OMe
OMe
N
NHMeO
OMe
N
NH OMe
OMe
HN
NMeO
OMeHN
N OMe
OMe
Experimental 208
1-(3,5-Dimethoxy-2-nitrophenyl)pyrrolidine-2,5-dione (295)
To a solution of nitroaniline 150 (0.25 g, 1.26 mmol) in dry
tetrahydrofuran (20 mL) containing anhydrous potassium
carbonate (0.50 g), succinyl chloride (0.15 mL, 1.26 mmol)
was added slowly over 15 min and the mixture stirred under
argon for 2 days. Water was then added to the reaction and the mixture was extracted
with ethyl acetate. The organic layer was washed with water, dried over magnesium
sulfate, and evaporated off to afford the title compound 295 as a yellow powder (0.18
g, 51%), m.p. 188-190 °C. (Found: C, 51.59; H, 4.61; N, 9.87. C12H12N2O6 requires C,
51.43; H, 4.32; N, 10.00 %). HRMS (+ESI): C12H12N2O6 [M+Na]+ requires 303.0588,
found 303.0592. max (KBr): 2994, 2942, 1788, 1716, 1604, 1518, 1466, 1350, 1332,
1301, 1256, 1232, 1180, 982, 844, 633 cm-1. max (MeOH): 205 nm ( 28,200 cm-1M-
1), 248 (6,200). 1H NMR (300 MHz, CDCl3): 2.87 (s, 4H, CH2), 3.85 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 6.36 (d, J = 2.25 Hz, 1H, aryl H4), 6.60 (d, J = 2.25 Hz, 1H, aryl
H6). 13C NMR (75 MHz, CDCl3): 28.56 (CH2), 55.98, 56.77 (OCH3), 100.49,
105.76 (aryl CH), 128.05, 131.88, 154.60, 162.28 (aryl C), 174.92 (C=O). Mass
Spectrum (+EI): m/z (%) 281 (M+1, 20), 251 (100), 235 (95), 199 (59), 193 (20).
2-(3,5-Dimethoxy-2-nitrophenyl)isoindoline-1,3-dione (296)
This compound was prepared as described for the 2,5-dione
295 from a solution of nitroaniline 150 (5 g, 25.25 mmol) in
dry tetrahydrofuran (100 mL) containing anhydrous
potassium carbonate (5 g), phthaloyl dichloride (2.60 g,
12.80 mmol) under argon for 7 days to afford the 1,3-dione
296 as a yellow powder (3.84 g, 46%), m.p. 240 °C. (Found: C, 58.30; H, 3.80; N,
8.48. C16H12N2O6 0.10 MeOH requires C, 58.34; H, 3.77; N, 8.45 %). HRMS (+ESI):
[M+Na]+ requires 351.0588, found 351.0585. max (KBr): 1787, 1766, 1715, 1597,
1521, 1459, 1434, 1391, 1343, 1288, 1206, 1158, 1123, 1083, 1064, 946, 885, 840,
715, 659 cm-1. max (MeOH): 206 nm ( 26,000 cm-1M-1), 219 (28,600). 1H NMR (300
MHz, CDCl3): 3.87 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 6.49 (d, J = 2.64 Hz, 1H,
aryl H4), 6.64 (d, J = 2.64 Hz, 1H, aryl H6), 7.77-7.80 (m, 2H, aryl H), 7.92-7.95 (m,
2H, aryl H). 13C NMR (75 MHz, CDCl3): 55.96, 56.75 (OCH3), 100.29, 106.21,
OMe
MeO NO
O
NO2
OMe
MeO NO
O
NO2
Experimental 209
124.05, 134.59 (aryl CH), 127.54, 131.59, 132.56, 154.42, 162.08 (aryl C), 166.03
(C=O). Mass Spectrum (+ESI): m/z 329 (M+1).
Bis(4,6-dimethoxy-7-nitrobenzimidazol-2-yl)methanone (299)
To an ice cooled suspension of
bisbenzimidazole 246 (0.10 g, 0.27 mmol) in
acetonitrile (15 mL), concentrated nitric acid
(0.05 mL) was slowly added to form a yellow
to brown solution. The solution was refluxed for 15 min, cooled to room temperature
and concentrated. The residue was extracted with ethyl acetate, washed with sodium
bicarbonate solution and water. The organic solvent was evaporated off and the solid
was recrystallized form ethanol to afford the compound 299 as a brown solid (84 mg,
66%), m.p. 287 °C. HRMS (+ESI): C19H16N6O9 [M+Na]+ requires 495.0874, found
495.0870. max (KBr): 3415, 1627, 1590, 1530, 1506, 1460, 1434, 1354, 1301, 1221,
1153, 1026, 977,890, 813, 753 cm-1. max (MeOH): 205 nm ( 16,300 cm-1M-1), 352
(7,900). Mass Spectrum (+EI): m/z (%) 474 (M+2, 25%), 473 (M+1, 100), 463 (30),
462 (52), 450 (22), 428 (18), 227 (20), 213 (24).
Bis(4,6-dimethoxy-2-methylbenzimidazol-1-yl)methane (300) and
Bis(5,7-dimethoxy-2-methylbenzimidazol-1-yl)methane (301)
To a solution of benzimidazole 141 (0.50 g, 2.60 mmol) in dry dimethyl sulfoxide (5
mL) crushed potassium hydroxide (0.50 g) was added and the mixture stirred for half
an hour. Diiodomethane (0.40 g, 1.50 mmol) was added to this solution and the
mixture stirred at room temperature for 2 h, before water was added. The resulting
precipitate was collected, washed with water and recrystallized from ethanol to afford
the isomeric mixture of the benzimidazoles 300, 301 in a (1: 0.5) ratio (by 1H NMR)
as an off white solid (0.49 g, 95%), m.p. 188-190 °C. (Found: C, 62.74; H, 6.26; N,
13.96. C21H24N4O4 0.3H2O requires C, 62.77; H, 6.17; N, 13.94 %). max (KBr): 3387,
3006, 2935, 2839, 1604, 1527, 1501, 1433, 1316, 1238, 1199, 1149, 1113, 1042, 816,
656 cm-1. max (MeOH): 214 nm ( 58,700 cm-1M-1), 253 (12,900), 284 (6,300). Mass
Spectrum (+EI): m/z (%) 398 (M+2, 28), 397 (M+1, 100)
N
NHMeO
OMe
N
NH OMe
OMe
NO2 NO2
O
Experimental 210
(i) Bis(4,6-dimethoxy-2-methylbenzimidazol-1-yl)methane (300) 1H NMR (300 MHz, CDCl3): 2.28 (s, 6H, CH3), 3.83 (s,
6H, OCH3), 3.91 (s, 6H, OCH3), 6.19 (s, 2H, CH2), 6.43 (s,
2H, aryl H5), 6.78 (s, 2H, aryl H7).
(ii) Bis(5,7-dimethoxy-2-methylbenzimidazol-1-yl)methane (301) 1H NMR (300 MHz, CDCl3): 2.34 (s, 6H, CH3), 3.88 (s,
6H, OCH3), 3.92 (s, 6H, OCH3), 6.26 (s, 2H, CH2), 6.60 (s,
2H, aryl H5), 7.11 (s, 2H, aryl H7).
Reaction of 2-phenyl-4,6-dimethoxybenzimidazole (142) and indolin-2-one (308)
with phosphoryl chloride
To an ice cooled solution of benzimidazole 142 (1 g, 3.93 mmol) and indolin-2-one
308 (0.58 g, 4.3 mmol) in anhydrous chloroform (50 mL) phosphoryl chloride (0.75
mL, 7.86 mmol) was added dropwise. The mixture was gently refluxed overnight
under argon. The reaction was quenched with ice water and made basic by 2 M
sodium hydroxide solution, and extracted with chloroform. The organic extract was
washed with water, and dried over magnesium sulfate. The solvent was evaporated off
and the residue was column chromatographed using dichloromethane/light petroleum
(70/30) as eluent to give compounds 312, 313, 317, 318 together with the starting
benzimidazole 142.
(i) 2-Chloroindole (312) was obtained as a brown solid (0.18 g,
28%), m.p. 90-92 °C (lit.226 88-89 °C). 1H NMR (300 MHz, CDCl3):
6.40-6.41 (m, 1H, aryl H), 7.10-7.30 (m, 3H, aryl H), 7.51 (d, =
7.9 Hz, 1H, aryl H), 8.05 (br s, 1H, NH).
NH
Cl
N
N
OMe
MeOMe
N
N
OMe
MeOMe
N
NMe
N
NMe
OMe
MeO
OMe
MeO
Experimental 211
(ii) 2-Chloro-3-(indolyl-2)-indole (313) was obtained as a brown
solid (57 mg, 10%), m.p. 140-142 °C (lit.206 136-138 °C). HRMS
(+ESI): C16H11ClN2 [M+H]+ requires 267.0684, found 267.0684. 1H
NMR (300 MHz, CDCl3): 6.928 (d, = 1.53 Hz, 1H, aryl H), 7.15-
7.30 (m, 5H, aryl H), 7.44 (d, = 8.28 Hz, 1H, aryl H), 7.70 (d, =
7.53 Hz, 1H, aryl H), 7.91-7.94 (m, 1H, aryl H), 8.11 (br s, 1H, NH), 8.58 (br s, 1H,
NH).
(iii) 3-[3-(Indolyl-2)-indolyl-2]-2-chloroindole (317) was
obtained as a brown solid, m.p. >350 °C. HRMS (+ESI):
C24H16ClN3 [M+H]+ requires 382.1106 found 382.1104. 1H
NMR (300 MHz, CDCl3): 6.44 (d, = 1.1 Hz, 1H, aryl H),
6.91-7.61 (m, 12H, aryl H), 7.89 (br s, 1H, NH), 8.20 (br s, 1H,
NH), 8.50 (br s, 1H, NH).
(iv) 3[3-(3-(Indolyl-2)-indolyl-2)indolyl-2]-2-chloroindole (318)
was obtained as a brown solid, m.p. >350°C. HRMS
(+ESI): C32H21ClN4 [M+H]+ requires 497.1528, found
497.1527. 1H NMR (300 MHz, CDCl3): 6.82 (d, = 1.5
Hz, 1H, aryl H), 6.91-7.61 (m, 16H, aryl H), 7.97 (br s, 1H,
NH), 8.02 (br s, 1H, NH), 8.29 (br s, 1H, NH), 8.41 (br s,
1H, NH).
4,6-Dimethoxy-2-phenyl-1-(trifluoromethylsulfonyl)-benzimidazole (321) and
7-(Indol-2-yl)-4,6-dimethoxy-2-phenylbenzimidazole (311)
To an ice cooled solution of benzimidazole 142 (0.50 g, 1.96 mmol) and indolin-2-one
308 (0.78 g, 5.88 mmol) in anhydrous chloroform (20 mL), triflic anhydride (1.67 mL,
9.8 mmol) was added dropwise while stirring under argon. The reaction mixture was
allowed to come to room temperature and then heated at 65-70°C for 7 days under
argon. The reaction was allowed to cool to room temperature before ice water was
added and the solution made basic by 20% sodium hydroxide solution. The mixture
was extracted with ethyl acetate, the organic extract washed with water several times,
then with brine and finally dried over magnesium sulfate. The solvent was evaporated
off and the residue was column chromatographed using dichloromethane/light
petroleum (50/50) as eluent to give the following two compounds.
NH
Cl
NH
NH
Cl
NHNH
NH Cl
NH
NH
NH
Experimental 212
(i) 4,6-Dimethoxy-2-phenyl-1-(trifluoromethylsulfonyl)-benzimidazole (321)
was obtained as a white powder in a yield of (0.10 g,
13%). m.p. 155-156oC. (Found: C, 49.76; H, 3.48; N,
7.20. C16H13F3N2O4S requires C, 49.74; H, 3.39; N, 7.25
%) HRMS (+ESI): C16H13F3N2O4S [M+Na]+ requires
409.0440, found 409.0426. max (KBr): 1769, 1603, 1499,
1463, 1420, 1352, 1322, 1275, 1216, 1166, 1120, 1067, 1034, 927, 839, 828, 807,
773, 767, 755, 698 cm-1. max (MeOH): 205 nm ( 31,000 cm-1M-1), 227 (16,000), 281
(12,800). 1H NMR (300 MHz, CDCl3): 3.89 (s, 3H, OCH3), 4.00 (s, 3H, OCH3),
6.56 (d, J = 2.25Hz, 1H, aryl H7), 7.01 (d, J = 2.28Hz, 1H, aryl H5), 7.41-7.54 (m,
3H, aryl H), 7.62-7.65 (m, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 56.46, 56.58
(OCH3), 117.39 (CF3), 90.80, 98.43, 128.07, 131.01, 131.05 (aryl CH), 127.40,
129.29, 135.32, 151.41, 152.52, 160.51(aryl C). Mass Spectrum (+EI): m/z (%) 388
(M+1, 18), 387 (M, 95), 255 (100).
(ii) 7-(Indol-2-yl)-4,6-dimethoxy-2-phenylbenzimidazole (311)
was obtained as a yellow solid (0.07 g, 10%), m.p. 112-
114°C. HRMS (+ESI): C23H19N3O2 [M+Na]+ requires
392.1369, found 392.1368. max (KBr): 3568, 3434,
3274, 1636, 1614, 1600, 1456, 1421, 1328, 1308, 1219,
1168, 1120, 989, 928, 796, 698 cm-1. max (MeOH): 206
nm ( 31,000 cm-1M-1), 258 (17,200), 303 (16,300), 317
(16,600), 330 (14,100). 1H NMR (300 MHz, CDCl3): 4.00 (s, 3H, OCH3), 4.03 (s,
3H, OCH3), 6.53 (s, 1H, aryl H5), 7.10-7.21 (m, 3H, aryl H), 7.50-7.55 (m, 5H, aryl
H+NH), 7.67 (d, J = 7.89 Hz, 1H, aryl H), 8.07 (d, J = 6.42 Hz, 2H, aryl H), 11.96 (br
s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.69, 57.15 (OCH3), 92.95, 110.75,
119.15, 120.02, 121.21, 126.40, 128.94, 130.12 (aryl CH), 101.59, 128.60, 128.79,
129.23, 133.83, 135.42, 150.31, 153.82 (aryl C). Mass Spectrum (+EI): m/z (%) 371
(M+2, 28), 370 (M+1, 100).
NH
N
OMe
NH
MeO
N
N
OMe
MeOS C F
FO
O
F
Experimental 213
7-(Indol-2-yl)-4,6-dimethoxy-2-methylbenzimidazole (322)
This compound was prepared as described for the compound
311 from a solution of benzimidazole 141 (0.50 g, 2.60 mmol)
and indolin-2-one 308 (0.69 g, 5.20 mmol) in anhydrous
chloroform (25 mL) and triflic anhydride (1.30 mL, 7.8 mmol)
at 65-70oC for 7 days to yield the indolylbenzimidazole 322 as
a light brown solid (52 mg, 7%), m.p. 182-184°C. HRMS
(+ESI): C18H17N3O2 [M+Na]+ requires 330.1212, found 330.1220. max (KBr): 3389,
3259, 1636, 1590, 1614, 1455, 1408, 1326, 1305, 1207, 1124, 1084, 1026, 992, 798,
750 cm-1. max (MeOH): 206 nm ( 23,300 cm-1M-1), 323 (11,000). 1H NMR (300
MHz, CDCl3): 2.56 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.46 (s,
1H, aryl H5), 7.06-7.19 (m, 4H, aryl H), 7.47 (d, J = 7.89 Hz, 1H, aryl H), 7.64 (d, J =
7.89 Hz, 1H, aryl H), 11.37 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 14.80
(CH3), 55.60, 57.20 (OCH3), 92.21, 101.23, 110.76, 119.11, 119.92, 121.12 (aryl CH),
102.65, 128.79, 133.79, 135.39, 139.85, 140.09, 145.55, 149.85, 153.45 (aryl C).
Mass Spectrum (+EI): m/z (%) 309 (M+2, 18), 309 (M+1, 100).
7-(Indol-2-yl)-4,6-dimethoxy-2-(4'-methoxyphenyl)-benzimidazole (323)
This compound was prepared as described for the
compound 311 from a solution of benzimidazole
161 (0.50 g, 1.76 mmol) and indolin-2-one 308
(0.47 g, 3.52 mmol) in anhydrous chloroform (25
mL) and triflic anhydride (0.90 mL, 5.28 mmol) at
65-70oC for 7 days to yield the
indolylbenzimidazole 323 as an off white powder (0.06 g, 9%), m.p. 214-216°C.
(Found: C, 70.82; H, 5.93; N, 9.79. C24H21N3O3. 0.6 C2H6O requires C, 70.87; H,
5.81; N, 9.84 %). max (KBr): 3441, 3263, 1613, 1600, 1464, 1440, 1328, 1312, 1251,
1228, 1204, 1173, 1134, 1112, 1027, 992, 832, 792, 707 cm-1. max (MeOH): 205 nm
( 32,600 cm-1M-1), 220 (26,900), 256 (24,400), 317 (16,800), 344 (18,600). 1H NMR
(300 MHz, CDCl3): 3.90 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 4.07 (s, 3H, OCH3),
6.62 (s, 1H, aryl H5), 7.02-7.14 (m, 5H, aryl H), 7.33 (br s, 1H, NH), 7.48-7.74 (m, 4
H, aryl H), 12.22 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.37, 55.70, 57.28
NH
N
OMe
NH
OMeMeO
NH
N
OMe
NH
MeMeO
Experimental 214
(OCH3), 93.40, 101.99, 110.89, 114.14, 118.78, 119.92, 120.80, 130.93 (aryl CH),
104.44, 122.29, 128.89, 134.15, 135.36, 137.34, 142.05, 145.53, 153.04, 153.70,
160.86 (aryl C). Mass Spectrum (+ESI): m/z (%) 400 (M+1, 100).
2-(4,6-Dimethoxy-2,3-diphenyl-indol-7-yl)-benzimidazole (330)
To an ice cooled solution of 4,6-dimethoxy-2,3-
diphenylindole 53 (0.50 g, 1.52 mmol) and 2-
benzimidazolinone 329 (0.22 g, 1.67 mmol) in anhydrous
chloroform (25 mL), triflic anhydride (0.51 mL, 3.04
mmol) was added dropwise while stirring under argon.
The reaction mixture was heated at 65-70oC for 7 days
under argon. The reaction was allowed to cool to room
temperature before ice water was added and the solution made basic by 2 M sodium
hydroxide solution. The mixture was extracted with ethyl acetate, the organic extract
was washed with water several times, then with brine and finally dried over
magnesium sulfate. The solvent was evaporated off and the residue was purified by
column chromatography using dichloromethane/light petroleum (50/50) as eluent to
yield the indolylbenzimidazole 330 as a white powder (0.08 g, 12%), m.p. 248-249 °C
(lit.5 242-243°C). (Found: C, 78.29; H, 5.35; N, 9.43. C29H23N3O2 requires C, 78.18;
H, 5.20; N, 9.43 %). HRMS (+ESI): C29H23N3O2 [M+H]+ requires 446.1863, found
446.1825. max (KBr): 3437, 3294, 1617, 1602, 1465, 1453, 1428, 1333, 1276, 1247,
1216, 1150, 995, 749, 696 cm-1. max (MeOH): 206 nm ( 44,900 cm-1M-1), 242
(26,600), 256 (25,500), 287 (11,800), 324 (25,700), 341 (28,100), 357 (24,500). 1H
NMR (300 MHz, CDCl3): 3.79 (s, 3H, OCH3), 4.17 (s, 3H, OCH3), 6.35 (s, 1H, aryl
H5), 7.27-7.32 (m, 8H, aryl H), 7.43-7.47 (m, 5H, aryl H), 7.80-7.82 (m, 1H, aryl H),
10.60 (br s, 1H, NH), 12.18 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.29,
56.78 (OCH3), 87.80, 122.27, 125.88, 126.94, 127.27, 128.22, 128.29, 131.46 (aryl
CH), 122.26, 132.81, 133.67, 135.94, 156.77, 174.64, 176.70 (aryl C). Mass Spectrum
(+EI): m/z (%) 447 (M+2, 32), 446 (M+1, 100).
NH
OMe
MeO
N NH
Experimental 215
7-(Indol-2-yl)-4,6-dimethoxy-2,3-dimethylindole (333)
Bis(4,6-dimethoxy-2,3-dimethyl-indol-7-yl)methane (334) and
7-(4,6-Dimethoxy-2,3-dimethylindol-7-yl)-4,6-dimethoxy-2,3-dimethylindole(335)
To an ice cooled solution of 4,6-dimethoxy-2,3-dimethylindole 52 (1 g, 4.87 mmol)
and 2-benzimidazolinone 329 (0.98 g, 7.32 mmol) in anhydrous chloroform (25 mL),
triflic anhydride (1.64 mL, 9.75 mmol) was added dropwise while stirring under
argon. The reaction mixture was allowed to stir at room temperature for 7 days under
argon. Ice water was added to quench the reaction and the mixture was made basic by
2 M sodium hydroxide solution. The mixture was extracted with ethyl acetate, the
organic extract washed with water several times, then with brine and finally dried over
magnesium sulfate. The solvent was evaporated off and the residue was purified by
column chromatography using dichloromethane/light petroleum (50/50) as eluent to
yield the following three products.
(i) Bis(4,6-dimethoxy-2,3-dimethyl-indol-7-yl)methane (333)
was obtained as a white powder (22 mg, 2%), m.p. 288-290
°C. (Found: C, 70.04; H, 7.26; N, 6.45. C25H30N2O4 0.3H2O
requires C, 70.17; H, 7.21; N, 6.55). HRMS (+ESI):
C25H30N2O4 [M+Na]+ requires 445.2097, found 445.2099.
max (KBr): 3337, 2935, 1626, 1600, 1520, 1464, 1341, 1258,
1215, 1151, 1118, 991, 778 cm-1. max (MeOH): 213 nm (
33,100 cm-1M-1), 228 (37,200), 276 (11,400). 1H NMR (300
MHz, CDCl3): 2.25 (s, 12H, CH3), 3.84 (s, 6H, OCH3), 4.09 (s, 6H, OCH3), 4.12 (s,
2H, CH2), 6.22 (s, 2H, aryl H5), 9.27 (br s, 2H, NH). 13C NMR (75 MHz, CDCl3)
10.35, 11.25 (CH3), 18.63 (CH2), 55.40, 58.03 (OCH3), 88.70 (aryl CH), 104.40,
106.49, 114.37, 128.28, 136.34, 150.30, 152.81 (aryl C). Mass Spectrum (+EI): m/z
(%) 424 (M+2, 27), 423 (M+1, 100), 218 (32).
(ii) 7-(4,6-Dimethoxy-2,3-dimethylindol-7-yl)-4,6-
dimethoxy-2,3-dimethylindole (335) was obtained as an off
white powder (0.15 g, 15%), m.p. 185-186 °C. (Found: C,
66.29; H, 6.55; N, 6.27. C24H28N2O4. 0.4 CH2Cl2 requires C,
66.23; H, 6.56; N, 6.33 %). HRMS (+ESI): [M+Na]+ requires
431.1941, found 431.1942. max (KBr): 3472, 2934, 1597,
NH
OMe
MeOMe
HN
OMe
MeOMe
Me
Me
NH
OMe
HN
OMe
Me
Me
Me
Me
MeO
MeO
Experimental 216
1453, 1433, 1325, 1207, 1145, 1116, 992, 790 cm-1. max (MeOH): 229 nm ( 46,800
cm-1M-1), 279 (14,500). 1H NMR (300 MHz, CDCl3): 2.18 (s, 6H, CH3), 2.39 (s, 6H,
CH3), 3.73 (s, 6H, OCH3), 3.97 (s, 6H, OCH3), 6.40 (s, 2H, aryl H5), 7.34 (br s, 2H,
NH). 13C NMR (75 MHz, CDCl3): 10.57, 11.05 (CH3), 55.28, 57.99 (OCH3), 90.01
(aryl CH), 99.07, 106.86, 113.78, 128.26, 136.15, 153.25, 154.00 (aryl C). Mass
Spectrum (+EI): m/z (%) 410 (M+2, 30), 409 (M+1, 100).
(iii) (7-(Indol-2-yl)-4,6-dimethoxy-2,3-dimethylindole (333)
was obtained as a light brown solid (4 mg, 5%), m.p. 197-198
°C (lit.5 196-197 °C). HRMS (+ESI): C19H19N3O2 [M+Na]+
requires 344.1369, found 344.1376. 1H NMR (300 MHz,
CDCl3): 2.36 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.97 (s, 3H,
OCH3), 4.13 (s, 3H, OCH3), 6.25 (s, 1H, aryl H5), 7.24-7.27
(m, 1H, aryl H), 7.50-7.53 (m, 1H, aryl H), 7.68-7.71 (m, 2H, aryl H), 11.28 (br s, 1H,
NH), 11.96 (br s, 1H, NH). Mass Spectrum (+EI): m/z (%) 322 (M+1, 100).
2-(3,5-Dimethoxyphenylimino)-1,2-diphenylethanone (347)and
4,6-Dimethoxy-2,3-diphenylindol-3-ol (348)
To a solution of benzil 343 (7 g, 33.3 mmol) and acetic acid ( 2 g, 33.3 mmol) in
absolute ethanol was added the 3,5-dimethoxyaniline 39 (5 g, 32.67 mmol) at room
temperature. After stirring under reflux for 24 h the solvent was evaporated and the
residue was extracted with ethyl acetate. The organic solvent was washed with a
saturated solution of ammonium chloride, dried over magnesium sulfate and
concentrated under reduced pressure. The crude product was chromatographed using
dichloromethane/light petroleum (4:1) to give the following two products.
(i) 2-(3,5-Dimethoxyphenylimino)-1,2-diphenylethanone (347)
was obtained after recrystallization from ethanol as yellow
crystals (4.73 g, 42 %), m.p. 118-119°C. (Found: C, 76.22;
H, 5.60; N, 4.00. C22H19NO3 requires C, 76.50; H, 5.54; N,
4.06 %). max (KBr): 3000, 2962, 1666, 1588, 1471, 1327,
1218, 1202, 1163, 1136, 1066, 947, 899, 839, 728 cm-1. max (MeOH): 206 nm (
42,900 cm-1M-1), 255 (24,700). 1H NMR (300 MHz, CDCl3): 3.62 (s, 6H, OCH3),
6.06 (s, 3H, aryl H), 7.33-7.53 (m, 6H, aryl H), 7.77-7.88 (m, 4H, aryl H). 13C NMR
NH
OMe
MeOMe
Me
N NH
OMe
N
O
MeO
Experimental 217
(75 MHz, CDCl3): 55.16 (OCH3), 97.46, 98.76, 124.51, 128.06, 128.71, 129.23,
131.64, 134.18 (aryl CH), 128.37, 134.81, 134,90, 150.95, 160.62 (aryl C), 166.35
(C=N), 197.26 (C=O). Mass Spectrum (+EI): m/z (%) 347 (M+2, 21), 346 (M+1,
100).
(ii) 4,6-Dimethoxy-2,3-diphenylindol-3-ol (348)
was obtained as a yellow powder (1.12 g, 10%), m.p. 207-
208 °C. (Found: C, 76.24; H, 5.60; N, 3.99. C22H19NO3
requires C, 76.50; H, 5.54; N, 4.06 %). max (KBr): 3441,
3164, 1614, 1600, 1541, 1490, 1451, 1321, 1219, 1147, 1119, 1054, 830, 771, 703 cm-
1. max (MeOH): 207 nm ( 27,500 cm-1M-1), 252 (16,200), 319 (9,600). 1H NMR (300
MHz, CDCl3): 3.65 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.24 (d, = 1.86 Hz, aryl
H5) 6.89 (d, = 1.86 Hz, aryl H7), 7.18-7.39 (m, 9H, aryl H+OH), 8.07-8.10 (m, 2H,
aryl H). 13C NMR (75 MHz, CDCl3): 55.51, 55.61 (OCH3), 97.37, 99.10, 124.55,
127.12, 128.18, 128.20, 129.29, 131.22 (aryl CH), 87.77 (aliphatic C), 121.99, 130.73,
139.22, 155.36, 162.89, 172.56, 181.39 (aryl C). Mass Spectrum (+EI): m/z (%) 347
(M+2, 25), 346 (M+1, 100), 268 (M-Ph, 71).
4'-Chloro-N-(3,5-dimethoxyphenyl)benzamide (351)
This compound was prepared as described for the
compound 154 from a solution of 3,5-
dimethoxyaniline 39 (10 g, 65.36 mmol) in dry
dichloromethane (50 mL) containing anhydrous
potassium carbonate and 4-chlorobenzoyl chloride (13.7 g, 78.4 mmol) under stirring
for 2 h to give the benzamide 351 as a white solid (11.8 g, 62 %), m.p. 120-121 °C.
(Found: C, 61.81; H, 4.95; N, 4.74. C15H14ClNO3 requires C, 61.76; H, 4.84; N, 4.80
%). max (KBr): 3486, 3406, 3281, 2997, 1627, 1594, 1480, 1455, 1423, 1342, 1300,
1208, 1160, 1073, 835, 750 cm-1. max (MeOH): 205 nm ( 38,100 cm-1M-1), 230
(16,800), 273 (10,600). 1H NMR (300 MHz, CDCl3): 3.71 (s, 6H, OCH3), 6.26-6.27
(m, 1H, aryl H4), 6.86 (d, J = 2.25 Hz, 2H, aryl H2,6), 7.39-7.42 (m, 2H, aryl H),
7.75-7.77 (m, 2H, aryl H), 7.92 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.31
(OCH3), 97.09, 98.50, 128.36, 128.92 (aryl CH), 133.16, 138.06, 139.35, 161.02 (aryl
MeO
OMe
NHCO Cl
OMe
NMeO
HO
Experimental 218
C), 164.71 (C=O). Mass Spectrum (+EI): m/z (%) 295 (M+2, 37Cl, 5), 294 (M+1, 37Cl,
35), 293 (M+2, 35Cl, 18), 292 (M+1, 35Cl, 100), 154 (18).
N-(3,5-Dimethoxyphenyl)-4'-nitrobenzamide (352)
To a solution of 3,5-dimethoxyaniline 39 (5 g,
32.68 mmol) in pyridine (50 mL) at 0 °C 4-
nitrobenzoyl chloride (7.27 g, 39.2 mmol) was
added slowly portionwise and the mixture was
stirred at room temperature overnight. Water was added and the resulting precipitate
was filtered, washed with water and recrystallized from ethanol to give the benzamide
352 as yellow crystals (9.87 g, 86 %), m.p. 209-210 °C. (Found: C, 59.62; H, 4.76; N,
9.20. C15H14N2O5 requires C, 59.60; H, 4.67; N, 9.27 %). max (KBr): 3264, 2937,
1652, 1600, 1521, 1480, 1459, 1422, 1343, 1291, 1206, 1155, 1067, 830 cm-1. max
(MeOH): 217 nm ( 33,900 cm-1M-1), 249 (14,300). 1H NMR (300 MHz, CDCl3):
3.81 (s, 6H, OCH3), 6.31-6.32 (m, 1H, aryl H4), 6.87 (d, J = 2.25 Hz, 2H, aryl H2,6),
7.75 (br s, 1H, NH), 8.02 (d, J = 9.03 Hz, 2H, aryl H), 8.34 (d, J = 9.03 Hz, 2H, aryl
H). 1H NMR (300 MHz, Acetone-d6): 3.77 (s, 6H, OCH3), 6.30 (s, 1H, aryl H4),
7.11 (d, J = 2.25 Hz, 2H, aryl H2,6), 8.02 (d, J = 9.03 Hz, 2H, aryl H), 8.34 (d, J =
9.03 Hz, 2H, aryl H), 9.73 (br s, 1H, NH), 13C NMR (75 MHz, Acetone-d6): 54.64
(OCH3), 96.14, 98.48, 123.39, 128.77 (aryl CH), 140.48, 140.93, 149.59, 163.71 (aryl
C), 161.03 (C=O). Mass Spectrum (+EI): m/z (%) 304 (M+2, 16), 303 (M+1, 100).
N-(3,5-Dimethoxyphenyl)-2'-nitrobenzamide (353)
This compound was prepared as described for the amide
352 from a solution of 3,5-dimethoxyaniline 39 (5 g,
32.68 mmol) in pyridine (50 mL) and 2-nitrobenzoyl
chloride (7.27 g, 39.2 mmol) under reflux for 2 h to afford the benzamide 353 as an
off white powder (9.87 g, 86%), m.p. 180-181 °C. (Found: C, 59.10; H, 4.78; N, 8.98.
C15H14N2O5 0.2CH3OH requires C, 59.14; H, 4.83; N, 9.07 %). max (KBr): 3266,
3105, 2967, 1662, 1623, 1600, 1566, 1533, 1456, 1422, 1348, 1196, 1152 1061, 841,
731 cm-1. max (MeOH): 215 nm ( 19,800 cm-1M-1), 252 (8,400). 1H NMR (300 MHz,
Acetone-d6): 3.74 (s, 6H, OCH3), 6.27 (s, 1H, aryl H4), 6.99 (s, 2H, aryl H2,6),
MeO
OMe
NHCO NO2
MeO
OMe
NHCO
O2N
Experimental 219
7.71-7.83 (m, 3H, aryl H), 8.06-8.08 (m, 1H, aryl H), 9.70 (br s, 1H, NH). 13C NMR
(75 MHz, Acetone-d6): 54.62 (OCH3), 95.95, 97.99, 124.13, 128.88, 130.67, 133.63
(aryl CH), 133.07, 140.61, 146.87, 164.07 (aryl C), 161.10 (C=O). Mass Spectrum
(+EI): m/z (%) 304 (M+2, 15), 303 (M+1, 100), 242 (16), 241 (90).
N-(3,5-Dimethoxyphenyl)methanethioamide (354)
To a solution of formamide 148 (5 g, 27.59 mmol) in pyridine
(50 mL) phosphorus pentasulfide (6.70 g, 30.35 mmol) was
added portionwise and the mixture was refluxed for 3 h. The solution was allowed to
come to room temperature and the resulting precipitate was filtered, washed with
water and column chromatographed (dichloromethane/light petroleum; 2:1) to yield
the thioamide 354 as a light yellow powder (0.51 g, 9%), m.p. 184-185 °C. (Found: C,
54.89; H, 5.82; N, 7.12. C9H11NO2S requires C, 54.80; H, 5.62; N, 7.10 %). HRMS
(+ESI): C9H11NO2S [M+Na]+ requires 220.0402, found 220.0401. max (KBr): 3290,
1620, 1604, 1562, 1468, 1295, 1211, 1155, 982, 816 cm-1. max (MeOH): 207 nm (
15,000 cm-1M-1), 233 (4,800), 313 (10,400). 1H NMR (300 MHz, CDCl3): 3.79 (s,
6H, OCH3), 6.26 (d, J = 2.25 Hz, 2H, aryl H2,6), 6.31 -6.32 (m, 1H, aryl H4), 9.22 (br
s, 1H, NH), 9.75 (d, J = 14.7 Hz, 1H, CSH). 13C NMR (75 MHz, CDCl3): 55.46
(OCH3), 96.09, 97.73 (aryl CH), 140.04, 161.77 (aryl C), 187.35 (C=S). Mass
Spectrum (+EI): m/z (%) 198 (M+1, 100), 182 (23).
N-(3,5-Dimethoxyphenyl)ethanethioamide (355)
A mixture of acetamide 152 (5 g, 25.61 mmol) and
Lawesson’s reagent (6.18 g, 15.3 mmol, 0.6 eq.) in toluene
(20 mL) was heated under reflux for 3 h. The solvent was
removed and the product was extracted with dichloromethane. The organic extract
was washed with water, brine, and dried over magnesium sulfate. The product was
purified by short column chromatography using dichloromethane/light petroleum
(70:30) as eluent and recrystallized from methanol/water to give the thioamide 355 as
a brown solid (4.12, 76%), m.p. 88-89 °C. HRMS (+ESI): C10H13NO2S [M+Na]+
requires 234.0559, found 234.0558. (Found: C, 57.44; H, 6.35; N, 6.69. C10H13NO2S
requires C, 56.85; H, 6.20; N, 6.63 %). max (KBr): 3213, 3151, 3059, 1618, 1596,
MeO
OMe
NHCSCH3
MeO
OMe
NHCSH
Experimental 220
1549, 1477, 1460, 1426, 1345, 1300, 1213, 1199, 1163, 1060, 839, 727 cm-1. max
(MeOH): 206 nm ( 22,600 cm-1M-1), 300 (10,200). 1H NMR (300 MHz, CDCl3):
2.50 (s, 3H, CH3), 3.76 (s, 6H, OCH3), 6.27 (d, J = 2.25, 2H, aryl H2,6), 6.38 (t, J =
2.28 Hz, 1H, aryl H4), 9.79 (br s, 1H, NH). 1H NMR (300 MHz, CDCl3): 2.66 (s,
3H, CH3), 3.72 (s, 6H, OCH3), 6.31 (t, J = 2.25 Hz, 1H, aryl H4), 6.93 (d, J = 2.25,
2H, aryl H2,6), 9.03 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 56.12, 56.62
(OCH3), 91.84, 127.55, 128.93, 131.33 (aryl CH), 112.02, 116.70, 133.12, 156.65,
158.73, 162.62, 171.43 (aryl C), 188.80 (C=S). Mass Spectrum (+EI): m/z (%) 212
(M+1, 26), 211(M, 5), 210 (M-1, 40), 196 (21), 178 (100), 171 (34), 154 (32).
N-(3,5-Dimethoxyphenyl)benzothioamide (356)
A mixture of benzamide 153 (1 g, 3.89 mmol) and
Lawesson’s reagent (0.94 g, 2.34 mmol, 0.6 eq.) in
toluene (10 mL) was heated under reflux for 3 h. The
solution was allowed to cool to room temperature, the resulting precipitate was
collected and recrystallized from ethanol to give the thioamide 356 as yellow needles
(0.86 g, 81%), m.p. 139-141 °C (lit.31 m.p. 135-136°C). (Found: C, 65.81; H, 5.66; N,
5.07. C15H15NO2S requires C, 65.91; H, 5.53; N, 5.12 %). max (KBr): 3212, 1608,
1517, 1475, 1371, 1328, 1282, 1236, 1202, 1155, 1067, 1006, 941, 864, 771, 708 cm-
1. max (MeOH):206 nm ( 53,300 cm-1M-1), 235 (26,800), 267 (16,800), 318 (13,800). 1H NMR (300 MHz, CDCl3): 3.77 (s, 6H, OCH3), 6.37(s, 1H, aryl H4), 7.04 (s, 2H,
aryl H2H6), 7.39-7.46 (m, 3H, aryl H), 7.77 (s, 2H, aryl H), 9.01 (br s, 1H, NH). 13C
NMR (75 MHz, CDCl3): 55.43 (OCH3), 99.10, 101.54, 126.62, 128.49, 131.06 (aryl
CH), 140.56, 143.32, 160.86 (aryl C), 198.10 (C=S). Mass Spectrum (+EI): m/z (%)
274 (M+1, 32), 273 (M, 15), 272 (M-1, 100), 258 (17), 240 (25), 171 (24).
N-(3,5-Dimethoxyphenyl)-4'-methoxybenzothioamide (357)
This compound was prepared as described for the
thioamide 356 from a mixture of benzamide 154
(5 g, 17.42 mmol) and Lawesson’s reagent (4.22
g, 10.45 mmol) in toluene (50 mL) under reflux
for 3 h to afford the benzothioamide 357 as a yellow solid (4.07 g, 77%), m.p. 130-
MeO
OMe
NHCS
MeO
OMe
NHCS OMe
Experimental 221
131 °C. (Found: C, 63.50; H, 5.72; N, 4.59. C16H17NO3S requires C, 63.34; H, 5.65;
N, 4.62 %). max (KBr): 3162, 3002, 2965, 1599, 1507, 1455, 1344, 1291, 1255, 1208,
1158, 1059, 1015, 835 cm-1. max (MeOH): 207 nm ( 31,600 cm-1M-1), 293 (16,700). 1H NMR (300 MHz, CDCl3): 3.77 (s, 6H, OCH3), 3.85 (s, 3H, OCH3), 6.36 (s, 1H,
aryl H4), 6.88-6.97 (m, 4H, aryl H), 7.80 (d, J = 7.53, 2H, aryl H), 8.92 (br s, 1H,
NH). 13C NMR (75 MHz, CDCl3): 55.43, 55.71 (OCH3), 98.93, 101.68, 113.63,
128.68 (aryl CH), 137.21, 140.76, 160.87, 162.21 (aryl C), 197.41 (C=S). Mass
Spectrum (+EI): m/z (%) 304 (M+1, 45), 303 (M, 18), 320 (M-1, 100), 288 (23), 270
(21).
4'-Chloro-N-(3,5-dimethoxyphenyl)benzothioamide (358)
This compound was prepared as described for the
thioamide 356 from a mixture of benzamide 351
(10 g, 34.3 mmol) and Lawesson’s reagent (8.30 g,
20.6 mmol) in toluene (100 mL) under reflux for 3
h to afford the thioamide 358 as a yellow powder (6.95 g, 66%), m.p. 115-116 °C.
(Found: C, 58.81; H, 4.63; N, 4.52. C15H14ClNO2S requires C, 58.53; H, 4.58; N, 4.55
%). max (KBr): 1618, 1517, 1479, 1461, 1399, 1342, 1208, 1150, 1089, 1058, 1010,
925, 836, 748, 735 cm-1. max (MeOH): 214 nm ( 35,300 cm-1M-1), 241 (15,900), 271
(12,900), 318 (8,400). 1H NMR (300 MHz, CDCl3): 3.71 (s, 6H, OCH3), 6.31 (s,
1H, aryl H4), 6.91 (s, 2H, aryl H2,6), 7.26 (d, J = 8.28 Hz, 2H, aryl H), 7.62 (d, J =
8.28 Hz, 2H, aryl H), 9.20 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.41
(OCH3), 99.05, 101.88, 128.14, 128.46 (aryl CH), 137.22, 140.34, 141.02, 160.75
(aryl C), 196.50 (C=S). Mass Spectrum (+EI): m/z (%) 310 (M+1, 37Cl, 11), 309 (M, 37Cl, 30), 308 (M+1, 35Cl, 100), 307 (M, 35Cl, 9) 294 (37Cl, 20) 292 (35Cl, 54).
N-(3,5-Dimethoxyphenyl)-4'-nitrobenzothioamide (359)
This compound was prepared as described for the
thioamide 356 from a mixture of benzamide 352
(9 g, 29.8 mmol) and Lawesson’s reagent (7.18 g,
17.88 mmol) in toluene (100 mL) under reflux for
12 h to afford the thioamide 359 as an orange red powder (6.55 g, 69%), m.p. 151-152
MeO
OMe
NHCS NO2
MeO
OMe
NHCS Cl
Experimental 222
°C. (Found: C, 54.80; H, 4.35; N, 8.43. C15H14N2O4S 0.2CH2Cl2 requires C, 54.44; H,
4.33; N, 8.35 %). max (KBr): 1611, 1547, 1512, 1473, 1434, 1407, 1380, 1351, 1217,
1164, 1070, 1001, 946, 852, 732, 695 cm-1. max (MeOH): 205 nm ( 37,000 cm-1M-1),
280 (15,400). 1H NMR (300 MHz, CDCl3): 3.81 (s, 6H, OCH3), 6.41 (s, 1H, aryl
H4), 7.04 (s, 2H, aryl H2,6), 7.92 (d, J = 8.67 Hz, 2H, aryl H), 8.26 (d, J = 8.67 Hz,
2H, aryl H), 8.99 (br s, 1H, NH). 13C NMR (75 MHz, Acetone-d6): 55.46 (OCH3),
99.41, 101.36, 123.75, 127.57 (aryl CH), 127.33, 139.14, 140.00, 148.78 (aryl C),
195.07 (C=S). Mass Spectrum (+EI): m/z (%) 319 (M+1, 35), 318 (M, 18), 317 (100).
N-(3,5-Dimethoxyphenyl)-2'-nitrobenzothioamide (360)
This compound was prepared as described for the
thioamide 354 from a solution of benzamide 353 (4.20
g, 13.9 mmol) and phosphorus pentasulfide (3.08 g,
13.9 mmol) in pyridine (25 mL) under reflux for 3 h to
afford the thioamide 360 as a light brown powder (1.81 g, 41%), m.p. 159 °C. (Found:
C, 55.52; H, 4.30; N, 8.62. C15H14N2O4S 0.1CH2Cl2 requires C, 55.49; H, 4.38; N,
8.57 %). max (KBr): 3434, 3304, 1610, 1573, 1489, 1442, 1324, 1225, 1164, 1149,
1125, 1034, 941, 824, 763 cm-1. max (MeOH): 207 nm ( 20,200 cm-1M-1), 232
(26,100), 289 (9,100), 372 (8,600). 1H NMR (300 MHz, Acetone-d6): 3.89 (s, 3H,
OCH3), 3.99 (s, 3H, OCH3), 6.59 (d, J = 1.89 Hz, 1H, aryl H), 6.63-6.69 (m, 1H, aryl
H), 6.87-6.90 (m, 1H, aryl H), 7.04 (s, 1H, NH), 7.14-7.22 (m, 3H, aryl H), 7.66-7.69
(m, 1H, aryl H). 13C NMR (75 MHz, Acetone-d6): 55.12, 55.49 (OCH3), 96.40,
97.26, 115.80, 116.58, 129.57, 131.46 (aryl CH), 113.29, 114.14, 147.67, 154.21,
155.42, 160.58 (aryl C), 170.11 (C=S). Mass Spectrum (+ESI): m/z (%) 657 (2M+Na,
100), 341 (M+Na, 78).
5,7-Dimethoxybenzothiazole.(11)
The thioamide 354 (0.10 g, 0.51 mmol) was suspended in little
absolute ethanol (1 mL) and 30% sodium hydroxide solution (0.55
mL, 8 eq.) was added dropwise with stirring. The resulting mixture was stirred for 5
min, diluted with water to make 10% sodium hydroxide solution and stirred again for
5 min. This solution was slowly added to a previously heated (80 °C) solution of
MeO
OMe
NHCS
O2N
N
S
OMe
MeO
Experimental 223
potassium ferricyanide (0.67 g, 2.02 mmol, 4 eq.) in water (5 mL) and the mixture
stirred for 30 min. The reaction was cooled to room temperature and the resulting
precipitate was filtered, washed with water, purified by flash chromatography and
recrystallized from ethanol and dried to give the benzothiazole 11 as a brown solid (94
mg, 19%), m.p. 110-112 °C. HRMS (+ESI): C9H9NO2S [M+H]+ requires 196.0427,
found 196.0440. max (KBr): 3440, 1745, 1650, 1600,1537, 1463, 1415, 1302, 1207,
1161, 1033 cm-1. max (MeOH): 206 nm ( 23,900 cm-1M-1), 252 (10,600). 1H NMR
(300 MHz, CDCl3): 3.78 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.47 (d, J = 2.25 Hz,
1H, aryl H6), 7.06 (d, J = 2.25 Hz, 1H, aryl H4), 8.39 (d, J = 2.25 Hz, 1H, aryl H2).
Mass Spectrum (+ESI): m/z (%) 197 (M+2, 13), 196 (M+1, 12), 195 (M, 10).
5,7-Dimethoxy-2-methylbenzothiazole (361)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 355 (10 g,
47.40 mmol) in absolute ethanol (10 mL), 30% sodium hydroxide solution (50 mL, 8
eq.) and a solution of potassium ferricyanide (62.5 g, 0.19 mol, 4 eq.) in water (120
mL) at 80-90°C for 1 h to give the benzothiazole 361 as a brown solid (5.4 g, 55%),
m.p. 91-92 °C. (Found: C, 57.12; H, 5.39; N, 6.64. C10H11NO2S requires C, 57.39; H,
5.30; N, 6.69 %). max (KBr): 2970, 1597, 1575, 1522, 1473, 1453, 1427, 1412, 1343,
1308, 1220, 1202, 1172, 1152, 1119, 1094, 1034, 930, 829, 648 cm-1. max (MeOH):
205 nm ( 25,200 cm-1M-1), 224 (21,400), 307 (2,500). 1H NMR (300 MHz, CDCl3):
2.79 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6.45 (d, J = 2.25 Hz, 1H,
aryl H6), 7.06 (d, J = 2.25 Hz, 1H, aryl H4). 13C NMR (75 MHz, CDCl3): 19.99
(CH3), 55.63, 55.76 (OCH3), 96.21, 97.11 (aryl CH), 116.41, 154.06, 155.03, 160.01,
168.00 (aryl C). Mass Spectrum (+EI): m/z (%) 211 (M+2, 12), 210 (M+1, 100), 195
(13).
5,7-Dimethoxy-2-phenylbenzothiazole (362)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 356 (5 g,
18.31 mmol) in absolute ethanol (20 mL), 30% sodium hydroxide solution (20 mL, 8
eq.) and a solution of potassium ferricyanide (24.11 g, 73.24 mmol, 4 eq.) in water
N
S
OMe
MeOMe
N
S
OMe
MeO
Experimental 224
(120 mL) at 80-90 °C for 1 h to give the benzothiazole 362 as an off white solid (3.71
g, 74%), m.p. 81-82 oC. (Found: C, 66.49; H, 4.97; N, 5.12. C15H13NO2S requires C,
66.40; H, 4.83; N, 5.16 %). max (KBr): 2992, 1602, 1578, 1470, 1445, 1421, 1306,
1214, 1199, 1149, 1124, 1040, 936, 803, 755, 681, 635 cm-1. max (MeOH): 207
(29,200 nm ( cm-1M-1), 238 (16,000), 294 (12,700). 1H NMR (300 MHz, CDCl3):
3.89 (s, 6H, OCH3), 3.95 (s, 3H, OCH3), 6.49 (d, J = 2.25 Hz, 1H, aryl H6), 7.19 (d, J
= 2.25 Hz, 1H, aryl H4), 7.46-7.49 (m, 3H, aryl H), 8.05-8.08 (m, 2H, aryl H). 13C
NMR (75 MHz, CDCl3): 55.67, 55.82 (OCH3), 96.86, 97.48, 127.24, 128.90, 130.73
(aryl CH), 116.14, 133.58, 154.25, 155.64, 160.32, 169.17 (aryl C). Mass Spectrum
(+EI): m/z (%) 273 (M+2, 19), 272 (M+1, 100).
5,7-Dimethoxy-2-(4'-methoxyphenyl)benzothiazole (363)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 357
(4.80 g, 15.84 mmol) in absolute ethanol (25 mL),
30% sodium hydroxide solution (17 mL, 8 eq.) and a solution of potassium
ferricyanide (20.86 g, 63.36 mmol, 4 eq.) in water (50 mL) at 80-90 °C for 1 h to give
the benzothiazole 363 as white crystals (4.77 g, 95%), m.p. 131-131 °C. (Found: C,
64.07; H, 5.18; N, 4.63. C16H15NO3S requires C, 63.77; H, 5.02; N, 4.65 %). max
(KBr): 3000, 1605, 1598, 1462, 1430, 1413, 1351, 1307, 1252, 1224, 1203, 1158,
1121, 1111, 1036, 1023, 935, 831, 732 cm-1. max (MeOH): 211 nm ( 24,200 cm-1M-
1), 306 (15,600). 1H NMR (300 MHz, CDCl3): 3.87 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 6.47 (d, J = 2.25 Hz, 1H, aryl H6), 6.98 (d, J = 8.28 Hz,
2H, aryl H), 7.16 (d, J = 2.25 Hz, 1H, aryl H4), 8.01 (d, J = 8.28 Hz, 2H, aryl H). 13C
NMR (75 MHz, CDCl3): 58.88, 59.20, 59.34 (OCH3), 99.98, 100.83, 117.77, 132.31
(aryl CH), 119.27, 129.97, 157.72, 159.29, 163.74, 165.24, 172.53 (aryl C). Mass
Spectrum (+EI): m/z (%) 303 (M+2, 20), 302 (M+1, 100).
2-(4'-Chlorophenyl)-5,7-dimethoxybenzothiazole (364)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 358 (8
g, 18.86 mmol) in absolute ethanol (10 mL), 30% N
S
OMe
MeOCl
N
S
OMe
MeOOMe
Experimental 225
sodium hydroxide solution (20 mL, 8 eq.) and a solution of potassium ferricyanide
(24.8 g, 75.44 mmol, 4 eq.) in water (100 mL) at 80-90 °C for 1 h to give the
benzothiazole 364 as a white solid (5.23 g, 91%), m.p. 201-202 °C. (Found: C, 58.98;
H, 4.05; N, 4.52. C15H12ClNO2S requires C, 58.92; H, 3.96; N, 4.58 %). max (KBr):
1580, 1470, 1446, 1312, 1218, 1204, 1152, 1126, 1085, 1039, 934, 813 cm-1. max
(MeOH): 209 nm ( 27,900 cm-1M-1), 239 (14,200), 260 (11,800), 302 (14,400). 1H
NMR (300 MHz, CDCl3): 3.89 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.50 (d, J = 1.50
Hz, 1H, aryl H6), 7.17 (d, J = 1.50 Hz, 1H, aryl H4), 7.44 (d, J = 8.67 Hz, 2H, aryl H),
8.03 (d, J = 8.67 Hz, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 55.71, 55.87 (OCH3),
97.08, 97.43, 128.41, 129.16 (aryl CH), 116.16, 132.05, 136.80, 154.25, 155.54,
160.46, 167.76 (aryl C). Mass Spectrum (+EI): m/z (%) 309 (M+2, 37Cl, 10), 308
(M+1, 37Cl, 38), 307 (M+2, 35Cl, 18), 306 (M+1, 35Cl, 100), 272 (12).
5,7-Dimethoxy-2-(4'-nitrophenyl)benzothiazole (365)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 359
(5 g, 15.72 mmol) in absolute ethanol (10 mL), 30%
sodium hydroxide solution (16.7 mL, 8 eq.) and a solution of potassium ferricyanide
(20.70 g, 62.88 mmol, 4 eq.) in water (25 mL) at 80-90 °C for 1 h to give the
benzothiazole 365 as a yellow solid (4.77 g, 96%), m.p. 240-241 °C. (Found: C,
56.04; H, 3.89; N, 8.66. C15H12N2O4S 0.3H2O requires C, 56.00; H, 3.95; N, 8.71 %).
max (KBr): 1604, 1578, 1527, 1428, 1351, 1311, 1154, 1126, 853 cm-1. max (MeOH):
203 nm ( 40,400 cm-1M-1), 229 (23,800), 333 (17,600). 1H NMR (300 MHz, CDCl3):
3.91 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.55 (d, J = 2.25 Hz, 1H, aryl H6), 7.21 (d,
J = 2.25 Hz, 1H, aryl H4), 8.23 (d, J = 9.03 Hz, 2H, aryl H), 8.33 (d, J = 9.03 Hz, 2H,
aryl H). 13C NMR (75 MHz, CDCl3): 55.74, 55.96 (OCH3), 97.65, 97.80, 124.27,
127.86 (aryl CH), 103.05, 139.19, 148.80, 154.30, 155.73, 160.75, 165.85 (aryl C).
Mass Spectrum (+EI): m/z (%) 318 (M+2, 20), 317 (M+1, 100).
N
S
OMe
MeONO2
Experimental 226
5,7-Dimethoxy-2-(2'-nitrophenyl)benzothiazole (366)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 360 (1
g, 3.14 mmol) in absolute ethanol (1 mL), 30% sodium
hydroxide solution (3.3 mL, 8 eq.) and a solution of
potassium ferricyanide (4 g, 12.56 mmol, 4 eq.) in water (10 mL) at 80-90 °C for 1 h
to give the benzothiazole 366 as a yellow powder (0.20 g, 20%), m.p. 202 °C. (Found:
C, 57.04; H, 3.93; N, 8.89. C15H12N2O4S requires C, 56.95; H, 3.82; N, 8.86 %). max
(KBr): 1600, 1580, 1531, 1463, 1413, 1360, 1303, 1224, 1155, 1125, 1040 cm-1. max
(MeOH): 206 nm ( 27,500 cm-1M-1), 227 (20,500), 296 (8,500). 1H NMR (300 MHz,
CDCl3): 3.88 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.53 (d, J = 2.28 Hz, 1H, aryl H6),
7.16 (d, J = 2.28 Hz, 1H, aryl H4), 7.58-7.80 (m, 2H, aryl H), 7.86 (d, J = 1.14 Hz,
1H, aryl H), 7.89 (d, J = 1.14 Hz, 1H, aryl H). 13C NMR (75 MHz, CDCl3): 55.73,
55.92 (OCH3), 97.54, 97.82, 124.33, 130.71, 131.53, 132.15 (aryl CH), 117.15,
127.83, 148.85, 154.18, 155.18, 160.51, 163.26 (aryl C). Mass Spectrum (+EI): m/z
(%) 318 (M+2, 18), 317 (M+1, 100).
N-(2,4-Dimethoxyphenyl)formamide (367)
A solution of 2,4-dimethoxy aniline 342 (10 g, 65.35 mmol) in
formic acid (10 mL, 80%) was heated to reflux for 2 h before
ice water was added to quench the reaction. The resulting
precipitate was collected, washed with water and dried to give the formanilide 367 as
a light pink powder (11.44 g, 97 %), m.p. 144-145 °C. (lit.227 140-141 °C). (Found: C,
59.72; H, 6.19; N, 7.66. C9H11NO3 requires C, 59.66; H, 6.12; N, 7.73 %). max (KBr):
3245, 2899, 1680, 1655, 1598, 1537, 1464, 1413, 1390, 1301, 1233, 1203, 1167,
1109, 1032, 931, 827 cm-1. max (MeOH): 215 nm ( 19,800cm-1M-1), 252 (9,800), 289
(4,100). 1H NMR (300 MHz, CDCl3) 3.77 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.43-
6.49 (m, 2H, aryl H3,5), 7.65 (br s, 1H, NH), 8.21 (d, J = 8.28 Hz, 1H, aryl H6),), 8.37
(d, J = 1.86 Hz 1H, CHO). 1H NMR (300 MHz, CDCl3): 3.78 (s, 3H, OCH3), 3.81
(s, 3H, OCH3), 6.47-6.49 (m, 2H, aryl H3,5), 7.05 (d, J = 8.67 Hz, 1H, aryl H6), 7.49
(br s, 1H, NH) ), 8.51 (d, J = 11.67 Hz 1H, CHO). 13C NMR (75 MHz, CDCl3):
55.43, 55.63 (OCH3), 98.57, 99.41, 103.70, 104.10, 119.23, 121.21 (aryl CH), 119.38,
OMe
MeO
NHCHO
N
S
OMe
MeOO2N
Experimental 227
120.21, 149.16, 150.96, 156.67, 158.12 (aryl C), 158.46, 162.22 (C=O). Mass
Spectrum (+EI): m/z (%) 182 (M+1, 72), 154 (100).
N-(2,4-Dimethoxyphenyl)acetamide (368)
A solution of 2,4-dimethoxy aniline 342 (5 g, 32.68 mmol)
in acetic anhydride was stirred at 0 °C for 12 h before ice
water was added to the mixture. The resulting precipitate
was filtered, washed with water and recrystallized from ethanol to afford the
acetamide 368 as off white needles (3.35 g, 53%), m.p. 114-115 °C. (Found: C, 61.02;
H, 6.77; N, 7.10. C10H13NO3 0.1H2O requires C, 60.96; H, 6.75; N, 7.11 %). max
(KBr): 3283, 2964, 1662, 1614, 1542, 1466, 1415, 1375, 1280, 1206, 1159, 1126,
1041, 1023, 967, 837, 800 cm-1. max (MeOH): 217 nm ( 19,700 cm-1M-1), 248
(19,900), 285 (3,200). 1H NMR (300 MHz, CDCl3) 2.16 (s, 3H, CH3), 3.77 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3), 6.44-6.46 (m, 2H, aryl H3,5), 7.52 (br s, 1H, NH), 8.18
(d, J = 9.78 Hz, 1H, aryl H6). 13C NMR (75 MHz, CDCl3) 24.54 (CH3), 55.41, 55.54
(OCH3), 98.45, 103.67, 120.75 (aryl CH), 121.13, 149.10, 156.26 (aryl C), 167.84
(C=O). Mass Spectrum (+EI): m/z (%) 197 (M+2, 12), 196 (M+1, 100).
N-(2,4-Dimethoxyphenyl)benzamide (369)
To a solution of 2,4-dimethoxy aniline 342 (7.50 g, 49 mmol)
in dry dichloromethane (100 mL) containing anhydrous
potassium carbonate (5 g), benzoyl chloride was added
dropwise and the mixture stirred for overnight at room temperature. Water was added
to the mixture and the organic extract was washed with water and brine, and dried
over magnesium sulfate. The organic solvent was evaporated off and the crude solid
was recrystallized from ethanol to give the title benzamide 369 as a white solid (9.33
g, 74%), m.p. 158-160°C. (Found: C, 69.95; H, 5.96; N, 5.41. C15H15NO, requires C,
70.02; H, 5.88; N, 5.44 %). max (KBr): 3240, 3006, 1650, 1600, 1525, 1510, 1489,
1463, 1313, 1273, 1209, 1155, 1134, 1043, 1030, 929, 825, 713 cm-1. max (MeOH):
202 nm ( 22,900 cm-1M-1), 221 (13,200), 282 (6,100). 1H NMR (300 MHz, CDCl3):
3.80 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.51-6.54 (m, 2H, aryl H3,5), 7.44-7.53 (m,
3H, aryl H), 7.86-7.89 (m, 2H, aryl H), 8.33 (br s, 1H, NH), 8.38-8.41 (m, 1H, aryl
OMe
MeO
NHCOCH3
OMe
MeO
NHCOPh
Experimental 228
H6). 13C NMR (75 MHz, CDCl3): 55.46, 55.73 (OCH3), 98.57, 103.79, 120.64,
126.88, 128.60, 131.42 (aryl CH), 121.31, 135.33, 149.44, 156.45 (aryl C), 164.87
(C=O). Mass Spectrum (+EI): m/z (%) 259 (M+2, 13), 258 (M+1, 73), 105 (100).
N-(2,4-Dimethoxyphenyl)-4'-methoxybenzamide (370)
This compound was prepared as described for the
compound 369 from an ice cooled solution of 2,4-
dimethoxy aniline 342 (5 g, 32.68 mmol) in dry
dichloromethane (100 mL) containing anhydrous potassium carbonate (5 g) and 4-
methoxybenzoyl chloride (6.14 g, 36 mmol) under stirring overnight to give the
benzamide 370 as a light brown powder (6.73 g, 72%), m.p. 123-124 °C. (Found: C,
66.70; H, 6.10; N, 4.76. C16H17NO4 requires C, 66.89; H, 5.96; N, 4.88 %). max
(KBr): 3323, 3006, 1640, 1610, 1534, 1514, 1494, 1462, 1418, 1284, 1257, 1206,
1187, 1156, 1133, 1044, 1030, 834 cm-1. max (MeOH): 208 nm ( 41,700 cm-1M-1),
255 (16,700). 1H NMR (300 MHz, CDCl3): 3.80 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
3.89 (s, 3H, OCH3), 6.50-6.54 (m, 2H, aryl H3,5), 6.96 (d, J = 9.03 Hz, 2H, aryl H),
7.84 (d, J = 9.03 Hz, 2H, aryl H), 8.25 (br s, 1H, NH), 8.37 (d, J = 9.42 Hz, 1H, aryl
H6). 13C NMR (75 MHz, CDCl3): 55.31, 55.44, 55.72 (OCH3), 98.53, 103.78,
113.78, 120.56, 128.69 (aryl CH), 121.46, 127.53, 149.39, 156.28, 162.16 (aryl C),
164.44 (C=O). Mass Spectrum (+EI): m/z (%) 289 (M+2, 18), 288 (M+1, 100).
4'-Chloro-N-(2,4-dimethoxyphenyl)benzamide (371)
This compound was prepared as described for the
compound 369 from an ice cooled solution of 2,4-
dimethoxy aniline 342 (10 g, 65.36 mmol) in dry
dichloromethane (100 mL) containing anhydrous potassium carbonate (5 g) and 4-
chlorobenzoyl chloride (13.7 g, 78.43 mmol) under stirring for 4 h to give the
benzamide 371 as an off white solid (14.91 g, 78 %), m.p. 112-113 °C. (Found: C,
62.04; H, 4.96; N, 4.79. C15H14ClNO3 requires C, 61.76; H, 4.84; N, 4.80 %). max
(KBr): 3436, 2989, 1661, 1613, 1542, 1501, 1483, 1461, 1415, 1285, 1258, 1209,
1155, 1039, 918, 838, 744 cm-1. max (MeOH): 211 nm ( 25,500 cm-1M-1), 224
(14,000) , 286 (5,900). 1H NMR (300 MHz, CDCl3): 3.81 (s, 3H, OCH3), 3.89 (s,
OMe
MeO
NHCO OMe
OMe
MeO
NHCO Cl
Experimental 229
3H, OCH3), 6.51-6.54 (m, 2H, aryl H3,5), 7.45 (d, J = 8.28 Hz, 2H, aryl H), 7.81 (d, J
= 8.28 Hz, 2H, aryl H), 8.26 (br s, 1H, NH), 8.36 (d, J = 9.42 Hz, 1H, aryl H6). 13C
NMR (75 MHz, CDCl3): 55.43, 55.72 (OCH3), 98.53, 103.78, 120.78, 128.32,
128.80 (aryl CH), 120.96, 133.61, 137.61, 149.52, 156.64 (aryl C), 163.77 (C=O).
Mass Spectrum (+EI): m/z (%) 295 (M+2, 37Cl, 5), 294 (M+1, 37Cl, 35), 293 (M+2, 35Cl, 18), 292 (M+1, 35Cl, 100).
N-(2,4-Dimethoxyphenyl)-4'-nitrobenzamide (372)
This compound was prepared as described for the
amide 352 from an ice cooled solution of 2,4-
dimethoxyaniline 342 (5 g, 32.67 mmol) and 4-
nitrobenzoyl chloride (7.27 g, 39.2 mmol) in pyridine (50 mL) under stirring at room
temperature for 24 h to afford the benzamide 372 as yellow crystals (9.50 g, 96%),
m.p. 174-175 °C. (Found: C, 59.67; H, 4.77; N, 9.23. C15H14N2O5 requires C, 59.60;
H, 4.67; N, 9.27 %). max (KBr): 3432, 2943, 1679, 1604, 1535, 1422, 1343, 1286,
1213, 1157, 1035 cm-1. max (MeOH): 207 nm ( 23,500 cm-1M-1), 253 (10,500). 1H
NMR (300 MHz, CDCl3): 3.82 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.52-6.53 (m,
2H, aryl H3,5), 8.03 (d, J = 8.64 Hz, 2H, aryl H), 8.32 (d, J = 8.64 Hz, 2H, aryl H),
8.34 (d, J = 9.42 Hz, 1H, aryl H6), 8.38 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3):
55.48, 55.81 (OCH3), 98.62, 103.86, 120.83, 123.84, 128.05 (aryl CH), 120.57,
140.82, 149.47, 149.52, 157.03 (aryl C), 162.64 (C=O). Mass Spectrum (+EI): m/z
(%) 304 (M+2, 17), 303 (M+1, 100).
N-(2,4-Dimethoxyphenyl)-2'-nitrobenzamide (373)
This compound was prepared as described for the amide
352 from an ice cooled solution of 2,4-dimethoxyaniline
342 (10 g, 65.36 mmol) in pyridine (50 mL) and 2-
nitrobenzoyl chloride (14.5 g, 78.4 mmol) under stirring at room temperature
overnight to afford the benzamide 373 as a yellow powder (9.98 g, 51%), m.p. 134-
135 °C. (Found: C, 59.34; H, 4.69; N, 9.27. C15H14N2O5 requires C, 59.60; H, 4.67; N,
9.27 %). max (KBr): 3293, 1651, 1607, 1543, 1468, 1418, 1347, 1302, 1250, 1207,
1167, 1033, 829 cm-1. max (MeOH): 210 nm ( 23,400 cm-1M-1), 249 (8,500). 1H
OMe
MeO
NHCO NO2
OMe
MeO
NHCO
O2N
Experimental 230
NMR (300 MHz, CDCl3): 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.49-6.55 (m,
2H, aryl H3,5), 7.61-7.71 (m, 3H, aryl H), 7.86 (br s, 1H, NH), 8.07-8.10 (m, 1H, aryl
H), 8.33 (d, J = 8.64 Hz, 1H, aryl H6). 13C NMR (75 MHz, CDCl3): 55.48, 55.66
(OCH3), 98.57, 103.88, 121.06, 124.54, 128.52, 130.55, 133.65 (aryl CH), 120.71,
133.01, 146.55, 149.48, 156.96 (aryl C), 163.51 (C=O). Mass Spectrum (+EI): m/z
(%) 304 (M+2, 18), 303 (M+1, 100), 153 (24).
N-(2,4-Dimethoxyphenyl)methanethioamide (374)
This compound was prepared as described for the thioamide
355 from a solution of amide 367 (10 g, 55.25 mmol) and
Lawesson’s reagent (13.3 g, 33.15 mmol) in toluene (70 mL)
under reflux for 3 h. The crude product was chromatographed using
dichloromethane/light petroleum (70:30) as eluent to give the thioamide 374 as a light
brown solid (0.68 g, 6 %), m.p. 78-80 °C. (Found: C, 55.84; H, 5.69; N, 6.91.
C9H11NO2S requires C, 54.80; H, 5.62; N, 7.10 %). max (KBr): 3225, 1605, 1542,
1467, 1285, 1211, 1159, 1030, 974, 823, 782 cm-1. max (MeOH): 203 nm ( 27,700
cm-1M-1), 292 (10,500), 320 (13,800). 1H NMR (300 MHz, CDCl3): 3.80 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 6.44-6.50 (m, 2H, aryl H3,5), 7.15 (d, J = 8.64 Hz, 1H,
aryl H6), 9.44 (br s, 1H, NH), 9.65 (d, J = 15.06 Hz, 1H, CSH). 13C NMR (75 MHz,
CDCl3): 55.56, 55.77 (OCH3), 99.31, 104.66, 116.98 (aryl CH), 121.79, 149.12,
158.67 (aryl C), 185.25 (C=S). Mass Spectrum (+EI): m/z (%) 198 (M+1, 100).
N-(2,4-Dimethoxyphenyl)ethanethioamide (375)
This compound was prepared as described for the thioamide
354 from a solution of amide 368 (1.70 g, 8.70 mmol) and
phosphorus pentasulfide (1.95 g, 8.80 mmol) in pyridine (15
mL) under reflux for 2 h to yield the thioamide 375 as a dark brown solid (0.97 g,
53%), m.p. 78-80 °C. (Found: C, 56.59; H, 6.14; N, 6.55. C10H13NO2S requires C,
56.85; H, 6.20; N, 6.63 %). HRMS (+ESI): C10H13NO2S [M+H]+ requires 212.0739,
found 212.0730. max (KBr): 3361, 1617, 1539, 1497, 1451, 1389, 1328, 1285, 1267,
1206, 1158, 1125, 1043, 1027, 830, 676 cm-1. max (MeOH): 205 nm ( 26,600 cm-1M-
1), 280 (11,500). 1H NMR (300 MHz, CDCl3): 2.71 (s, 3H, CH3), 3.79 (s, 3H,
OMe
MeO
NHCSCH3
OMe
MeO
NHCSH
Experimental 231
OCH3), 3.84 (s, 3H, OCH3), 6.44-6.50 (m, 2H, aryl H3,5), 8.68 (d, J = 9.42 Hz, 1H,
aryl H6), 8.93 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 36.54 (CH3), 55.44,
55.74 (OCH3), 98.57, 103.15, 123.58 (aryl CH), 121.60, 151.25, 158.32 (aryl C),
197.67 (C=S). 1H NMR (300 MHz, CDCl3): 2.42 (s, 3H, CH3), 3.80 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 6.44-6.50 (m, 2H, aryl H3,5), 7.03 (d, J = 8.28 Hz, 1H, aryl H6),
9.12 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 29.45 (CH3), 55.51, 55.61
(OCH3), 99.20, 104.15, 127.02 (aryl CH), 120.23, 154.19, 160.30 (aryl C), 204.88
(C=S). Mass Spectrum (-EI): m/z (%) 210 (M-1, 100).
N-(2,4-Dimethoxyphenyl)benzothioamide (376)
This compound was prepared as described for the
thioamide 354 from a solution of amide 369 (8.50 g,
33.07 mmol) and phosphorus pentasulfide (8.08 g, 36.38
mmol) in pyridine (30 mL) under reflux for 2 h to yield the benzothioamide 376 as
yellow crystals (6.92 g, 77 %), m.p. 85-86 °C. (Found: C, 65.99; H, 5.63; N, 5.10.
C15H15NO2S requires C, 65.91; H, 5.53; N, 5.12 %). max (KBr): 3347, 2998, 1614,
1594, 1521, 1468, 1436, 1419, 1379, 1329, 1283, 1236, 1208, 1161, 1126, 1033, 990,
915, 836, 794, 744 cm-1. max (MeOH): 204 nm ( 36,100 cm-1M-1), 236 (19,400), 281
(11,000). 1H NMR (300 MHz, CDCl3): 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
6.53 (m, 2H, aryl H3,5), 7.39-7.50 (m, 3H, aryl H), 7.83-7.86 (m, 2H, aryl H), 8.95 (d,
J = 9.42 Hz, 1H, aryl H6), 9.43 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.50,
55.89 (OCH3), 98.62, 103.16, 122.95, 126.63, 128.49, 130.78 (aryl CH), 122.16,
143.82, 151.41, 158.31 (aryl C), 195.11 (C=S). Mass Spectrum (+EI): m/z (%) 274
(M+1, 53), 272 (M-1, 24), 242 (20), 240 (69), 121 (100).
N-(2,4-Dimethoxyphenyl)-4'-methoxybenzothioamide (377)
This compound was prepared as described for the
thioamide 356 from a solution of amide 370 (5 g,
17.42 mmol) and Lawesson’s reagent (4.2 g, 10.45
mmol) in toluene (50 mL) under reflux for 3 h to give the thioamide 377 as a yellow
solid (3.28 g, 62 %), m.p. 102-103 °C (lit.31 m.p. 103-104 °C). (Found: C, 63.64; H,
5.62; N, 4.62. C16H17NO3S requires C, 63.34; H, 5.65; N, 4.62 %). max (KBr): 3366,
OMe
MeO
NHCS
OMe
MeO
NHCS OMe
Experimental 232
1601, 1525, 1461, 1436, 1370, 1283, 1258, 1204, 1177, 1153, 1032, 988, 830 cm-1.
max (MeOH): 204 nm ( 41,300 cm-1M-1), 290 (20, 500). 1H NMR (300 MHz,
CDCl3): 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.53 (s, 2H,
aryl H3,5), 6.92 (d, J = 8.67 Hz, 2H, aryl H), 7.86 (d, J = 8.67 Hz, 2H, aryl H), 8.90
(d, J = 8.28 Hz, 1H, aryl H6), 9.34 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
55.75, 55.82, 56.09 (OCH3), 99.48, 104.80, 113.50, 129.16, 129.86 (aryl CH), 122.36,
133.86, 155.15, 159.67, 162.01 (aryl C), 197.46 (C=S). Mass Spectrum (+EI): m/z (%)
305 (M+2, 21), 304 (M+1, 100), 302 (37), 288 (63), 272 (21).
4'-Chloro-N-(2,4-dimethoxyphenyl)benzothioamide (378)
This compound was prepared as described for the
thioamide 356 from a solution of amide 371 (14 g,
48 mmol) and Lawesson’s reagent (11.58 g, 28.8
mmol) in toluene (120 mL) under reflux for 3 h to give the benzothioamide 378 as
yellow crystals (8.85 g, 60%), m.p. 137-138 °C. (Found: C, 58.76; H, 4.73; N, 4.50.
C15H14ClNO2S requires C, 58.53; H, 4.58; N, 4.55 %). max (KBr): 1613, 1526, 1496,
1460, 1401, 1370, 1330, 1284, 1260, 1201, 1154, 1125, 1087, 1033, 988, 828 cm-1.
max (MeOH): 208 nm ( 23,900 cm-1M-1), 244 (12,300). 1H NMR (300 MHz, CDCl3):
3.80 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.50-6.52 (m, 2H, aryl H3,5), 7.35 (d, J =
8.67 Hz, 2H, aryl H), 7.76 (d, J = 8.67 Hz, 2H, aryl H), 8.83 (d, J = 9.42 Hz, aryl H6),
9.38 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.50, 55.92 (OCH3), 98.58,
103.20, 123.02, 127.99, 128.58 (aryl CH), 121.91, 136.96, 141.88, 151.45, 158.46
(aryl C), 193.42 (C=S). Mass Spectrum (+EI): m/z (%) 311 (M+1, 37Cl, 6), 310 (M, 37Cl, 33), 309 (M+1, 35Cl, 18), 308 (M, 35Cl, 100).
N-(2,4-Dimethoxyphenyl)-4'-nitrobenzothioamide (379)
This compound was prepared as described for the
thioamide 356 from a solution of amide 372 (9 g,
29.8 mmol) and Lawesson’s reagent (7.20 g, 17.88
mmol) in toluene (100 mL) under reflux for 12 h. The crude product was
chromatographed using dichloromethane/light petroleum (70:30) as eluent to give the
benzothioamide 379 as a red solid (7.51 g, 79%), m.p. 188-190 °C. (Found: C, 56.56;
OMe
MeO
NHCS Cl
OMe
MeO
NHCS NO2
Experimental 233
H, 4.46; N, 8.78. C15H14N2O4S requires C, 56.59; H, 4.43; N, 8.80 %). max (KBr):
3356, 1615, 1535, 1519, 1348, 1200, 1157, 1118, 1035, 857, 825, 674 cm-1. max
(MeOH): 203 nm ( 42,600 cm-1M-1), 264 (18,600). 1H NMR (300 MHz, CDCl3):
3.84 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.55 (d, J = 2.64 Hz, 2H, aryl H3,5), 7.95 (d,
J = 8.66 Hz, 2H, aryl H), 8.27 (d, J = 8.66 Hz, 2H, aryl H), 8.95 (d, J = 9.78 Hz, 1H,
aryl H6), 9.45 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.52, 55.96 (OCH3),
98.68, 103.20, 122.57, 123.78, 127.57 (aryl CH), 121.75, 148.70, 148.73, 151.24,
158.70 (aryl C), 191.80 (C=S). Mass Spectrum (+EI): m/z (%) 320 (M+2, 19), 319
(M+1, 100), 318 (M. 15), 317 (76), 303 (52), 287 (25).
N-(2,4-Dimethoxyphenyl)-2'-nitrobenzothioamide (380)
This compound was prepared as described for the
thioamide 354 from a solution of amide 373 (2.50 g,
8.27 mmol) and phosphorus pentasulfide (2.02 g, 9.1
mmol) in pyridine (15 mL) under reflux for 3 h to yield the benzothioamide 380 as a
light orange powder (1.2 g, 46 %), m.p. 167-168 °C. (Found: C, 55.52; H, 4.43; N,
8.60. C15H14N2O4S 0.3H2O requires C, 55.65; H, 4.55; N, 8.65 %). max (KBr): 3190,
1605, 1518, 1459, 1438, 1382, 1340, 1294, 1260, 1209, 1110, 1037, 1025, 988, 936,
825, 733, 701 cm-1. max (MeOH): 211 nm ( 23,600 cm-1M-1). 1H NMR (300 MHz,
CDCl3): 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.50-6.57 (m, 2H, aryl H3,5),
7.51-7.58 (m, 3H, aryl H), 8.01 (d, J = 7.92 Hz, 1H, aryl H), 8.89 (d, J = 8.67 Hz, 1H,
aryl H6), 9.13 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): 55.52, 55.86 (OCH3),
98.75, 103.31, 123.04, 124.61, 128.82, 129.49, 133.44 (aryl CH), 121.47, 133.17,
139.83, 151.29, 158.70 (aryl C), 191.71 (C=S). Mass Spectrum (+EI): m/z (%) 320
(M+2, 10), 319 (M+1, 40), 287 (21), 273 (100), 255 (20).
4,6-Dimethoxybenzothiazole (12)
This compound was prepared as described for the benzothiazole 11
from a solution of thioamide 374 (0.50 g, 2.53 mmol) in absolute
ethanol (1 mL), 30% sodium hydroxide solution (2.7 mL, 8 eq.)
and a solution of potassium ferricyanide (3.34 g, 10.15 mmol, 4 eq.) in water (10 mL)
at 80 °C for 30 min to give the benzothiazole 12 as a brown solid (25 mg, 25%), m.p.
S
N
OMe
MeO
OMe
MeO
NHCS
O2N
Experimental 234
106-108°C. max (KBr): 3441, 1673, 1602, 1578, 1451, 1406, 1308, 1218, 1151, 1121,
1089, 852, 822 cm-1. max (MeOH): 220 nm ( 29,800 cm-1M-1), 308 (4,800). 1H NMR
(300 MHz, CDCl3): 3.90 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 6.53 (d, J = 2.25 Hz,
1H, aryl H5), 6.76 (d, J = 2.25 Hz, 1H, aryl H7), 8.99 (d, J = 2.25 Hz, 1H, aryl H2). 13C NMR (75 MHz, CDCl3): 55.72, 55.87 (OCH3), 97.17, 97.64, 98.20 (aryl CH),
132.10, 143.44, 153.56, 160.28 (aryl C). Mass Spectrum (+ESI): m/z (%) 196 (M+1,
100), 195 (M, 35).
4,6-Dimethoxy-2-methylbenzothiazole (381)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 375 (0.50 g,
2.36 mmol) in absolute ethanol (2 mL), 30% sodium
hydroxide solution (2.5 mL, 8 eq.) and a solution of potassium ferricyanide (3.1 g,
9.44 mmol, 4 eq.) in water (10 mL) at 80-90°C for 1 h to give the benzothiazole 381
as a brown solid (0.13 g, 27%), m.p. 46-48°C. (Found: C, 57.58; H, 4.59; N, 6.67.
C10H11NO2S requires C, 57.39; H, 5.30; N, 6.69 %). HRMS (+ESI): C10H11NO2S
[M+Na]+ requires 232.0402, found 232.0401. max (KBr): 1599, 1572, 1525, 1457,
1432, 1332, 1287, 1219, 1198, 1159, 1045 818 cm-1. max (MeOH): 227 nm ( 25,400
cm-1M-1), 270 (7,300). 1H NMR (300 MHz, CDCl3): 2.76 (s, 3H, CH3), 3.82 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.48 (d, J = 2.25 Hz, 1H, aryl H5), 6.82 (d, J = 2.25 Hz,
1H, aryl H7). 13C NMR (75 MHz, CDCl3): 19.69 (CH3), 55.66, 55.75 (OCH3),
94.96, 97.30 (aryl CH), 137.58, 137.97, 152.96, 158.43, 162.80 (aryl C). Mass
Spectrum (+EI): m/z (%) 211 (M+2, 12), 210 (M+1, 100).
4,6-Dimethoxy-2-phenylbenzothiazole (346)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 376 (6.50 g,
23.8 mmol) in absolute ethanol (10 mL), 30% sodium
hydroxide solution (25.3 mL, 8 eq.) and a solution of potassium ferricyanide (31.3 g,
95.2 mol, 4 eq.) in water (100 mL) at 80-90°C for 1 h to give the benzothiazole 346 as
a yellow solid (5.05 g, 78%), m.p. 122-123 °C (lit.215 125-127 °C). (Found: C, 64.72;
H, 4.79; N, 4.96. C15H13NO2S 0.1CH2Cl2 requires C, 64.81; H, 4.75; N, 5.01 %). max
S
N
OMe
MeOMe
S
N
OMe
MeO
Experimental 235
(KBr): 1592, 1573, 1510, 1479, 1447, 1289, 1211, 1150, 1051, 1034, 974, 812, 682
cm-1. max (MeOH): 214 nm ( 29,000 cm-1M-1), 265 (8,800), 316 (16,000). 1H NMR
(300 MHz, CDCl3): 3.88 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 6.55 (d, J = 1.89 Hz,
1H, aryl H5), 6.93 (d, J = 1.89 Hz, 1H, aryl H7), 7.43-7.45 (m, 3H, aryl H), 8.04-8.08
(m, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 55.70, 55.99 (OCH3), 95.12, 97.86,
127.22, 128.70, 130.21 (aryl CH), 133.62, 137.38, 139.22, 153.76, 158.90, 163.99
(aryl C). Mass Spectrum (+EI): m/z (%) 273 (M+2, 17), 272 (M+1, 100).
4,6-Dimethoxy-2-(4'-methoxyphenyl)benzothiazole (382)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 377
(2.50 g, 8.25 mmol) in absolute ethanol (5 mL),
30% sodium hydroxide solution (8.8 mL, 8 eq.) and a solution of potassium
ferricyanide (10.86 g, 33 mmol, 4 eq.) in water (20 mL) at 80-90°C for 1 h to give the
benzothiazole 382 as a yellow powder (1.77 g, 71 %), m.p. 122-123 °C (lit.31 m.p.
123-124 °C). (Found: C, 63.81; H, 5.10; N, 4.67. C16H15NO3S requires C, 63.77; H,
5.02; N, 4.65 %). max (KBr): 1604, 1571, 1519, 1487, 1452, 1412, 1332, 1304, 1287,
1248, 1214, 1154, 1043, 969, 840, 824, 790 cm-1. max (MeOH): 214 nm ( 51,750 cm-
1M-1), 321 (40,200). 1H NMR (300 MHz, CDCl3): 3.85 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 4.02 (s, 3H, OCH3), 6.53 (d, J = 2.28 Hz, 1H, aryl H5), 6.90 (d, J = 8.64 Hz,
1H, aryl H7), 6.95 (d, J = 8.64 Hz, 2H, aryl H), 7.99 (d, J = 8.64 Hz, 2H, aryl H). 13C
NMR (75 MHz, CDCl3): 55.32, 55.72, 55.97 (OCH3), 95.17, 97.70, 114.05, 128.75
(aryl CH), 126.50, 137.05, 139.16, 153.47, 158.57, 161.34, 163.97 (aryl C). Mass
Spectrum (+EI): m/z (%) 303 (M+2, 20), 302 (M+1, 100).
2-(4'-Chlorophenyl)-4,6-dimethoxybenzothiazole (383)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 378 (8
g, 26.01 mmol) in absolute ethanol (10 mL), 30%
sodium hydroxide solution (28 mL, 8 eq.) and a solution of potassium ferricyanide (34
g, 104.04 mol, 4 eq.) in water (100 mL) at 80-90°C for 1 h to give the benzothiazole
383 as a yellow powder (5.03 g, 87 %), m.p. 146-147 °C. HRMS (+ESI):
S
N
OMe
MeOCl
S
N
OMe
MeOOMe
Experimental 236
C15H12ClNO2S [M+H]+ requires 306.0350, found 306.0342. max (KBr): 1600, 1567,
1510, 1453, 1289, 1269, 1211, 1152, 1089, 1045, 823 cm-1. max (MeOH): 215 nm (
37,000 cm-1M-1), 236 (19,300), 268 (12,000), 322 (19,800). 1H NMR (300 MHz,
CDCl3): 3.88 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 6.55 (d, J = 2.25 Hz, 1H, aryl H5),
6.92 (d, J = 2.25 Hz, 1H, aryl H7), 7.41 (d, J = 8.28 Hz, 2H, aryl H), 7.99 (d, J = 8.28
Hz, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 55.72, 56.01 (OCH3), 95.09, 97.98,
128.36, 128.94 (aryl CH), 132.10, 136.18, 137.42, 139.17, 153.79, 159.08, 162.54
(aryl C). Mass Spectrum (+EI): m/z (%) 309 (M+1, 37Cl, 6), 308 (M, 37Cl, 42), 307
(M+1, 35Cl, 18), 306 (M, 35Cl, 100).
4,6-Dimethoxy-2-(4'-nitrophenyl)benzothiazole (384)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 379
(7 g, 22.01 mmol) in absolute ethanol (5 mL), 30%
sodium hydroxide solution (23.5 mL, 8 eq.) and a solution of potassium ferricyanide
(29 g, 88.05 mmol, 4 eq.) in water (40 mL) at 80-90°C for 1 h to give the
benzothiazole 384 as a yellow solid (5.96 g, 86%), m.p. 218-220 °C. (Found: C,
56.79; H, 3.85; N, 8.88. C15H12N2O4S requires C, 56.95; H, 3.82; N, 8.86 %). max
(KBr): 1589, 1523, 1340, 1292, 1213, 1156, 1047, 852 cm-1. max (MeOH): 205 nm (
43,300 cm-1M-1), 228 (25,200), 279 (12,400), 372 (20,800). 1H NMR (300 MHz,
CDCl3): 3.90 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 6.58 (d, J = 2.25 Hz, 1H, aryl H5),
6.96 (d, J = 2.28 Hz, 1H, aryl H7), 8.22 (d, J = 8.64 Hz, 2H, aryl H), 8.31(d, J = 8.64
Hz, 2H, aryl H). The sample was not soluble enough for 13C NMR measurement.
Mass Spectrum (+EI): m/z (%) 318 (M+2, 19), 317 (M+1, 100).
4,6-Dimethoxy-2-(2'-nitrophenyl)benzothiazole (385)
This compound was prepared as described for the
benzothiazole 11 from a solution of thioamide 380 (1 g,
3.14 mmol) in absolute ethanol (1 mL), 30% sodium
hydroxide solution (3.3 mL, 8 eq.) and a solution of potassium ferricyanide (4.1 g,
12.56 mmol, 4 eq.) in water (10 mL) at 80-90°C for 1 h to give the benzothiazole 385
as a light brown powder (0.25 g, 25%), m.p. 141-143 °C. (Found: C, 57.12; H, 3.94;
N, 8.85. C15H12N2O4S requires C, 56.95; H, 3.82; N, 8.86 %). max (KBr): 1599, 1566,
S
N
OMe
MeONO2
S
N
OMe
MeO
O2N
Experimental 237
1537, 1467, 1360, 1289, 1216, 1158, 1043, 970, 828, 744, 712 cm-1. max (MeOH):
209 nm ( 44,500 cm-1M-1). 1H NMR (300 MHz, CDCl3): 3.80 (s, 3H, OCH3), 3.98
(s, 3H, OCH3), 6.54 (d, J = 2.25 Hz, 1H, aryl H5), 6.91 (d, J = 2.25 Hz, 1H, aryl H7),
7.57-7.67 (m, 2H, aryl H), 7.74-7.77 (m, 1H, aryl H), 7.90-7.93 (m, 1H, aryl H). 13C
NMR (75 MHz, CDCl3): 55.76, 56.13 (OCH3), 94.90, 98.36, 124.33, 130.42,
131.95, 132.29 (aryl CH), 128.46, 138.48, 138.72, 148.70, 154.18, 157.92, 159.41
(aryl C). Mass Spectrum (+EI): m/z (%) 318 (M+2, 19), 317 (M+1, 100).
5,7-Dimethoxy-2-phenylbenzothiazole-4-carbaldehyde (390)
This compound was prepared as described for the
compound 165 from an ice cooled solution of
benzothiazole 362 (2 g, 7.32 mmol) in anhydrous N,N-
dimethylformamide (9 mL) and addition of a previously
cooled mixture of phosphoryl chloride (1.06 mL, 10.98 mmol, 1.5 eq.) in anhydrous
N,N-dimethylformamide (3 mL) followed by heating at 70 °C for 3 h. Base workup
and recrystallization from ethanol afforded the 4-formylbenzothiazole 390 as a light
brown powder (1.97 g, 90%), m.p. 193-194 °C. (Found: C, 64.29; H, 4.52; N, 4.61.
C16H13NO3S requires C, 64.20; H, 4.38; N, 4.68 %). max (KBr): 2846, 1673, 1569,
1470, 1448, 1431, 1375, 1216, 1179, 1136, 952, 804, 701 cm-1. max (MeOH): 205 nm
( 15,400 cm-1M-1), 229 (14,600), 266 (19,000), 313 (11,900), 353 (6,900). 1H NMR
(300 MHz, CDCl3): 4.03 (s, 3H, OCH3), 4.07 (s, 3H, OCH3), 6.51 (s, 1H, aryl H6),
7.48-7.50 (m, 3H, aryl H), 8.11-8.15 (m, 2H, aryl H), 10.96 (s, 1H, CHO). 13C NMR
(75 MHz, CDCl3): 56.12, 56.62 (OCH3), 91.84, 127.55, 128.93, 131.33 (aryl CH),
112.02, 116.70, 133.12, 156.65, 158.73, 162.62, 171.43 (aryl C), 188.80 (C=O). Mass
Spectrum (+EI): m/z (%) 301 (M+2, 19), 300 (M+1, 100).
5,7-Dimethoxy-2-(4'-methoxyphenyl)benzothiazole-4-carbaldehyde (391)
This compound was prepared as described for the
compound 165 from an ice cooled solution of
benzothiazole 363 (3 g, 10 mmol) in anhydrous
N,N-dimethylformamide (10 mL) and addition of a
previously cooled mixture of phosphoryl chloride (1.43 mL, 15 mmol, 1.5 eq.) in
anhydrous N,N-dimethylformamide (3 mL) followed by heating at 70 °C for 2 h. Base
N
S
OMe
MeO
OH
N
S
OMe
MeO
O
OMe
H
Experimental 238
workup and recrystallization from ethanol afforded the title 4-formylbenzothiazole
391 as a white solid (3.03 g, 92%), m.p. 231-232 °C. (Found: C, 60.93; H, 4.73; N,
4.10. C17H15NO4S 0.4 H2O requires C, 60.99; H, 4.70; N, 4.18 %). max (KBr): 3448,
1676, 1577, 1477, 1366, 1340, 1257, 1234, 1214, 1134, 1032, 957, 825 cm-1. max
(MeOH): 207 nm ( 20,800cm-1M-1), 227 (21,100), 279 (23,600), 324 (20,400), 353
(15,600). 1H NMR (300 MHz, CDCl3): 3.88 (s, 3H, OCH3), 4.03 (s, 3H, OCH3),
4.07 (s, 3H, OCH3), 6.49 (s, 1H, aryl H6), 6.99 (d, J = 8.28 Hz, 2H, aryl H), 8.08 (d, J
= 8.28 Hz, 2H, aryl H), 10.94 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3): 55.41,
56.17, 56.74 (OCH3), 91.66, 114.29, 129.26 (aryl CH), 112.11, 116.42, 126.06,
156.99, 158.68, 162.25, 162.54, 172.85 (aryl C), 188.90 (C=O). Mass Spectrum (+EI):
m/z (%) 331 (M+2, 24), 330 (M+1, 100).
2-(4'-Chlorophenyl)-5,7-dimethoxybenzothiazole-4-carbaldehyde (392)
This compound was prepared as described for the
compound 165 from an ice cooled solution of
benzothiazole 364 (3.05 g, 10 mmol) in anhydrous
N,N-dimethylformamide (25 mL) and addition of a
previously cooled mixture of phosphoryl chloride (1.43 mL, 15 mmol, 1.5 eq.) in
anhydrous N,N-dimethylformamide (3 mL) followed by heating at 70 °C for 2 h. Base
workup and recrystallization from ethanol afforded the title 4-formylbenzothiazole
392 as an off white solid (2.97 g, 89%), m.p. 361-362 °C. (Found: C, 57.00; H, 3.70;
N, 4.24. C16H12ClNO3S 0.1H2O requires C, 57.26; H, 3.66; N, 4.17 %). HRMS
(+ESI): C16H12ClNO3S [M+Na]+ requires 356.0119, found 356.0110. max (KBr):
3434, 1691, 1575, 1471, 1340, 1213, 1136, 1090, 953, 825 cm-1. max (MeOH): 203
nm ( 15,900 cm-1M-1), 231 (13,400), 269 (19,400), 315 (12,50). 1H NMR (300 MHz,
CDCl3): 4.04 (s, 3H, OCH3), 4.09 (s, 3H, OCH3), 6.53 (s, 1H, aryl H6), 7.46 (d, J =
8.64 Hz, 2H, aryl H), 8.07 (d, J = 8.64 Hz, 2H, aryl H), 10.92 (s, 1H, CHO). 13C NMR
(75 MHz, CDCl3): 56.17, 56.75 (OCH3), 92.16, 128.81, 129.23 (aryl CH), 99.53,
112.31, 131.70, 137.48, 156.54, 158.76, 162.91, 170.18 (aryl C), 188.67 (C=O). Mass
Spectrum (+ESI): m/z (%) 358 (M+Na, 37Cl, 20), 356(M+Na, 35Cl, 100).
N
S
OMe
MeO
O
Cl
H
Experimental 239
4,6-Dimethoxy-2-phenylbenzothiazole-7-carbaldehyde (393)
This compound was prepared as described for the
compound 165 from an ice cooled solution of
benzothiazole 346 (0.50 g, 1.84 mmol) in anhydrous N,N-
dimethylformamide (3 mL) and addition of a previously
cooled mixture of phosphoryl chloride (0.26 mL, 2.76 mmol, 1.5 eq.) in anhydrous
N,N-dimethylformamide (2 mL) followed by heating at 70 °C for 2 h. Base workup
and recrystallization from ethanol afforded the title 7-formylbenzothiazole 393 as a
light brown powder (0.41 g, 75%), m.p. 160-162 °C. (Found: C, 64.10; H, 4.28; N,
4.79. C16H13NO3S requires C, 64.20; H, 4.38; N, 4.68 %). max (KBr): 1677, 1649,
1567, 1465, 1385, 1302, 1270, 1215, 1148, 1065, 1044, 765 cm-1. max (MeOH): 205
nm ( 14,800 cm-1M-1), 298 (16,000). 1H NMR (300 MHz, CDCl3): 3.99 (s, 3H,
OCH3), 4.14 (s, 3H, OCH3), 6.51 (s, 1H, aryl H5), 7.43-7.44 (m, 3H, aryl H), 8.09-
8.12 (m, 2H, aryl H), 10.42 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3): 56.41, 56.64
(OCH3), 92.91, 127.33, 128.79, 130.52 (aryl CH), 112.28, 133.43, 135.96, 139.61,
159.16, 163.26, 168.26 (aryl C), 185.83 (C=O). Mass Spectrum (+EI): m/z (%) 301
(M+2, 18), 300 (M+1, 100).
2-(4'-Chlorophenyl)-4,6-dimethoxybenzothiazole-7-carbaldehyde (394)
This compound was prepared as described for the
compound 165 from an ice cooled solution of
benzothiazole 383 (3.05 g, 10 mmol) in anhydrous
N,N-dimethylformamide (25 mL) and addition of a
previously cooled mixture of phosphoryl chloride (1.43 mL, 15 mmol, 1.5 eq.) in
anhydrous N,N-dimethylformamide (3 mL) followed by heating at 70 °C for 2 h. Base
workup and recrystallization from ethanol afforded the title 7-formylbenzothiazole
394 as a light yellow solid (2.7 g, 82 %), m.p. 365-366 °C. (Found: C, 57.23; H, 3.65;
N, 4.20. C16H12ClNO3S 0.1H2O requires C, 57.26; H, 3.66; N, 4.17 %). max (KBr):
3444, 1655, 1568, 1462, 1388, 1300, 1214, 1153, 1065, 1045, 975, 826 cm-1. max
(MeOH): 202 nm ( 35,500 cm-1M-1), 301 (43,200), 327 (29,700). 1H NMR (300
MHz, Acetone-d6): 4.15 (s, 3H, OCH3), 4.21 (s, 3H, OCH3), 6.99 (s, 1H, aryl H5),
7.58 (d, J = 8.64 Hz, 2H, aryl H), 8.15 (d, J = 8.64 Hz, 2H, aryl H), 10.43 (s, 1H,
S
N
OMe
MeO
OH
S
N
OMe
MeO
OH
Cl
Experimental 240
CHO). Compound is too insoluble for 13C NMR in Acetone-d6 or DMSO-d6. Mass
Spectrum (+EI): m/z (%) 337 (M+2, 37Cl, 7), 336 (M+1, 37Cl, 40), 335 (M+2, 35Cl,
20), 334 (M+1, 35Cl, 100).
5,7-Dimethoxy-2-phenyl-4-hydroxymethylbenzothiazole (395)
This compound was prepared as described for the
compound 167 from a solution of 4-formylbenzothiazole
390 (0.20 g, 0.67 mmol) in anhydrous methanol (20 mL)
and sodium borohydride (0.20 g) under reflux for 1.5 h to
yield the 4-hydroxymethylbenzothiazole 395 as a white solid (0.197 g, 98%), m.p.
134-135 °C. (Found: C, 63.77; H, 5.00; N, 4.60. C16H15NO3S requires C, 63.77; H,
5.02; N, 4.65 %). max (KBr): 3457, 2938, 2840, 1585, 1477, 1326, 1207, 1120, 982,
764 cm-1. max (MeOH): 212 nm ( 29,300 cm-1M-1), 244 (19,400), 299 (15,300). 1H
NMR (300 MHz, CDCl3): 3.93 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 5.19 (s, 2H,
CH2), 6.53 (s, 1H, aryl H6), 7.46-7.48 (m, 3H, aryl H), 8.05-8.09 (m, 2H, aryl H). 13C
NMR (75 MHz, CDCl3): 55.87, 56.73 (OCH3), 57.58 (CH2), 93.01, 127.38, 128.89,
130.99 (aryl CH), 115.31, 116.01, 133.30, 153.53, 154.13, 156.55, 169.30 (aryl C).
Mass Spectrum (+EI): m/z (%) 303 (M+2, 15), 302 (M+1, 100), 301 (M, 5), 300 (46),
284 (70).
5,7-Dimethoxy-2-(4'-methoxyphenyl)-4-hydroxymethylbenzothiazole (396)
This compound was prepared as described for the
compound 167 from a solution of 4-
formylbenzothiazole 391 (0.20 g, 0.61 mmol) in
anhydrous methanol (10 mL) and sodium
borohydride (0.20 g) under reflux for 3 h to yield the 4-hydroxymethylbenzothiazole
396 as a white solid (0.198 g, 98%), m.p. 178-179 °C. (Found: C, 61.32; H, 5.28; N,
4.10. C17H17NO4S requires C, 61.61; H, 5.17; N, 4.23 %). max (KBr): 3377, 2940,
2837, 1589, 1484, 1486, 1332, 1315, 1257, 1216, 1175, 1125, 1034, 825 cm-1. max
(MeOH): 216 nm ( 47,400 cm-1M-1), 310 (37,500). 1H NMR (300 MHz, CDCl3):
3.74 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.96 (s, 2H, CH2), 6.48
(s, 1H, aryl H6), 6.79 (d, J = 9.03 Hz, 2H, aryl H), 7.91 (d, J = 9.03 Hz, 2H, aryl H).
N
S
OMe
MeO
OH
N
S
OMe
MeO
OH
OMe
Experimental 241
13C NMR (75 MHz, CDCl3): 55.25, 55.69, 57.40 (OCH3), 56.90 (CH2), 94.17,
113.93, 128.91 (aryl CH), 115.68, 118.01, 126.98, 151.94, 155.21, 157.35, 161.37,
166.58 (aryl C). Mass Spectrum (+EI): m/z (%) 332 (M+1, 5), 331 (M, 9), 330 (M-1,
44), 315 (20), 314 (100).
4,6-Dimethoxy-2-phenyl-7-hydroxymethylbenzothiazole (397)
This compound was prepared as described for the
compound 167 from a solution of 7-formylbenzothiazole
393 (0.20 g, 0.67 mmol) in anhydrous methanol (20 mL)
and sodium borohydride (0.20 g) under reflux for 1.5 h to
yield the 7-hydroxymethylbenzothiazole 397 as a white solid (0.16 g, 80 %), m.p.
134-135 °C. (Found: C, 63.77; H, 5.02; N, 4.54. C16H15NO3S requires C, 63.77; H,
5.02; N, 4.65 %). max (KBr): 3455, 2938, 2841, 1585, 1477, 1327, 1207, 1120, 1003,
805 cm-1. max (MeOH): 212 nm ( 32,300 cm-1M-1), 245 (23,100), 299 (18,100). 1H
NMR (300 MHz, CDCl3): 3.88 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 4.86 (s, 2H,
CH2), 6.53 (s, 1H, aryl H5), 7.41-7.44 (m, 3H, aryl H), 8.04-8.07 (m, 2H, aryl H). 13C
NMR (75 MHz, CDCl3): 56.24, 56.35 (OCH3), 59.93 (CH2), 93.95, 127.27, 128.70,
130.29 (aryl CH), 113.31, 133.55, 137.42, 138.82, 153.26, 155.48, 164.86 (aryl C).
Mass Spectrum (+EI): m/z (%) 302 (M+1, 100), 301 (9), 300 (50< 285 (16), 284 (71).
Bis(5,7-dimethoxy-2-phenylbenzothiazol-4-yl)methane (398)
To a solution of 4-hydroxymethylbenzothiazole 395 (50
mg, 0.16 mmol) in tetrahydrofuran (2 mL), glacial acetic
acid (2 mL) was added and the mixture stirred at room
temperature for 6 h and then heated at 80 °C for 2 h. The
solution was allowed to come to room temperature before
ice water was added and the resulting precipitate was
filtered, washed with water and dried to yield the
benzothiazolylmethane 398 as a white solid (35 mg, 88 %), m.p. 183-184 °C. (Found:
C, 63.81; H, 5.05; N, 4.81. C31H26N2O4S2 1.5H2O requires C, 64.01; H, 5.02; N, 4.82
%). max (KBr): 2935, 1579, 1478, 1495, 1371, 1327, 1212, 1119, 948, 768, 693 cm-1.
max (MeOH): 211 nm ( 10,800 cm-1M-1), 239 (8,100), 262 (7,300), 294 (6,400). 1H
N
S
OMe
MeO
N
S
OMe
MeO
S
N
OMe
MeO
OH
Experimental 242
NMR (300 MHz, CDCl3): 3.95 (s, 6H, OCH3), 4.02 (s, 6H, OCH3), 5.68 (s, 2H,
CH2), 6.56 (s, 2H, aryl H6), 7.46-7.48 (m, 6H, aryl H), 8.08-8.11 (m, 4H, aryl H). 13C
NMR (75 MHz, CDCl3): 55.88, 56.78 (OCH3), 58.31 (CH2), 92.78, 127.47, 128.83,
130.86 (aryl CH), 110.12, 116.04, 133.62, 154.77, 155.60, 158.73, 169.38 (aryl C).
Mass Spectrum (+EI): m/z (%) 556 (M+1, 7), 555 (M, 18), 316 (35), 302 (25), 284
(100).
Bis(4,6-dimethoxy-2-phenylbenzothiazol-7-yl)methane (399)
This compound was prepared as described for the
benzothiazole 398 from a solution of 7-
hydroxymethylbenzothiazole 397 (50 mg, 0.16 mmol) in
glacial acetic acid (2 mL) at 80 °C for 2 h to yield the
benzothiazolylmethane 399 as a white solid (40 mg, 93%),
m.p. 112-114 °C. (Found: C, 63.74; H, 4.64; N, 4.78.
C31H26N2O4S2 0.3CHCl3 requires, C, 63.66; H, 4.49; N,
4.74 %). HRMS (+ESI): C31H26N2O4S2 [M+Na]+ requires 577.1226, found 577.1235.
max (KBr): 2932, 1729, 1580, 1459, 1435, 1372, 1305, 1249, 1133, 1046, 974, 763
cm-1. max (MeOH): 213 nm ( 58, 100 cm-1M-1), 269 (31,900), 315 (34,700). 1H NMR
(300 MHz, CDCl3): 3.95 (s, 6H, OCH3), 4.10 (s, 6H, OCH3), 5.35 (s, 2H, CH2), 6.61
(s, 2H, aryl H5), 7.44-7.45 (m, 6H, aryl H), 8.07-8.08 (m, 4H, aryl H). 13C NMR (75
MHz, CDCl3): 56.28, 56.67 (OCH3), 60.42 (CH2), 94.12, 127.32, 128.72, 130.41
(aryl CH), 108.50, 133.44, 138.85, 154.06, 156.52, 164.77, 171.03 (aryl C). Mass
Spectrum (+EI): m/z (%) 556 (M+2, 13), 555 (M+1, 35), 344 (100), 316 (35), 302
(52).
1-(5,7-Dimethoxy-2-phenylbenzothiazol-4-yl)ethanone (400)
Acetyl chloride (0.29 g, 3.68 mmol) was added to an ice
cooled solution of benzothiazole 362 (0.50 g, 1.84 mmol)
in anhydrous chloroform (25 mL) followed by antimony
pentachloride (1.10 g, 2.76 mmol). The mixture was
stirred under argon for 24 h and the resulting crude precipitate was filtered and
chromatographed (chloroform/methanol; 95:5) to afford the 4-acetylbenzothiazole 400
S
N
OMe
MeO
S
N
OMe
MeO
N
S
OMe
MeO
OMe
Experimental 243
as a brown solid (0.39 g, 68%), m.p. 180-182 °C. HRMS (+ESI): C17H15NO3S
[M+H]+ requires 314.0845, found 313.0850. max (KBr): 1602, 1460, 1401, 1368,
1256, 1222, 1000, 948, 761 cm-1. max (MeOH): 210 nm ( 5,300 cm-1M-1), 238
(5,800), 262 (8,800), 295 (5,700). 1H NMR (300 MHz, Acetone-d6): 2.75 (s, 3H,
COCH3), 4.24 (s, 3H, OCH3), 4.29 (s, 3H, OCH3), 7.26 (s, 1H, aryl H6), 7.74-7.79 (m,
3H, aryl H), 8.25-8.28 (m, 2H, aryl H). 13C NMR (75 MHz, Acetone-d6): 29.08
(COCH3), 57.11, 57.14 (OCH3), 95.59, 128.56, 129.91, 134.76 (aryl CH), 103.41,
114.41, 129.71, 145.12, 155.13, 163.80, 172.55 (aryl C), 205.18 (C=O). Mass
Spectrum (+EI): m/z (%) 315 (M+2, 20), 314 (M+1, 100).
1-(4,6-Dimethoxy-2-phenylbenzothiazol-7-yl)ethanone (401)
This compound was prepared as described for the
compound 400 from an ice cooled solution of
benzothiazole 346 (0.50 g, 1.84 mmol) in anhydrous
chloroform (25 mL), acetyl chloride (0.29 g, 3.68 mmol)
and antimony pentachloride (1.10 g, 2.76 mmol) under argon for 24 h to afford the 7-
acetylbenzothiazole 401 as a brown solid (0.37 g, 64%), m.p. 150-152°C. HRMS
(+ESI): C17H15NO3S [M+H]+ requires 314.0845 found 314.0824. max (KBr): 1599,
1527, 1468, 1414, 1302, 1218, 1158, 1038, 730 cm-1. max (MeOH): 212 nm ( 6,600
cm-1M-1), 268 (4,500), 296 (4,800), 315 (4,700). 1H NMR (300 MHz, Acetone-d6):
2.77 (s, 3H, COCH3), 4.30 (s, 3H, OCH3), 4.33 (s, 3H, OCH3), 7.39 (s, 1H, aryl H5),
7.75-7.78 (m, 3H, aryl H), 8.22-8.25 (m, 2H, aryl H). 13C NMR (75 MHz, Acetone-
d6): 32.35 (COCH3), 56.18, 56.26 (OCH3), 96.39, 127.04, 129.65, 130.98 (aryl CH),
133.52, 137.33, 138.86, 153.88, 159.17, 162.87, 167.11 (aryl C), 194.40 (C=O). Mass
Spectrum (+EI): m/z (%) 315 (M+2, 19), 314 (M+1, 100), 272 (34).
5,7-Dimethoxy-4-nitro-2-phenylbenzothiazole (402) and
5-Methoxy-2-phenylbenzothiazole-4,7-dione (403)
A previously cooled solution of nitric acid (0.37 mL, 0.56 mmol) in acetic anhydride
(2 mL) was added dropwise over 10 min to an ice cooled solution of benzothiazole
362 (0.10 g, 0.378 mmol) in acetic anhydride (30 mL). The mixture was stirred at 0°C
for 1 h before ice water was added and the mixture stirred for a further 1 h. The
mixture was made neutral by 2 M sodium hydroxide solution and the resulting
S
N
OMe
MeO
Me O
Experimental 244
precipitate was filtered, washed with water and dried. The crude solid was column
chromatographed (chloroform) to afford the following two products.
(i) 5,7-Dimethoxy-4-nitro-2-phenylbenzothiazole (402)
was isolated as the first band, recrystallized from
ethanol/water and dried to afford as a yellow solid (28 mg,
24 %), m.p. 237-238 °C. (Found: C, 57.10; H, 3.91; N,
8.75. C15H12N2O4S requires C, 56.95; H, 3.82; N, 8.86 %).
max (KBr): 1604, 1572, 1525, 1468, 1383, 1322, 1216, 1164, 1113, 950 cm-1. max
(MeOH): 209 nm ( 19,500 cm-1M-1), 256 (12,200), 294 (10,600). 1H NMR (300
MHz, CDCl3): 4.02 (s, 3H, OCH3), 4.06 (s, 3H, OCH3), 6.53 (s, 1H, aryl H6), 7.47-
7.51 (m, 3H, aryl H), 8.07-8.10 (m, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 56.33,
57.37 (OCH3), 92.30, 127.78, 128.96, 131.64 (aryl CH), 116.96, 129.44, 132.76,
147.80, 152.47, 155.59, 172.34 (aryl C). Mass Spectrum (+EI): m/z (%) 318 (M+2,
17), 317 (M+1, 100).
(ii) 5-Methoxy-2-phenylbenzothiazole-4,7-dione (403)
was isolated as the second band, recrystallized from
methanol/water and dried to afford as a light orange
solid (25 mg, 25%), m.p. 226-227 °C. (Found: C,
61.41; H, 3.75; N, 4.91. C14H9NO3S 0.3CH3OH
requires C, 61.14; H, 3.66; N, 4.99 %). max (KBr): 1697, 1639, 1599, 1460, 1328,
1256, 1107 cm-1. max (MeOH): 205 nm ( 13,700 cm-1M-1), 273 (26,200). 1H NMR
(300 MHz, CDCl3): 3.92 (s, 3H, OCH3), 6.06 (s, 1H, aryl H6), 7.49-7.54 (m, 3H,
aryl H), 8.06-8.09 (m, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 56.92 (OCH3),
107.96, 127.48, 129.16, 132.09 (aryl CH), 131.85, 140.31, 151.63, 160.09, 173.73
(aryl C), 173.76, 179.29 (C=O). Mass Spectrum (+EI): m/z (%) 273 (M+2, 18), 272
(M+1, 100).
This compound 403 was also prepared according to the general procedure for the
synthesis of indole-4,7-diones (117-120). Treatment of 7-formylbenzothiazole 390
(0.25 g, 0.836 mmol) in tetrahydrofuran/methanol (50 mL) with concentrated
hydrochloric acid (2 drops) and 30% hydrogen peroxide solution (5 mL) afforded the
benzothiazole-4,7-dione 403 as a light orange solid (90 mg, 40%).
N
S
OMe
MeONO2
N
S
O
OMeO
Experimental 245
4,6-Dimethoxy-7-nitro-2-phenylbenzothiazole (404)
This compound was prepared as described for the 7-
nitrobenzothiazole 402 from an ice cooled solution of
benzothiazole 346 (0.10 g, 0.378 mmol) in acetic
anhydride (30 mL), and a previously cooled solution of
nitric acid (0.37 mL, 0.56 mmol) in acetic anhydride (2 mL) under 0°C for 1 h to
afford the 7-nitrobenzothiazole 404 as a yellow solid (74 mg, 64%), m.p. 239 °C.
(Found: C, 56.74; H, 3.89; N, 8.70. C15H12N2O4S requires C, 56.95; H, 3.82; N, 8.86
%). max (KBr): 1592, 1563, 1494, 1474, 1348, 1276, 1218, 1123, 1040, 814, 761 cm-
1. max (MeOH): 210 nm ( 15,600 cm-1M-1), 306 (16,400). 1H NMR (300 MHz,
CDCl3): 4.13 (s, 3H, OCH3), 4.21 (s, 3H, OCH3), 6.64 (s, 1H, aryl H5), 7.47-7.49
(m, 3H, aryl H), 8.09-8.11 (m, 2H, aryl H). 13C NMR (75 MHz, CDCl3): 56.99,
57.33 (OCH3), 94.43, 127.31, 128.95, 130.98 (aryl CH), 107.69, 127.59, 132.83,
140.26, 156.93, 158.56, 172.07 (aryl C). Mass Spectrum (+EI): m/z (%) 318 (M+2,
19), 317 (M+1, 100).
2-(5,7-Dimethoxy-2-phenylbenzothiazol-4-yl)-benzimidazole (404)
This compound was prepared as described for the
bisbenzimidazole 193 from a solution of 4-
formylbenzothiazole 390 (1.0 g, 3.34 mmol) in anhydrous
N,N-dimethylformamide (10 mL) and 1,2-
diaminobenzene (0.39 g, 3.68 mmol) at 110 °C overnight
to yield the benzothiazolylbenzimidazole 404 as a brown
powder (0.82 g, 52 %), m.p. 245-246 °C. (Found: C, 68.30; H, 4.43; N, 10.82.
C22H17N3O2S requires C, 68.20; H, 4.42; N, 10.85 %). max (KBr): 3458, 1585, 1450,
1416, 1331, 1278, 1217, 1142, 1118, 1099, 950, 743 cm-1. max (MeOH): 207 nm (
31,900 cm-1M-1), 254 (22,100), 294 (21,700), 322 (17,300). 1H NMR (300 MHz,
CDCl3): 4.00 (s, 3H, OCH3), 4.13 (s, 3H, OCH3), 6.63 (s, 1H, aryl H6), 7.26-7.29
(m, 2H, aryl H), 7.52-7.54 (m, 3H, aryl H), 7.76-7.79 (m, 2H, aryl H), 8.03-8.06 (m,
2H, aryl H), 11.97 (br s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 56.99, 57.30
(OCH3), 94.49, 115.19, 122.29, 127.71, 129.62, 131.95 (aryl CH), 106.06, 115.53,
S
N
OMe
MeONO2
N
S
OMe
MeO
N NH
Experimental 246
132.83, 138.30, 147.09, 154.05, 155.60, 159.37, 169.36 (aryl C). Mass Spectrum
(+EI): m/z (%) 389 (M+2, 30), 388 (M+1, 100).
2-(5,7-Dimethoxy-2-(4'-methoxyphenyl)benzothiazol-4-yl)-benzimidazole (405)
This compound was prepared as described for the
bisbenzimidazole 193 from a solution of 4-
formylbenzothiazole 391 (1.0 g, 3.34 mmol) in
anhydrous N,N-dimethylformamide (10 mL) and
1,2-diaminobenzene (0.39 g, 3.68 mmol) at 110 °C
overnight to yield the benzothiazolylbenzimidazole
405 as a light brown powder (0.88 g, 68%), m.p. 124-126 °C. (Found: C, 65.73; H,
4.62; N, 9.95. C23H19N3O3S 0.1H2O requires C, 65.89; H, 4.62; N, 10.02 %). HRMS
(+ESI): C23H19N3O3S [M+H]+ requires 418.1220, found 418.1204. max (KBr): 3441,
1581, 1464, 1324, 1257, 1221, 1175, 1139, 1115, 1029, 952, 744 cm-1. max (MeOH):
208 nm ( 18,400 cm-1M-1), 289 (15,600), 300 (15,800), 337 (14,100). 1H NMR (300
MHz, CDCl3): 3.94 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 4.13 (s, 3H, OCH3), 6.70 (s,
1H, aryl H6), 7.09 (d, J = 8.67 Hz, 2H, aryl H), 7.47-7.50 (m, 2H, aryl H), 8.04 (d, J =
8.67 Hz, 2H, aryl H), 8.22-8.25 (m, 2H, aryl H), 11.56 (br s, 1H, NH). 13C NMR (75
MHz, DMSO-d6): 55.92, 57.26, 57.59 (OCH3), 94.14, 114.93, 115.06, 123.80,
129.87 (aryl CH), 104.84, 115.56, 125.21, 135.39, 146.08, 153.61, 156.76, 160.03,
162.61, 170.41 (aryl C). Mass Spectrum (+EI): m/z (%) 419 (M+2, 30), 418 (M+1,
100).
N
S
OMe
MeO
N NH
OMe
References 247
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Appendix 259
APPENDIX
X-ray crystallography data
Introduction
The X-ray crystallography data shown in the appendix were obtained by Don Craig at
the University of New South Wales, Sydney.
Structure determination:
Reflexion data were measured with an Enraf-Nonius CAD-4 diffractometer in /2
scan mode using nickel filtered copper radiation ( 1.5418Å). Reflexions with I>3 (I)
were considered observed. The structures were determined by direct phasing and
Fourier methods. Hydrogen atoms were included in calculated positions and were
assigned thermal parameters equal to those of the atom to which they were bonded.
Positional and anisitropic thermal parameters for the non-hydrogen atoms were
refined using full matrix least squares. Reflexion weights used were 1/ 2(Fo), with
(Fo) being derived from (Io) = [ 2(Io) + (0.04Io)2]1/2. The weighted residual is
defined as Rw = ( w 2/ wFo2)1/2. Atomic scattering factors and anomalous dispersion
parameters were from International Tables for X-ray crystallography1. Structure
solutions were performed by SIR922 and refinements used RAELS3. ORTEP-
II4running on a Macintosh was used for the structural diagrams.
1. Ibers, J.A. and Hamilton, W.C., (Eds) International Tables for X-Ray
Crystallography Vol. 4 , Kynoch Press, Birmingham, 1974. 2. Altomare, A., Burla, M.C., Camalli, M., Cascarano, G., Giacovazzo, C., Guagliardi,
A., Polidori, G., J. Appl. Cryst., 1994, 27, 435. 3. Rae, A.D., RAELS. A comprehensive Constrained Least Squares Refinement
Program, University of New South Wales, 1989. 4. Johnson, C.K.,'ORTEP-II', Oak Ridge National Laboratory, Tennessee, U.S.A.,
1976.
Appendix 260
1. Crystal data for the compound 187 (Ref: DDB 108)
The X-ray crystal data for 187: Crystal was grown from dichloromethane. Colorless,
C22H18N2O3.H2O, M = 376.40, monoclinic, space group Cc, a = 13.025(3) Å, b =
17.568(3)Å, c = 8.952(2)Å, = 90o, = 93.32(1)o, = 90o, V = 2045.0(8)Å3; Z = 4,
Dc = 1.34 g cm-3; T = 294 K, μ(Mo K ) = 0.218 mm-1( = 0.71073Å), 1597 observed
reflections [I>2 (I)], R1 = 0.039, wR2 = 0.044 (observed data), variable parameters
261, GOF = 1.45, .
Table 1. Non hydrogen atomic parameters (Esd in parentheses).
x y z (U11+U22+U33)/3O1 0.6239 0.4152(2) 0.8414 0.0582(8) O2 0.3961(3) 0.2949(2) 0.4655(5) 0.0537(8) O3 0.5239(3) 0.6196(2) 0.7349(5) 0.0600(8) N1 0.3841(3) 0.5517(2) 0.5048(5) 0.0400(8) N2 0.3198(3) 0.4483(2) 0.4029(5) 0.0423(8) C1 0.3125(4) 0.5235(2) 0.4034(6) 0.0415(9) C2 0.4389(3) 0.4915(2) 0.5706(5) 0.0386(9) C3 0.5239(4) 0.4903(2) 0.6773(5) 0.0411(9) C4 0.5545(4) 0.4177(2) 0.7233(6) 0.045(1) C5 0.5148(4) 0.3502(2) 0.6557(6) 0.046(1) C6 0.4371(4) 0.3542(2) 0.5428(6) 0.0421(9) C7 0.3978(3) 0.4263(2) 0.5064(6) 0.0404(9) C8 0.2408(4) 0.5694(2) 0.3100(6) 0.0425(9) C9 0.2503(4) 0.6477(3) 0.3022(6) 0.058(1) C10 0.1853(5) 0.6904(3) 0.2099(8) 0.069(1) C11 0.1103(5) 0.6547(3) 0.1186(7) 0.071(2) C12 0.1025(5) 0.5768(4) 0.1213(8) 0.083(2) C13 0.1671(5) 0.5338(3) 0.2159(8) 0.067(1) C14 0.6711(6) 0.3455(4) 0.8850(8) 0.101(2) C15 0.4431(5) 0.2221(3) 0.4873(8) 0.077(2) C16 0.5740(4) 0.5608(2) 0.7283(6) 0.043(1) C17 0.6875(4) 0.5648(2) 0.7585(5) 0.042(1) C18 0.7532(4) 0.5219(3) 0.6770(7) 0.062(1) C19 0.8592(5) 0.5318(4) 0.6959(8) 0.080(2) C20 0.8980(4) 0.5850(3) 0.7991(8) 0.073(2) C21 0.8340(5) 0.6266(3) 0.8810(7) 0.067(2) C22 0.7282(4) 0.6177(2) 0.8606(6) 0.052(1) OW1 0.3790(3) 0.7119(2) 0.5971(5) 0.073(1)
Appendix 261
Table 2. Hydrogen atom positional parameters. Thermal parameters equal to those of bonded atom.
x y z (U11+U22+U33)/3
HN1 0.3955 0.6068 0.5282 0.040 HN2 0.2763 0.4130 0.3384 0.042 HC5 0.5426 0.2996 0.6892 0.046 HC9 0.3058 0.6737 0.3651 0.058 HC10 0.1920 0.7471 0.2085 0.069 HC11 0.0624 0.6855 0.0515 0.071 HC12 0.0494 0.5509 0.0540 0.083 HC13 0.1608 0.4770 0.2164 0.067 H1C14 0.7199 0.3542 0.9737 0.101 H2C14 0.6172 0.3081 0.9116 0.101 H3C14 0.7097 0.3250 0.8004 0.101 H1C15 0.4050 0.1836 0.4234 0.077 H2C15 0.5162 0.2247 0.4590 0.077 H3C15 0.4412 0.2071 0.5949 0.077 HC18 0.7244 0.4834 0.6037 0.062 HC19 0.9067 0.5010 0.6362 0.080 HC20 0.9740 0.5928 0.8132 0.073 HC21 0.8631 0.6639 0.9564 0.067 HC22 0.6813 0.6495 0.9195 0.052 H1OW1 0.4339 0.6790 0.6457 0.073 H2OW1 0.3108 0.6974 0.6345 0.073
Table 3. Bond lengths (Å) (Esd in parentheses).
Bond length Bond length O1 C4 1.350(5) O1 C14 1.414(6) O2 C6 1.344(5) O2 C15 1.426(5) O3 C16 1.226(5) N1 C1 1.356(5) N1 C2 1.387(5) N2 C1 1.326(5) N2 C7 1.390(5) C1 C8 1.460(5) C2 C3 1.420(5) C2 C7 1.376(5) C3 C4 1.391(6) C3 C16 1.461(6) C4 C5 1.416(6) C5 C6 1.390(6) C6 C7 1.397(5) C8 C9 1.383(5) C8 C13 1.389(7) C9 C10 1.371(7) C10 C11 1.386(8) C11 C12 1.373(7) C12 C13 1.385(8) C16 C17 1.489(6) C17 C18 1.380(6) C17 C22 1.387(5) C18 C19 1.392(7) C19 C20 1.390(8) C20 C21 1.355(8) C21 C22 1.388(7)
Appendix 262
Table 4. Bond angles (o) (Esd in parentheses).
Bond angle Bond angle C4 O1 C14 120.3(4) C6 O2 C15 118.0(3) C1 N1 C2 108.9(3) C1 N2 C7 108.9(4) N1 C1 N2 108.6(3) N1 C1 C8 125.1(4) N2 C1 C8 126.3(4) N1 C2 C3 131.3(3) N1 C2 C7 106.2(3) C3 C2 C7 122.5(3) C2 C3 C4 114.4(4) C2 C3 C16 120.9(4) C4 C3 C16 124.7(3) O1 C4 C3 115.4(4) O1 C4 C5 121.3(4) C3 C4 C5 123.3(3) C4 C5 C6 120.1(4) O2 C6 C5 125.8(3) O2 C6 C7 117.0(3) C5 C6 C7 117.2(4) N2 C7 C2 107.4(3) N2 C7 C6 130.6(4) C2 C7 C6 122.0(3) C1 C8 C9 121.4(4) C1 C8 C13 119.7(4) C9 C8 C13 118.6(4) C8 C9 C10 121.3(4) C9 C10 C11 119.9(4) C10 C11 C12 119.4(5) C11 C12 C13 120.8(5) C8 C13 C12 119.9(4) O3 C16 C3 120.0(4) O3 C16 C17 118.5(4) C3 C16 C17 121.2(4) C16 C17 C18 121.1(4) C16 C17 C22 119.3(4) C18 C17 C22 119.3(4) C17 C18 C19 120.5(5) C18 C19 C20 119.0(5) C19 C20 C21 120.7(5) C20 C21 C22 120.4(4) C17 C22 C21 120.0(4)
Table 5. Torsion bond angles (o) (Esd in parentheses).
Bond angle Bond angle C14 O1 C4 C3 -171.3(5) C14 O1 C4 C5 10.5(7) C15 O2 C6 C5 -7.8(6) C15 O2 C6 C7 172.4(4) C2 N1 C1 N2 0.1(4) C2 N1 C1 C8 -179.2(4) C1 N1 C2 C3 176.9(4) C1 N1 C2 C7 -0.3(4) C7 N2 C1 N1 0.1(5) C7 N2 C1 C8 179.4(4) C1 N2 C7 C2 -0.3(5) C1 N2 C7 C6 -177.4(4) N1 C1 C8 C9 9.7(6) N1 C1 C8 C13 -176.5(5) N2 C1 C8 C9 -169.5(5) N2 C1 C8 C13 4.3(7) N1 C2 C3 C4 176.5(4) N1 C2 C3 C16 -5.0(6) C7 C2 C3 C4 -6.7(5) C7 C2 C3 C16 171.8(4) N1 C2 C7 N2 0.4(4) N1 C2 C7 C6 177.8(4) C3 C2 C7 N2 -177.1(3) C3 C2 C7 C6 0.3(6) C2 C3 C4 O1 -169.8(3) C2 C3 C4 C5 8.4(6) C16 C3 C4 O1 11.7(6) C16 C3 C4 C5 -170.1(4) C2 C3 C16 O3 31.4(6) C2 C3 C16 C17 -142.5(4) C4 C3 C16 O3 -150.3(4) C4 C3 C16 C17 35.8(6) O1 C4 C5 C6 174.5(4) C3 C4 C5 C6 -3.6(6) C4 C5 C6 O2 176.9(4) C4 C5 C6 C7 -3.2(6) O2 C6 C7 N2 1.4(6) O2 C6 C7 C2 -175.3(4)
Appendix 263
C5 C6 C7 N2 -178.4(4) C5 C6 C7 C2 4.9(6) C1 C8 C9 C10 177.4(5) C13 C8 C9 C10 3.5(8) C1 C8 C13 C12 -176.6(5) C9 C8 C13 C12 -2.6(9) C8 C9 C10 C11 -2.1(9) C9 C10 C11 C12 -0.3(10) C10 C11 C12 C13 1.2(10) C11 C12 C13 C8 0.2(10) O3 C16 C17 C18 -141.4(4) O3 C16 C17 C22 32.6(6) C3 C16 C17 C18 32.6(6) C3 C16 C17 C22 -153.4(4) C16 C17 C18 C19 173.5(5) C22 C17 C18 C19 -0.4(7) C16 C17 C22 C21 -174.6(4) C18 C17 C22 C21 -0.6(6) C17 C18 C19 C20 0.6(9) C18 C19 C20 C21 0.3(9) C19 C20 C21 C22 -1.4(8) C20 C21 C22 C17 1.5(7)
2. Crystal data for the compound 194 (Ref: DDB 102)
The X-ray crystal data for 194: Crystal was grown from dichloromethane/ether.
Yellow, C22H18N4O2.H2O, M = 388.4, monoclinic, space group P21/c, a = 11.210(3)
Å, b = 8.823(1) Å, c = 20.068(4) Å, = 90o, = 101.60(1)o, = 90o, V = 1944.3(7)Å3;
Z = 4, Dc = 1.33 g cm-3; T = 294 K, μ(Mo K ) = 0.090 mm-1( = 0.71073 Å), 2094
observed reflections [I>2 (I)], R1 = 0.044, wR2 = 0.051 (observed data), variable
parameters 190, GOF = 1.48.
Table 6. Non hydrogen atomic parameters (Esd in parentheses).
x y z (U11+U22+U33)/3
O1 0.41381(16) 0.04138(22) 0.60272(9) 0.0700(6) O2 0.44900(16) 0.32683(21) 0.40105(8) 0.0673(6) N1 0.74093(17) 0.34723(23) 0.61355(9) 0.0509(6) N2 0.6397(2) 0.1870(3) 0.6681(1) 0.0564(6) N3 0.77983(16) 0.50599(22) 0.50068(9) 0.0515(4) N4 0.64188(17) 0.50581(22) 0.40263(9) 0.0524(4) C1 0.7374(2) 0.2738(3) 0.6736(1) 0.0514(7) C2 0.5774(2) 0.2057(3) 0.6013(1) 0.0509(7) C3 0.4683(2) 0.1419(3) 0.5670(1) 0.0556(7) C4 0.4245(2) 0.1827(3) 0.4999(1) 0.0568(7) C5 0.4897(2) 0.2854(3) 0.4673(1) 0.0540(7) C6 0.5994(2) 0.3505(3) 0.4992(1) 0.0474(6) C7 0.6387(2) 0.3057(3) 0.5670(1) 0.0468(6) C8 0.8316(2) 0.2896(2) 0.7350(1) 0.0529(7) C9 0.8245(2) 0.2016(3) 0.7912(1) 0.0707(6) C10 0.9125(2) 0.2125(3) 0.8502(1) 0.0816(8) C11 1.0089(2) 0.3114(2) 0.8537(1) 0.0709(8) C12 1.0166(2) 0.3995(3) 0.7979(1) 0.0696(6)
Appendix 264
C13 0.9285(2) 0.3886(3) 0.7390(1) 0.0625(6) C14 0.2983(3) -0.0204(3) 0.5699(2) 0.0778(9) C15 0.3399(3) 0.2629(4) 0.3628(2) 0.083(1) C16 0.6722(2) 0.4535(3) 0.4678(1) 0.0491(4) C17 0.8206(2) 0.5987(3) 0.4536(1) 0.0522(4) C18 0.9289(2) 0.6797(3) 0.4593(1) 0.0621(5) C19 0.9455(2) 0.7620(3) 0.4031(1) 0.0683(6) C20 0.8572(3) 0.7650(3) 0.3427(1) 0.0691(7) C21 0.7502(3) 0.6835(3) 0.3365(1) 0.0637(6) C22 0.7345(2) 0.6006(3) 0.3927(1) 0.0530(4) OW1 0.5012(2) 0.0269(4) 0.7615(1) 0.127(1)
Table 7. Hydrogen atom positional parameters. Thermal parameters equal to those of bonded atom.
x y z (U11+U22+U33)/3
HN1 0.8061 0.4180 0.6053 0.051 HN4 0.5666 0.4802 0.3685 0.060 HC4 0.3462 0.1388 0.4745 0.057 HC9 0.7550 0.1295 0.7891 0.092 HC10 0.9062 0.1482 0.8904 0.113 HC11 1.0725 0.3193 0.8964 0.081 HC12 1.0861 0.4715 0.8001 0.090 HC13 0.9350 0.4529 0.6988 0.080 H1C14 0.2686 -0.0922 0.6015 0.078 H2C14 0.2381 0.0637 0.5575 0.078 H3C14 0.3078 -0.0757 0.5277 0.078 H1C15 0.3238 0.3056 0.3156 0.083 H2C15 0.3490 0.1504 0.3606 0.083 H3C15 0.2703 0.2879 0.3851 0.083 HC18 0.9921 0.6784 0.5023 0.072 HC19 1.0225 0.8210 0.4057 0.080 HC20 0.8719 0.8272 0.3035 0.081 HC21 0.6871 0.6842 0.2935 0.074 H1OW1 0.5471 0.0800 0.7305 0.127 H2OW1 0.4187 0.0328 0.7313 0.127
Table 8. Bond lengths (Å) (Esd in parentheses).
Bond length Bond length O1 C3 1.360(3) O1 C14 1.437(3) O2 C5 1.366(3) O2 C15 1.423(3) N1 C1 1.376(3) N1 C7 1.375(3) N2 C1 1.323(3) N2 C2 1.392(3) N3 C16 1.336(3) N3 C17 1.395(3)
Appendix 265
N4 C16 1.364(3) N4 C22 1.379(3) C1 C8 1.459(3) C2 C3 1.395(3) C2 C7 1.384(3) C3 C4 1.384(3) C4 C5 1.406(4) C5 C6 1.391(3) C6 C7 1.400(3) C6 C16 1.447(3) C8 C9 1.384(2) C8 C13 1.384(2) C9 C10 1.383(3) C10 C11 1.380(2) C11 C12 1.380(2) C12 C13 1.383(3) C17 C18 1.393(3) C17 C22 1.396(3) C18 C19 1.385(4) C19 C20 1.402(4) C20 C21 1.382(4) C21 C22 1.385(3)
Table 9. Bond angles (o) (Esd in parentheses).
Bond angle Bond angle C3 O1 C14 117.6(2) C5 O2 C15 120.2(2) C1 N1 C7 107.6(2) C1 N2 C2 105.0(2) C16 N3 C17 104.8(2) C16 N4 C22 107.1(2) N1 C1 N2 111.7(2) N1 C1 C8 123.4(2) N2 C1 C8 124.9(2) N2 C2 C3 130.4(2) N2 C2 C7 110.6(2) C3 C2 C7 119.1(2) O1 C3 C2 116.4(2) O1 C3 C4 124.9(3) C2 C3 C4 118.6(3) C3 C4 C5 120.3(2) O2 C5 C4 121.5(2) O2 C5 C6 115.4(2) C4 C5 C6 123.1(2) C5 C6 C7 114.0(2) C5 C6 C16 125.6(2) C7 C6 C16 120.4(2) N1 C7 C2 105.2(2) N1 C7 C6 129.9(2) C2 C7 C6 124.9(2) C1 C8 C9 118.9(2) C1 C8 C13 122.4(2) C9 C8 C13 118.7(2) C8 C9 C10 120.7(2) C9 C10 C11 120.3(2) C10 C11 C12 119.4(3) C11 C12 C13 120.3(2) C8 C13 C12 120.7(2) N3 C16 N4 112.5(2) N3 C16 C6 122.3(2) N4 C16 C6 125.2(2) N3 C17 C18 130.1(2) N3 C17 C22 109.7(2) C18 C17 C22 120.2(2) C17 C18 C19 117.4(3) C18 C19 C20 121.8(3) C19 C20 C21 121.1(3) C20 C21 C22 116.8(2) N4 C22 C17 105.9(2) N4 C22 C21 131.3(2) C17 C22 C21 122.7(3)
Table 10. Torsion bond angles (o) (Esd in parentheses).
Bond angle Bond angle C2 C3 O1 C14 177.0(2) C4 C3 O1 C14 -4.0(4) C4 C5 O2 C15 -1.6(4) C6 C5 O2 C15 177.8(2) N2 C1 N1 C7 0.5(3) C8 C1 N1 C7 179.8(2)
Appendix 266
C2 C7 N1 C1 -0.8(2) C6 C7 N1 C1 179.2(2) N1 C1 N2 C2 0.0(3) C8 C1 N2 C2 -179.2(2) C3 C2 N2 C1 -179.9(3) C7 C2 N2 C1 -0.5(3) N4 C16 N3 C17 0.4(3) C6 C16 N3 C17 179.4(2) C18 C17 N3 C16 -178.0(3) C22 C17 N3 C16 0.5(3) N3 C16 N4 C22 -1.2(3) C6 C16 N4 C22 179.9(2) C17 C22 N4 C16 1.4(3) C21 C22 N4 C16 -179.9(3) C9 C8 C1 N1 -174.9(2) C13 C8 C1 N1 4.5(3) C9 C8 C1 N2 4.2(3) C13 C8 C1 N2 -176.3(2) O1 C3 C2 N2 -2.3(4) C4 C3 C2 N2 178.7(2) O1 C3 C2 C7 178.3(2) C4 C3 C2 C7 -0.7(4) N1 C7 C2 N2 0.8(3) C6 C7 C2 N2 -179.1(2) N1 C7 C2 C3 -179.7(2) C6 C7 C2 C3 0.4(4) C5 C4 C3 O1 -178.5(2) C5 C4 C3 C2 0.4(4) O2 C5 C4 C3 179.6(2) C6 C5 C4 C3 0.3(4) C7 C6 C5 O2 -180.0(2) C16 C6 C5 O2 -1.1(4) C7 C6 C5 C4 -0.6(3) C16 C6 C5 C4 178.2(2) N1 C7 C6 C5 -179.6(2) C2 C7 C6 C5 0.3(3) N1 C7 C6 C16 1.5(4) C2 C7 C6 C16 -178.6(2) N3 C16 C6 C5 -176.7(2) N4 C16 C6 C5 2.1(4) N3 C16 C6 C7 2.1(4) N4 C16 C6 C7 -179.1(2) C10 C9 C8 C1 179.5(2) C12 C13 C8 C1 -179.5(2) C19 C18 C17 N3 179.3(2) C19 C18 C17 C22 0.9(4) N4 C22 C17 N3 -1.2(3) C21 C22 C17 N3 179.9(2) N4 C22 C17 C18 177.5(2) C21 C22 C17 C18 -1.4(4) C20 C19 C18 C17 0.2(4) C21 C20 C19 C18 -1.0(4) C22 C21 C20 C19 0.6(4) N4 C22 C21 C20 -178.0(2) C17 C22 C21 C20 0.6(4)
3. Crystal data for the compound 222 (Ref: DDB 100)
The X-ray crystal data for 222: Crystal was grown from chloroform. Colorless,
C17H19NO4, M = 301.3, triclinic, space group P , a = 10.950(5) Å, b = 11.435(6) Å, c
= 13.646(7) Å, = 86.67(2)o, = 84.00(2)o, = 68.85 (3)o, V = 1584(1) Å3; Z = 4, Dc
= 1.26 g cm-3; T = 294 K, μ(Mo K ) = 0.088 mm-1( = 0.71073 Å), 2620 observed
reflections [I>2 (I)], R1 = 0.080, wR2 = 0.131 (observed data), variable parameters
246, GOF = 1.93, .
Appendix 267
Table 11. Non hydrogen atomic parameters (Esd in parentheses).
x y z (U11+U22+U33)/3
O1A 0.4499(6) 0.2617(5) 0.4090(5) 0.077(2) O2A 0.7269(6) -0.1613(5) 0.3613(4) 0.066(2) O3A 0.8158(6) 0.0951(5) 0.5948(4) 0.066(2) O4A 0.6339(6) 0.4639(5) 0.5892(4) 0.062(2) N1A 0.6010(7) 0.2898(6) 0.5488(5) 0.047(2) C1A 0.6379(7) 0.1740(7) 0.5002(5) 0.043(1) C2A 0.5596(7) 0.1594(7) 0.4320(6) 0.047(1) C3A 0.5900(7) 0.0448(7) 0.3871(5) 0.046(1) C4A 0.7023(7) -0.0557(7) 0.4112(5) 0.045(1) C5A 0.7817(8) -0.0448(7) 0.4813(6) 0.047(1) C6A 0.7463(8) 0.0733(7) 0.5252(5) 0.044(1) C7A 0.5033(9) 0.3099(8) 0.6342(7) 0.066(3) C8A 0.6620(8) 0.3741(8) 0.5342(6) 0.046(2) C9A 0.7678(6) 0.3573(5) 0.4521(4) 0.042(2) C10A 0.7609(6) 0.3214(5) 0.3584(5) 0.056(2) C11A 0.8587(7) 0.3166(6) 0.2839(4) 0.068(2) C12A 0.9651(7) 0.3479(6) 0.3026(5) 0.067(2) C13A 0.9722(6) 0.3838(6) 0.3965(6) 0.068(3) C14A 0.8740(6) 0.3884(5) 0.4706(4) 0.056(2) C15A 0.3693(9) 0.2550(8) 0.3320(7) 0.066(3) C16A 0.8337(11) -0.2716(9) 0.3839(8) 0.092(4) C17A 0.9186(9) -0.0093(9) 0.6356(7) 0.068(3) O1B 0.2834(6) 1.0097(6) 0.0646(5) 0.083(2) O2B 0.7057(6) 0.6668(6) 0.0575(5) 0.083(3) O3B 0.3737(6) 0.6621(5) -0.1360(4) 0.064(1) O4B 0.0046(6) 0.8742(6) -0.0790(4) 0.067(2) N1B 0.2043(6) 0.8851(6) -0.0687(5) 0.048(2) C1B 0.3318(8) 0.8319(7) -0.0342(6) 0.047(1) C2B 0.3704(8) 0.8968(8) 0.0328(6) 0.054(1) C3B 0.5003(8) 0.8397(8) 0.0658(6) 0.055(1) C4B 0.5815(8) 0.7274(8) 0.0292(6) 0.055(1) C5B 0.5453(8) 0.6637(8) -0.0397(6) 0.053(1) C6B 0.4205(8) 0.7164(7) -0.0698(5) 0.047(1) C7B 0.1885(9) 0.9689(9) -0.1556(7) 0.070(3) C8B 0.1084(9) 0.8425(7) -0.0378(6) 0.049(2) C9B 0.1254(6) 0.7517(5) 0.0474(5) 0.048(2) C10B 0.1526(6) 0.7803(6) 0.1378(5) 0.062(2) C11B 0.1652(6) 0.6964(8) 0.2169(5) 0.083(2) C12B 0.1506(7) 0.5824(7) 0.2062(6) 0.087(2) C13B 0.1234(7) 0.5536(6) 0.1156(6) 0.088(3) C14B 0.1110(6) 0.6379(6) 0.0368(5) 0.070(3) C15B 0.3123(10) 1.0746(9) 0.1447(7) 0.075(3) C16B 0.7489(10) 0.7209(12) 0.1311(8) 0.097(4) C17B 0.4573(10) 0.5401(8) -0.1735(6) 0.067(3)
Appendix 268
Table 12. Hydrogen atom positional parameters. Thermal parameters equal to those of bonded atom.
x y z (U11+U22+U33)/3
HC3A 0.5326 0.0345 0.3384 0.062 HC5A 0.8603 -0.1175 0.4997 0.068 H1C7A 0.4855 0.3942 0.6619 0.066 H2C7A 0.4200 0.3060 0.6134 0.066 H3C7A 0.5379 0.2434 0.6856 0.066 HC10A 0.6845 0.2988 0.3443 0.072 HC11A 0.8525 0.2906 0.2165 0.093 HC12A 1.0358 0.3445 0.2490 0.081 HC13A 1.0485 0.4066 0.4108 0.092 HC14A 0.8800 0.4144 0.5381 0.071 H1C15A 0.2954 0.3372 0.3263 0.066 H2C15A 0.4247 0.2361 0.2677 0.066 H3C15A 0.3329 0.1872 0.3495 0.066 H1C16A 0.8382 -0.3408 0.3405 0.092 H2C16A 0.9177 -0.2547 0.3727 0.092 H3C16A 0.8206 -0.2968 0.4545 0.092 H1C17A 0.9599 0.0219 0.6852 0.068 H2C17A 0.8803 -0.0705 0.6681 0.068 H3C17A 0.9867 -0.0515 0.5816 0.068 HC3B 0.5303 0.8823 0.1152 0.074 HC5B 0.6081 0.5822 -0.0665 0.073 H1C7B 0.0949 0.9993 -0.1716 0.070 H2C7B 0.2128 1.0423 -0.1416 0.070 H3C7B 0.2470 0.9225 -0.2128 0.070 HC10B 0.1632 0.8623 0.1462 0.081 HC11B 0.1848 0.7182 0.2820 0.121 HC12B 0.1597 0.5218 0.2632 0.115 HC13B 0.1127 0.4716 0.1071 0.125 HC14B 0.0913 0.6163 -0.0282 0.098 H1C15B 0.2378 1.1556 0.1579 0.075 H2C15B 0.3240 1.0203 0.2057 0.075 H3C15B 0.3949 1.0918 0.1246 0.075 H1C16B 0.8406 0.6666 0.1440 0.097 H2C16B 0.7471 0.8061 0.1083 0.097 H3C16B 0.6894 0.7281 0.1931 0.097 H1C17B 0.4101 0.5124 -0.2211 0.067 H2C17B 0.5402 0.5460 -0.2079 0.067 H3C17B 0.4791 0.4779 -0.1175 0.067
Appendix 269
Table 13. Bond lengths (Å) (Esd in parentheses).
Bond length Bond length O1A C2A 1.391(9) O1A C15A 1.462(9) O2A C4A 1.349(9) O2A C16A 1.421(10) O3A C6A 1.363(9) O3A C17A 1.444(10) O4A C8A 1.235(9) N1A C1A 1.419(9) N1A C7A 1.466(10) N1A C8A 1.353(9) C1A C2A 1.385(10) C1A C6A 1.379(10) C2A C3A 1.392(10) C3A C4A 1.401(10) C4A C5A 1.396(10) C5A C6A 1.415(10) C8A C9A 1.493(10) C9A C10A 1.383(5) C9A C14A 1.383(5) C10A C11A 1.385(6) C11A C12A 1.387(6) C12A C13A 1.387(6) C13A C14A 1.385(6) O1B C2B 1.362(9) O1B C15B 1.477(10) O2B C4B 1.370(10) O2B C16B 1.414(11) O3B C6B 1.362(9) O3B C17B 1.452(10) O4B C8B 1.245(9) N1B C1B 1.426(9) N1B C7B 1.465(10) N1B C8B 1.331(10) C1B C2B 1.396(10) C1B C6B 1.405(10) C2B C3B 1.443(11) C3B C4B 1.359(11) C4B C5B 1.392(11) C5B C6B 1.376(11) C8B C9B 1.493(10) C9B C10B 1.383(5) C9B C14B 1.383(5) C10B C11B 1.385(6) C11B C12B 1.387(6) C12B C13B 1.387(6) C13B C14B 1.385(6)
Table 14. Bond angles (o) (Esd in parentheses).
Bond angle Bond angle C2A O1A C15A 121.1(6) C4A O2A C16A 119.6(7) C6A O3A C17A 119.2(6) C1A N1A C7A 116.9(6) C1A N1A C8A 126.1(7) C7A N1A C8A 116.1(7) N1A C1A C2A 119.7(7) N1A C1A C6A 120.5(7) C2A C1A C6A 119.7(7) O1A C2A C1A 118.6(7) O1A C2A C3A 120.5(7) C1A C2A C3A 120.8(7) C2A C3A C4A 118.9(7) O2A C4A C3A 114.7(7) O2A C4A C5A 123.6(7) C3A C4A C5A 121.7(7) C4A C5A C6A 117.3(7) O3A C6A C1A 115.8(7) O3A C6A C5A 122.6(7) C1A C6A C5A 121.6(7) O4A C8A N1A 121.2(7) O4A C8A C9A 118.9(7) N1A C8A C9A 119.9(7) C8A C9A C10A 123.9(5) C8A C9A C14A 116.9(5) C10A C9A C14A 119.0(6) C9A C10A C11A 120.7(5) C10A C11A C12A 120.2(5) C11A C12A C13A 119.2(6) C12A C13A C14A 120.2(5) C9A C14A C13A 120.7(5) C2B O1B C15B 120.8(7) C4B O2B C16B 118.4(7) C6B O3B C17B 118.5(6)
Appendix 270
C1B N1B C7B 117.8(7) C1B N1B C8B 122.0(7) C7B N1B C8B 118.8(7) N1B C1B C2B 119.9(7) N1B C1B C6B 120.3(7) C2B C1B C6B 119.8(7) O1B C2B C1B 118.6(7) O1B C2B C3B 123.3(7) C1B C2B C3B 118.1(7) C2B C3B C4B 119.4(8) O2B C4B C3B 122.9(8) O2B C4B C5B 114.2(8) C3B C4B C5B 122.9(8) C4B C5B C6B 117.9(8) O3B C6B C1B 115.0(7) O3B C6B C5B 123.2(7) C1B C6B C5B 121.8(7) O4B C8B N1B 122.0(8) O4B C8B C9B 118.4(8) N1B C8B C9B 119.6(7) C8B C9B C10B 1 21.2(6) C8B C9B C14B 119.8(6) C10B C9B C14B 119.0(6) C9B C10B C11B 120.7(5) C10B C11B C12B 120.2(5) C11B C12B C13B 119.2(6) C12B C13B C14B 120.2(5) C9B C14B C13B 120.7(5)
4. Crystal data for the compound 226 (Ref: DDB 105)
The X-ray crystal data for 226: Crystal was grown from dichloromethane. Colorless,
C16H16N2O4S, M = 332.4, triclinic, space group P , a = 5.017(3) Å, b = 10.358(7) Å, c
= 14.939(8) Å, = 76.27(2)o, = 87.52(2)o, = 84.41(3)o, V = 750.4(5) Å3; Z = 2, Dc
= 1.47 g cm-3; T = 294 K, μ(Mo K ) = 0.236 mm-1( = 0.71073 Å), 2401 observed
reflections [I>2 (I)], R1 = 0.033, wR2 = 0.060 (observed data), variable parameters
209, GOF = 1.78.
Table 15. Non hydrogen atomic parameters (Esd in parentheses).
x y z (U11+U22+U33)/3
S1 -0.01500(8) 0.47587(4) 0.32649(3) 0.0325(2) O1 0.43674(26) 0.70464(13) -0.02918(8) 0.0435(4) O2 0.75898(26) 0.91255(13) 0.19221(9) 0.0426(3) O3 -0.14535(25) 0.48181(13) 0.41207(9) 0.0429(4) O4 -0.16232(25) 0.47832(12) 0.24675(9) 0.0419(3) N1 0.15891(29) 0.61076(14) 0.29970(9) 0.0335(4) N2 0.4205(3) 0.7585(2) 0.3296(1) 0.0380(4) C1 0.2541(4) 0.6717(2) 0.3645(1) 0.0379(4) C2 0.2862(3) 0.6649(2) 0.2158(1) 0.0301(4) C3 0.2673(3) 0.6411(2) 0.1281(1) 0.0327(4) C4 0.4266(3) 0.7135(2) 0.0614(1) 0.0332(4) C5 0.5945(3) 0.8056(2) 0.0792(1) 0.0330(4) C6 0.6059(3) 0.8271(2) 0.1668(1) 0.0320(4) C7 0.4450(3) 0.7551(2) 0.2368(1) 0.0309(4) C8 0.2421(4) 0.6311(2) -0.0568(1) 0.0480(5) C9 0.9251(4) 0.9871(2) 0.1233(1) 0.0436(5)
Appendix 271
C10 0.2305(3) 0.3401(2) 0.3435(1) 0.0322(4) C11 0.3523(4) 0.2963(2) 0.4278(1) 0.0382(4) C12 0.5471(4) 0.1903(2) 0.4398(1) 0.0415(4) C13 0.6216(4) 0.1269(2) 0.3689(1) 0.0371(4) C14 0.4936(4) 0.1735(2) 0.2848(1) 0.0412(4) C15 0.3002(4) 0.2794(2) 0.2713(1) 0.0390(4) C16 0.8377(4) 0.0127(2) 0.3821(1) 0.0509(5)
Table 16. Hydrogen atom positional parameters. Thermal parameters equal to those of bonded atom.
x y z (U11+U22+U33)/3
HC1 0.1989 0.6502 0.4311 0.038 HC3 0.1474 0.5764 0.1150 0.033 HC5 0.7064 0.8558 0.0281 0.033 H1C8 0.2702 0.6319 -0.1236 0.048 H2C8 0.2611 0.5369 -0.0195 0.048 H3C8 0.0584 0.6728 -0.0467 0.048 H1C9 1.0266 1.0458 0.1511 0.044 H2C9 1.0540 0.9246 0.0976 0.044 H3C9 0.8113 1.0434 0.0727 0.044 HC11 0.3001 0.3406 0.4794 0.038 HC12 0.6367 0.1583 0.5006 0.041 HC14 0.5437 0.1289 0.2332 0.041 HC15 0.2111 0.3121 0.2104 0.039 H1C16 0.7778 -0.0606 0.3568 0.051 H2C16 1.0052 0.0443 0.3488 0.051 H3C16 0.8736 -0.0214 0.4493 0.051
Table 17. Bond lengths (Å) (Esd in parentheses).
Bond length Bond length
S1 O3 1.422(1) S1 O4 1.423(1) S1 N1 1.678(1) S1 C10 1.755(2) O1 C4 1.376(2) O1 C8 1.426(2) O2 C6 1.354(2) O2 C9 1.423(2) N1 C1 1.398(2) N1 C2 1.400(2) N2 C1 1.289(2) N2 C7 1.394(2) C2 C3 1.398(2) C2 C7 1.383(2) C3 C4 1.374(2) C4 C5 1.410(2) C5 C6 1.383(2) C6 C7 1.406(2) C10 C11 1.381(2) C10 C15 1.389(2) C11 C12 1.381(3) C12 C13 1.393(3) C13 C14 1.394(3) C13 C16 1.507(3) C14 C15 1.375(3)
Appendix 272
Table 18. Bond angles (o) (Esd in parentheses).
Bond angle Bond angle O3 S1 O4 121.62(8) O3 S1 N1 104.62(7) O3 S1 C10 109.47(8) O4 S1 N1 106.07(7) O4 S1 C10 109.11(8) N1 S1 C10 104.50(7) C4 O1 C8 117.1(1) C6 O2 C9 117.7(1) S1 N1 C1 124.2(1) S1 N1 C2 128.1(1) C1 N1 C2 106.3(1) C1 N2 C7 104.8(1) N1 C1 N2 113.1(2) N1 C2 C3 131.3(2) N1 C2 C7 104.0(1) C3 C2 C7 124.7(2) C2 C3 C4 114.7(2) O1 C4 C3 123.7(2) O1 C4 C5 113.4(1) C3 C4 C5 122.9(2) C4 C5 C6 120.6(2) O2 C6 C5 125.9(2) O2 C6 C7 116.0(2) C5 C6 C7 118.1(2) N2 C7 C2 111.9(1) N2 C7 C6 129.2(2) C2 C7 C6 119.0(2) S1 C10 C11 119.7(1) S1 C10 C15 119.1(1) C11 C10 C15 121.2(2) C10 C11 C12 119.0(2) C11 C12 C13 121.3(2) C12 C13 C14 118.1(2) C12 C13 C16 121.0(2) C14 C13 C16 120.9(2) C13 C14 C15 121.4(2) C10 C15 C14 118.9(2)
Table 19. Torsion bond angles (o) (Esd in parentheses).
Bond angle Bond angle O3 S1 N1 C1 27.2(2) O3 S1 N1 C2 -168.3(1) O4 S1 N1 C1 156.9(1) O4 S1 N1 C2 -38.6(2) C10 S1 N1 C1 -87.8(2) C10 S1 N1 C2 76.7(2) O3 S1 C10 C11 -28.2(2) O3 S1 C10 C15 152.3(1) O4 S1 C10 C11 -163.5(1) O4 S1 C10 C15 17.0(2) N1 S1 C10 C11 83.4(1) N1 S1 C10 C15 -96.1(1) C8 O1 C4 C3 9.5(2) C8 O1 C4 C5 -169.9(2) C9 O2 C6 C5 -0.3(2) C9 O2 C6 C7 179.9(1) S1 N1 C1 N2 168.6(1) C2 N1 C1 N2 1.3(2) S1 N1 C2 C3 13.4(3) S1 N1 C2 C7 -167.4(1) C1 N1 C2 C3 -179.9(2) C1 N1 C2 C7 -0.7(2) C7 N2 C1 N1 -1.2(2) C1 N2 C7 C2 0.7(2) C1 N2 C7 C6 -178.3(2) N1 C2 C3 C4 -179.6(2) C7 C2 C3 C4 1.3(2) N1 C2 C7 N2 0.0(2) N1 C2 C7 C6 179.2(1) C3 C2 C7 N2 179.3(1) C3 C2 C7 C6 -1.6(3) C2 C3 C4 O1 -179.9(1) C2 C3 C4 C5 -0.5(2) O1 C4 C5 C6 179.5(1) C3 C4 C5 C6 0.0(3) C4 C5 C6 O2 179.9(1) C4 C5 C6 C7 -0.2(2) O2 C6 C7 N2 -0.2(3) O2 C6 C7 C2 -179.2(1) C5 C6 C7 N2 179.9(2) C5 C6 C7 C2 0.9(2) S1 C10 C11 C12 -179.3(1) C15 C10 C11 C12 0.2(3) S1 C10 C15 C14 179.7(1)
Appendix 273
C11 C10 C15 C14 0.2(3) C10 C11 C12 C13 -0.3(3) C11 C12 C13 C14 0.0(3) C11 C12 C13 C16 179.0(2) C12 C13 C14 C15 0.3(3) C16 C13 C14 C15 -178.6(2) C13 C14 C15 C10 -0.4(3)
5. Crystal data for the compound 227 (Ref: DDB 104)
The X-ray crystal data for 227: Crystal was grown from dichloromethane. Colorless,
C17H18N2O4S, M = 346.4, monoclinic, space group P21/c, a = 9.875(3) Å, b = 9.197(2)
Å, c = 20.117(7) Å, = 90o, = 114.38(1)o, = 90o, V = 1664.1(9) Å3; Z = 4, Dc =
1.38 g cm-3; T = 294 K, μ(Mo K ) = 0.216 mm-1( = 0.71073 Å), 2346 observed
reflections [I>2 (I)], R1 = 0.036, wR2 = 0.051 (observed data), variable parameters
218, GOF = 1.76.
Table 20. Non hydrogen atomic parameters (Esd in parentheses).
x y z (U11+U22+U33)/3
S1 0.89637(6) 0.05099(6) 0.62462(3) 0.0441(2) O1 0.51139(17) 0.05711(19) 0.32221(9) 0.0622(5) O2 0.31331(17) 0.37587(17) 0.44586(9) 0.0586(4) O3 0.93375(18) 0.02174(18) 0.69955(8) 0.0594(5) O4 0.89133(17) -0.06418(16) 0.57633(9) 0.0520(4) N1 0.72679(18) 0.12557(19) 0.59059(9) 0.0436(4) N2 0.5499(2) 0.2880(2) 0.5818(1) 0.0519(5) C1 0.6681(3) 0.2229(2) 0.6271(1) 0.0486(5) C2 0.6354(2) 0.1400(2) 0.5153(1) 0.0408(5) C3 0.6390(2) 0.0714(2) 0.4540(1) 0.0440(5) C4 0.5264(2) 0.1120(3) 0.3883(1) 0.0474(5) C5 0.4162(2) 0.2133(3) 0.3829(1) 0.0484(6) C6 0.4149(2) 0.2776(2) 0.4446(1) 0.0466(5) C7 0.5275(2) 0.2397(2) 0.5122(1) 0.0439(5) C8 0.7317(3) 0.2460(3) 0.7075(1) 0.0670(7) C9 0.6192(3) -0.0440(3) 0.3218(1) 0.0734(8) C10 0.1949(3) 0.4129(3) 0.3780(2) 0.0682(8) C11 1.0104(2) 0.1898(2) 0.6174(1) 0.0408(5) C12 1.0893(2) 0.2765(3) 0.6776(1) 0.0507(6) C13 1.1784(3) 0.3850(3) 0.6712(1) 0.0571(6) C14 1.1900(2) 0.4128(2) 0.6060(1) 0.0513(6) C15 1.1099(3) 0.3239(3) 0.5465(1) 0.0586(6) C16 1.0214(2) 0.2131(3) 0.5520(1) 0.0509(6) C17 1.2872(3) 0.5325(3) 0.6000(2) 0.0770(9)
Appendix 274
Table 21. Hydrogen atom positional parameters. Thermal parameters equal to those of bonded atom. x y z (U11+U22+U33)/3
HC3 0.7169 -0.0013 0.4575 0.044 HC5 0.3379 0.2393 0.3338 0.048 H1C8 0.6823 0.3315 0.7188 0.067 H2C8 0.7147 0.1574 0.7317 0.067 H3C8 0.8409 0.2648 0.7258 0.067 H1C9 0.5951 -0.0749 0.2705 0.073 H2C9 0.7197 0.0025 0.3429 0.073 H3C9 0.6191 -0.1309 0.3516 0.073 H1C10 0.1285 0.4857 0.3865 0.068 H2C10 0.2366 0.4555 0.3447 0.068 H3C10 0.1364 0.3236 0.3552 0.068 HC12 1.0812 0.2600 0.7250 0.051 HC13 1.2368 0.4459 0.7148 0.057 HC15 1.1168 0.3411 0.4989 0.059 HC16 0.9655 0.1498 0.5089 0.051 H1C17 1.3647 0.4907 0.5856 0.077 H2C17 1.2253 0.6040 0.5623 0.077 H3C17 1.3367 0.5826 0.6482 0.077
Table 22. Bond lengths (Å) (Esd in parentheses).
Bond length Bond length
S1 O3 1.422(2) S1 O4 1.424(2) S1 N1 1.672(2) S1 C11 1.748(2) O1 C4 1.372(3) O1 C9 1.416(3) O2 C6 1.358(3) O2 C10 1.425(3) N1 C1 1.425(3) N1 C2 1.413(3) N2 C1 1.293(3) N2 C7 1.396(3) C1 C8 1.488(3) C2 C3 1.399(3) C2 C7 1.387(3) C3 C4 1.382(3) C4 C5 1.402(3) C5 C6 1.381(3) C6 C7 1.399(3) C11 C12 1.390(3) C11 C16 1.381(3) C12 C13 1.372(3) C13 C14 1.387(3) C14 C15 1.395(3) C14 C17 1.497(3) C15 C16 1.376(3)
Table 23. Bond angles (o) (Esd in parentheses).
Bond angle Bond angle
O3 S1 O4 120.2(1) O3 S1 N1 106.83(9) O3 S1 C11 109.4(1) O4 S1 N1 106.18(9) O4 S1 C11 109.2(1) N1 S1 C11 103.70(9) C4 O1 C9 117.8(2) C6 O2 C10 117.6(2)
Appendix 275
S1 N1 C1 126.8(2) S1 N1 C2 124.5(1) C1 N1 C2 106.1(2) C1 N2 C7 106.5(2) N1 C1 N2 111.6(2) N1 C1 C8 124.8(2) N2 C1 C8 123.6(2) N1 C2 C3 131.7(2) N1 C2 C7 104.5(2) C3 C2 C7 123.8(2) C2 C3 C4 114.8(2) O1 C4 C3 123.4(2) O1 C4 C5 113.5(2) C3 C4 C5 123.1(2) C4 C5 C6 120.6(2) O2 C6 C5 125.6(2) O2 C6 C7 116.4(2) C5 C6 C7 117.9(2) N2 C7 C2 111.3(2) N2 C7 C6 128.9(2) C2 C7 C6 119.8(2) S1 C11 C12 119.6(2) S1 C11 C16 120.0(2) C12 C11 C16 120.4(2) C11 C12 C13 119.0(2) C12 C13 C14 122.1(2) C13 C14 C15 117.7(2) C13 C14 C17 121.2(2) C15 C14 C17 121.2(2) C14 C15 C16 121.3(2) C11 C16 C15 119.6(2)
Table 24. Torsion bond angles (o) (Esd in parentheses).
Bond angle Bond angle O3 S1 N1 C1 36.3(2) O3 S1 N1 C2 -164.8(2) O4 S1 N1 C1 165.7(2) O4 S1 N1 C2 -35.3(2) C11 S1 N1 C1 -79.3(2) C11 S1 N1 C2 79.7(2) O3 S1 C11 C12 -16.2(2) O3 S1 C11 C16 164.0(2) O4 S1 C11 C12 -149.6(2) O4 S1 C11 C16 30.5(2) N1 S1 C11 C12 97.5(2) N1 S1 C11 C16 -82.3(2) C9 O1 C4 C3 -1.4(3) C9 O1 C4 C5 178.7(2) C10 O2 C6 C5 2.1(3) C10 O2 C6 C7 -178.1(2) S1 N1 C1 N2 164.4(2) S1 N1 C1 C8 -16.7(3) C2 N1 C1 N2 2.4(2) C2 N1 C1 C8 -178.7(2) S1 N1 C2 C3 17.9(3) S1 N1 C2 C7 -164.4(1) C1 N1 C2 C3 -179.5(2) C1 N1 C2 C7 -1.8(2) C7 N2 C1 N1 -1.9(2) C7 N2 C1 C8 179.2(2) C1 N2 C7 C2 0.7(2) C1 N2 C7 C6 -180.0(2) N1 C2 C3 C4 178.3(2) C7 C2 C3 C4 0.9(3) N1 C2 C7 N2 0.7(2) N1 C2 C7 C6 -178.7(2) C3 C2 C7 N2 178.7(2) C3 C2 C7 C6 -0.7(3) C2 C3 C4 O1 179.8(2) C2 C3 C4 C5 -0.3(3) O1 C4 C5 C6 179.4(2) C3 C4 C5 C6 -0.5(3) C4 C5 C6 O2 -179.4(2) C4 C5 C6 C7 0.8(3) O2 C6 C7 N2 0.7(3) O2 C6 C7 C2 180.0(2) C5 C6 C7 N2 -179.5(2) C5 C6 C7 C2 -0.2(3) S1 C11 C12 C13 180.0(2) C16 C11 C12 C13 -0.2(3) S1 C11 C16 C15 179.1(2) C12 C11 C16 C15 -0.8(3) C11 C12 C13 C14 1.3(4) C12 C13 C14 C15 -1.4(4) C12 C13 C14 C17 179.6(2) C13 C14 C15 C16 0.4(4) C17 C14 C15 C16 179.4(2) C14 C15 C16 C11 0.6(4)
Appendix 276
6. Crystal data for the compound 321 (Ref: DDB 111)
The X-ray crystal data for 321: Crystal was grown from chloroform. Colorless,
C16H13F3N2O4S, M = 386.3, triclinic, space group P , a = 5.377(2) Å, b = 9.816(3) Å,
c = 15.814(5) Å, = 94.43(3)o, = 92.06(3)o, = 98.23(2)o, V = 822.7(4) Å3; Z = 2,
Dc = 1.56 g cm-3; T = 294 K, μ(Mo K ) = 0.253 mm-1( = 0.71073 Å), 2526 observed
reflections [I>2 (I)], R1 = 0.048 , wR2 = 0.068 (observed data), variable parameters
235, GOF = 1.82.
Table 25. Non hydrogen atomic parameters (Esd in parentheses).
x y z (U11+U22+U33)/3S 0.05511(10) 0.63437(6) 0.16576(4) 0.0426(2) F1 0.3939(4) 0.5868(2) 0.0585(1) 0.0978(7) F2 0.1367(4) 0.7170(2) 0.0174(1) 0.0855(6) F3 0.4301(3) 0.7969(2) 0.1093(1) 0.0835(6) O1 0.9108(4) 0.6191(2) 0.4304(1) 0.0629(5) O2 0.6142(4) 1.0454(2) 0.3954(1) 0.0640(5) O3 -0.0948(3) 0.5114(2) 0.1325(1) 0.0639(5) O4 -0.0457(3) 0.7544(2) 0.1931(1) 0.0532(4) N1 0.2482(3) 0.5993(2) 0.2412(1) 0.0411(5) N2 0.5252(4) 0.4868(2) 0.3075(1) 0.0469(5) C1 0.3390(4) 0.4709(2) 0.2518(1) 0.0422(5) C2 0.5683(4) 0.6270(2) 0.3357(1) 0.0420(5) C3 0.7521(4) 0.6973(2) 0.3951(1) 0.0464(6) C4 0.7586(5) 0.8366(3) 0.4123(1) 0.0486(6) C5 0.5844(5) 0.9069(2) 0.3714(2) 0.0477(6) C6 0.4014(5) 0.8414(2) 0.3125(2) 0.0461(5) C7 0.4020(4) 0.7003(2) 0.2967(1) 0.0408(5) C8 0.2331(4) 0.3372(2) 0.2063(1) 0.0436(5) C9 0.3661(5) 0.2790(3) 0.1436(2) 0.0538(6) C10 0.2782(6) 0.1502(3) 0.1044(2) 0.0635(7) C11 0.0572(6) 0.0767(3) 0.1277(2) 0.0617(7) C12 -0.0757(5) 0.1339(3) 0.1913(2) 0.0653(7) C13 0.0082(5) 0.2639(3) 0.2298(2) 0.0589(7) C14 1.0886(5) 0.6859(3) 0.4955(2) 0.0645(8) C15 0.4326(6) 1.1225(3) 0.3614(2) 0.0636(7) C16 0.2690(5) 0.6865(3) 0.0826(2) 0.0547(6)
Appendix 277
Table 26. Hydrogen atom positional parameters. Thermal parameters equal to those of bonded atom.
x y z (U11+U22+U33)/3HC4 0.8882 0.8889 0.4542 0.049 HC6 0.2781 0.8917 0.2835 0.046 HC9 0.5278 0.3309 0.1266 0.054 HC10 0.3756 0.1097 0.0586 0.064 HC11 -0.0065 -0.0169 0.0991 0.062 HC12 -0.2344 0.0803 0.2095 0.065 HC13 -0.0919 0.3055 0.2744 0.059 H1C14 1.1934 0.6176 0.5160 0.064 H2C14 1.1999 0.7632 0.4721 0.064 H3C14 0.9969 0.7234 0.5439 0.064 H1C15 0.4745 1.2217 0.3834 0.064 H2C15 0.4354 1.1150 0.2980 0.064 H3C15 0.2613 1.0847 0.3789 0.064
Table 27. Bond lengths (Å) (Esd in parentheses).
Bond length Bond length S O3 1.405(2) S O4 1.411(2) S N1 1.642(2) S C16 1.833(3) F1 C16 1.305(3) F2 C16 1.309(3) F3 C16 1.318(3) O1 C3 1.359(3) O1 C14 1.432(3) O2 C5 1.368(3) O2 C15 1.433(3) N1 C1 1.435(3) N1 C7 1.420(3) N2 C1 1.293(3) N2 C2 1.397(3) C1 C8 1.475(3) C2 C3 1.404(3) C2 C7 1.383(3) C3 C4 1.369(3) C4 C5 1.407(3) C5 C6 1.382(3) C6 C7 1.389(3) C8 C9 1.378(3) C8 C13 1.394(3) C9 C10 1.376(3) C10 C11 1.377(4) C11 C12 1.385(4) C12 C13 1.377(4)
Table 28. Bond angles (o) (Esd in parentheses).
Bond angle Bond angle
O3 S O4 123.0(1) O3 S N1 109.2(1) O3 S C16 106.1(1) O4 S N1 108.8(1) O4 S C16 105.3(1) N1 S C16 102.5(1) C3 O1 C14 117.4(2) C5 O2 C15 117.1(2) S N1 C1 127.8(2) S N1 C7 124.6(2) C1 N1 C7 106.2(2) C1 N2 C2 106.6(2) N1 C1 N2 111.2(2) N1 C1 C8 124.8(2) N2 C1 C8 124.0(2) N2 C2 C3 128.9(2)
Appendix 278
N2 C2 C7 111.9(2) C3 C2 C7 119.2(2) O1 C3 C2 116.1(2) O1 C3 C4 125.6(2) C2 C3 C4 118.3(2) C3 C4 C5 120.5(2) O2 C5 C4 113.7(2) O2 C5 C6 123.5(2) C4 C5 C6 122.8(2) C5 C6 C7 114.8(2) N1 C7 C2 104.2(2) N1 C7 C6 131.5(2) C2 C7 C6 124.3(2) C1 C8 C9 119.8(2) C1 C8 C13 120.8(2) C9 C8 C13 119.3(2) C8 C9 C10 120.6(2) C9 C10 C11 120.5(3) C10 C11 C12 119.1(2) C11 C12 C13 120.7(2) C8 C13 C12 119.7(2) S C16 F1 110.8(2) S C16 F2 108.8(2) S C16 F3 111.1(2) F1 C16 F2 109.2(2) F1 C16 F3 108.9(2) F2 C16 F3 108.1(2)
Table 29. Torsion bond angles (o) (Esd in parentheses).
Bond angle Bond angle
O3 S N1 C1 25.0(2) O3 S N1 C7 -170.7(2) O4 S N1 C1 161.6(2) O4 S N1 C7 -34.1(2) C16 S N1 C1 -87.2(2) C16 S N1 C7 77.1(2) O3 S C16 F1 -54.8(2) O3 S C16 F2 65.2(2) O3 S C16 F3 -176.0(2) O4 S C16 F1 173.4(2) O4 S C16 F2 -66.6(2) O4 S C16 F3 52.2(2) N1 S C16 F1 59.7(2) N1 S C16 F2 179.6(2) N1 S C16 F3 -61.5(2) C14 O1 C3 C2 -175.7(2) C14 O1 C3 C4 4.8(4) C15 O2 C5 C4 -175.5(2) C15 O2 C5 C6 4.6(4) S N1 C1 N2 167.2(2) S N1 C1 C8 -13.6(3) C7 N1 C1 N2 0.6(2) C7 N1 C1 C8 179.8(2) S N1 C7 C2 -167.4(2) S N1 C7 C6 12.4(3) C1 N1 C7 C2 -0.3(2) C1 N1 C7 C6 179.6(2) C2 N2 C1 N1 -0.7(2) C2 N2 C1 C8 -179.9(2) C1 N2 C2 C3 -178.9(2) C1 N2 C2 C7 0.5(3) N1 C1 C8 C9 108.0(3) N1 C1 C8 C13 -76.5(3) N2 C1 C8 C9 -72.9(3) N2 C1 C8 C13 102.6(3) N2 C2 C3 O 10.0(4) N2 C2 C3 C4 179.6(2) C7 C2 C3 O1 -179.4(2) C7 C2 C3 C4 0.2(3) N2 C2 C7 N1 -0.1(2) N2 C2 C7 C6 180.0(2) C3 C2 C7 N1 179.3(2) C3 C2 C7 C6 -0.5(3) O1 C3 C4 C5 179.8(2) C2 C3 C4 C5 0.2(4) C3 C4 C5 O2 179.8(2) C3 C4 C5 C6 -0.4(4) O2 C5 C6 C7 180.0(2) C4 C5 C6 C7 0.1(4) C5 C6 C7 N1 -179.4(2) C5 C6 C7 C2 0.3(3) C1 C8 C9 C10 175.7(2) C13 C8 C9 C10 0.2(4) C1 C8 C13 C12 -174.4(2) C9 C8 C13 C12 1.1(4) C8 C9 C10 C11 -0.7(4) C9 C10 C11 C12 -0.1(4) C10 C11 C12 C13 1.4(4) C11 C12 C13 C8 -1.9(4)