iron(iii) chloride hexahydrate catalyzed one-pot...
TRANSCRIPT
IRON(III) CHLORIDE HEXAHYDRATE CATALYZED ONE-POT THREE-
COMPONENT AZA-FRIEDEL-CRAFTS REACTION OF ACTIVATED
ARENES WITH A COMBINATION OF N-BOC CARBAMATE AND
ALDEHYDES AND ITS APPLICATION FOR THE SYNTHESIS OF
UNSYMMETRICAL TRIARYLMETHANES
SUREEPORN RUENGSANGTONGKUL
A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF
THE REQUIREMENTS FOR THE MASTER DEGREE OF SCIENCE
IN CHEMISTRY
FACULTY OF SCIENCE
BURAPHA UNIVERSITY
JUNE 2015
COPYRIGHT OF BURAPHA UNIVERSITY
iii
ACKNOWLEDGEMENT
I am indebted to the Department of Chemistry, Faculty of Science, Burapha
University, Thailand, where I performed my experiments and study. This thesis was
completed with the help of many people. Firstly, I would like to express my sincere
gratitude and deep appreciation to Assistant Professor Dr. Jaray Jaratjaroonphong, my
principal advisor, for teaching me scientific reasoning, valuable instructions, expert
guidance, excellent suggestions and kindness.
I am also grateful to Dr. Tinnagon Keawin, from Department of Chemistry,
Ubon Ratchathani University and Dr. Anan Athipornchai, who accepted the request to
participate in the jury of my thesis.
I would to express my sincere gratitude and deep appreciation to Dr.
Prapapan Techasauvapak, Assistant Professor Dr. Jongkolnee Jongaramruong,
Assistant Professor Dr. Rungnapha Saeeng, Assistant Professor Dr. Ekaruth Srisook,
Dr. Uthaiwan Sirion and Dr. Anan Athipornchai, my organic chemistry lecturers for
teaching me basic knowledge and scientific reasoning and expert guidance.
I thank the Thailand Research Fund for financial support to J.J. Financial
support from the Center for Innovation in Chemistry (PERCH-CIC), Commission on
Higher Education, Ministry of Education and a Grant from the Faculty of Science,
Burapha University, Thailand are also gratefully acknowledged.
Finally, my success will not be happened if without great support from my
family. Therefore, I would like to take this opportunity to appreciate all of them. For
their great support and help full to success education for my Master degree.
Sureeporn Ruengsangtongkul
iv
55910079: MAJOR: CHEMISTRY; M.Sc. (CHEMISTRY)
KEYWORD: FeCl3∙6H2O/ Bi(OTf)3/ ΑLPHA-BRANCHED AMINES /
UNSYMMETRICAL TRIARYLMETHANES/ AZA-FRIEDEL-
CRAFTS REACTION/ FRIEDEL-CRAFTS REACTION
SUREEPORN RUENGSANGTONGKUL: IRON(III) CHLORIDE
HEXAHYDRATE CATALYZED ONE-POT THREE-COMPONENT AZA-
FRIEDEL-CRAFTS REACTION OF ACTIVATED ARENES WITH A
COMBINATION OF N-BOC CARBAMATE AND ALDEHYDES AND ITS
APPLICATION FOR THE SYNTHESIS OF UNSYMMETRICAL TRIARYL-
METHANES. ADVISORY COMMITTEE: JARAY JARATJAROONPHONG, Ph.D.
194 P. 2015.
Iron(III) chloride hexahydrate (FeCl3∙6H2O) is found to be an efficient
catalyst for a one-pot synthesis of α-branched amines via aza-Friedel-Crafts reaction
of electron-rich arenes or heteroarenes with a combination of aldehydes and tert-butyl
carbamate for in dichloroethane or toluene under "open flask" and mild conditions.
In the presence of 5 mol% of FeCl3∙6H2O in toluene or dichloroethane (ClCH2CH2Cl)
at room temperature the reaction give the corresponding N-Boc protected α-branched
amines in moderate to high yields. These N-Boc protected α-branched amines can be
transformed to unsymmetrical triarylmethanes through sequential reactions with the
different arenes.
Ar1 Ar2/R2
HN O
O
H2N O
O
Ar2/R2CHO
FeCl3 6H2O
solvent, 0-rt
Ar1 H
Het H
or
Ar2 = aryl or heteroaryl
R2 = alkyl
Ar1
Ar3
Ar2
solvent, rt
Ar3 H
-Branched amines UnsymmetricalTriarylmethanes
FeCl3 6H2O
CONTENTS
Page
ABSTRACT......................................................................................................... iv
CONTENTS......................................................................................................... v
LIST OF TABLES................................................................................................ viii
LIST OF FIGURES.............................................................................................. ix
LIST OF ABBREVIATIONS............................................................................... xx
THE RELEVANCE OF THE RESEARCH WORK TO THAILAND................ xxiii
CHAPTER
1. INTRODUCTION..................................................................................... 1
Objectives............................................................................................. 5
Contribution to knowledge................................................................... 6
Scope of the study................................................................................ 6
2. LITERATURE REVIEWS........................................................................ 7
3. RESEARCH METHODOLOGY.............................................................. 43
1. The aza-Friedel-Crafts reaction of electron-rich arenes with
aldehyde and tert-butyl carbamate in the presence of FeCl3∙6H2O:
Synthesis of the corresponding α-branched amines........................
44
1.1 Optimization of the reaction condition for aza-Friedel-Crafts
alkylation of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde.....................................................
44
1.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde in various of solvent
using FeCl3∙6H2O as catalyst..........................................
45
1.1.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde in various catalyst
loading of FeCl3∙6H2O using toluene as solvent............
47
1.1.3 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde in various catalyst loading
of FeCl3∙6H2O using ClCH2CH2Cl as solvent.................
48
vi
CONTENTS (CONTINUED)
Chapter Page
1.2 The aza-Friedel-Crafts alkylation of 1,3,5-trimethoxybenzene
with tert-butyl carbamate and various aldehydes in the
presence of FeCl3∙6H2O under optimized reaction condition....
49
1.2.1 The reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and various aromatic aldehydes in the
presence of FeCl3∙6H2O as catalyst: The synthesis of
α-branched amines III-4…..………………….………...
49
1.2.2 The reaction of 1,3,5-trimethoxybenzene, tert-butyl
carbamate with various heteroaromatic aldehydes in
the presence of FeCl3∙6H2O as catalyst: The synthesis
of α-branched amines III-6..............................................
58
1.2.3 The reaction of 1,3,5-trimethoxybenzene, tert-butyl
carbamate with various aliphatic aldehydes in the
presence of FeCl3∙6H2O as catalyst: The synthesis of
α-branched amines III-7..................................................
60
1.3 FeCl3∙6H2O catalyzed aza-Friedel-Crafts reaction of various
electron-rich arenes, tert-butyl carbamate with aromatic and
aliphatic aldehydes under optimized reaction condition...........
67
1.3.1 Reaction of electron-rich arenes with tert-butyl
carbamate and aromatic aldehydes using FeCl3∙6H2O as
catalyst …………..…………………………....………...
68
1.3.2 Reaction of electron-rich arenes, tert-butyl carbamate
with aliphatic aldehydes using FeCl3∙6H2O as catalyst...
75
2. The Friedel-Crafts reaction of electron-rich arenes with N-Boc
diarylmethylcarbamate: Synthesis of the corresponding
unsymmetrical triarylmethanes........................................................
81
2.1 Reaction of 2-methylfuran with N-Boc diarylmethylcarbamate
in various catalyst……………………………………………..
81
vii
CONTENTS (CONTINUED)
Chapter Page
2.2 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various
N-Boc diarylmethylcarbamate as alkylating agent with
different arene under optimized reaction condition...................
86
2.2.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4a with different arene...................
86
2.2.2 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with different arene...................
87
2.2.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)
methylcarbamate III-8b or tert-butyl (5-methylfuran-2-
yl)(4-nitrophenyl)methylcarbamate III-8c with different
arene.................................................................................
93
2.3 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various
N-Boc diarylmethylcarbamate as alkylating agent with indole
under optimized reaction condition...........................................
104
4. RESULTS DISSCUSSION AND CONCLUSION................................... 107
CONCLUSION.................................................................................... 142
Compound characterization.................................................................. 143
REFERENCES..................................................................................................... 187
BIOGRAPHY.......................................................................................................
.
194
LIST OF TABLES
Tables Page
4-1 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl
carbamate in various of solvent...............................................................
109
4-2 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl
carbamate in various catalyst loading …….............................................
111
4-3 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with
various aromatic aldehydes.....................................................................
113
4-4 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with
disubstituted aromatic aldehydes.............................................................
115
4-5 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with
heteroaromatic aldehydes........................................................................
116
4-6 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with
aliphatic aldehydes..................................................................................
118
4-7 Reaction of various arenes, tert-butyl carbamate with benzaldehyde,
2-methylpropanal under the optimized reaction condition......................
122
4-8 Reaction of N-Boc diarylmethylcarbamates and 2-methylfuran in
various catalysts loading..........................................................................
129
4-9 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl
carbamate III-4a with different arene....................................................
133
4-10 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl
carbamate III-8a with different arene.....................................................
135
4-11 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate
III-8b or tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methyl-
carbamate III-8c with different arene....................................................
138
4-12 Reaction of various N-Boc diarylmethylcarbamate as alkylating agent
with indole...............................................................................................
141
LIST OF FIGURES
Figures Page
1-1 Examples of bioactive α-branched amine derivatives............................ 2
1-2 Examples of bioactive unsymmetrical triarymethane derivatives.......... 3
1-3 Main current synthetic approaches of unsymmetrical triarylmethanes.. 4
1-4 FeCl3·6H2O-catalyzed formation of α-branched amines and
unsymmetrical triarylmethanes...............................................................
5
2-1 The enantioselective Friedel-Crafts reaction of indoles with imines
II-2 using chiral organic catalysts...........................................................
8
2-2 The reaction of 1,3,5-trimethoxybenzene with imines II-7 under the
Iron(III) chloride catalyst.......................................................................
9
2-3 The reaction of 1,2-dimethoxybenzene with imines II-10 under the
Iron(III) chloride catalyst........................................................................
9
2-4 The reactions of arenes with aziridines under the Iron(III) chloride
catalyst....................................................................................................
9
2-5 Ir(III)-SnCl3 catalyzed aza-Friedel-Crafts reaction................................. 10
2-6 The synthesis of triarylmethanes by Ir(III)-SnCl3 catalyst..................... 10
2-7 The three component reaction of aromatic compounds, carbamates
and aldehydes using H2SO4 as catalyst...................................................
11
2-8 The three-component aza Friedel-Craft reaction of 2-naphthaldehyde,
o-anisidine and 1-methylindole using C9H19COOH in water.................
12
2-9 The synthesis of triarylmethanes II-32................................................... 13
2-10 Transformations of aza-Friedel-Crafts Products..................................... 13
2-11 I2-catalyzed three-component aza-Friedel–Crafts reaction..................... 14
2-12 Fe(III)-catalyzed three-component aza-Friedel–Crafts reaction............. 14
2-13 Bi(OTf)3-catalyzed three-component aza-Friedel–Crafts reaction......... 15
2-14 The synthesis of α-branched amines using Bi(OTf)3 as catalyst............ 15
2-15 Transformations of aza-Friedel-Crafts Products..................................... 16
x
LIST OF FIGURES (CONTINUED)
Figures Page
2-16 The synthesis of aminoalkyl naphthols using sulfamic acid as
catalyst....................................................................................................
16
2-17 The synthesis of aminoalkyl naphthols using I2 as catalyst.................... 17
2-18 The synthesis of aminoalkyl naphthols using SiO2-NaHSO4 as catalyst 17
2-19 The synthesis of aminoalkyl naphthols using Brønsted acidic ionic
liquid ([TEBSA][HSO4]) as catalyst...................
18
2-20 The synthesis of aminoalkyl naphthols using VB1 as catalyst................ 19
2-21 The synthesis of aminoalkyl naphthols using P2O5 as catalyst............... 19
2-22 The synthesis of aminoalkyl naphthols/phenols using EAN as catalyst. 20
2-23 [RuCl2(p-cymene)]2 catalyzed arylation of benzylic amines witharyl
bromides and aryl iodides.......................................................................
20
2-24 The possible mechanism for the ruthenium(II) catalyzed arylation of
benzylic amines with aryl halides...........................................................
21
2-25 The Synthesis of (p-Nitroaryl)diarylmethane......................................... 22
2-26 The Synthesis of unsymmetrical triarylmethane derivatives using
Brønsted acid or Lewis acid as catalyst..........................................................
23
2-27 The Synthesis of unsymmetrical bis(indolyl)alkanes............................. 24
2-28 The Synthesis of unsymmetrical triarylmethane derivatives using
FeCl3 as catalyst......................................................................................
24
2-29 Reaction of carbinol with 1- and 2-naphthol.......................................... 25
2-30 The synthesis of thiophene containing triarylmethanes.......................... 26
2-31 The synthesis of unsymmetrical tri-, tetra- arylmethanes....................... 26
2-32
The synthesis of unsymmetrical triarylmethanes using AuCl4Na∙2H2O
as catalyst................................................................................................
27
2-33 The chemoselective synthesis for Friedel-Crafts reaction of
diarylmethanols and nucleophiles...........................................................
27
xi
LIST OF FIGURES (CONTINUED)
Figures Page
2-34 The chemoselective synthesis of unprotected anilines and mono-, di-
arylmethanol using Re2O7 as catalyst...................................................
28
2-35 The mechanism for the benzylation of anilines.................................... 28
2-36 The synthesis of di-, tri- arylmethanes using o-benzenedisulfonimide
as catalyst..............................................................................................
29
2-37 FeCl3 catalyzed symmetrical triarylmethanes formations..................... 29
2-38 FeCl3 catalyzed the mono-aromatic substitution product..................... 30
2-39 FeCl3 catalyzed unsymmetrical triarylmethanes formations................. 30
2-40 The synthesis of unsymmetrical triarylmethane derivatives using
Cu(OTf)2/(±)-binap as catalyst..............................................................
31
2-41 Sc(OTf)3 catalyzed aza-Friedel-Crafts alkylation of sulfonamide
adducts and electron-rich aromatic and heteroaromatic compounds....
31
2-42 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using
achiral Brønsted acid II-159 as catalyst................................................
32
2-43 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using
chiral Brønsted acid II-156 as catalyst.................................................
33
2-44 The synthesis of N-arylsufoylamido sulfones using FeCl3·6H2O as
catalyst..................................................................................................
33
2-45 Transformation of α-amido sulfones into unsymmetrical
triarylmethane derivatives with FeCl3·6H2O........................................
34
2-46 The mechanism for the iron(III) catalyzed Friedel-Crafts reaction..... 35
2-47 Transformation of α-amido sulfones into unsymmetrical
triarylmethane derivatives with [B(C6F5)3]...........................................
35
2-48 Reaction of benzylation and silylation.................................................. 36
2-49 Reaction of [3+3]-cyclocondensation follow by cyclization and
aromatization.........................................................................................
36
xii
LIST OF FIGURES (CONTINUED)
Figures Page
2-50 The synthesis of Friedel-Crafts alkylation of diketone and arenes
using SiO2-NaHSO4 as catalyst.............................................................
37
2-51 FeCl3 catalyzed one-pot three-component Friedel-Crafts reactions..... 37
2-52 Binuclear complex catalyzed one-pot three-component Friedel-Crafts
reactions................................................................................................
38
2-53 ZnCl2 catalyzed one-pot three-component Friedel-Crafts reactions..... 39
2-54 Transformation of bis(indolyl)methane into 3-diarylmethylindoles or
3-arylmethylindoles..............................................................................
39
2-55 The cationic Pd(II)/bpy-catalyzed one-pot synthesis of
unsymmetrical triarylmethane derivatives............................................
40
2-56 The synthesis of triarylmethanes via deprotonative-cross-coupling..... 40
2-57 The stereospecific synthesis for Suzuki-Miyaura cross-coupling of
enantio enrich triarylmethanes..............................................................
41
2-58 Palladium-catalyzed arylation of diarylmethanol derivatives and
oxazoles.................................................................................................
42
4-1 A model reaction for the synthesis of α-branched amine derivatives
and unsymmetrical triarylmethanes......................................................
107
4-2 A model reaction for the synthesis of α-branched amines.................... 108
4-3 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as
catalyst..................................................................................................
112
4-4 The one-pot three-component aza-Friedel-Crafts reactionof arenes or
heteroarenes with aldehydes and tert-butyl carbamates........................
120
4-5 Plausible reaction mechanism............................................................... 126
4-6 A model reaction for the synthesis of unsymmetrical triarylmethanes
using FeCl3∙6H2O as the catalyst..........................................................
127
xiii
LIST OF FIGURES (CONTINUED)
Figures Page
4-7 A model reaction for the synthesis of unsymmetrical triarylmethanes
of N-Boc diarylmethylcarbamate III-4a or III-8a and
2-methylfuran........................................................................................
128
4-8 Plausible reaction mechanism............................................................... 131
4-9 The synthesis of unsymmetrical triarylmethane derivatives using
FeCl3∙6H2O as the catalyst....................................................................
132
4-10 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as
catalyst..................................................................................................
142
4-11 The synthesis of unsymmetrical triaylmethane derivatives using
FeCl3∙6H2O as catalyst..........................................................................
143
4-12 Structure of tert-butyl[(2,4,6-trimethoxyphenyl)phenylmethyl]-
carbamate III-4a.................................................................................
143
4-13 Structure of tert-butyl (2-fluorophenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4b........................................................................
144
4-14 Structure of tert-butyl (4-fluorophenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4c........................................................................
144
4-15 Structure of tert-butyl (4-chlorophenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4d........................................................................
145
4-16 Structure of tert-butyl (4-bromophenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4e........................................................................
145
4-17 Structure of tert-butyl (4-nitrophenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4f........................................................................
146
4-18 Structure of tert-butyl (4-methoxyphenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4g........................................................................
147
xiv
LIST OF FIGURES (CONTINUED)
Figures Page
4-19 Structure of methyl 4-((tert-butoxycarbonylamino)(2,4,6-trimethoxy-
phenyl)methyl)benzoate III-4h............................................................
147
4-20 Structure of tert-butyl (4-formylphenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4j.........................................................................
148
4-21 Structure of tert-butyl 1,4-phenylenebis((2,4,6-trimethoxyphenyl)-
methylene)dicarbamatee III-5a............................................................
148
4-22 Structure of tert-butyl furan-2-yl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-6a...................................................................................
149
4-23 Structure of tert-butyl pyridin-2-yl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-6b..................................................................................
150
4-24 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)propylcarbamate
III-7a.....................................................................................................
150
4-25 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)pentylcarbamate
III-7b....................................................................................................
151
4-26 Structure of tert-butyl 3-phenyl-1-(2,4,6-trimethoxyphenyl)propyl-
carbamate III-7c...................................................................................
151
4-27 Structure of tert-butyl 2-methyl-1-(2,4,6-trimethoxyphenyl)propyl-
carbamate III-7d...................................................................................
152
4-28 Structure of tert-butyl 2-ethyl-1-(2,4,6-trimethoxyphenyl)butyl-
carbamate III-7e...................................................................................
153
4-29 Structure of tert-butyl 3-methyl-1-(2,4,6-trimethoxyphenyl)butyl-
carbamate III-7f....................................................................................
153
4-30 Structure of tert-butyl cyclopropyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-7g...................................................................................
154
4-31 Structure of tert-butyl cyclopentyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-7h...................................................................................
154
xv
LIST OF FIGURES (CONTINUED)
Figures Page
4-32 Structure of tert-butyl cyclohexyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-7i...................................................................................
155
4-33 Structure of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl-
carbamate III-8a...................................................................................
156
4-34 Structure of 5,5'-(phenylmethylene)bis(1,2,4-trimethoxybenzene)
III-9a.....................................................................................................
156
4-35 Structure of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate
III-8b....................................................................................................
157
4-36 Structure of 5,5'-(phenylmethylene)bis(2-methylfuran) III-9b............ 157
4-37 Structure of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methyl-
carbamate III-8c..................................................................................
158
4-38 Structure of 5,5'-((4-nitrophenyl)methylene)bis(2-methylfuran)
III-9c....................................................................................................
158
4-39 Structure of tert-butyl (5-ethylfuran-2-yl)(phenyl)methylcarbamate
III-8d...................................................................................................
159
4-40 Structure of 5,5'-(phenylmethylene)bis(2-ethylfuran) III-9d.............. 159
4-41 Structure of tert-butyl (5-methylthiophen-2-yl)(phenyl)methyl-
carbamate III-8e...................................................................................
160
4-42 Structure of 5,5'-(phenylmethylene)bis(2-methylthiophene) III-9e.... 160
4-43 Structure of tert-butyl (5-ethylthiophen-2-yl)(phenyl)methyl-
carbamate III-8f....................................................................................
161
4-44 Structure of tert-butyl 2-((tert-butoxycarbonylamino)(phenyl)-
methyl)- 1H-pyrrole-1-carboxylate III-8g............................................
161
4-45 Structure of tert-butyl (1H-indol-3-yl)(phenyl)methylcarbamate
III-8h....................................................................................................
162
4-46 Structure of 3,3'-(phenylmethylene)bis(1H-indole) III-9h................... 162
xvi
LIST OF FIGURES (CONTINUED)
Figures Page
4-47 Structure of tert-butyl 2-methyl-1-(2,4,5-trimethoxyphenyl)propyl-
carbamate III-10a.................................................................................
163
4-48 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(1,2,4-trimethoxy-
benzene) III-11a...................................................................................
163
4-49 Structure of tert-butyl 2-methyl-1-(5-methylfuran-2-yl)propyl-
carbamate III-10b.................................................................................
164
4-50 Structure of tert-butyl 1-(5-ethylfuran-2-yl)-2-methylpropyl-
carbamate III-10c.................................................................................
165
4-51 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(2-ethylfuran) III-11c 165
4-52 Structure of tert-butyl 2-methyl-1-(5-methylthiophen-2-yl)propyl-
carbamate III-10d................................................................................
166
4-53 Structure of tert-butyl 1-(5-ethylthiophen-2-yl)-2-methylpropyl-
carbamate III-10e................................................................................
166
4-54 Structure of tert-butyl 2-(1-(tert-butoxycarbonylamino)-2-
methylpropyl)-1H-pyrrole-1-carboxylate III-10f................................
167
4-55 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonyl-
amino)-2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a................
167
4-56 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonyl-
amino)- 2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a..............
168
4-57 Structure of 2-methyl-5-(phenyl(2,4,6-trimethoxyphenyl)methyl)-
furan III-13a.........................................................................................
169
4-58 Structure of 1,3,5-trimethoxybenzene III-1a........................................ 169
4-59 Structure of 2-methyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
furan III-13b........................................................................................
170
xvii
LIST OF FIGURES (CONTINUED)
Figures Page
4-60 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)furan
III-13c...................................................................................................
170
4-61 Structure of 2-methyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
thiophene III-13d..................................................................................
171
4-62 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
thiophene III-13e..................................................................................
172
4-63 Structure of tert-butyl 2-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
1H-pyrrole-1-carboxylate III-13f.........................................................
172
4-64 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-
pyrrole III-13g.....................................................................................
173
4-65 Structure of 3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-indole
III-13h..................................................................................................
173
4-66 Structure of 5-methoxy-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
1H-indole III-13i.................................................................................
174
4-67 Structure of 6-fluoro-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-
indole III-13j........................................................................................
175
4-68 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)furan
III-13k..................................................................................................
175
4-69 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-
furan III-13l..........................................................................................
176
4-70 Structure of (5-((5-methylfuran-2-yl)(phenyl)methyl)furan-2-yl)-
methanol III-13m................................................................................
177
4-71 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(phenyl)methyl)-
furanIII-13o..........................................................................................
177
xviii
LIST OF FIGURES (CONTINUED)
Figures Page
4-72 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(4-nitrophenyl)-
methyl)furan III-13p.............................................................................
178
4-73 Structure of 2-((5-ethylthiophen-2-yl)(phenyl)methyl)-5-methylfuran
III-13q..................................................................................................
178
4-74 Structure of 2-((5-ethylthiophen-2-yl)(4-nitrophenyl)methyl)-5-
methylfuran III-13r..............................................................................
179
4-75 Structure of tert-butyl 2-((5-methylfuran-2-yl)(phenyl)methyl)-1H-
pyrrole-1-carboxylate III-13s..............................................................
180
4-76 Structure of tert-butyl 2-((5-methylfuran-2-yl)(4-nitrophenyl)-
methyl)-1H-pyrrole-1-carboxylate III-13t............................................
180
4-77 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)-1H-
pyrrole III-13u......................................................................................
181
4-78 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-
1H-pyrrole III-13v................................................................................
181
4-79 Structure of 3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-indole
III-13w..................................................................................................
182
4-80 Structure of 3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-
indole III-13x........................................................................................
182
4-81 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-
indole III-13y......................................................................................
183
4-82 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(4-nitrophenyl)-
methyl)-1H-indole III-13z...................................................................
183
4-83 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-
indole III-13aa......................................................................................
184
4-84 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-
xix
1H-indole III-13ab............................................................................... 184
LIST OF FIGURES (CONTINUED)
Figures Page
4-85 Structure of 3-((5-methylthiophen-2-yl)(phenyl)methyl)-1H-indole
III-13ac.................................................................................................
185
4-86 Structure of tert-butyl 2-((1H-indol-3-yl)(phenyl)methyl)-1H-
pyrrole-1-carboxylate III-13ad.............................................................
185
LIST OF ABBREVIATIONS
Ar aryl
br s broad singlet (spectral)
br t broad triplet (spectral)
Calcd calculated
chemical shift relative of TMS (spectra)
J coupling constant
oC degree celsius
ClCH2CH2Cl dichloroethane
CH2Cl2 dichloromethane
d doublet (spectral)
dd doublet of doublets (spectral)
ddd doublet of doublet of doublets (spectral)
ESI electrospray ionization
equiv equivalent
EtOAc ethyl acetate
HRMS High Resolution Mass Spectrometry
h or hr hour
IR infrared
max maximum absorption frequencies
MHz megahertz
m.p. melting point
MeOH methanol
xxi
LIST OF ABBREVIATIONS (CONTINUED)
Me methyl
mm millimetre
mL millilitre
mg milligram
min minute
mmol millimole
m multiplet (spectral)
NaCl sodium chloride
NaHCO3 sodium hydrogen carbonate
Na2S2O3 sodium thiosulfate
Na2SO4 sodium sulfate
NMR Nuclear Magnetic Resonance
ppm parts per million (in NMR)
% percentage
Ph phenyl
q quartet (spectral)
cm-1
reciprocal centimeter (wave number in IR spectra)
Rf retardation factor
RT or rt room temperature
s singlet (spectral)
SiO2 silicon dioxide
t triplet (spectral)
xxii
LIST OF ABBREVIATIONS (CONTINUED)
td triplet of doublets (spectral)
TMS tetramethylsilane
THF tetrahydrofuran
TLC Thin Layer Chromatography
m/z value of mass divided by charge
CHAPTER 1
INTRODUCTION
1. Alpha-branched amines
Synthetic and biological interest in highly functionalized acyclic and cyclic
of α-branched amines (Gall, Haurena, Sengmany, Martens, & Troupel, 2009;
Shirakawa & Kobayashi, 2006, Kogen et al., 2002) have contributed to the wealth of
the experimental methodology developed (Figure 1-1). In particular, the addition of
nucleophiles to the carbon-nitrogen double bond of imines and its derivertives. Imines
are highly desirable, owing to their versatile applications as electrophilic reagents in
many organic reactions. However, many of these methods entail important practical
enhancement of the reactivity of imino derivative such as N-sulfinyl imines (Weix,
Shi, & Ellman, 2005; Brak & Ellman, 2010; Guijarro, Pablo, & Yus, 2010; Chen,
Wang, & Lin, 2010; Reddy, Gupta, Villhauer, & Liu, 2012; Zhang, Yang, Wang,
Lin, & Wang, 2012; Fernández-Salas, Maestro, Rodríguez-Fernández, García-Ruano,
& Alonso, 2013) and N-sulfonyl imines (Esquivias, Arrayás, & Cerretero, 2006;
Kang, Zhao, & You, 2007; Arrayás et al., 2008; Wang, Sun, & Wu, 2008; Marques &
Burke, 2010; Mei, Ji, Han, & Pan, 2011; Wang et al., 2011; Hesp, Bergman, &
Ellman, 2012; Tauchert, Incarvito, Rheingold, Bergman, & Ellman, 2012) have
important for use in asymmetric synthesis. However, the cleavage of
N-protective sulfinyl and sulfonyl groups required harsh conditions and multistep
process for prepared imine precursors. Recently, interesting approach have been
reported which use N-acyl imines (Schneider & Manolikakes, 2013; Muskawar,
Kumar, & Bhagat, 2013) and N-Boc imines (Jaratjaroonphong, Tuengpanya, &
Ruengsangtongkul, 2015; Jaratjaroonphong, Krajangsri, & Reutrakul, 2012) as imine
acceptors. These classes of imines can prepared in single step and without isolating
the imines intermediate. Moreover, N-protective Boc group is also easily removed
under mild acidic conditions. Therefore, the development of processes that allow
the formation of carbon-nitrogen bond in a single operation is highly desirable for
reducing the number of reaction steps, inexpensive starting materials and mild
conditions.
2
Cl
N
NO
OH
O
N
CNNC
N
N
N
H
N
HN
ON
O
CetirizingAnti-histamine agent
Selegiline Rasagiline
Treatment for Parkinson's disease
RivastigmineAnti-hyperparathyroidism agent
LetrozoleAnti-cancer agent
N
N
NF
Br
Et
Nonsteroidal aromatase inhibitoragainst breast cancer
F3C
HN
Cl
N
CO2Me
S
ClopidogrelAntiplatelet agent
CinacalcetTreatment for Alzheimer's disease
O
Me2N O
O
NO2
NHMe HCl
O
Me2N O
O
NO2
NHMe HCl
Acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitor
Figure 1-1 Examples of bioactive α-branched amine derivatives.
2. Unsymmetrical triarylmethanes
Triarylmethanes (TRAMs) have attracted considerable attention of chemists
due to their varied biological activities such as anti-cancer (Zhuo et al., 2014; Yin,
Hu, & Hartmann, 2013; Taylor, Harris, & Jarvo, 2012; Shirakawa & Kobayashi,
2006), anti-tubercular (Parai, Panda, Chaturvedi, Manju, & Sinha, 2008; Das et al.,
2007), anti-implantation (Srivastava, Sangita, Ray, Singh, Dwivedi, & Kumar, 2004)
and inhibition of PDE-4 leads to a reduction in inflammatory cell activity (O’Shea
et al., 2005) (Figure 1-2).
3
O
OMe
R O
OMe
R
OH
Diaryloxy methanophenanthrene derivertives
R = 2o or 3o amines, NMe2, NEt2, , and
Antitubercular activity
N N N
OMe
NMe2
Anti-breast cancer agent
N
N
NF
Br
Et
Anti-breast cancer agent
S
OMe
OH
Anti-tuberculosis agent
NN
N
Cl NN
NH
VorozoleAnti-cancer agent
N
S
N
O
HF2CO
O
F3C
CF3
OH
Anti-inflammatory activity
R2R1
R3
Anti-implantation
R1 = OCH3, R2 = OH, R3 = OCH3/OH
NNO
Anti-cancer agent
Figure 1-2 Examples of bioactive unsymmetrical triarymethane derivatives.
Numerous available methods for the construction of triarylmethanes and
their heterocyclic analogous have been developed. However, the method for
the synthesis of unsymmetric triarylmethane is far less explored. To the best of
our knowledge, there are six approaches for construction of unsymmetrical triaryl-
methanes: (1) Friedel-Crafts type arylation of diaryl methanols (Katritzky & Toader,
1997; Das, Panda, & Panda, 2005; Zeng, Ji, & Wang, 2005; Jana, Maiti, & Biswas,
2007; Das et al., 2007; Parai et al., 2008; McCubbin & Krokhin, 2010; Hikawa,
Suzuki, & Azumaya, 2013; Yokoyama et al., 2013; Nallagonda, Rehan, & Ghorai,
2014; Barbero et al., 2014), (2) arylation of diarylmethyl acetate (Li, Daun, Kang,
4
Wang, Yu, & Wu, 2008), (3) Friedel-Crafts type arylation of diarylmethyl amines
(Esquivias, Arrayás, & Carretero, 2006; He, Sun, Zheng, & You, 2009; Gu et al.,
2010; Thirupathi & Kim, 2010; Neupane et al., 2011), (4) arylation of diarylmethyl
diketone (Ahmad, Riahi, & Langer, 2009; Aoyama et al., 2014), (5) one-pot three-
component Friedel-Crafts-type reaction of arene, aldehyde and tertiary amines or o-
methoxyaniline (Liu, He, & Wang, 2011; Zhang et al., 2014; Ganesan & Ganesan,
2014) and (6) cross-coupling reaction (Lin & Lu, 2007; Zhang, Bellomo, Creamer,
Dreher, & Walsh, 2012; Harris, Hanna, Greene, Moore, & Jarvo, 2013; Hirano, Satoh,
& Miura, 2014). However, some of the reported methods suffer from disadvantages
such as the use of expensive and corrosive reagents, multistep process, and low yields
of products. As a results, there still exists a need for development of new approaches
to the synthesis of unsymmetrical triarylmethanes in more simple, efficient, catalytic
and environmental unfriendliness way.
Ar1 Ar2
Ar3
Ar1 Ar2
OR1
Ar3-H Ar1 Ar2
OAc
Ar3-H
Ar1 Ar2
NR2Ar3-HUnsymmetricalTriarymethanes
Ar1 Ar2
R3
O
R3
O
Ar1-CHO
Ar3-H
Ar2-H
Ar1 Ar2
[M] Ar3
Diarylmethyl diketones
One-pot three-componentFriedel-Crafts reaction
Diarylmethyl amines
Diarylmethyl acetates
Diaryl methanols
Cross-coupling reaction
1)
2)
3)
4) Ar3-H
5)
6)
X
or Ar3-H
X = H, Br Cl, OTf
Ar2 = N,N-dimethylaniline
Figure 1-3 Main current synthetic approaches of unsymmetrical triarylmethanes.
Iron salts as effective, alternative, and promising transition-metal catalysts
have received much more attention because of their less expensive, readily available,
5
and environmentally benign properties. These iron salts were found to have promising
catalytic abilities in many organic transformations including iron-catalyzed oxidation,
hydrogenation, hydrosilylation rearrangement, Michael addition, C-C bond and
C-heteroatom bond forming reactions and tandem reactions (Liu, He, & Wang, 2011).
Iron(III) chloride hexahydrate (ferric chloride hexahydrate, FeCl3·6H2O) is one type
of the iron salts were found to have promising catalytic abilities in Friedel-Crafts
reactions (Thirupathi & Kim, 2010).
In this research, we have interested to study a simple, mild and efficient
method for the synthesis of α-branched amines via FeCl3·6H2O catalyzed aza-Friedel-
Crafts reaction of electron-rich arenes and a combination of aldehyde and carbamate,
which diverse unsymmetrical triarylmethanes through sequential reactions with the
different arenes as shown in Figure 1-4.
Ar1 Ar2/R2
HN O
O
H2N O
O
Ar2/R2CHO
FeCl3 6H2O
solvent, 0-rt
Ar1 H
Het H
or
Ar2 = aryl or heteroaryl
R2 = alkyl
Ar1
Ar3
Ar2
solvent, rt
Ar3 H
-Branched amines UnsymmetricalTriarylmethanes
FeCl3 6H2O
Figure 1-4 FeCl3·6H2O-catalyzed formation of α-branched amines and
unsymmetrical triarylmethanes.
Objectives
1. To study the synthesis of corresponding α-branched amines via a novel
aza-Friedel-Crafts reactions of electron-rich arenes with combination of aldehyde and
tert-butylcarbamate in the presence of FeCl3·6H2O as catalyst.
2. To study the synthesis of corresponding unsymmetrical triarylmethanes
via a novel Friedel-Crafts alkylation of different arenes with α-branched amines as
alkylating agent in the presence of FeCl3·6H2O as catalyst.
6
Contribution to Knowledge
1. This new exploratory study will provided a simple, mild and efficient
method for the synthesis of the corresponding α-branched amines and unsymmetrical
triarylmethanes via aza-Friedel-Crafts and Friedel-Crafts reaction of electron-rich
arenes using FeCl3·6H2O which is an inexpensive, nontoxic and environmental
friendly catalyst.
2. The application of these new methodologies to the synthesis of
α-branched amine and unsymmetrical triarylmethane derivatives are ubiquitous
in medicals, materials and dyes.
Scope of the study
1. Optimizing the reaction conditions of 1,3,5-trimethoxybenzene,
benzaldehyde and tert-butyl carbamate for the synthesis of the corresponding
α-branched amines in term of chemical yield by varying the catalyst loading of
FeCl3·6H2O, quantity of solvents, and type of solvents.
2. Synthesis of α-branched amines by using a variety of electron-rich arenes
or heteroarenes, and tert-butyl carbamate with a series of aldehydes including
aromatic and aliphatic aldehydes under optimized reaction condition.
3. Synthesis of unsymmetrical triarylmethanes via Friedel-Crafts reaction
using α-branced amines as an alkylating agent under optimized reaction condition.
4. Elucidating the structures of the resulting α-branched amines and
unsymmetrical triarylmethanes by using spectroscopic techniques.
CHAPTER 2
LITERATURE REVIEWS
α-Branched amines
Synthetic and biological interests in highly functionalized N-protected
α-branched amine derivatives have contributed to the wealth of experimental
methodology developed by numerous strategies. Among these methods, the Friedel-
Crafts reaction of imine derivatives known as aza-Friedel-Crafts reaction (AFCR) is
one of the most widely utilized chemical transformations for the construction of
the functionalized N-protected α-branched amine derivatives. Only recently, several
groups have reported a one-pot three-component aza-Friedel-Crafts reaction without
preparation of imine substrates. The selected examples for the synthesis of
N-protected α-branched amine derivatives using aza-Friedel-Crafts reaction are shown
below.
Selected examples of α-branched amines formations by aza-Friedel-Crafts
alkylation of electron-rich arenes with imine derivatives
Aza-Friedel-Crafts reaction (AFCR) is one of the most powerful tools in
organic synthesis for a synthetically outstanding C-C bond-forming process leading to
functionalized amine derivatives.
Wang, Song, Hong, Li, and Deng (2006) developed the first highly
enantioselective Friedel-Crafts reaction of indoles II-1 with imines II-2 using chiral
organic catalysts II-3 or II-4. With unprecedented scope for both indoles and imines
as well as utilizing practical chiral catalysts, this reaction provided a direct and
broadly useful catalytic enantioselective approach toward 3-indolyl alkylamines,
which should facilitate the asymmetric synthesis of biologically interesting indole
compounds (Figure 2-1). Its unique applicability to alkyl imines, in particular, should
open new possibilities in the total synthesis of indole alkaloids and their analogues.
8
+
N
H R2
P
10 mol% II-3 or II-4
EtOAc, 50 oC
8-72 h
P = SO2Ph, Ts
N
II-5 (53-98 % yield, 86-96 %ee)
H
R1
N
MeO
N
H
HN
S
HN
CF3
CF3
II-3
HNR2*
P
II-1 II-2
N
MeO
N
H
HN
S
HN
CF3
CF3
II-4
R2 = H, 4-ClC6H4, 3-MeOC6H4, 2-BrC6H4,
4-F3CC6H4, 4-MeC6H4, furyl, cyclohexyl,
(CH3)2CH, (CH3)2CHCH2, CH3(CH2)2CH2,
BnOCH2
NH
R1
R1 = H, 6-Cl, 6-Br,
6-OMe, 5-Me,
4-OMe
Figure 2-1 The enantioselective Friedel-Crafts reaction of indoles with imines II-2
using chiral organic catalysts.
Later on, Wang, Sun, and Wu (2008) used Iron(III) chloride as catalyst in
the Friedel-Crafts reaction of electron-rich arenes with imines or aziridines. It was
found that reactions of imines were highly substrate dependent, which generated
mono- or double-addition products. The FeCl3-catalyzed Friedel-Crafts reactions of
electron-rich arenes with imines was examined using 1,3,5-trimethoxybenzene and
imines II-7 to give the desired products II-8 in moderate to good yields (Figure 2-2).
Whereas, when 1,2-dimethoxybenzene reacted with imines II-7 under the same
conditions, triarylmethanes II-10 was obtained via a double Friedel-Crafts reaction in
low yields (Figure 2-3). Furthermore, the reactions of arenes with aziridines were also
studied and the reactions proceed smoothly to afford β-branched amines II-13 with
excellent regioselectivity (Figure 2-4). The advantages of this method include high
efficiency and excellent regioselectivity (less than 2 min), experimentally operational
ease, and mild conditions.
9
R1
NTs
H+FeCl3 (5 mol%)
CH3NO2rt, 12 h
OMe
MeO OMe
NHTs
R1
II-8 (52-72 %)
(R1 = H, 4-F)
OMe
OMeMeO
II-6 II-7
Figure 2-2 The reaction of 1,3,5-trimethoxybenzene with imines II-7 under the
Iron(III) chloride catalyst.
R1
NTs
H+FeCl3 (5 mol%)
CH3NO2rt, 12 h
OMeR1
II-10 (20-21 %)
(R1 = H, 4-F)
MeO
OMeMeO
OMe
OMe
II-9 II-7
Figure 2-3 The reaction of 1,2-dimethoxybenzene with imines II-10 under the
Iron(III) chloride catalyst.
R1R2+
FeCl3 (5 mol%)
CH3NO2
rt, < 2 min
R2
II-13(0-90%)
NHTsN
Ts
R1
II-11 II-12
R2 = H, 4-Cl, 4-Me, 4-FR1 = 1,3,5-trimethoxybenzene,
1,2-dimethoxybenzene,
1,4-dimethoxybenzene,
anisole
1,2-dimethylbenzene,
chlorobenzene,
trifluoromethylbenzene
N,N-dimethylaniline,
furan,
benzo[d][1,3]dioxole
Figure 2-4 The reactions of arenes with aziridines under the Iron(III) chloride
catalyst.
10
Very recently, Chatterjee, Maity, Mohapatra, and Roy (2013) reported
a heterobimetallic catalyst aza-Friedel-Crafts reaction of N-sulfonyl adimines and
highly electron-rich arenes as well as heteroarenes (1,3,5-trimethoxybenzene and
indole derivatives, respectively) (Figure 2-5). This methodology afforded α-branced
amines in good yields and structurally diverse symmetrical and unsymmetrical
triarylmethanes via cleavage of sp3 carbon-nitrogen bond in good to high yields
(Figure 2-6).
NTs
Ar2-H/Het2-HAr1
Ar2 = 1,3,5-trimethoxybenzene,
indole
+
1 mol% IrIII-SnCl3 cat.
ClCH2CH2Cl,
0-rt oC
Ar2/Het2
HN Ar2/Het2
Ar2/Het2
+
II-14 II-15 II-16 (77-88%) II-17 (0-10%)
Ar1 = C6H5
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-OMeC6H4
3-MeC6H4
4-MeC6H4
Ts
Ar1
Figure 2-5 Ir(III)-SnCl3 catalyzed aza-Friedel-Crafts reaction.
Ar2/Het2 = 1,3,5-trimethoxybenzene,
indole
1 mol% IrIII-SnCl3 cat.
ClCH2CH2Cl,
rt-80 oC
Ar2/Het2
HN
Ar1 = C6H5,
4-ClC6H4,
4-BrC6H4,
4-MeC6H4
+ Ar-H3/Het-H3
Ar3/Het3 = anisole,
indole,
2-methylfuran,
2,5-dimethylfuran,
2-methylthiophene
Ar2/Het2
Ar3/Het3
Ar1
II-16 II-15 II-18 (70-89%)
Ts
Ar1
Figure 2-6 The synthesis of triarylmethanes by Ir(III)-SnCl3 catalyst.
11
Selected examples of α-branched amines formations by one-pot theree component
aza-Friedel-Crafts alkylation of electron-rich arenes, aldehydes and amines or
carbamate
In recent years, multi-component aza-Friedel-Crafts reactions have gained
much importance in organic synthesis to furnish the desired products in a single
operation without isolating the imine intermediates. Thus, the reaction times are
reduced and both the energy and raw materials are also saved. On the best of our
knowledge, only few examples of this strategy were reported.
In 1999, Bensel, Pevere, Desmurs, Wagner, and Mioskowski synthesized
a wide range of alkoxycarbonyl protected benzylic amines using a three-component
reaction involving carbamates, aromatic aldehydes and aromatic substrates (Figure
2-7). This reaction proceeds through electrophilic substitution of the aromatic
compound by a N-carbamoyl iminium which is generated in situ by condensation of
the carbamate with the aromatic aldehyde. Unfortunately, using aliphatic aldehydes
in this case was unsuccessful.
R3 = Et,
iPr,
CH2CCI3,
Bn
R1+
H2SO4, AcOH
rt, 12 h
HN
R2
R1
O
R2 H
O
H2N OR3
O
OR3
II-19 II-21II-20 II-22 (0-85%)
R1 = 2,5-dimethylanisole,
benzodioxole,
ter t-butylbenzene,
bromobenzene,
1,2-dichlorobenzene
R2 = benzaldehyde,
4-trifluoromethylbenzaldehyde
2,5-dichlorobenzaldehyde
+
Figure 2-7 The three-component reaction of aromatic compounds, carbamates and
aldehydes using H2SO4 as catalyst.
Later, Shirakawa, and Kobayashi (2006) developed a novel protocol for
three-component aza-Friedel-Crafts reactions of aldehydes, primary amines, and
indoles in water catalyzed by carboxylic acids. The aza-Friedel-Crafts reactions
(AFCR) have been known to be difficult to control, but the present reaction system
12
enabled the desired products to be obtained in high yields. It is noted that the reaction
proceeded under nonmetallic conditions in water and that various 3-substituted
indoles including biologically active compounds were prepared by utilizing
the reactive C-N bond. This simple system offers a novel efficient method for
the synthesis of various 3-substituted indoles (Figure 2-8).
NH2
OMeH
O
N+ +
C9H19COOH
(5 mol%)
H2O, rt, 24 h
HN
N
MeO
II-26 (91%)II-25II-23 II-24
Figure 2-8 The three-component aza-Friedel-Craft reaction of 2-naphthaldehyde, o-
anisidine and 1-methylindole using C9H19COOH in water.
After the AFCR, the crude products were treated with 1,1'-carbonyldi-
imidazole (CDI) in the presence of Sc(OTf)3 as a catalyst. The reactions of various
3-substituted indole derivatives, aldehydes bearing aromatic, heteroaromatic, and
alkyl groups gave the corresponding products II-32 in moderate to high yields in two
steps (Figure 2-9).
Further examples of the synthetic utility of the present method are
demonstrated by the transformation of the AFCR products. As a result of the high
reactivity of the C-N bond, AFCR product was readily converted to various
nucleophiles in the presence of C9H19COOH as a catalyst. Substitution using thiol,
allyltin, and silyl enol ether nucleophiles also proceeded smoothly and gave
the valuable compounds in good yields (Figure 2-10).
13
R1
+
C9H19COOH(10 mol%)
N
R4
R3
R2
HN
NR3
R2
R4
O
N NNN
Sc(OTf)3(10 mol%)
toluene, 70 oC, 3 h
R1
N
NR3
R2
R4N
II-32 (53-90%, 2 steps)
nonsteroidal aromatase inhibitor againstbreast cancer
II-27 II-29II-28 II-30
II-31 (CDI)
+H2O, rt, 24 h
R1 = 2-naphthyl,
Ph,
4-MeO-C6H4,
4-Cl-C6H4,
4-F-C6H4,
3-thienyl,
(CH3)2CHCH2,
c-C6H11
R1-CHO
R2 = Me, R3, R4 = H,
R2, R3, R4 = H,
R2, R3 = Me, R4 = H,
R2 = Me, R3 = H, R4 = OMe,
R2 = Et, R3 = H, R4 = Br
NH2
OMe
MeO
Figure 2-9 The synthesis of triarylmethanes II-32.
+
C9H19COOH(10 mol%)
N
Me
HN
N
Me
N
N
N
S
N
Me
N
Me
O
II-23
II-24
II-25 II-26
+
II-34
II-36
OMe
NH2
H
O
H2O, rt, 24 h
MeO
Me
II-38
CDI
Sc(OTf)3, toluene
70 oC, 3 h
II-33
SH
Sc(OTf)3, toluene
70 oC, 24 h
II-35
Sc(OTf)3, toluene
70 oC, 24 h
Me3SiO(Ph)C CH2 II-37
Figure 2-10 Transformations of aza-Friedel-Crafts Products.
14
In 2012, Jaratjaroonphong, Krajangsri, and Reutrakul demonstrated
an efficient iodine-catalyzed one-pot three-component aza-Friedel-Crafts reaction of
arenes/heteroarenes, benzyl/tert-butyl carbamate and a wide variety of aldehydes in
toluene under ‘open-flask’ and mild conditions. Typically, the reaction proceed
smoothly to provide, selectively the corresponding N-Cbz or N-Boc protected
α-branched amines in good to excellent yields (Figure 2-11). It should be noted that
small amount of triarylmethane derivatines were obtained in some cases.
Ar-H
NH2CO2R
H R1
O I2 (5 mol%)
toluene, rt Ar R1
NHCO2R
R = benzyl, tert -butyl
+Ar Ar
R1
+
Ar = 1,2,4-trimethoxybenzene2-naphthol2-methylfuran2-ethylfuran2-methylthiophene
II-39 II-40
II-41
II-42 II-43
(major products) (minor products)
R1 = C6H5, 4-ClC6H4, (CH3)2CH
Figure 2-11 I2-catalyzed three-component aza-Friedel-Crafts reaction.
Late on, Halli and Manolikakes (2013) reported an eco-friendly and efficient
catalyst of Fe(III) chloride hexahydrate for catalyzed three-component aza-Friedel-
Crafts reaction of amides, glyoxalates and arenes or heteroarenes in nitromethane
under thermal conditions to give the corresponding arylglycines in moderate to high
yields (Figure 2-12).
R2 NH2
O
H CO2R1
O
Ar/Het-H
FeCl3.6H2O (2-5mol%)
or Fe(ClO4)3.xH2O (2-5 mol%)
MeNO2, 80-100 oC, 24 h Het/Ar CO2R1
HN R2
O
II-44 II-45 II-46 II-47 (32-94 %)
Ar = 1,2-dimethylbenzene, 1,3-dimrthylbenzene,1,4-dimethylbenzene, 1,3,5-trimethylbenzene,anisole, 2-Cl-anisole, 2-Br-anisole,2-I-anisole, 2-Me-anisole, 2-PivHN-anisole,4-PivHN-anisole, pyrene, anthracene
Het = 2-Br-thiophene, 2-Cl-thiophene, 2-Me-thiophene,benzofuran, 1-tosylindole, 1-tosylpyrrole
R1 = H, Et, iPr
R2 = Me, tBu, Ph, OEt, OBn, Fmoc,
4-MeO-C6H4, 4-Br-C6H4,
4-O2N-C6H4, CH2CHCH2O,
1-(2-nitrophenyl)ethyl carbamate,
Figure 2-12 Fe(III)-catalyzed three-component aza-Friedel-Crafts reaction.
15
In the same year, Schneider and Manolikakes (2013) found that treatment of
a combination of amides, formaldehyde and arenes or heteroarenes with Bi(OTf)3
gave their respective amidomethylarenes and heteroarenes in moderate to high yields
(Figure 2-13).
R NH2
O
H H
O
Ar/Het-H
Bi(OTf)3 (5 mol%)
MeNO2, rt-100 oC, 18 h Het/Ar H
HN R
O
II-48 II-49 II-50 II-51 (45-96 %)
Ar = 1,3-dimethylbenzene, 1,3,5-trimethylbenzene,anisole, 2-Cl-anisole, 2-Br-anisole,2-I-anisole, N -o-tolylpivalamide, 4-Br-phenol,ethyl 4-methoxybenzoate
Het = 2-Br-thiophene, 2-Cl-thiophene, 2-Me-thiophene,benzofuran, 1-tosylindole
R = Me, tBu, Ph, OBz, OEt, Cl-CH2, NCCH2, CH2CH,4-MeO-C6H4, 4-MeO-C6H4, oxazolidin-2-one,
2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanamide
Figure 2-13 Bi(OTf)3-catalyzed three-component aza-Friedel-Crafts reaction.
Recently, Jaratjaroonphong, Tuengpanya, and Ruengsangtongkul reported
a catalyst behavior of Bi(OTf)3 for catalyzed one-pot three-component aza-Friedel-
Crafts reaction of arenes/heteroarenes, benzyl/tert-butyl carbamates and a wide
variety of aldehydes to provide N-Cbz or N-Boc protected α-branched amines in good
to excellent yields (Figure 2-14). Furthermore, these conditions can also be
transformed N-Cbz or N-Boc protected α-branched amines into the unsymmetrical
triarylmethanes with good to high yields (Figure 2-15).
Ar-H
NH2CO2R2
H R1
OBi(OTf)3 (5 mol%)
toluene, rt Ar R1
NHCO2R
R2 = benzyl, ter t-butyl
+Ar Ar
R1
+
Ar = 1,3,5-trimethoxybenzene1,2,4-trimethoxybenzene2-methylfuran, 2-ethylfuran2-methylthiophene, 2-ethylthiophene2-ethylpyrrole, indole
II-52 II-53
II-41
II-54 II-55
(major) (minor)
R1 = C6H5, 2-FC6H4, 4-FC6H4,
4-ClC6H4, 4-BrC6H4, 4-O2NC6H4,
4-MeOC6H4, CH3CH2, CH3(CH2)2CH2,
PhCH2CH2, (CH3)2CHCH2, (CH3)2CH,
cyclopropyl, cyclopentyl, cyclohexyl
Figure 2-14 The synthesis of α-branched amines using Bi(OTf)3 as catalyst.
16
R = benzyl, ter t-butyl
NHCO2R
II-54
Bi(OTf)3 (10 mol%)
toluene, rtO
OMe
MeO
OMe
II-57
OMe
MeO
OMe
II-56
O
Figure 2-15 Transformations of aza-Friedel-Crafts Products.
Selected examples of amidoalkyl naphthol formations by one-pot, theree component
aza-Friedel-Crafts alkylation of β-naphthol, aldehydes and carbamates or urea
Patil, Singh, Surpur, and Samant (2007) reported a method for the synthesis
of 1-amidoalkyl-2-naphthols by a one-pot three-component condensation of
2-naphthol, ureas/amides and aldehydes in the presence of sulfamic acid as a catalyst
under ultrasonic irradiation and ambient conditions giving 1-amidoalkyl-2-naphthols
in excellent yields and in short reaction time (Figure 2-16).
R1 = C6H5, 4-CH3C6H4, 2-CH3C6H4,
3-O2NC6H4, 2-ClC6H4, 4-ClC6H4,
4-FC6H4, 2-BrC6H4, 3-BrC6H4,
4-BrC6H4, Furyl
OH
+ + R2CONH2
H3N+SO3-
)))) 28-30 oC
neat or ClCH2CH2Cl
10-120 min.
OH
NHCOR2R1
II-58 II-59 II-60 II-61 (55-94%)
R2 = CH3, CH3NH, Ph, NH2
R1CHO
Figure 2-16 The synthesis of aminoalkyl naphthols using sulfamic acid as catalyst.
Later on, Das, Laxminarayana, Ravikanth, and Rao (2007) developed a very
simple and efficient method for the high-yielding synthesis of amidoalkyl naphthols
by one-pot three-component coupling reaction of 2-naphthol, aromatic aldehydes and
urea or amides. In the presence of iodine as a catalyst in dichloethane at room
temperature or under solvent-free conditions at higher temperature, the reaction
17
proceed smoothly to afford common the corresponding amidoalkyl naphthols in high
yields (Figure 2-17).
+ R1CHO + R2CONH2
I2 (5 mol%)
ClCH2CH2Cl, rt
or
neat, 125 oC
OH
Ar NHCOR
II-62 II-63 II-64 (20-93 %)II-58
R2 = NH2, CH3, Ph, CH2=CH
OH
R1 = C6H5, 4-CH3C6H4,
3-O2NC6H4, 2,4-Cl2C6H3,
4-ClC6H4, 2-BrC6H4,
naphthal, CH3CH2
Figure 2-17 The synthesis of aminoalkyl naphthols using I2 as catalyst.
Shaterian, Hosseinian, and Ghashang (2008) reported a highly efficient
synthesis of 1-carbamatoalkyl-2-naphthol derivatives via a new one-pot three-
component condensation reaction between aryl aldehydes, 2-naphthol and
methyl/benzyl carbamates in the presence of silica supported sodium hydrogen sulfate
(SiO2-NaHSO4) as an effective heterogeneous catalyst under thermal and solvent-free
conditions. The reactions were successful to provide the desired products in moderate
to high yields (Figure 2-18). Moreover, the products can be deprotected and used to
prepare potentially biologically active 1-aminomethyl-2-naphthol derivatives.
R1 = C6H5, 4-O2NC6H4,
4-FC6H3, 2-ClC6H3,
4-ClC6H4, 2,4-Cl2C6H3,
3-ClC6H4, 3-O2NC6H4,
2,5-(OMe)2C6H3, 3-OMeC6H3,
C5H4N, CH3CH2
CH3(CH2)4CH2
+
OH
+ R2O NH2
O
R2 = Me, CH2Ph
SiO2-NaHSO4
Solvent-free
100 oCII-65II-58 II-66 II-67 (0-95 %)
R1CHO
OH
R1 NHCOOR2
Figure 2-18 The synthesis of aminoalkyl naphthols using SiO2-NaHSO4 as catalyst.
18
Hajipour, Ghayeb, Sheikhan, and Ruoho (2009) developed a facile,
convenient and solvent-free method for the one-pot synthesis of amidoalkyl naphthols
derivatives. Condensation of aldehydes with amides or urea and 2-naphthol in
the presence of a catalytic amount of Brønsted acidic ionic liquid ([TEBSA][HSO4])
under thermal solvent-free conditions to afford the products in good yields.
Gratifyingly, high yields, short reaction time, easy work-up and reusability of
the catalyst are advantages of this procedure (Figure 2-19).
R1 = C6H5, 2-ClC6H4, 4-ClC6H4, 2,6-Cl2C6H3,
4-BrC6H4, 3-O2NC6H4, 4-O2NC6H4,
4-MeC6H4, 3-MeOC6H4, 2,5-(MeO)2C6H3
4-NCC6H4, 4-CH3OCOC6H4
OH
R2 = CH3, C6H5, NH2
+ + R2CONH2
OH
R1 NHCOR2
5 mol% IL
120 oC, solvent-free, 10 min
IL = (CH3CH2)3NCH2(CH2)2CH2SO3H HSO4
II-68 II-69 II-70 (73-91%)II-58
R1CHO
Figure 2-19 The synthesis of aminoalkyl naphthols using Brønsted acidic ionic liquid
([TEBSA][HSO4]) as catalyst.
Later, Lei, Ma, and Hu (2009) reported a facile, efficient, and practical
method for the preparation of amidoalkyl naphthol derivatives. The reaction was
carried out by treatment of β-naphthol with aromatic aldehyde and different amide
including benzamide, acetamide, acrylamide, and N-substituted amides in
the presence of VB1 in ethanol at 80 oC to give the aminoalkyl naphthol derivatives in
good yields (Figure 2-20).
19
N
N
NS
H3C
OH
H3C
NH3Cl Cl
OH
+ R1-CHO + R2CONH2
10 mol% VB1
80 oC, EtOH
OH
R1 NHCOR2
II-58 II-71 II-72 II-73 (0-93%)
R2 = Ph, CH3, NH2, CH2=CH2
VB1
R1 = C6H5, 4-MeC6H4,
3-O2NC6H4, 4-MeOC6H4,
CH3CH2, CH3CH2CH2
PhCH=CH
Figure 2-20 The synthesis of aminoalkyl naphthols using VB1 as catalyst.
In the same year, Nandi, Samai, Kumar, and Singh (2009) studied
multicomponent, one-pot reaction of 2-naphthol with aromatic aldehydes and amides
using P2O5 as catalyst at 60 oC. The results provided the corresponding amidoalkyl
naphthol derivatives in excellent yields (Figure 2-21). The present approach offers
several advantages such as reduced reaction times, moderate temperature, higher
yields, eco-friendly reaction condition, easy purification and economic availability of
the catalyst.
R1 = C6H5, 4-NO2C6H4, 3-NO2C6H4, 2- NO2C6H4,
4-ClC6H4, 2-ClC6H4, 4-OMeC6H4, 2-OMeC6H4,
4-MeC6H4, 2,4-Cl2C6H3, 4-NMe2C6H4
OH
+
CHO
+ H2N R2
O P2O5 (10 mol%)
solvent-free
60 oC
NH
O
R2
OH
II-58 II-74 II-75 II-76 (80-97%)
R2 = CH3, Ph, CH3Cl
R1
R1
Figure 2-21 The synthesis of aminoalkyl naphthols using P2O5 as catalyst.
In recently, Mulla, Salama, Pathan, Inamdar, and Chavan (2013) found that
ionic liquids, ethylammonium nitrate (EAN) can catalyzed one-pot three-component
20
reaction of various aldehydes, amides/carbamates/urea, and naphthols/phenols under
the absence of solvent to give 1-amido and 1-carbamatoalkyl naphthols/phenols
in high yields (Figure 2-22).
R1 = 2-naphthol, 2,5-Me-phenol
OH
+ + H2N R3
OEAN
solvent-free, rt, 1 hNH
O
R3
OH
II-77 II-78 II-79 II-80 (85-96%)
R2-CHO
R1
R2
R1
R2 = C6H5, 4-ClC6H4, 4-MeOC6H4,
4-MeC6H4, 2-furyl, 2-thienyl,
3-formyl chromone
R3 = CH3, C6H5, C6H5CH2,
CH3CH2O, C6H5CH2O, NH2
Figure 2-22 The synthesis of aminoalkyl naphthols/phenols using EAN as catalyst.
Selected examples of α-branched amines formations with other reaction
Dastbaravardeh, Schnürch, and Mihovilovic (2013) developed
a regioselective direct arylation of benzylic amines with aryl bromides and aryl
chlorides in the presence of [RuCl2(p-cymene)]2 in a o-xylene. The uses of K2CO3
as a base, PPh3 and cyclohexanol as an additives play a key role in the reaction
to afford the corresponding α-branched amine derivatives in moderate to high yields
(Figure 2-23). The proposed mechanism for the ruthenium(II) catalyzed reaction
are also illustrated as shown in Figure 2-24.
N
R
NH
Ph
Ar X
[RuCl2(p-cymene)]2
PPh3, cyclohexanol
K2CO3, o-xylene
160 oC, 30 h
N
R
NH
PhAr
R = Me, C6H5
X = Br, I
II-81 II-82 II-84 (39-79 %)
II-83
Ar = C6H5, 2-Me-C6H4, 3-Me-C6H4,3-MeO-C6H4, 3-Cl-C6H4, 4-Me-C6H4,4-tBu-C6H4, 4-nBu-C6H4, 4-MeO-C6H4,4-Me2NC6H4, 4-F-C6H4, 4-Cl-C6H4,4-EtO2C-C6H4, 4-MeOC-C6H4, 4-O2N-C6H4,4-NC-C6H4, 1-naphthyl, 2-thienyl, 3-pyridyl
Figure 2-23 [RuCl2(p-cymene)]2 catalyzed arylation of benzylic amines with
aryl bromides and aryl iodides.
21
Ru
Cl
ClCl
Ru
Cl
iPr
Me
Me
iPr
+II
+II
2 KOPiv
2 KCl
1/2
Me iPr
Ru
PivO
O
OtBu
Me iPr
RuPivO
OPiv
N
N
R
NH
H Ph
NH
H
Ph
R
Me iPr
RuO OPiv
N
NH
H
R
Ph
O
tBu
Me iPr
Ru OPiv
N
NH
R
Ph
Ar
Me iPr
Ru OPiv
N
NH
R
Ph
tBu
OH
O
K2CO3KHCO3
KOPivKX
N
R
NH
Ar Ph
Ar X
KOPiv
oxidativeaddition
reductiveelimination
CMDconcer ted metalation deprotonat ion
II-81
II-84
II-82
II-83
II-85
II-86
II-87
II-88
II-89
+II
+II
+II
+II
+IV
Figure 2-24 The possible mechanism for the ruthenium(II) catalyzed arylation of
benzylic amines with aryl halides.
22
Unsymmetrical triarylmethanes
The synthesis of unsymmetrical triarylmethane has attracted much attention
from the synthetic community because of their versatile applications such biological
activity, photochromic agents, dyes, protective groups, building blocks for dendrimers
and applications in material science. Despite, this broad range of applications, only
a few methodology of this compound have been reported. Moreover, the most of
development of synthetic methods for the preparation of unsymmetrical
triarylmethanes are limited to the preparation of starting material in two steps
leading to the corresponding unsymmetrical triarylmethanes.
Selected examples of unsymmetrical triarylmethane formations by Friedel-Crafts-
type arylations of diarylmethanols
Katritzky and Toader (1997) developed a regiospecific Friedel-Crafts
alkylation method for the synthesis of unsymmetrical triarylmethane derivatives,
(p-nitroaryl)diarylmethane. Condensation of benzotiazole with diaylmethanols
in the presence of p-toluenesulfonic acid gave the corresponding (diarylmethyl)-
benzotiazole II-91 as an alkylating agent. Then, the carefully temperature controlled
for Friedel-Crafts reaction of alkylated product with 2- or 3-methoxy nitrobenzenes
II-92 in the presence of potassium tert-butoxide in dry THF at -20 oC provided
expected products in low to excellent yields (Figure 2-25).
OH
R1 R2
Bt
R1 R2
BtH
p-TsOH, reflux,PFCLs, 24 h
R1 R2
t -BuOK
dry THF, -20 oC, 4 h
NO2
OMeNO2
OMe
R1 = H, 4-Me, 4-MeO, 4-(N,N-dimethylamino)
R2 = H, 2-Me, 4-Cl, 2-MeO, 4-MeO, 3,4,5-MeO,
4-biphenyl, 4-n-hexyloxy, 5-methylthien-2-yl
II-90 II-91 II-93
II-92
Figure 2-25 The Synthesis of (p-Nitroaryl)diarylmethanes
23
In 2005, Das, Panda, and Panda used the addition of aromatic aldehydes
with Grignard reagent for preparation of heteroarylcarbinol such as thienyl, pyridyl
and (5-methyl)-furyl cabinols II-96 which were used as electrophilic partner of
Frieldel-Crafts alkylation. The carbinol II-96 were treated with various nucleophiles
in the presence of Brønsted acid or Lewis acid under heat condition to give
unsymmetrical triarylmethanes in low to high yields (Figure 2-26).
Het
OHHet
X
II-94
II-96 (65-68 %)
II-99 (5-76 %)
Het CHO
II-95
OMe
Het = 2-Thienyl, 3-pyridyl, (5-mrthyl)-2-furyl
THF
rt, 1-2 h
X Y
or R1
II-97 II-98 OMe
Het
II-100 (60-80 %)
OMe
Y
R1
or
conc. H2SO4 or anh. AlCl3
benzene, 60-70 oC,
0.5-2 h
X = OH, OCH3, NHC2H5, N(CH3)2, NH2, Y = SH
R = H, 2-CH3, 3-CH3
MgBrMeO
Figure 2-26 The Synthesis of unsymmetrical triarylmethane derivatives using
Brønsted acid or Lewis acid as catalyst.
In the same year, Zeng, Ji, and Wang (2005) reported an efficient synthesis
of unsymmetrical bis(indolyl)alkanes II-103 at ambient temperature using
inexpensive ceric ammonium nitrate (CAN) catalyzed Friedel-Crafts alkylation of
(indolyl)alkyl methanols II-101 with various substituted indole derivatives under
ultrasonic irradiation in Figure 2-27.
24
R2
OH
N
R1
NH
R3CAN
))), EtOH, rt2-5 h
R2
N
R1
NHR3
II-101 II-102 II-103 (75-96 %)
R1 = H, Ts
R2 = Ph, n-nonanyl, n-octanyl, n-hexanyl, n-butanyl,
R3 = H, CH3, BnO, Ts
Figure 2-27 The Synthesis of unsymmetrical bis(indolyl)alkanes.
Jana, Maiti, and Biswas (2007) developed a practical reaction system
involving mild, environmentally benign and atom economic of C-C bond formation,
which was using inexpensive FeCl3 activated varieties of carbinols such as allylic,
benzylic and propargylic alcohols and follow by nucleophilic addition of electron rich
indole and pyrrole in nitromethane as solvent, the reaction proceeded efficiently
to afford the unsymmetrical triarylmethanes in moderate to excellent yields (Figure
2-28).
Het-H
Ar1
OH
Ar2/ R Ar1
Het
Ar2/ RFeCl3 (10 mol%),
CH3NO2, rt-55 oC, 1-4 hII-104 II-106 (56-98 %)
II-105
Ar1 = allylic phenyl,
4-MeO-allylic phenyl,
4-Cl-allylic phenyl
phenyl,
4-MeO-phenyl,
2-thienyl
propargyl
Ar2 = phenyl, R = methyl
Het = indole,1-methylindole1-tosylindole,2-methylindole,pyrrole
Figure 2-28 The Synthesis of unsymmetrical triarylmethane derivatives using FeCl3
as catalyst.
Des et al. (2007) reported a simple and practical method for the synthesis of
unsymmetrical triarylmethanes for enhanced anti-tubercular activity via reduction of
commercially available benzophenone derivatives leading to benzohydrol derivatives.
Next, the carbinols were used as alkylating agents in the Friedel-Crafts alkylation of
25
1- and 2-naphthols. The reaction was performed by refluxing a mixture of 1- or 2-
naphthols and carbinols in dry benzene to provide unsymmetrical triarylmethane
II-109 and II-110, respectively in moderate to high yields as shown in Figure 2-29.
II-109 (84-89 %)
O
XNaBH4, methanol
0 oC-rt, 2 h
OH
X
X
X
HO
OH
1-naphthol
ref lux, 2 h
2-naphthol
X = H, Cl, F
II-110 (68-73 %)
II-107 II-108
dry benzene
ref lux, 2 h
dry benzene
Figure 2-29 Reaction of carbinol with 1- and 2-naphthols.
One year later, Parai et al. (2008) developed methodology for the synthesis
of unsymmetrical triarymethane via replace one of the aryl rings with thiophene
in the triarylmethane nucleus for enhanced anti-tubercular activity. Nucleophilic
addition of Grignard reagents onto thiophene-2-carbaldehyde and p-chloro-
benzaldehyde in THF furnished the carbinol derivatives. Then Friedel-Crafts
alkylation of carbinols with phenol led to the mixtures of unsymmetrical
triarylmethane II-115 and II-116 in 6-12 % and 58-61 %, respectively (Figure 2-30).
26
R1
X SY
Mg, THF
0 oC, rt, 2 h
R1
OH
S
R1 = m-OCH3, X = Br
= p-OCH3, X = Br
= p-SCH3, X = Br
= p-Cl, X = CHO
Y = CHO= Br
II-111 II-112 II-113
conc. H2SO4 (cat.)
dry benzene,ref lux, 2 h
R1
S
HO
R1
S
OH
II-114
II-115 (6-12 %) II-116 (58-61 %)
OH
Figure 2-30 The synthesis of thiophene containing triarylmethanes.
McCubbin and Krokhin (2010) demonstrated that arylboronic acid
catalyzing Friedel-Crafts reaction of mono-, di-, and triarylmethanols as well as
electron-rich arenes in refluxing dichloroethane or toluene to provide the
corresponding unsymmetrical tri-, tetra- arylmethanes in excellent yields. Excepted
diarylmethane was not observed or shown in low to high yields (Figure 2-31).
Ar1-H Ar2
OH
R2
R1
C6F5B(OH)2 (10 mol%)
ClCH2CH2Cl or toluene,
4 A M.S., ref lux, 16 ho
II-117 II-118
Ar2
Ar1
R2
R1
II-119 (0-99%)
Ar1 = indole, pyrrole, 2-naphthol
2-methylfurane,
1,2-dimethoxybenzene,
1,3,5-trimethoxybenzene,
2-methoxynaphthalene
Ar2 = 4-MeO-C6H4, 4-HO-C6H4,
4-NH2-C6H4, 2-MeO-4-HO-C6H3
3,4-Cl-C6H3, 2-HO-5-Br-C6H3
3-Br-4-MeO-5-HO-C6H2, naphthyl
R1 = H, Me, (CH2)5, R2 = H, Me, (CH2)5,
Figure 2-31 The synthesis of unsymmetrical tri-, and tetraarylmethanes.
In 2013, Hikawa, Suzuki, and Azumaya (2013) reported the direct
substitution reaction of benzhydryl and benzylic alcohols with strong π-nucleophile
indoles using a water soluble gold(III)/TPPMS catalyst system in water at 80 oC.
They found that reaction of benzhydryl alcohol were highly substitutents on the aryl
27
ring dependent, which enhance the stability of the carbocations into the corresponding
triarylmethane as shown in Figure 2-32.
NHO
R4
R2 R3
R1AuCl4Na 2H2O (0.5-2 mol%)
TPPM (0.5-2 mol%)
H2O, 80 oC, 16 hN
R2
R1
R4 R3
H2O
R1 = H, CN, Cl, CO2Me, Me, CO2H
R2 = H, Me
R3 = OMe, Me, Cl, Br, F
R4 = Ph, Me, H
II-120 II-121 II-122 (0-95 %) II-123
Figure 2-32 The synthesis of unsymmetrical triarylmethanes using AuCl4Na∙2H2O
as catalyst.
Later on, Yokoyama et al. (2013) employed a similar reaction condition
to convert diarylmethanol into N-benzylation or C-benzylation by using chemo-
selective behavior of substituted on diarylmethanol and on nucleophiles controlled
the Friedel-Crafts reaction. However, according to the above mentioned method,
the reaction did not occur without water and water-soluble phosphine ligand, TPPMS
(Figure 2-33).
OH
R1 R2
NH
R3
CO2HR4
R1 R2
N
CO2HR4
R1 R2
HNR3
HO2C
C-benzylation N-benzylation
Conditions : AuCl4Na.2H2O (5 mol%),
TPPM (5 mol%), H2O,
80-120 oC, 16-24 h
R1 or R2 = H, OMe, Me, F
R3 = H, Me
R4 = H
R4
R1 or R2 = H, Cl, Me
R3 = H
R4 = H, Br, I, F, CF3, Me
R3
II-124
II-125 II-127 (22-94 %)II-126 (74-86 %)
Figure 2-33 The chemoselective synthesis for Friedel-Crafts reaction of
diarylmethanols and nucleophiles.
28
Recently, Nallagonda, Rehan, and Ghorai (2014) reported the chemo-
selective synthesis of unprotected anilines and mono- as well as di- arylmethanols
in acetonitrile at elevated temperature (60-80 oC) using Re2O7 as catalyst, leading to
excellent chemoselective formation of C-alkylated over N-alkylated products (Figure
2-34). Furthermore, they proposed the mechanism for the current benzylation of
anilines as shown in Figure 2-35.
H/R
OH
Ar/Het
NH2
FG
C-benzylation
NH2
H/R
NH
Ar/Het
FG
II-128
II-129
II-131 (41-88 %)II-130
Re2O7 (5 mol%)
CH3CN, 60-80 oC
4-72 h
R = Me, iPr, allyl, propargyl, Et
Ar = phenyl, 2-methoxybenzene,4-methoxybenzene,3,4-methoxybenzene, naphthyl
Het = thiophene, 2-bromothiophene,N-Boc pyrrole, 2,3-dihydrobenzo[b][1,4]dioxine,9H -xanthene, 9H -thioxanthene, benzofuran,benzo[b]thiophene, indole
FG
R/H
Ar/Het
Figure 2-34 The chemoselective synthesis of unprotected anilines and mono-, di-
arylmethanols using Re2O7 as catalyst.
Ar
OH
R
H/R Ar/HetH/R
NH
Ar/Het
Re2O7
Ar
O
R
ReO3
Ar R ReO4
NH2
FG
NH2FG
HOReO3
II-133 II-134
thermodynamicallycontrolled
kineticallycontrolled
HOReO3
NH
ReO4
FG
FG
II-134
II-129 II-132 II-133
II-128
II-130 II-131
Figure 2-35 The mechanism for the benzylation of anilines.
29
More recently, Barbero et al. (2014) found that strong Brønsted acid,
o-benzenedisulfonimide, can catalyzed diarylmethanols/styrenes and variety of arenes
into their corresponding di- and tri-arylmethanes in absence of solvents (Figure 2-36).
Ar1 R1
OH
II-135
or
R2
II-136
Ar2/Het-Hneat conditions
II-138 (10 mol%)
II-137
II-139
Ar R1
Ar/Het
or
R2
Ar/Het
II-140
O
Ar
R1Ar
R1
R1 = H, Me, C6H5,
4-MeO-C6H5,
4-F-C6H5,
4-(CH3)2N-C6H5
Ar1 = C6H5,
4-MeO-C6H5,
4-F-C6H5,
4-O2N-C6H5
4-(CH3)2N-C6H5
Ar2 = 1,3-dimethoxybenzene,
1,2,4-ttimethoxybenzene,
2-methylfuran, pyrrole,
indole,1-methylindole,
2-methylindole,
7-isopropyl-1,4-dimethylazulene
R2 = 4-MeO-C6H5
S
NHS
O
O
II-141
II-138
Figure 2-36 The synthesis of di-, tri- arylmethanes using o-benzenedisulfonimide as
catalyst.
Selected examples of unsymmetrical triarylmethane formations by Friedel-Crafts-
type arylations of diarylmethyl acetate
Li et al. (2008) demonstrated that FeCl3 in the presence of acetic anhydride
can serve as an effective catalyzed for the reaction of various arenes with aromatic
aldehyde to proceed the corresponding triarylmethanes (Figure 2-37). However, the
reaction required high temperature (80 ºC) and acetic anhydride as an activating agent.
Ar1
ArAr+
FeCl3 (10 mol%)
Ac2O, 80 oC, 22 hAr1-CHO Ar-H
Ar1 = 4-BrC6H4, 3-BrC6H4, 2-BrC6H4, 2-ClC6H4
Ar-H = p-xylene, 4-bromoanisole, 4-chloroanisole, 1,3,5-trimethoxybenzene
II-139 II-140 II-141 (59-90 %)
Figure 2-37 FeCl3 catalyzed symmetrical triarylmethanes formations.
30
Interestingly, when the reaction between benzaldehyde and 1,3,5-trimethyl-
benzene was carried out at room temperature, the mono-aromatic substitution product
was isolated in 92% yield (Figure 2-38).
CHO FeCl3 (10 mol%)
Ac2O (2 equiv)
CH2Cl2, rt, 2h
OAc
II-142 II-143 II-144 (92 %)
Figure 2-38 FeCl3 catalyzed the mono-aromatic substitution product.
Furthermore, the mono-aromatic substitution procedure leading to
diarylmethyl acetate could be applied for a convenient one-pot synthesis of
unsymmetrical triarylmethanes starting from aromatic aldehydes and two type of
arenes (Figure 2-39). However, this sequential one-pot procedure proceeded very well
using bulky arenes (1,3,5-trimethylbenzene and 1,2,4,5-tetramethylbenzene) as first
arene.
Ar2
Ar1Ph+
II-148 (47-89 %)
Ar1-HPh H
O
FeCl3
Ac2OPh Ar1
OAc
Ar2-H
II-142 II-145 II-146
II-147
Ar1 = 1,3,5-trimethylbenzene,
1,2,4,5-tetramethylbenzene
Ar2 = 1,3,5-trimethylbenzene,
1-bromo-4-methoxybenzene
indole, 2,5-dimethylthiophene
Figure 2-39 FeCl3 catalyzed unsymmetrical triarylmethanes formations.
Selected examples of unsymmetrical triarylmethane formations by Friedel-Crafts-
type arylations of diarylmethylamines
Esquivias et al. (2006) demonstrated that Cu(OTf)2/(±)-binap can serve as
an effective catalyst for aza-Friedel-Crafts alkylation of N-sulfonyl imines with
electron-rich aromatic and heteroaromatic compounds base on the use of the
2-pyridylsulfonyl moiety as the key controlled double electrophilic aromatic
31
substitution, which provided unsymmetrical triarylmethanes in moderate to high
yields as shown in Figure 2-40.
Ar1 H
NSO2(2-Py)
Ar2 H
10 mol% Cu(OTf)2
10 mol% ( )-binap
CH2Cl2, rt Ar1 Ar2
HNSO2(2-Py)
Ar3 H
40 oC, 20-120 minAr1 Ar2
Ar3
II-149 II-150 II-151
II-152
II-153 (43-73 %)
Ar1 = C6H5,
3-Me-C6H4,
4-F-C6H4,
naphthyl
Ar2 = 1-methylindole,
2-methylindole,
5-methoxy-1-methylindole
Ar3 = 1,3,5-trimethoxybenzene,
N ,N-dimethylaniline,
3-methoxy-N,N-dimethylaniline
2-methoxyfuran, 2-methoxythiophene
2-methylindole,
5-methoxy-1-methylindole
Figure 2-40 The synthesis of unsymmetrical triarylmethane derivatives using
Cu(OTf)2/(±)-binap as catalyst.
To further extend this methodology to the case of triarylmethanes that do not
necessarily contain an indole moiety, the second electrophilic aromatic substitution
was investigated with isolated sulfonamide adducts. They found that this reaction
occured cleanly using Sc(OTf)3 as catalyst in CH3CN at 60 oC and this methodology
provided access to unsymmetrical triarylmethanes containing both electron-rich and
electron-poor aromatic rings. (Figure 2-41)
Ar1 Ar2
HNSO2(2-Py)
Ar3 HCH3CN, 60 oC, 12 h
Ar1 Ar2
Ar310 mol% Sc(OTf)3
II-154 II-155 II-156 (44-65 %)
Ar1 = C6H5, 4-O2NC6H4
3,4-FC6H3, 2-naphthyl
Ar2 = 3-MeO-4-(CH3)2NC6H3,
1-MeO-naphthyl
Ar3 = 2-methoxythiophene,
3-methylindole,
1,3,5-trimethoxybenzene
Figure 2-41 Sc(OTf)3 catalyzed aza-Friedel-Crafts alkylation of sulfonamide adducts
and electron-rich aromatic and heteroaromatic compounds.
32
He, Sun, Zheng, and You (2009) developed an efficient method for
the synthesis of unsymmetrical 3,3'-bis(indolyl)methanes II-160 via Friedel-Crafts
alkylation of N-methylindole and variety of α-(3-indolyl)benzylamines using achiral
Brønsted acid II-159 as catalyst in toluene at room temperature to provide
the corresponding unsymmetrical triarylmethane derivatives in good to excellent
yields (Figure 2-42).
NHTs
Ar
HN
R
N
Ar
HN
R
N
NP
N O
OH
Ts
Ts
R = H, 2-Me, 4-Me,5-F, 5-Br, 5-Me,5-MeO, 6-Br,6-BnO
Ar = Ph, 2-BrC6H4, 4-BrC6H4,3-O2NC6H4, 4-O2NC6H4,4-MeC6H4, 4-MeOC6H4
II-157 II-158 II-160 (61-98 %)
II-159
II-159 (5 mol%)
toluene, rt
Figure 2-42 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using achiral
Brønsted acid II-159 as catalyst.
Later on, Gu et al. (2010) carried out the synthesis of unsymmetrical
3,3'-bis(indolyl)methane from N-methylindole and variety of α-(3-indolyl)benzyl-
amines in the presence of chiral Brønsted acid. The reaction proceeded in toluene
at room temperature and the products were obtained in good to excellent yields and
moderate enantioselectivities (45-68% ee).
33
NHTs
Ar
HN
R
N
Ar
HN
R
N
R = H,5-F,5-Br,5-Me,5-MeO,6-Br,6-BnO
Ar = Ph,4-BrC6H4,4-MeC6H4,4-MeOC6H4
II-160 II-158 II-162 (61-96 % yields, 45-68% ee)
II-161-(S) (5 mol%)
toluene, rt
R
R
O
O
POH
O
CF3
CF3
R2 =
II-161-(S)
Figure 2-43 The synthesis of unsymmetrical 3,3'-bis(indolyl)methanes using chiral
Brønsted acid II-161 as catalyst.
In the same year, Thirupathi and Kim (2010) used FeCl3·6H2O as Lewis
acid catalyst for the condensation of arenes with N-arylsufoylamido sulfones. Under
these conditions, not only α-amido sulfones II-165 was found but also bis-arene II-
166
was observed by TLC during the course of the reaction and had completely
disappeared at end of the reaction, which was applied to preparation of triarylmethane
derivatives (Figure 2-44).
CbzHN
R
SO2Ar
OMe
MeO
OMe
R
SO2Ar
OMe
OMe
MeO
FeCl3.6H2O (10 mol%)
CH2Cl2, rt
ROMe
OMe
MeO
OMe
OMe
OMe
R = C6H5, 2-ClC6H4,3-ClC6H4, 4-ClC6H4,4-MeC6H4, 4-MeOC6H4,4-O2NC6H4, 4-CNC6H4,3-Me-4-MeOC6H3, 3-F-4-MeOC6H3,3,4-MeOC6H3, 3,4,5-MeOC6H2, PhCH2CH2,(CH3)2CH, CH3CH2CH2, cyclohexyl,cyclohex-2-enyl, (5-methyl)-2-furyl,(5-methyl)-2-thienyl, 2-naphthyl
Ar = C6H5, 4-MeC6H4
II-163 II-164 II-165
II-166
Figure 2-44 The synthesis of N-arylsufoylamido sulfones using FeCl3·6H2O as
catalyst.
34
Later, they were carried out for the assumptions by using Lewis acid
to promoted Friedel-Crafts alkylation of α-amido sulfones reacted with arenes and
or difference arenes to afford the corresponding addition products (Figure 2-45) and
they proposed the mechanism for the iron(III) catalyzed reaction as shown in Figure
2-46.
R1OMe
OMe
MeO
FeCl3.6H2O (10-30 mol%)
CH2Cl2, rt
R1 = C6H5, 3-MeC6H4, 3-FC6H4,
4-MeOC6H4, 3,4-MeOC6H3
Ar = C6H5, 4-MeC6H4
II-166 II-167 II-168 (38-60 %)
R1
SO2Ar
OMe
OMe
MeONH
R2
NH
R2
R2 = H, MeO
Figure 2-45 Transformation of α-amido sulfones into unsymmetrical triarylmethane
derivatives with FeCl3·6H2O.
35
NH
R2
R1
SO2Ar
OMe
OMe
MeO
R1
S
OMe
OMe
MeOO
O
Ar
FeIII
FeIII
R1OMe
OMe
MeO
ArSO2FeIII
R1
S
OMe
OMe
MeOO
O
Ar
FeIII
R1OMe
OMe
MeO NH
R2
ROMe
OMe
MeO
OMe
OMe
OMe
OMe
OMe
MeO
or
or
II-165
II-169
II-170
II-171
II-163II-167
II-166 II-168
Figure 2-46 The mechanism for the iron(III) catalyzed Friedel-Crafts reaction.
One year later, Neupane et al. (2011) found that treatment of hetero-
aromatic or electron-rich arenes and α-amido sulfones with [B(C6F5)3] gave
respective unsymmetrical triarylmethanes in moderate yields (Figure 2-47).
R1OMe
OMe
MeO
B(C6F5)3 (5 mol%)
CH2Cl2, ref lux
II-165 II-167 II-168 (0-58 %)
R1
SO2Ar
OMe
OMe
MeONH
R2
NH
R2
Figure 2-47 Transformation of α-amido sulfones into unsymmetrical triarylmethane
derivatives with [B(C6F5)3].
36
Selected examples of unsymmetrical triarylmethane formations by Friedel-Crafts-
type arylations of diarylmethyldiketones
Ahmad, Riahi, and Langer (2011) reported the combination methods of
benzylation and [3+3]-cyclocondensation for the synthesis of triarylmethane
derivatives. FeCl3 catalyzed benzylation of acetylacetone and diarylmethanol gave
benzylate product, which was treated with trimethylsilyl chloride proceed to provide
silyl enol ether (Figure 2-48). Then, TiCl4 mediate [3+3]-cyclocondensation of
silyl enol ether precursor reacted with 1,3-bis(silyl enol ether), follow by cyclization
and aromatization to give triarylmethane derivatives in moderate yields (Figure 2-49).
R1 R2
OH
Me
O
Me
O
Me
O
Me
O
R1 R2
Me
Me3SiO
Me
O
R1 R2
FeCl3.6H2O (5 mol%)
CH3NO2, 50 oC, 4 h
Me3SiCl, NEt3
C6H6, 20 oC, 72 h
II-169
II-170
R1 = Ph, 4-MeOC6H4,
4-FC6H4, 4-ClC6H4,
Me
R2 = Ph, 4-MeOC6H4,
4-FC6H4, 4-ClC6H4
II-171 (81-92 %)II-170 (85-94 %)
Figure 2-48 Reaction of benzylation and silylation.
R1 = Ph, 4-MeOC6H4,
4-FC6H4, 4-ClC6H4,
Me
R2 = Ph, 4-MeOC6H4,
4-FC6H4, 4-ClC6H4
R3 = H, Me, Et
R4 = Me, Et
Me
Me3SiO
Me
O
R1 R2
II-170
Me3SiO OSiMe3
R3
OR4
TiCl4, CH2Cl2
-78 20 oC, 20 h
R1 R2
O
OR4
OH
R3
Me Me
II-171 II-172 (31-55 %)
Figure 2-49 Reaction of [3+3]-cyclocondensation follow by cyclization and
aromatization.
Recently, Aoyama et al. (2014) employed an efficient silica gel supported
sodium hydrogen sulfate (SiO2-NaHSO4) as catalyst to catalyzed Friedel-Crafts
37
alkylation of diketone and arenes in nitromethane under thermal condition leading to
triarylmethane derivatives in low to excellent yields (Figure 2-50).
R1 R2
OO
Ar/Het-H
NaHSO4/SiO2 (2.1 mmol)
chlorobenzene, 110 oC, 6 hR1 R2
Ar/Het
II-176 II-177 II-178 (4-99 %)
R1 = Ph,
4-ClC6H4,
4-MeOC6H4
R2 = Me,
4-ClC6H4,
4-MeOC6H4
Ar = 1,2-dimethoxybenzene,1,3-dimethoxybenzene,1,4-dimethoxybenzene,1,3,5-trimethoxybenzene,1,3,5-trimethylbenzene,4-Me-phenol,4-MeO-phenol,4-O2N-phenol,phenol,anisole
Het = benzo[b]thiophene,2-bromo-thiophene,2methylfuran
or ZnCl2/SiO2 (1.5 mmol)
Figure 2-50 The synthesis of Friedel-Crafts alkylation of diketone and arenes using
SiO2-NaHSO4 as catalyst.
Selected examples of unsymmetrical triarylmethane formations by one-pot three
component Friedel-Crafst-type reactions
Liu, He, and Wang (2011) reported the first and highly efficient FeCl3
as Lewis acid catalyzed one-pot three-component Friedel-Crafts reactions of indoles,
aldehydes, and tertiary aromatic amines. The reactions generated the corresponding
unsymmetrical triarylmethanes in moderate to good yields under mild reaction
condition as shown in Figure 2-51.
N
R1 R2 CHON
R3
10 mol% FeCl3
ClCH2CH2Cl, N2
100 oC, 24 h
R2
NNR1
R3
II-179 II-180 II-181 II-182 (48-72 %)
R1 = H, 3-MeO R2 = H, C6H5, 3-MeO-C6H4,
4-MeO-C6H4, 2-Cl-C6H4,
4-Cl-C6H4, CH3CH2CH2,
2-naphthyl
R3 = H, Me
Figure 2-51 FeCl3 catalyzed one-pot three-component Friedel-Crafts reactions.
38
A closely related approach to above mentioned method was reported by
Zhang et al. (2014). They found that aza-Friedel-Crafts alkylation can also use
binuclear complex of bis(ethylcyclopentadienyl)zirconium perfluorooctanesulfonate
as catalyst for condensation of indoles, aldehydes and N,N-dimethylaniline to give
the corresponding 3-diarylmethylindoles in moderate to high yields (Figure 2-52).
N
R1 CHONH
II-186 (2.5 mol%)
ClCH2CH2Cl,
100 oC, 24 h
R1
NHN
II-183 II-184 II-185 II-187 (0-82 %)
R2 = H, 2-CH3, 5-OCH3, 5-F,
5-Cl, 5-Br, 5-NO2, 6-F,7-CH3
R2
R2
R1 = C6H5, 4-Me-C6H4,
4-MeO-C6H4, 4-NC-C6H4,
4-O2N-C6H4, 2,4-Cl-C6H3,
2-naphthylZr
OH
Zr
HO
H2O OH2
H2OOH2
OH2
H2O
O S C8F17
O
O 4
4H2O.
2THF
II-186 binuclear complex
Figure 2-52 Binuclear complex catalyzed one-pot three-component Friedel-Crafts
reactions.
Recently, Ganesan and Ganesan (2014) reported the synthesis of
unsymmetrical triarylmethanes via three-component Friedel-Crafts alkylation of
indole, aldehydes, and tertiary aromatic amines using anhydrous ZnCl2 as catalyst.
Condensation of indole, aldehydes and tertiary aromatic amines in the presence of
anhydrous ZnCl2 (1 eq) in toluene or methanol at room temperature to 100 oC
gave 3-diarylmethylindoles or 3-arylmethylindoles as a major products. Moreover,
bis(indolyl)methane was obtained as a minor product (Figure 2-53).
39
NR1R1
R2 CHONH
anh. ZnCl2 (1 eq)
toluene or methanol
rt-100 oC, 5-12 h
R2
NHN
R1
R1
II-185 II-186 II-187
II-188 (51-68 %)
R2 = H, C6H5, 2-Cl-C6H4,
4-Cl-C6H4, 4-MeO-C6H4,
R1 = Me, Et
R2
NHHN
II-189
Figure 2-53 ZnCl2 catalyzed one-pot three-component Friedel-Crafts reactions.
Further research was carried out to clarify the mechanism for the
transformation of bis(indolyl)methane into 3-diarylmethylindoles or 3-arylmethyl-
indoles. Interestingly, the reaction of bis(indolyl)methane with tertiary aromatic
amines in the presence of ZnCl2 (1 eq) in toluene at 140 oC for 5 h gave the resulting
3-diarylmethylindole II-193 in 54% yield (Figure 2-54).
HN NH
anh. ZnCl2 (1 eq)
toluene, 140 oC, 5 h,
in pressure tube
N
NHN
II-193 (54 %)II-188II-192
Figure 2-54 Transformation of bis(indolyl)methane into 3-diarylmethylindoles or 3-
arylmethylindoles.
Selected examples of unsymmetrical triarylmethane formations by Palladium
catalyzed cross coupling reaction
Lin and Lu (2007) reported the cationic Pd(II)/bpy-catalyzed one-pot
synthesis of unsymmetrical triarylmethanes from arylboronic acids, aryl aldehydes
and electron-rich arenes with low catalyst loading in moderate to high yields. (Figure
2-55)
40
Ar1 B(OH)2 Ar2 CHOcationic PdII
CH3NO2, 80 oC, 24 hAr3 H
Ar3
Ar1 Ar2
II-197 (cationic PdII)
II-194 II-195 II-196
II-197
II-198 (57-99 %)
N
N
Pd
HO
OH
PdN
N
2+
2 BF4
Ar1 = C6H5,
4-Me-C6H4,
4-MeO-C6H4,
4-F-C6H4
Ar2 = 3-O2N-C6H4,
4-O2N-C6H4
Ar3 = 1,2-dimethoxybenzene,
1,3,5-trimethoxybenzene
Figure 2-55 The cationic Pd(II)/bpy-catalyzed one-pot synthesis of unsymmetrical
triarylmethane derivatives.
In 2012, Zhang et al. developed method for the palladium-catalyzed
C(sp3)-H arylation of diarylmethanes at room temperature for synthesis of
triarylmethanes via deprotonative-cross-coupling process in high yields (Figure 2-56).
Ar1
H
5 mol% Pd(OAc)2
7.5 mol% NiXantphos
KN(SiMe3)2 (3 equiv)
cyclopentyl methyl ether
rt, 12 h
Ar1
Ar2Ar2 Br
II-199 II-200 II-201 (66-99 %)
Ar1 = C6H5, 2-Me-C6H4,
4-Me-C6H4, 4-MeO-C6H4,
4-Cl-C6H4, 4-F-C6H4,
indolyl, thienyl
Ar2 = 4-tBu-C6H4,
4-(CH3)2N-C6H4
HN
O
PPh2 PPh2
NiXantphos
Figure 2-56 The synthesis of triarylmethanes via deprotonative-cross-coupling.
Later on, Harris, Hanna, Greene, Moore, and Jarvo (2013) demonstrated
the nikel can serve as efficient catalyst for Suzuki-Miyaura cross-coupling of enantio-
enrich triarylmethanes from benzylic carbamates and pivalates with aryl- and
heteroarylboronic esters which used bulky SIMes and PCy3 ligand of nikel
41
to controlled the setereospecific to give the desire products in excellent specificity and
moderate to high yields.
O O
N
OB
O
Ar
MeMe Ni(cod)2 (10 mol%),
ligand
t-BuOK, n-BuOH,THF:PhMe, rt, 24 h
Ar
Ar
ligand: PCy3
ligand: SIMes
orII-202 II-203
II-204 (67-90 % yields, 57-94 % ee)
II-205 (0-98 % yields, ND-97 % ee)
Ar = 4-FC6H4, 4-MeOC6H4,4-F3CC6H4, 4-(CH3)2NC6H4,4-HOH2CC6H4, 4-MeOCC6H4,4-(CH2)(Boc)HNC6H4,(2-N,N-dimethylamine)-5-pyrimidine,3-furane, (1-methyl)-5-indole
Figure 2-57 The stereospecific synthesis for Suzuki-Miyaura cross-coupling of
enantio enrich triarylmethanes
Recently, Tabuchi, Hirano, Satoh, and Miura (2014) developed method for
the palladium-catalyzed arylation of diarylmethanol derivatives and oxazoles under
thermal conditions for synthesis of triarylmethanes via cross-coupling process
in moderate to high yields (Figure 2-58).
42
Ar1
OR1
Ar2
PdCl2(MeCN)2 (10 mol%),PPhCy2 (20 mol%)
LiO-t -Bu, 1,4-dioxane
120 oC, 6h
O
N
Ar1 Ar2
NO
R2 O
N
Ar1 Ar2
NO
R2
R1 = Boc, Piv, CO2Me
R2 = C6H5, 4-Me-C6H4,
4-MeO-C6H4, 4-Cl-C6H4,
4-F3C-C6H4, 3,4-MeO-C6H3,
PhCHCH, 1-naphthyl
Ar1 = Me, Ph, 2-MeO-C6H4,
4-MeO-C6H4, 4-Cl-C6H4,
4-NC-C6H4, 2-thienyl, 2-furyl
Ar2 = phenyl, biphenyl, 1-naphthyl, 2-naphthyl,
2-benzofuryl, 3-benzo[b]thienyl
II-206
II-207
II-209
II-208 (7-82 %)
II-210 (31-80 %)
Figure 2-58 Palladium-catalyzed arylation of diarylmethanol derivatives and
oxazoles.
CHAPTER 3
RESEARCH METHODOLOGY
General Methods
The high resolution 400 MHz 1H NMR and 100 MHz
13C NMR spectra
were performed on BRUKER AVANCE 400 spectrometer at Department of
Chemistry, Faculty of Science, Burapha University. Spectra were recorded using
deutero chloroform, tetradeuteromethanol, and hexadeuterobenzene solutions and
recorded as δ value in ppm down field from TMS (internal standard δ 0.00) or with
residue non-deuterated solvent peak as the internal standard. The IR spectra were
recorded on a Perkin Elmer System 2000 FT-IR. Mass spectrometric analyses were
recorded on a Finnigan MAT mass spectrometer. High resolution mass spectra were
recorded on Finnigan MAT 95. Melting points were recorded using GALLENKAMP
Melting point apparatus Griffin. All reagents and solvents were commercially
available in high purity. Solvent extracts were dried over anhydrous magnesium
sulfate or sodium sulfate. Solvents were removed by using rotary evaporator at water
aspirator pressure. A trace amount of solvent was removed under vacuum (ca. 0.1
mmHg). Radial chromatography on a Chromatotron was performe using Merck silica
gel 60 PF254 with CaSO4 1/2 H2O and was activated by heating in an oven at 80 oC for
45 min. For column chromatography, 70-230 mesh Merck silica gel 60 [E. Merck,
Darmstadt, Germany] was employed. Thin layer chromatography (TLC) was
performed with Merck silica gel 60 PF254 aluminium plate. Flash chromatography was
performed using 230-400 mesh Merck silica gel 60.
44
1. The aza-Friedel-Crafts reaction of electron-rich arenes with
aldehyde and tert-butyl carbamate in the presence of FeCl3∙6H2O:
Synthesis of the corresponding α-branched amines
1.1 Optimization of the reaction condition for aza-Friedel-Crafts
alkylation of 1,3,5-trimethoxybenzene with tert-butyl carbamate
and benzaldehyde
III-1a III-2a
H2N O
O
solvent, rt
FeCl3.6H2O (x mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-3
III-4a
H
O
General procedure A
To a sovent (THF, DMF, CH3NO2, CH3OH, H2O/CH3OH, ClCH2CH2Cl,
toluene; 1 mL) of 1,3,5-trimethoxybenzeneIII-1a (0.1682 g, 1.0 mmol), tert-butyl
carbamate III-3 (0.1172 g, 1.0 mmol) and benzaldehyde III-2a (0.11 mL, 1.1 mmol)
in a test-tube open to air at room temperature was added FeCl3∙6H2O (x mol%).
After the reaction was stirred until completion (TLC analysis), the reaction mixture
was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2
(2 x 10 mL). The combined organic layer was washed with water (10 mL),
saturated aqueous NaCl dried over anhydrous Na2SO4 and filtered. The filtrate was
evaporated (aspirator then vacuo) to give a crude product, which was purified by
radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as eluent) to give
α-branched amine III-4a.
45
1.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl carbamate
and benzaldehyde in various of solvent using FeCl3∙6H2O as
catalyst
III-1a
H2N O
O
solvent, rt
FeCl3.6H2O (10 mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-2a
III-3
III-4a
H
O
1.1.1.1 Reaction in the presence of tetrahydrofuran (THF)
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and THF (1 mL) were employed. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.1663 g, 44%).
1.1.1.2 Reaction in the presence of dimethylformamide (DMF)
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and DMF (1 mL) were employed. The reaction was stirred at room temperature for
48 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.1329 g, 36%).
1.1.1.3 Reaction in the presence of nitromethane (CH3NO2)
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and CH3NO2 (1 mL) were employed. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.3043 g, 81%).
1.1.1.4 Reaction in the presence of methanol (CH3OH)
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and CH3OH (1 mL) were employed. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.2680 g, 72%).
1.1.1.5 Reaction in the presence of water (H2O)
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%),
H2O (1 mL) and CH3OH (0.25 mL) were employed. The reaction was stirred at room
46
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a
(0.1311 g, 35%).
1.1.1.6 Reaction in the presence of dichloroethane (ClCH2CH2Cl)
Reaction in the presence of dichloroethane (ClCH2CH2Cl) for 24 h
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a
(0.3197 g, 86%).
Reaction in the presence of dichloroethane (ClCH2CH2Cl) for 12 h
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 12 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a
(0.3295 g, 88%).
Reaction in the presence of dichloroethane (ClCH2CH2Cl) for 2 h
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a
(0.3383 g, 90%).
1.1.1.7 Reaction in the presence of toluene
Reaction in the presence of toluene for 24 h
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and toluene (1 mL) were employed. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.3278 g, 88%).
Reaction in the presence of toluene for 12 h
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and toluene (1 mL) were employed. The reaction was stirred at room temperature for
47
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.3339 g, 89%).
Reaction in the presence of toluene for 2 h
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and toluene (1 mL) were employed. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.3421 g, 91%).
1.1.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl carbamate
and benzaldehyde in various catalyst loading of FeCl3∙6H2O
using toluene as solvent
III-1a III-2a
H2N O
O
toluene, rt
FeCl3.6H2O (x mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-3
III-4a
H
O
1.1.2.1 Reaction in the presence of 10 mol% of FeCl3∙6H2O
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and toluene (1 mL) were employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to α-branched amine III-4a (0.3421 g, 91%).
1.1.2.2 Reaction in the presence of 5 mol% of FeCl3∙6H2O
Following the general procedure A, FeCl3∙6H2O (0.0135 g, 5 mol%)
and toluene (1 mL) were employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.3201 g, 86%).
1.1.2.3 Reaction in the presence of 2.5 mol% of FeCl3∙6H2O
Following the general procedure A, FeCl3∙6H2O (0.0068 g, 2.5 mol%)
and toluene (1 mL) were employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4a (0.2222 g, 59%).
48
1.1.3 Reaction of 1,3,5-trimethoxybenzene with tert-butyl carbamate
and benzaldehyde in various catalyst loading of FeCl3∙6H2O
using ClCH2CH2Cl as solvent
III-1a III-2a
H2N O
O
ClCH2CH2Cl, rt
FeCl3.6H2O (x mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-3
III-4a
H
O
1.1.3.1 Reaction in the presence of 10 mol% of FeCl3∙6H2O
Following the general procedure A, FeCl3∙6H2O (0.0270 g, 10 mol%)
and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to α-branched amine III-4a (0.3383 g,
90%).
1.1.3.2 Reaction in the presence of 5 mol% of FeCl3∙6H2O
Following the general procedure A, FeCl3∙6H2O (0.0135 g, 5 mol%)
and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a
(0.3371 g, 89%).
1.1.3.3 Reaction in the presence of 2.5 mol% of FeCl3∙6H2O
Following the general procedure A, FeCl3∙6H2O (0.0068 g, 2.5 mol%)
and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a
(0.2990 g, 80%).
49
1.2 The aza-Friedel-Crafts alkylation of 1,3,5-trimethoxybenzene with
tert-butyl carbamate and various aldehydes in the presence of
FeCl3∙6H2O under optimized reaction condition
III-1a III-2
HNOMe
OMeMeO
MeO
MeO OMe
RR-CHO
H2N O
O
toluene or ClCH2CH2Cl, rt
5 mol% FeCl3.6H2O
III-3
III-4
O
O
General procedure B
To a toluene or dichloroethane solution (1 mL) of 1,3,5-trimethoxybenzene
III-1a (0.1682 g, 1.0 mmol), tert-butyl carbamate III-3 (0.1172 g, 1.0 mmol) and
benzaldehyde III-2a (0.11 mL, 1.1 mmol) in a test-tube open to air at room
temperature was added FeCl3∙6H2O (5 mol%, 0.0135 g). After the reaction was
stirred until completion (TLC analysis), the reaction mixture was quenched with
saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL).
The combined organic layer was washed with water (10 mL), saturated aqueous NaCl
dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated (aspirator then
vacuo) to give a crude product, which was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/hexane as eluent) to give α-branched amine III-4a.
1.2.1 The reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and various aromatic aldehydes in the presence of
FeCl3∙6H2O as catalyst: The synthesis of α-branched amines
III-4
1.2.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde.
III-1atoluene or ClCH2CH2Cl, rt
III-2a
III-3
III-4a
H2N O
O
FeCl3.6H2O (5 mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
50
1.2.1.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde using toluene as solvent
Following the general procedure B, benzaldehyde (0.11 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/ hexane as eluent) to give α-branched amine III-4a (0.3201 g, 86%).
1.2.1.1.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde using ClCH2CH2Cl as
solvent
Following the general procedure B, benzaldehyde (0.11 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/ hexane as eluent) to give α-branched amine III-4a (0.3371 g, 89%).
1.2.1.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-fluorobenzaldehyde
III-1a III-2b III-4b
HN O
O
OMe
OMeMeO
MeO
MeOOMe
H
O
FF
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.1.2.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-fluorobenzaldehyde using toluene
as solvent
Following the general procedure B, 2-fluorobenzaldehyde (0.12
mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4b (0.3336 g, 85%).
51
1.2.1.2.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-fluorobenzaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 2-fluorobenzaldehyde
(0.12 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4b (0.3715 g, 95%).
1.2.1.3 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-fluorobenzaldehyde
III-1a III-2c III-4c
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
F Ftoluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.1.3.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-fluorobenzaldehyde using toluene
as solvent
Following the general procedure B, 4-fluorobenzaldehyde
(0.12 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4c (0.3264 g, 83%).
1.2.1.3.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-fluorobenzaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 4-fluorobenzaldehyde
(0.12 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4c (0.3722 g, 95%).
52
1.2.1.4 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-chlorobenzaldehyde
III-1a III-2d III-4d
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
Cl Cltoluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.1.4.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-chlorobenzaldehyde using toluene
as solvent
Following the general procedure B, 4-chlorobenzaldehyde
(0.1546 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4d (0.2781 g, 68%).
1.2.1.4.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-chlorobenzaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 4-chlorobenzaldehyde
(0.1546 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4d (0.3297 g, 81%).
1.2.1.5 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-bromobenzaldehyde
III-1a III-2e III-4e
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
Br Brtoluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
53
1.2.1.5.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-bromobenzaldehyde using toluene
as solvent
Following the general procedure B, 4-bromobenzaldehyde
(0.2035 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4e (0.2897 g, 64%).
1.2.1.5.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-bromobenzaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 4-bromobenzaldehyde
(0.2035 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4e (0.3939 g, 87%).
1.2.1.6 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-nitrobenzaldehyde
III-1a III-2f III-4f
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
O2N NO2toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.1.6.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-nitrobenzaldehyde using toluene
as solvent
Following the general procedure B, 4-nitorbenzaldehyde (0.1662 g,
1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/hexane as eluent) to give α-branched amine III-4f (0.2780 g, 66%).
54
1.2.1.6.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-nitrobenzaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 4-nitorbenzaldehyde (0.1662 g,
1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/hexane as eluent) to give α-branched amine III-4f (0.3730 g, 89%).
1.2.1.7 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-methoxybenzaldehyde
III-1a III-2g III-4g
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
MeO OMetoluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.1.7.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-methoxybenzaldehyde using toluene
as solvent
Following the general procedure B, 4-methoxybenzaldehyde
(0.13 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4g (0.3367 g, 83%).
1.2.1.7.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 4-methoxybenzaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 4-methoxybenzaldehyde
(0.13 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4g (0.3246 g, 80%).
55
1.2.1.8 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and methyl 4-formylbenzoate
III-1a III-2h III-4h
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
MeO
O O
OMetoluene, ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.1.8.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and methyl 4-formylbenzoate using toluene
as solvent
Following the general procedure B, methyl 4-formylbenzoate
(0.1642 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4h (0.3479 g, 81%).
1.2.1.8.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and methyl 4-formylbenzoate using
ClCH2CH2Cl as solvent
Following the general procedure B, methyl 4-formylbenzoate
(0.1642 g, 1.1 mmol) was employed. The reaction was stirred at room temperature for
4 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-4h (0.3550 g, 82%).
56
1.2.1.9 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and phthalaldehyde
III-1a III-2i
III-4i
OMe
OMeMeO
H
O
toluene orClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
III-5a
H
O
HN O
O
MeO
MeOOMe
H O
HN O
O
MeO
MeO
HN
OO
OMe OMe
OMeOMe
1.2.1.9.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and phthalaldehyde using toluene as
solvent
Following the general procedure B, phthalaldehyde (0.1475 g,
1.1 mmol) was employed. After stirring the reaction at room temperature for 24 h,
the complex mixture was observed.
1.2.1.9.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and phthalaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, phthalaldehyde (0.1475 g,
1.1 mmol) was employed. After stirring the reaction at room temperature for 24 h,
the complex mixture was observed.
57
1.2.1.10 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and terephthalaldehyde
III-1a III-2j
III-4j
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
H
O
O
H
toluene or ClCH2CH2Cl,rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
III-5b
HN O
O
MeO
MeO OMe
MeO OMe
OMeNH
O
O
1.2.1.10.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and terephthalaldehyde using toluene as
solvent
Following the general procedure B, terephthalaldehyde (0.1475 g,
1.1 mmol) was employed. The reaction was stirred at room temperature for 1 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 40%
EtOAc/hexane as eluent) to give α-branched amine III-4j (0.2081 g, 52%) and
α-branched amine III-5b (0.1281 g, 38%).
1.2.1.10.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and terephthalaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, terephthalaldehyde (0.1475 g,
1.1 mmol) was employed. The reaction was stirred at room temperature for 1 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 40%
EtOAc/hexane as eluent) to give α-branched amine III-4j (0.2129 g, 53%) and
α-branched amine III-5b (0.0861 g, 26%).
58
1.2.2 The reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate
with various heteroaromatic aldehydes in the presence of
FeCl3∙6H2O as catalyst: The synthesis of α-branched amines
III-6
1.2.2.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and furfural
III-1a III-2k III-6a
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
OOtoluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.2.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and furfural using toluene as solvent
Following the general procedure B, furfural (0.09 mL, 1.1 mmol)
was employed. The reaction was stirred at room temperature for 24 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/hexane as eluent) to give α-branched amine III-6a (0.1204 g, 33%).
1.2.2.1.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and furfural using ClCH2CH2Cl as
solvent
Following the general procedure B, furfural (0.09 mL, 1.1 mmol)
was employed. The reaction was stirred at room temperature for 24 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/hexane as eluent) to give α-branched amine III-6a (0.0416 g, 11%).
59
1.2.2.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-pyridinecarboxaldehyde
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
III-1a III-2l
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-6b
N
H
O
N
1.2.2.2.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-pyridinecarboxaldehyde using
toluene as solvent
Following the general procedure B, 2-pyridinecarboxaldehyde (0.11
mL, 1.1 mmol) in toluene (1.5 mL) was employed. The reaction was stirred at 80 oC
for 3 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 30% EtOAc/hexane as eluent) to give α-branched amine III-6b (0.2495 g,
67%).
1.2.2.2.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-pyridinecarboxaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, 2-pyridinecarboxaldehyde (0.11
mL, 1.1 mmol) was employed. The reaction was stirred at 80 oC for 3 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 30%
EtOAc/hexane as eluent) to give α-branched amine III-6b (0.3244 g, 87%).
60
1.2.3 The reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate
with various aliphatic aldehydes in the presence of FeCl3∙6H2O
as catalyst: The synthesis of α-branched amines III-7
1.2.3.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and propanal
III-1a III-2m III-7a
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.1.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and propanal using toluene as solvent
Following the general procedure B, propanal (0.08 mL, 1.1 mmol)
was employed. The reaction was stirred at room temperature for 2 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/hexane as eluent) to give α-branched amine III-7a (0.3137 g, 96%).
1.2.3.1.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and propanal using ClCH2CH2Cl as
solvent
Following the general procedure B, propanal (0.08 mL, 1.1 mmol)
was employed. The reaction was stirred at room temperature for 2 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 30%
EtOAc/hexane as eluent) to give α-branched amine III-7a (0.2233 g, 69%).
1.2.3.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and pentanal
III-1a III-2n III-7b
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
61
1.2.3.2.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and pentanal using toluene as solvent
Following the general procedure B, pentanal (0.12 mL, 1.1 mmol)
was employed. The reaction was stirred at room temperature for 4 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/
hexane as eluent) to give α-branched amine III-7b (0.3389 g, 96%).
1.2.3.2.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and pentanal using ClCH2CH2Cl as
solvent
Following the general procedure B, pentanal (0.12 mL, 1.1 mmol)
was employed. The reaction was stirred at room temperature for 4 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/
hexane as eluent) to give α-branched amine III-7b (0.3315 g, 94%).
1.2.3.3 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 3-phenylpropanal
III-1a III-2o III-7c
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.3.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 3-phenylpropanal using toluene as
solvent
Following the general procedure B, 3-phenylpropanal (0.14 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 1 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-7c (0.3640 g, 91%).
62
1.2.3.3.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 3-phenylpropanal using ClCH2CH2Cl
as solvent
Following the general procedure D, 3-phenylpropanal (0.14 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 1 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-7c (0.3811 g, 95%).
1.2.3.4 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-methylpropanal
III-1a III-2p III-7d
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.4.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-methylpropanal using toluene as
solvent
Following the general procedure B, 2-methylpropanal (0.10 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 1 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/ hexane as eluent) to give α-branched amine III-7d (0.3320 g, 98%).
1.2.3.4.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-methylpropanal using ClCH2CH2Cl
as solvent
Following the general procedure B, 2-methylpropanal (0.10 mL, 1.1
mmol) was employed. The reaction was stirred at room temperature for 1 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/
hexane as eluent) to give α-branched amine III-7d (0.3256 g, 99%).
63
1.2.3.5 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-ethylbutanal
III-1a III-2q III-7e
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.5.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-ethylbutanal using toluene as
solvent
Following the general procedure B, 2-ethylbutanal (0.14 mL,
1.1 mmol) in toluene (1.5 mL) was employed. The reaction was stirred at room
temperature for 4 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 20% EtOAc/ hexane as eluent) to give α-branched amine III-7e
(0.2976 g, 81%).
1.2.3.5.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 2-ethylbutanal using ClCH2CH2Cl
as solvent
Following the general procedure B, 2-ethylbutanal (0.14 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 4 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/ hexane as eluent) to give α-branched amine III-7e (0.2958 g, 80%).
1.2.3.6 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 3-methylbutanal
III-1a III-2r III-7f
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
64
1.2.3.6.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 3-methylbutanal using toluene as
solvent
Following the general procedure B, 3-methylbutanal (0.12 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 4 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 30%
EtOAc/ hexane as eluent) to give α-branched amine III-7f (0.3467 g, 98%).
1.2.3.6.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and 3-methylbutanal using ClCH2CH2Cl
as solvent
Following the general procedure B, 3-methylbutanal (0.12 mL,
1.1 mmol) was employed. The reaction was stirred at room temperature for 4 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to 30%
EtOAc/ hexane as eluent) to give α-branched amine III-7f (0.2272 g, 64%).
1.2.3.7 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclopropane carboxaldehyde
III-1a III-2s III-7g
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.7.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclopropane carboxaldehyde using
toluene as solvent
Following the general procedure B, cyclopropanecarbaldehyde
(0.08 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
30% EtOAc/hexane as eluent) to give α-branched amine III-7g (0.2814 g, 83%).
65
1.2.3.7.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclopropane carboxaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, cyclopropanecarbaldehyde
(0.08 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
30% EtOAc/hexane as eluent) to give α-branched amine III-7g (0.2150 g, 64%).
1.2.3.8 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclopentane carboxaldehyde
III-1a III-2t III-7h
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.8.1 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclopropanecarbaldehyde using
toluene as solvent
Following the general procedure B, cyclopropanecarbaldehyde
(0.08 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
90 min The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/hexane as eluent) to give α-branched amine III-7h (0.3310 g, 90%).
1.2.3.8.2 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclopropanecarbaldehyde using
ClCH2CH2Cl as solvent
Following the general procedure B, cyclopropanecarbaldehyde
(0.08 mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for
2 h. The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-7h (0.2500 g, 68 %).
66
1.2.3.9 Reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and cyclohexanecarboxaldehyde
III-1a III-2u III-7i
HN O
O
OMe
OMeMeO
MeO
MeO OMe
H
O
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.2.3.9.1 Reaction of 1,3,5-trimethoxybenzene with tert-
butyl carbamate and cyclohexanecarbaldehyde
using toluene as solvent
Following the general procedure B, cyclohexanecarbaldehyde (0.13
mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-7i (0.3647 g, 96%).
1.2.3.9.2 Reaction of 1,3,5-trimethoxybenzene with tert-
butyl carbamate and 3-methylbutanal using
ClCH2CH2Cl as solvent
Following the general procedure B, cyclohexanecarbaldehyde (0.13
mL, 1.1 mmol) was employed. The reaction was stirred at room temperature for 2 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give α-branched amine III-7i (0.2381 g, 63%).
67
1.3 FeCl3∙6H2O catalyzed aza-Friedel-Crafts reaction of various
electron-rich arenes, tert-butyl carbamate with aromatic
and aliphatic aldehydes under optimized reaction condition
Ar-H
III-8 R = arylIII-10 R = alkyl
III-2III-1
R-CHOArAr
R+
III-9 R = arylIII-11 R = alkyl
+
Het-H
R = aryl or alkyl
+HN O
O
Ar H
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
General procedure C
A mixture of tert-butyl carbamate (0.1172 g, 1.0 mmol), freshly distilled
aldehydes (0.11 mL, 1.1 mmol) and FeCl3∙6H2O (5 mol%) in a round-bottomed flask
was added toluene (5 mL) or ClCH2CH2Cl (5 mL). A solution of arenes (0.10 mL, 1.0
mmol) in solvent (10 mL) was added dropwise to the reaction mixture at 0 oC. After
the reaction was stirred until completion (TLC analysis), the reaction mixture was
quenched with aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (2 x 10 mL).
The combined organic layer was washed with brine (10 mL), dried over anhydrous
Na2SO4 and filtered. The filtrate was evaporated (aspirator then vacuo) to give a crude
product, which was purified by radial chromatography (SiO2, 100% hexane to 20%
EtOAc/hexane as eluent) to give the corresponding α-branched amines.
68
1.3.1 Reaction of electron-rich arenes with tert-butyl carbamate and
aromatic aldehydes using FeCl3∙6H2O as catalyst
1.3.1.1 Reaction of 1,2,4-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde
III-1b III-2a III-8a
HN O
O
MeO
H
O
OMe OMe
MeO
OMe
MeO
OMe OMe
OMe
OMe
+
MeO
OMe
III-9a
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.3.1.1.1 Reaction of 1,2,4-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde using toluene as solvent
Following the general procedure B, 1,2,4-trimethoxybenzene
(0.15 mL, 1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate
(0.1172 g, 1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at
room temperature for 24 h. The crude product was purified by radial chromatography
(SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give α-branched amine
III-8a (0.2508 g, 67%) and the corresponding triarylmethane III-9a (0.0679 g, 32%).
1.3.1.1.2 Reaction of 1,2,4-trimethoxybenzene with tert-butyl
carbamate and benzaldehyde using ClCH2CH2Cl as
solvent
Following the general procedure B, 1,2,4-trimethoxybenzene
(0.15 mL, 1.0 mmol), benzaldehyde (0.22 mL, 2.2 mmol), tert-butyl carbamate
(0.1172 g, 1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was
stirred at room temperature for 24 h. The crude product was purified by radial
chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give
α-branched amine III-8a (0.2090 g, 56%) and the corresponding triarylmethane
III-9a (0.0933 g, 44%).
69
1.3.1.2 Reaction of 2-methylfuran with tert-butyl carbamate and
benzaldehyde
III-2a
H
O
+
O OHN O
O
OO
III-1c III-8b III-9b
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.3.1.2.1 Reaction of 2-methylfuran with tert-butyl carbamate
and benzaldehyde using toluene as solvent
Following the general procedure B, 2-methylfuran (0.09 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8b
(0.2063 g, 72%) and the corresponding bis(furyl)methane III-9b (0.0049 g, 4%).
1.3.1.2.2 Reaction of 2-methylfuran with tert-butyl carbamate
and benzaldehyde using ClCH2CH2Cl as solvent
Following the general procedure B, 2-methylfuran (0.09 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 1 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8b
(0.1838 g, 64%) and the corresponding bis(furyl)methane III-9b (0.0454 g, 36%).
1.3.1.3 Reaction of 2-methylfuran with tert-butyl carbamate and
4-nitrobenzaldehyde
III-2f
H
O
+
O OHN O
O
OO
III-1c III-8c III-9c
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
O2N NO2NO2
70
1.3.1.2.1 Reaction of 2-methylfuran with tert-butyl carbamate
and benzaldehyde using toluene as solvent
Following the general procedure B, 2-methylfuran (0.09 mL, 1.0
mmol), 4-nitrobenzaldehyde (0.1664 g, 1.1 mmol), tert-butyl carbamate (0.1172 g, 1.0
mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8c
(0.2234 g, 66%) and the corresponding bis(furyl)methane III-9c (0.0065 g, 4%).
1.3.1.4 Reaction of 2-ethylfuran with tert-butyl carbamate and
benzaldehyde
III-2a
H
O
+
O OHN O
O
OO
III-1d III-8d III-9d
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.3.1.4.1 Reaction of 2-ethylfuran with tert-butyl carbamate
and benzaldehyde using toluene as solvent
Following the general procedure B, 2-ethylfuran (0.11 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol) and tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1.5 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8d
(0.1959 g, 65%) and the corresponding bis(furyl)methane III-9d (0.0240 g, 17%).
1.3.1.4.2 Reaction of 2-ethylfuran with tert-butyl carbamate
and benzaldehyde using ClCH2CH2Cl as solvent
Following the general procedure B, 2-ethylfuran (0.11 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
71
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8d
(0.0885 g, 29%) and the corresponding bis(furyl)methane III-9d (0.0981 g, 70%).
1.3.1.5 Reaction of 2-methylthiophene with tert-butyl carbamate
and benzaldehyde
III-2a
H
O
+
S SHN O
O
SS
III-1e III-8e III-9e
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.3.1.5.1 Reaction of 2-methylthiophene with tert-butyl
carbamate and benzaldehyde using toluene as solvent
Following the general procedure B, 2-methylthiophene (0.10 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1.5 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8e
(0.0675 g, 22%) as a sole product.
1.3.1.5.2 Reaction of 2-methylthiophene with tert-butyl
carbamate and benzaldehyde using ClCH2CH2Cl as
solvent
Following the general procedure B, 2-methylthiophene (0.10 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 3 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8e
(0.1716 g, 57%) and the corresponding bis(thienyl)methane III-9e (0.0055 g, 4%).
72
1.3.1.6 Reaction of 2-ethylthiophene with tert-butyl carbamate and
benzaldehyde
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
III-2a
H
O
+
S SHN O
O
SS
III-1f III-8f III-9f
1.3.1.6.1 Reaction of 2-ethylthiophene with tert-butyl carbamate
and benzaldehyde using toluene as solvent
Following the general procedure B, 2-ethylthiophene (0.11 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 2 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 5% EtOAc/hexane as eluent) to give α-branched amine III-8f
(0.0295 g, 9%) as a sole product.
1.3.1.6.2 Reaction of 2-methylthiophene with tert-butyl
carbamate and benzaldehyde using ClCH2CH2Cl as
solvent
Following the general procedure B, 2-ethylthiophene (1.0 mL,
9.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8f
(0.0861 g, 27%) as a sole product.
73
1.3.1.7 Reaction of N-Boc-pyrrole with tert-butyl carbamate and
benzaldehyde
III-2a
H
O
+
N N
HN O
O
NN
III-1g III-8g III-9g
Boc Boc
Boc Boc
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
1.3.1.7.1 Reaction of N-Boc-pyrrole with tert-butyl carbamate
and benzaldehyde using toluene as solvent
Following the general procedure B, N-Boc-pyrrole (1.0 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1.5 mL) were employed. The reaction was stirred at room
temperature for 3 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8g
(0.0904 g, 24%) as a sole product
1.3.1.7.2 Reaction of N-Boc-pyrrole with tert-butyl carbamate
and benzaldehyde using ClCH2CH2Cl as solvent
Following the general procedure B, N-Boc-pyrrole (1.0 mL,
1.0 mmol), benzaldehyde (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-8g
(0.1100 g, 29%) as a sole product.
1.3.1.8 Reaction of indole with tert-butyl carbamate and
benzaldehyde
III-2a
H
O
+
HN NHHN O
O
HN
III-1h
NH
III-8h III-9h
III-3H2N O
O
FeCl3.6H2O (5 mol%)
toluene or ClCH2CH2Cl, rt
74
1.3.1.8.1 Reaction of indole with tert-butyl carbamate and
benzaldehyde using toluene as solvent
Reaction of indole with tert-butyl carbamate and benzaldehyde
using 5 mol% of FeCl3∙6H2O for 30 min
Following the general procedure C, FeCl3∙6H2O (0.0135 g,
0.05 mmol) was added to a solution mixture of tert-butyl carbamate (0.1172 g,
1.0 mmol) and benzaldehyde (0.11 mL, 1.1 mmol) in toluene (5 mL). A solution of
indole (0.1172 g, 1.0 mmol) in toluene (10 mL) was added dropwise to the reaction
mixture at 0 oC for 30 min. The crude product was purified by radial chromatography
(SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as eluent) to give α-branched
amine III-8h (0.0118 g, 4%) and the corresponding bis(indolyl)methane III-9h
(0.0665 g, 41%).
Reaction of indole with tert-butyl carbamate and benzaldehyde
using 5 mol% of FeCl3∙6H2O for 2 h
Following the general procedure C, FeCl3∙6H2O (0.0135 g,
0.05 mmol) was added to a solution mixture of tert-butyl carbamate (0.1172 g,
1.0 mmol) and benzaldehyde (0.11 mL, 1.1 mmol) in toluene (5 mL). A solution of
indole (0.1172 g, 1.0 mmol) in toluene (10 mL) was added dropwise to the reaction
mixture at 0 oC for 2 h. The crude product was purified by radial chromatography
(SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as eluent) to give α-branched
amine III-8h (0.0151 g, 5%) and the corresponding bis(indolyl)methane III-9h
(0.1165 g, 72%).
Reaction of indole with tert-butyl carbamate and benzaldehyde
using 10 mol% of FeCl3∙6H2O
Following the general procedure C, FeCl3∙6H2O (0.0270 g,
0.10 mmol) was added to a solution mixture of tert-butyl carbamate (0.1172 g,
1.0 mmol) and benzaldehyde (0.11 mL, 1.1 mmol) in toluene (5 mL). A solution of
indole (0.1172 g, 1.0 mmol) in toluene (10 mL) was added dropwise to the reaction
mixture at -40 oC to room temperature for 7 h. The crude product was purified by
radial chromatography (SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as
eluent) to give α-branched amine III-8h (0.0114 g, 3%) and the corresponding
bis(indolyl)-methane III-9h (0.0429 g, 27%).
75
1.3.1.8.2 Reaction of indole with tert-butyl carbamate and
benzaldehyde using ClCH2CH2Cl as solvent
Following the general procedure C, FeCl3∙6H2O (0.0135 g, 0.05
mmol) was added to a solution mixture of tert-butyl carbamate (0.1172 g, 1.0 mmol)
and benzaldehyde (0.11 mL, 1.1 mmol) in ClCH2CH2Cl (5 mL). A solution of indole
(0.1172 g, 1.0 mmol) in ClCH2CH2Cl (10 mL) was added dropwise to the reaction
mixture at 0 oC for 17 min. The crude product was purified by radial chromatography
(SiO2, 100% hexane and 70:30:1 CH2Cl2:hexane:MeOH as eluent)to give α-branched
amine III-8h (0.0082 g, 2%) and the corresponding bis(indolyl)methane III-9h
(0.0609 g, 42%).
1.3.2 Reaction of electron-rich arenes, tert-butyl carbamate with
aliphatic aldehydes using FeCl3∙6H2O as catalyst
1.3.2.1 Reaction of 1,2,4-trimethoxybenzene with tert-butyl
carbamate and 2-methylpropanal
III-1b III-2p III-10a
HN O
O
MeO
H
O
OMe OMe
MeO
OMe
MeO
OMe OMe
OMe
OMe
+
MeO
OMe
III-11a
III-3H2N O
O
FeCl3.6H2O (5 mol%)
toluene or ClCH2CH2Cl, rt
1.3.2.1.1 Reaction of 1,2,4-trimethoxybenzene with tert-butyl
carbamate and 2-methylpropanal using toluene as
solvent
Following the general procedure B, 1,2,4-trimethoxybenzene
(1.0 mL, 1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate
(0.1172 g, 1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at
room temperature for 24 h. The crude product was purified by radial chromatography
(SiO2, 100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine
III-10a (0.2215 g, 63%) and the corresponding bis(aryl)alkane III-11a (0.0165 g,
9%).
76
1.3.2.1.2 Reaction of 1,2,4-trimethoxybenzene with tert-butyl
carbamate and 2-methylpropanal using ClCH2CH2Cl
as solvent
Following the general procedure B, 1,2,4-trimethoxybenzene
(1.0 mL, 1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate
(0.1172 g, 1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was
stirred at room temperature for 24 h. The crude product was purified by radial
chromatography (SiO2, 100% hexane to 10% EtOAc/hexane as eluent) to give
α-branched amine III-12a (0.2172 g, 64%) and the corresponding bis(aryl)alkane
III-13a (0.0478 g, 25%).
1.3.2.2 Reaction of 2-methylfuran with tert-butyl carbamate and
2-methylpropanal
III-2p
H
O
+ O O
HN O
O
OO
III-1c III-10b III-11b
III-3H2N O
O
FeCl3.6H2O (5 mol%)
toluene or ClCH2CH2Cl, rt
1.3.2.2.1 Reaction of 2-methylfuran with tert-butyl carbamate
and 2-methylpropanal using toluene as solvent
Following the general procedure B, 2-methylfuran (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10b
(0.2018 g, 80%) as a sole product.
1.3.2.2.2 Reaction of 2-methylfuran with tert-butyl carbamate
and 2-methylpropanal using ClCH2CH2Cl as solvent
Following the general procedure B, 2-methylfuran (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
77
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10b
(0.2260 g, 89%) as a sole product.
1.3.2.3 Reaction of 2-ethylfuran with tert-butyl carbamate and
2-methylpropanal
III-2p
H
O
+ O O
HN O
O
OO
III-1d III-10c III-11c
III-3H2N O
O
FeCl3.6H2O (5 mol%)
toluene or ClCH2CH2Cl, rt
1.3.2.3.1 Reaction of 2-ethylfuran with tert-butyl carbamate
and 2-methylpropanal using toluene as solvent
Following the general procedure B, 2-ethylfuran (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10c
(0.2561 g, 96%) and the corresponding bis(furyl)alkane III-11c (0.0042 g, 3%).
1.3.2.3.2 Reaction of 2-ethylfuran with tert-butyl carbamate
and 2-methylpropanal using ClCH2CH2Cl as solvent
Following the general procedure B, 2-ethylfuran (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10c
(0.2609 g, 98%) and the corresponding bis(aryl)alkane III-11c (0.0012 g, 1%).
78
1.3.2.4 Reaction of 2-methylthiophene with tert-butyl carbamate
and 2-methylpropanal
III-2p
H
O
+ S S
HN O
O
SS
III-1e III-10d III-11d
III-3H2N O
O
FeCl3.6H2O (5 mol%)
toluene or ClCH2CH2Cl, rt
1.3.2.4.1 Reaction of 2-methylthiophene with tert-butyl
carbamate and 2-methylpropanal using toluene as
solvent
Following the general procedure B, 2-methylthiophene (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10d
(0.0161 g, 6%) as a sole product.
1.3.2.4.2 Reaction of 2-methylthiophene with tert-butyl
carbamate and 2-methylpropanal using
ClCH2CH2Cl as solvent
Following the general procedure B, 2-methylthiophene (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10d
(0.0999 g, 37%) as a sole product.
79
1.3.2.5 Reaction of 2-ethylthiophene with tert-butyl carbamate and
2-methylpropanal
III-2p
H
O
+ S S
HN O
O
SS
III-1f III-10e III-11e
III-3H2N O
O
FeCl3.6H2O (5 mol%)
toluene or ClCH2CH2Cl, rt
1.3.2.5.1 Reaction of 2-ethylthiophene with tert-butyl
carbamate and 2-methylpropanal using toluene as
solvent
Following the general procedure B, 2-ethylthiophene (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10e
(0.0273 g, 12%) as a sole product.
1.3.2.5.2 Reaction of 2-ethylthiophene with tert-butyl
carbamate and 2-methylpropanal using ClCH2CH2Cl
as solvent
Following the general procedure B, 2-ethylthiophene (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10e
(0.0375 g, 13%) as a sole product.
80
1.3.2.6 Reaction of N-Boc-pyrrole with tert-butyl carbamate and
2-methylpropanal
III-2p
H
O
+
HN O
O
NN
III-1g III-10f
III-12a
III-3H2N O
O
FeCl3.6H2O (5 mol%)
Boc Boctoluene or ClCH2CH2Cl, rt
N
Boc
HN
HN
O
O O
O
N N
III-11f
Boc Boc
1.3.2.6.1 Reaction of N-Boc-pyrrole with tert-butyl carbamate
and 2-methylpropanal using toluene as solvent
Following the general procedure B, N-Boc-pyrrole (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and toluene (1.5 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10f
(0.0497 g, 15%) and (syn/anti)-α-branched amine III-12a (0.0123 g, 5%).
1.3.2.6.2 Reaction of N-Boc-pyrrole with tert-butyl carbamate
and 2-methylpropanal using ClCH2CH2Cl as solvent
Following the general procedure B, N-Boc-pyrrole (1.0 mL,
1.0 mmol), 2-methylpropanal (0.11 mL, 1.1 mmol), tert-butyl carbamate (0.1172 g,
1.0 mmol) and ClCH2CH2Cl (1 mL) were employed. The reaction was stirred at room
temperature for 24 h. The crude product was purified by radial chromatography (SiO2,
100% hexane to 10% EtOAc/hexane as eluent) to give α-branched amine III-10f
(0.1435 g, 42%) and (syn/anti)-α-branched amine III-12a (0.0868 g, 34%).
81
2. The Friedel-Crafts reaction of electron-rich arenes with N-Boc
diarylmethylcarbamate: Synthesis of the corresponding
unsymmetrical triarylmethanes
2.1 Optimization of the reaction condition for Friedel-Crafts reaction of
2-methylfuran with N-Boc diarylmethylcarbamate
HN O
O
MeO
MeO OMe
O
catalyst (x mol%)
ClCH2CH2Cl, rt
MeO
MeO OMe
III-4a III-1c III-13a
O
General procedure D
To a dichloroethane solution (2 mL) of N-Boc diaylmethylcarbamate III-4a
(0.1867 g, 0.5 mmol) and 2-methylfuran III-1c (0.04 mL, 0.5 mmol) in a test-tube
open to air at room was added catalyst (I2, Montmorillonite K10 clay, Bi(OTf)3,
In(OTf)3, NbCl5, AlCl3∙6H2O, FeCl3 or FeCl3∙6H2O; x mmol). After the reaction was
stirred until completion (TLC analysis), the reaction mixture was quenched with
distilled water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic
layer were washed with water (10 mL) and saturated aqueous NH4Cl (10 mL), dried
over anhydrous Na2SO4 and filtered. The filtrate was evaporated (aspirator then
vacuo) to give a crude product, which was purified by radial chromatography (SiO2,
100% hexane to 50% EtOAc/hexane as eluent) to give the corresponding
unsymmetrical triarylmethanes III-13.
82
2.1.1 Reaction of 2-methylfuran with N-Boc diarylmethylcarbamate
in various catalyst
Ar
HN O
O
O
catalyst (x mol%)
ClCH2CH2Cl, rt
Ar
III-4a or III-8a III-1c III-13
OO
III-9b III-1
OAr-H
Ar = 1,3,5-trimethoxybenzene, III-4a= 1,2,4-trimethoxybenzene, III-10a
III-13a, Ar = 1,3,5-trimethoxybenzeneIII-13b, Ar = 1,2,4-trimethoxybenzene
2.1.1.1 Reaction of 2-methylfuran with tert-butyl phenyl(2,4,6-
trimethoxyphenyl)methylcarbamate III-4a in various
catalyst
2.1.1.1.1 Reaction in the presence of 10 mol% of I2
Following the general procedure D, I2 (0.0127 g, 0.05 mmol) was
employed as catalyst. The reaction was stirred at room temperature for 24 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
(0.0701 g, 41%), triarylmethane III-9b (0.0141 g, 22%) and 1,3,5-trimethoxybenzene
III-1a (0.0027 g, 3%).
2.1.1.1.2 Reaction in the presence of 20 mol% of I2
Following the general procedure D, I2 (0.0254 g, 0.10 mmol) was
employed as catalyst. The reaction was stirred at room temperature for 24 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
(0.0562 g, 33%), triarylmethane III-9b (0.0215 g, 34%) and 1,3,5-trimethoxybenzene
III-1a (0.0252 g, 30%).
2.1.1.1.3 Reaction in the presence of 40 mol% of I2
Following the general procedure D, I2 (0.0508 g, 0.20 mmol) was
employed as catalyst. The reaction was stirred at room temperature for 24 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
83
(0.0420 g, 25%), triarylmethane III-9b (0.0226 g, 36%) and 1,3,5-trimethoxybenzene
III-1a (0.0244 g, 29%).
2.1.1.1.4 Reaction in the presence of 50 mg of montmorillonite
K10 clay
Following the general procedure D, montmorillonite K10 clay
(50 mg) was employed as catalyst. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
(0.0308 g, 18%), triarylmethane III-9b (0.0050 g, 8%) and 1,3,5-trimethoxybenzene
III-1a (0.0090 g, 14%).
2.1.1.1.5 Reaction in the presence of 100 mg of montmorillo-
nite K10 clay
Following the general procedure D, montmorillonite K10 clay
(100 mg) was employed as catalyst. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
(0.0470 g, 28%), triarylmethane III-9b (0.0066 g, 10%) and 1,3,5-trimethoxybenzene
III-1a (0.0087 g, 10%).
2.1.1.1.6 Reaction in the presence of 10 mol% of Bi(OTf)3
Following the general procedure D, Bi(OTf)3 (0.0328 g,
0.1 mmol) was employed as catalyst. The reaction was stirred at room temperature for
24 h. The crude product was purified by radial chromatography (SiO2, 100% hexane
to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
(0.0578 g, 34%), triarylmethane III-9b (0.0170 g, 27%) and 1,3,5-trimethoxybenzene
III-1a (0.0087 g, 10%).
2.1.1.1.7 Reaction in the presence of 10 mol% of In(OTf)3
Following the general procedure D, In(OTf)3 (0.0281 g,
0.05 mmol) was employed as catalyst. The reaction was stirred at room temperature
for 24 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane
III-13a (0.0332 g, 20%), triarylmethane III-9b (0.0075 g, 12%) and 1,3,5-
trimethoxybenzene III-1a (0.0078 g, 9%).
84
2.1.1.1.8 Reaction in the presence of 20 mol% of In(OTf)3
Following the general procedure D, In(OTf)3 (0.0562 g,
0.10 mmol) was employed as catalyst. The reaction was stirred at room temperature
for 24 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane
III-13a (0.0456 g, 27%), triarylmethane III-9b (0.0055 g, 9%) and 1,3,5-
trimethoxybenzene III-1a (0.0118 g, 14%).
2.1.1.1.9 Reaction in the presence of 40 mol% of In(OTf)3
Following the general procedure D, In(OTf)3 (0.1867 g,
0.20 mmol) was employed as catalyst. The reaction was stirred at room temperature
for 24 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane
III-13a (0.0625 g, 37%), triarylmethane III-9b (0.0245 g, 39%) and 1,3,5-
trimethoxybenzene III-1a (0.0294 g, 35%).
2.1.1.1.10 Reaction in the presence of 1.1 equivalent of
AlCl3∙6H2O
Following the general procedure D, AlCl3∙6H2O (0.1328 g,
0.55 mmol) was employed as catalyst. The reaction was stirred at room temperature
for 24 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane
III-13a (0.0043 g, 2%), in a small amount of triarylmethane III-9b and 1,3,5-
trimethoxybenzene III-1a (0.0022 g, 3%).
2.1.1.1.11 Reaction in the presence of 10 mol% of FeCl3
Following the general procedure D, FeCl3 (0.0081 g, 0.05 mmol)
was employed as catalyst. The reaction was stirred at room temperature for 24 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-13a
(0.0195 g, 12%), in a small amount of triarylmethane III-9b and 1,3,5-
trimethoxybenzene III-1a (0.0095 g, 11%).
2.1.1.1.12 Reaction in the presence of 10 mol% of FeCl3∙6H2O
Following the general procedure D, FeCl3∙6H2O (0.0135 g,
0.05 mmol) was employed as catalyst. The reaction was stirred at room temperature
85
for 24 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane
III-13a (0.0895 g, 53%), triarylmethane III-9b (0.0139 g, 22%) and 1,3,5-
trimethoxybenzene III-1a (0.0278 g, 33%).
2.1.1.2 Reaction of 2-methylfuran with tert-butyl phenyl(2,4,5-
trimethoxyphenyl)methylcarbamate III-8a in the presence
of 10 mol% of FeCl3∙6H2O
Following the general procedure D, FeCl3∙6H2O (0.0135 g,
0.05 mmol) was employed as catalyst. The reaction was stirred at room temperature
for 1 h. The crude product was purified by radial chromatography (SiO2, 100%
hexane to 20% EtOAc/ hexane as eluent) to give unsymmetrical triarylmethane III-
13b (0.1288 g, 76%) as a sole product.
86
2.2 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various N-Boc
diarylmethylcarbamate as alkylating agent with different arene
under optimized reaction condition
Ar1/Het
HN O
O
Ar2
Ar1/Het
III-4 = Ar1
III-8 = Het
III-13
Ar2 Ar2
III-9 or III-15 III-1
Ar1/Het H10 mol% FeCl3
.6H2O
ClCH2CH2Cl, rt
III-1
R R R
R = H, NO2
Ar2 H
2.2.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4a with different arene
2.2.1.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4a with 2-methylfuran
HN O
O
MeO
MeO OMe
O
ClCH2CH2Cl, rt
MeO
MeO OMe
III-4a III-1c III-13a
OO
OMe
OMeMeO
III-9b
III-1a
10 mol% FeCl3.6H2O
O
Following the general procedure D, tert-butyl phenyl(2,4,6-trimethoxy
phenyl)methylcarbamate III-4a (0.1866 g, 0.5 mmol), 2-methylfuran (0.05 mL,
0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13a (0.0895 g, 53%), triarylmethane
III-9b (0.0139 g, 22%) and 1,3,5-trimethoxybenzene III-1a (0.0278 g, 33%).
87
2.2.2 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl-
carbamate III-8a with different arene
2.2.2.1 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 2-methylfuran
HN O
O
MeO
MeO
O
ClCH2CH2Cl, rt
MeO
MeO
III-8a III-1c III-13b
OO
OMe
MeO
III-9b
III-1b
10 mol% FeCl3.6H2O
O
OMe OMe
OMe
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.1866 g, 0.5 mmol), 2-methylfuran (0.05 mL,
0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 1 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13b (0.1288 g, 76%) as a sole
product.
2.2.2.2 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 2-ethylfuran
HN O
O
MeO
MeO
OMeO
MeO
III-8a III-1d III-13c
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe OMe
O
OO
OMe
MeO
III-9d
III-1b
OMe
88
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.1491 g, 0.4 mmol), 2-ethylfuran (0.04 mL,
0.4 mmol) and FeCl3∙6H2O (0.0108 g, 0.04 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13c (0.1267 g, 95%) as a sole
product.
2.2.2.3 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 2-methylthiophene
HN O
O
MeO
MeO
SMeO
MeO
III-8a III-1e III-13d
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe OMe
S
SS
OMe
MeO
III-9e
III-1b
OMe
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.0933 g, 0.25 mmol), 2-methylthiophene (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 1 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13d (0.0533 g, 60%) as a sole
product.
89
2.2.2.4 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 2-ethylthiophene
HN O
O
MeO
MeO
SMeO
MeO
III-8a III-1f III-13e
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe OMe
S
SS
OMe
MeO
III-9f
III-1b
OMe
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.1495 g, 0.4 mmol), 2-ethylthiophene (0.05 mL,
0.4 mmol) and FeCl3∙6H2O (0.0108 g, 0.04 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13e (0.0983 g, 66%) as a sole
product.
2.2.2.5 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with N-Boc pyrrole
HN O
O
MeO
MeO
NMeO
MeO
III-8a III-1g
III-13f
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe
OMe
N
Boc
Boc
N
BocOMe
OMeMeO
MeO
MeOOMe
III-14aIII-9g
N N
BocBoc
OMe
MeO
III-1b
OMe
90
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.1495 g, 0.4 mmol), N-Boc pyrrole (0.07 mL,
0.4 mmol) and FeCl3∙6H2O (0.0108 g, 0.04 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13f (0.0571 g, 33%) and
unsymmetrical triarylmethane III-14a (0.0612 g, 36%).
2.2.2.6 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 2-ethylpyrrole
HN O
O
MeO
MeO
NHMeO
MeO
III-8a III-1i III-13g
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe OMe
NH
NH
NH
OMe
MeO
III-15a
III-1b
OMe
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.0933 g, 0.25 mmol), 2-ethylpyrrole (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 1 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13g (0.0417 g, 49%) as a sole
product.
91
2.2.1.7 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with indole
HN O
O
MeO
MeO
III-8a III-1h III-13h
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe
OMe
MeO
III-9h
III-1b
OMe
HN NH
NH
MeO
OMe
MeO
NH
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.1868 g, 0.5 mmol), indole (0.0598 g, 0.5 mmol)
and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were employed.
The reaction was stirred at room temperature for 12 h. The crude product was purified
by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent)
to give unsymmetrical triarylmethane III-13h (0.1337 g, 93%) as a sole product.
2.2.1.8 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 5-methoxyindole
HN O
O
MeO
MeO
III-8a III-1j III-13i
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe
OMe
MeO
III-15b
III-1b
OMe
HN NH
NH
MeO
OMe
MeO
NH
MeO
MeO
MeO OMe
92
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.0933 g, 0.25 mmol), 5-methoxyindole (0.0383 g,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 12 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13i (0.0969 g, 96%) as a sole
product.
2.2.1.9 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with 6-fluoroindole
HN O
O
MeO
MeO
III-8a III-1k III-13j
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe
OMe
MeO
III-15c
III-1b
OMe
HN NH
NH
MeO
OMe
MeO
NH
F
F F F
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy
phenyl)methylcarbamate III-8a (0.1495 g, 0.4 mmol), 6-fluoroindole (0.0556 g,
0.4 mmol) and FeCl3∙6H2O (0.0108 g, 0.04 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 12 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13j (0.1272 g, 80%) as a sole
product.
93
2.2.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b or tert-butyl (5-methylfuran-2-yl)(4-nitro-
phenyl)methylcarbamate III 8c with different arene
2.2.3.1 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b with 2-ethylfuran
III-8b III-1d III-13k
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtO
OO
III-9d
III-1c
HN O
O
O
O
O
O
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-ethylfuran (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 1 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13k (0.0640 g, 96%) as a sole
product.
2.2.3.2 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-
methylcarbamate III-8c with 2-ethylfuran
III-8c III-1d III-13l
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtO
OO
III-15d
III-1c
HN O
O
O
O
O
O
NO2NO2 NO2
94
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0827 g, 0.25 mmol), 2-ethylfuran (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (1 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13l (0.0349 g, 59%) as a sole
product.
2.2.3.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b with furfuryl alcohol
III-8b III-1l III-13m
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtO
OO
III-15e
III-1c
OH
HO OH
HN O
O
O
O
O
HO
O
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), furfuryl alcohol
(0.02 mL, 0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl
(2 mL) were employed. The reaction was stirred at room temperature for 24 h.
The crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13m (0.0279
g, 45%) as a sole product.
95
2.2.3.4 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-
methylcarbamate III-8c with furfuryl alcohol
III-8c III-1l III-13n
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtO
OO
III-15f
III-1c
OH
HO OH
HN O
O
O
O
O
HO
O
NO2NO2 NO2
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0664 g, 0.2 mmol), furfuryl alcohol (0.02
mL, 0.2 mmol) and FeCl3∙6H2O (0.0054 g, 0.02 mmol) in ClCH2CH2Cl (1 mL) were
employed. The reaction was stirred at room temperature for 24 h. No reaction was
observed and both starting materials were recovered in quantitative yields.
2.2.3.5 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b with 2-methylthiophene
III-8b III-1e III-13o
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtS
SS
III-9e
III-1c
HN O
O
O
S
O
O
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-methylthiophene (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 4 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 10% EtOAc/hexane as
96
eluent) to give unsymmetrical triarylmethane III-13o (0.0576 g, 86%) as a sole
product.
2.2.3.6 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-
methylcarbamate III-8c with 2-methylthiophene
III-8c III-1e III-13p
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtS
SS
III-15g
III-1c
HN O
O
O
S
O
O
NO2NO2 NO2
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 2-methylthiophene
(0.03 mL, 0.25 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL)
were employed. The reaction was stirred at room temperature for 24 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13p (0.0570
g, 71%) as a sole product.
2.2.3.7 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b with 2-ethylthiophene
III-8b III-1f III-13q
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtS
SS
III-9f
III-1c
HN O
O
O
S
O
O
97
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-ethylthiophene (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (1 mL) were
employed. The reaction was stirred at room temperature for 4 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13q (0.0628 g, 90%) as a sole
product.
2.2.3.8 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-
methylcarbamate III-8c with 2-ethylthiophene
III-8c III-1f III-13r
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtS
SS
III-15h
III-1c
HN O
O
O
S
O
O
NO2NO2 NO2
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 2-ethylthiophene
(0.03 mL, 0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl
(1 mL) were employed. The reaction was stirred at room temperature for 24 h. The
crude product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13r (0.0428
g, 74%) as a sole product.
98
2.2.3.9 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b with N-Boc pyrrole
III-8b III-1g
III-13s
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtN
Boc
N
Boc
III-14bIII-9g
N N
BocBoc
III-1c
HN O
O
O
NBoc
O
O
O O
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), N-Boc pyrrole (0.04 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (1 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13s (0.0472 g, 58%) as a sole
product.
2.2.3.10 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophe-
nyl)methylcarbamate III-8c with N-Boc pyrrole
III-8c III-1g
III-13t
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtN
Boc
N
Boc
III-14cIII-15i
N N
BocBoc
III-1c
HN O
O
O
NBoc
O
O
O O
NO2
NO2NO2 O2N NO2
99
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0665 g, 0.2 mmol), N-Boc pyrrole
(0.04 mL, 0.2 mmol) and FeCl3∙6H2O (0.0054 g, 0.02 mmol) in ClCH2CH2Cl (1 mL)
were employed. The reaction was stirred at room temperature for 24 h. The crude
product was purified by radial chromatography (SiO2, 100% hexane to
20% EtOAc/hexane as eluent) to give unsymmetrical triarylmethane III-13t (0.0431
g, 56%) as a sole product.
2.2.3.11 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)-
methylcarbamate III-8b with 2-ethylpyrrole
III-8b III-1i III-13u
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtNH
NH
NH
III-15a
III-1c
HN O
O
O
O
NH
O
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 2-ethylthiophene (0.03 mL,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13u (0.0063 g, 12%) as a sole
product.
100
2.2.3.12 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophe-
nyl)methylcarbamate III-8c with ethylpyrrole
III-8c III-1i III-13v
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtNH
NH
NH
III-15j
III-1c
HN O
O
O
O
NH
ONO2 NO2 NO2
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 2-ethylpyrrole
(0.03 mL, 0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl
(2 mL) were employed. After stirring the reaction at room temperature for 24 h,
the 20 mol% of FeCl3∙6H2O (0.0135 g, 0.025 mmol) was added to the reaction
mixture at room temperature to 70 oC for 33 h. The crude product was purified by
radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent) to give
unsymmetrical triarylmethane III-13v (0.0081 g, 11%) as a sole product.
2.2.3.13 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)-
methylcarbamate III-8b with indole
III-1h III-13w
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-9h
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8b
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0733 g, 0.25 mmol), indole (0.0302 g, 0.25 mmol)
and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were employed.
101
The reaction was stirred at room temperature for 24 h. The crude product was purified
by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as eluent)
to give unsymmetrical triarylmethane III-15r (0.0627 g, 85%) as a sole product.
2.2.3.14 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophe-
nyl)methylcarbamate III-8c with indole
III-1h III-13x
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-15k
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8c
NO2NO2 NO2
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.1329 g, 0.4 mmol), indole (0.0480 g,
0.4 mmol) and FeCl3∙6H2O (0.0108 g, 0.04 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13x (0.0692 g, 52%) as a sole
product.
2.2.3.15 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)-
methylcarbamate III-8b with 5-methoxyindoleindole
III-1j III-13y
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-15b
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8b
MeO
MeO OMe
MeO
102
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0718 g, 0.25 mmol), 5-methoxyindole (0.0385 g,
0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 1 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13y (0.0416 g, 87%) as a sole
product.
2.2.3.16 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophe-
nyl)methylcarbamate III-8c with 5-methoxyindole
III-1j III-13z
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-15l
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8c
MeO
MeO OMe
MeO
NO2
NO2
NO2
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.0830 g, 0.25 mmol), 5-methoxyindole
(0.0384 g, 0.25 mmol) and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl
(2 mL) were employed. After stirring the reaction at room temperature for 24 h,
the 10 mol% of FeCl3∙6H2O (0.0068 g, 0.025 mmol) was added to the reaction
mixture at room temperature for 3 h. The crude product was purified by radial
chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as eluent) to give
unsymmetrical triarylmethane III-13z (0.0216 g, 24%) as a sole product.
103
2.2.3.17 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)-
methylcarbamate III-8b with 6-fluoroindole
III-1k III-13aa
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-15c
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8b
F
F
F F
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0863 g, 0.3 mmol), 6-fluoroindole (0.0419 g, 0.3
mmol) and FeCl3∙6H2O (0.0083 g, 0.03 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 10% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-15t (0.0789 g, 86%) as a sole
product.
2.2.3.18 Reaction of tert-butyl (5-methylfuran-2-yl)(4-nitrophe-
nyl)methylcarbamate III-8c with 6-fluoroindole
III-1k III-13ab
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-15m
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8c
F
F
F F
NO2
NO2
NO2
104
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8c (0.1661 g, 0.5 mmol), 6-fluoroindole (0.0689
g, 0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13ab (0.0417 g, 24%) as a sole
product.
2.3 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various N-Boc
diarylmethylcarbamate as alkylating agent with indole under
optimized reaction condition
III-10 III-1j III-13
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtAr
HN O
O
ArNH
NH
III-9g
HN NH
Ar-H
III-1
2.3.1 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl-
carbamate III-8a with indole
HN O
O
MeO
MeO
III-8a III-1h III-13h
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
OMe
OMe
MeO
III-9h
III-1b
OMe
HN NH
NH
MeO
OMe
MeO
NH
Following the general procedure D, tert-butyl phenyl(2,4,5-trimethoxy-
phenyl)methylcarbamate III-8a (0.1868 g, 0.5 mmol), indole (0.0598 g, 0.5 mmol)
and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were employed.
The reaction was stirred at room temperature for 12 h. The crude product was purified
105
by radial chromatography (SiO2, 100% hexane to 30% EtOAc/hexane as eluent)
to give unsymmetrical triarylmethane III-13h (0.1337 g, 93%) as a sole product.
2.3.2 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b with indole
III-1h III-13w
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-9h
III-1c
HN NH
NH
HN O
O
O
O
NH
O
III-8b
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(phenyl)methylcarbamate III-8b (0.0733 g, 0.25 mmol), indole (0.0302 g, 0.25 mmol)
and FeCl3∙6H2O (0.0068 g, 0.025 mmol) in ClCH2CH2Cl (2 mL) were employed.
The reaction was stirred at room temperature for 24 h. The crude product was purified
by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as eluent)
to give unsymmetrical triarylmethane III-13w (0.0627 g, 85%) as a sole product.
2.3.3 Reaction of tert-butyl (5-methylthiophen-2-yl)(phenyl)methyl-
carbamate III-8e with indole
III-1h III-13ac
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-9h
III-1e
HN NH
NH
HN O
O
S
S
NH
S
III-8e
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8e (0.1516 g, 0.5 mmol), indole (0.0597 g,
0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were
106
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13ac (0.1418 g, 94%) as a sole
product.
2.3.4 Reaction of tert-butyl 2-((tert-butoxycarbonylamino)(phenyl)-
methyl)-1H-pyrrole-1-carboxylate III-8g with indole
III-1h III-13ad
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
III-9h
III-1g
HN NH
NH
HN O
O
N
N
NH
N
III-8g
Boc Boc
Boc
Following the general procedure D, tert-butyl (5-methylfuran-2-yl)-
(4-nitrophenyl)methylcarbamate III-8g (0.1862 g, 0.5 mmol), indole (0.0597 g,
0.5 mmol) and FeCl3∙6H2O (0.0135 g, 0.05 mmol) in ClCH2CH2Cl (2 mL) were
employed. The reaction was stirred at room temperature for 24 h. The crude product
was purified by radial chromatography (SiO2, 100% hexane to 20% EtOAc/hexane as
eluent) to give unsymmetrical triarylmethane III-13ad (0.1116 g, 60%) as a sole
product.
CHAPTER 4
RESULTS DISCUSSION & CONCLUSION
Results & Discussion
α-Branched amine derivatives and unsymmetrical triarylmethanes are
attractive target molecules because of their applications in medicinal and meterials
chemistry. Method for the synthesis of α-branched amine derivatives have been
developed which mainly centered on Friedel-Crafts alkylation of electron-rich arenes
with aldehydes in the presence of Lewis acids as catalyst. However, most methods
reported to date are multi-step processes, require harsh reaction conditions.
In recently, FeCl3∙6H2O has received considerable attention in organic synthesis
due to their less expensive, readily available, and environmentally benign properties.
These factors led the chemists to pay more attention towards the iron-based catalysis
for mild and green reactions. Moreover, FeCl3∙6H2O has a high tolerance to air
as well as moisture and can be easily removed from reaction systems. Therefore,
we will investigated the possibility of performing FeCl3∙6H2O catalyzed aza-Friedel-
Crafts reaction for the synthesis of α-branched amine derivatives via one-pot three-
component aza-Friedel-Crafts reaction of electron-rich arenes with a series of
aldehydes and tert-butyl carbamate. Furthermore, we will studied a novel efficient
aza-Friedel-Crafts reaction of the resulting α-branched amine products with difference
heteroaromatic or electron-rich arenes, leading to unsymmetrical triarylmethanes.
Ar1 Ar2/R2
HN O
O
H2N O
O
Ar2/R2CHO
FeCl3 6H2O
solvent, 0-rt
Ar1 H
Het H
or
Ar2 = aryl or heteroaryl
R2 = alkyl
Ar1
Ar3
Ar2
solvent, rt
Ar3 H
-Branched amines UnsymmetricalTriarylmethanes
FeCl3 6H2O
Figure 4-1 A model reaction for the synthesis of α-branched amine derivatives and
unsymmetrical triarylmethanes.
108
1. The aza-Friedel-Crafts reaction of arenes with aldehyde and tert-
butyl carbamate in the present of FeCl3∙6H2O: Synthesis of
the corresponding α-branched amine.
In a preliminary study, we developed a simple and efficient synthesis of
N-Boc protected α-branched amine via one-pot three-component aza-Friedel-Crafts
reaction of electron-rich arenes and a combination of aldehydes and tert-butyl
carbamate using FeCl3∙6H2O as catalyst.
1.1 Optimization studies on the reaction of 1,3,5-trimethoxybenzene
with benzaldehyde and tert-butyl carbamate.
Initially, the reaction of 1,3,5-trimethoxybenzene, benzaldehyde and tert-
butyl carbamate in the presence of FeCl3∙6H2O were employed as a model reaction for
the synthesis of α-branched amines (Figure 4-1).
III-1a III-2a
H2N O
O
solvent, rt
FeCl3.6H2O (x mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-3
III-4a
H
O
Figure 4-2 A model reaction for the synthesis of α-branched amines
1.1.1 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and
tert-butyl carbamate in various solvent using FeCl3∙6H2O as
catalyst.
The effect of solvent on FeCl3∙6H2O catalyzed coupling reaction of
1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl carbamate was first
studied. The reaction was carried out employing 10 mol% FeCl3∙6H2O as catalysts
in various solvents such as THF, DMF, CH3NO2, CH3OH, H2O, ClCH2CH2Cl,
toluene and the results are summarized in Table 4-1. In all solvents employed,
the desired product III-4a was obtained in moderate to high yields (35-91%).
From the results, it should be noted that the non-polar and weakly polar solvents
such as toluene and ClCH2CH2Cl, respectively, gave the desired product III-4a
109
in high yields. Decreasing the reaction time was not affect for the chemical yield of
products (86-91%, entries 6-11). When the reaction was carried out in polar solvent
such as CH3NO2 and CH3OH which can be occured the solvation with the catalyst,
the reaction gave the desired product in slightly lower yields (72-81%, entries 3-4).
Moreover, in the case of the highly coordinative solvent with the vacant coordinating
site of Fe(III) such as THF and DMF afforded the desired product in lower yields and
required longer reaction time (36-44%, entries 1-2). Additionally, the reaction
was also performed in water as a reaction medium due to its many advantages from
economic, environmental, and safety standpoints. However, the desired product was
obtained in moderate yield (35%, entry 5). The homogeneity of the reaction media
might be the cause of the lower yield and the longer reaction time when water was
employed as the solvent.
Table 4-1 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl
carbamate in various of solvent.a
III-1a
H2N O
O
solvent, rt
FeCl3.6H2O (10 mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-2a
III-3
III-4a
H
O
Entry FeCl3∙6H2O
(mol %)
Solvent Time (h) Yield III-4ab
(%)
1 10 THF 24 44
2 10 DMF 48 36
3 10 CH3NO2 24 81
4 10 CH3OH 24 72
5 10 H2O/CH3OH 24 35c
6 10 ClCH2CH2Cl 24 86
7 10 ClCH2CH2Cl 12 88
110
Table 4-1 (continued).a
Entry FeCl3∙6H2O
(mol %)
Solvent Time (h) Yield III-4ab
(%)
8 10 ClCH2CH2Cl 2 90
9 10 toluene 24 88
10 10 toluene 12 89
11 10 toluene 2 91
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (10 mol%) in toluene (1 mL) at room temperature. b Isolated yields.
c The reaction was carried out using 4:1 H2O/CH3OH as solvent.
1.1.2 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and
tert-butyl carbamate in various catalyst loading of FeCl3∙6H2O.
To optimize the amount of catalyst, the reactions of 1,3,5-trimethoxy-
benzene, benzaldehyde and tert-butyl carbamate in toluene or ClCH2CH2Cl at room
temperature were selected as a model reaction condition because FeCl3∙6H2O showed
comparable catalytic activity in both solvents. We found that the reaction
in the presence of 5 mol% of FeCl3∙6H2O gave the desired product III-4a in 86% and
89% yields, respectively (entries 2 and 5). When catalytic loading was raised to
10 mol%, the reaction gave the product in comparable yields (entries 1 and 4).
Interestingly, decreasing the catalyst loading to 2.5 mol% and stirring the reaction in
toluene decreased the chemical yield of the product (entry 3). Therefore, 5 mol% of
catalyst loading was found to be the optimal quantity and sufficient to push
the reaction forward.
111
Table 4-2 Reaction of 1,3,5-trimethoxybenzene with benzaldehyde and tert-butyl
carbamate in various catalyst loading.a
III-1a III-2a
H2N O
O
toluene or ClCH2CH2Cl, rt
FeCl3.6H2O (x mol%)
HN O
O
OMe
OMeMeO
MeO
MeO OMe
III-3
III-4a
H
O
Entry FeCl3∙6H2O
(mol %)
Solvent Time (h) Yield III-4ab
(%)
1 10 Toluene 2 91
2 5 Toluene 2 86
3 2.5 Toluene 2 59
4 10 ClCH2CH2Cl 2 90
5 5 ClCH2CH2Cl 2 89
6 2.5 ClCH2CH2Cl 2 80
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (10 mol%) in solvent (1 mL) at room temperature. b Isolated yields.
1.2 The aza-Friedel-Crafts reaction of 1,3,5-trimethoxybenzene, tert-
butyl carbamate in the presence of FeCl3∙6H2O with various
aldehydes under optimized reaction condition.
On the basis of the previously optimized reaction conditions, the scope of
this transformation in the direct three-component aza-Friedel-Crafts reaction of
1,3,5-trimethoxybenzene with a combination of tert-butyl carbamate and a number of
aromatic aldehydes was evaluated (Figure 4-2, Table 4-3 to Table 4-6).
112
III-1a III-2
HNOMe
OMeMeO
MeO
MeO OMe
RR-CHO
H2N O
O
toluene or ClCH2CH2Cl, rt
5 mol% FeCl3.6H2O
III-3
III-4, R = arylIII-6, R = heteroarylIII-7, R = alkyl
O
O
Figure 4-3 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as
catalyst.
1.2.1 The reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and aromatic aldehydes using FeCl3∙6H2O as
catalyst
At the beginning of exploratory studies for the scope of these reaction,
a variety of aromatic aldehydes containing electron-rich, electron-neutral, and
electron-deficient on the aromatic ring underwent one-pot three-component
aza-Friedel-Crafts reaction with 1,3,5-trimethoxybenzene and tert-butyl carbamate
using toluene and ClCH2CH2Cl as solvent were employed (Table 4-3). In the presence
of 5 mol% of FeCl3∙6H2O, 1,3,5-trimethoxybenzene reacted efficiently with tert-
butyl carbamate and a number of aromatic aldehydes possessing either electron-
withdrawing (F, Cl, Br and NO2) or electron-donating (OMe) substituents gave
the corresponding N-protected diarylmethylamines III-4a to III-4h in moderate to
high yields (64-95%). Not only monosubstituted aromatic carbaldehydes were
successful, but the reaction of disubstituted aromatic carbaldehyde under the same
condition also gave the α-branched amine III-4i as a major product in moderate yield.
Furthermore, α,α'-branched amine III-5a was obtained as minor product (Table 4-4).
In comparison to the reaction in toluene and ClCH2CH2Cl, the product yields
in the case of toluene were obtained slightly lower than those in ClCH2CH2Cl, but
the longer reaction time was required. From these results, the method for the synthesis
of α-branched amines was designed to test the effects of substitution on the aromatic
ring of aldehydes in terms of yields and reaction times which using different solvent.
It is observed that substituents on the aromatic ring of aldehydes have a delicate effect
on the reaction process in different solvent. The reaction using toluene as solvent was
113
found to be highly sensitive to the substituted of aromatic aldehyde. The reaction of
electron-rich aromatic aldehydes gave better chemical yield than the reaction of
electron poor aromatic aldehydes. On the other hand, the reaction in the presence of
ClCH2CH2Cl afforded the desired products with comparable yields. The homogeneity
of the reaction media might be the cause of the higher yields and shorter reaction time
when ClCH2CH2Cl was employed as the solvent.
Table 4-3 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with various
aromatic aldehydes.a
III-1a III-2
HNOMe
OMeMeO
MeO
MeO OMe
RR-CHO
H2N O
O
toluene or ClCH2CH2Cl, rt
5 mol% FeCl3.6H2O
III-3
III-4
O
O
Entry R-CHO Products Toluene ClCH2CH2Cl
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
1 H
O
HN O
O
OMeMeO
MeO
2 86
2 90
III-2a III-4a
2 H
O
F
HN O
O
OMeMeO
MeO
F
2 85
3 95
III-2b III-4b
3
F
H
O
HN O
O
OMeMeO
MeO
F
2 83
2 95
III-2c III-4c
114
Table 4-3 (continued).a
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (5 mol%) in toluene (1 mL) at room temperature. b Isolated yields.
Entry R-CHO Products Toluene ClCH2CH2Cl
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
4
Cl
H
O
HN O
O
OMeMeO
MeO
Cl
2 68
2 81
III-2d III-4d
5 H
O
Br
HN O
O
OMeMeO
MeO
Br
2 64
2 87
III-2e III-4e
6
O2N
H
O
HN O
O
OMeMeO
MeO
NO2
2 66
2 89
III-2f III-4f
7
MeO
H
O
HN O
O
OMeMeO
MeO
OMe
2 83
2 80
III-2g III-4g
8 MeO2C
H
O
HN O
O
MeO
MeO OMe CO2Me
4 81
2 82
III-2h III-4h
115
Table 4-4 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with di
substituted aromatic aldehydes.a
III-1a III-2
HNOMe
OMeMeO
MeO
MeO OMe
RH2N O
O
toluene or ClCH2CH2Cl, rt
5 mol% FeCl3.6H2O
III-3
III-4
O
O
H
O
OHC
R-CHO Time
(h)
Products Yields (%)b
H
O
O
H
III-2i
24
HN O
O
MeO
MeOOMe
H O
HN O
O
MeO
MeO
HN
OO
OMe OMe
OMeOMe
III-4i (NR) III-5a (NR)
III-4i (NR)c III-5a (NR)
c
H
O
H
O III-2j
1
HN O
O
MeO
MeO OMe
O
H
HN O
O
MeO
MeO OMe
MeO OMe
OMeNH
O
O
III-4j (52) III-5b (38)
III-4j (53)c III-5b (26)
c
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (5 mol%) in toluene (1 mL) at room temperature. b Isolated yields.
c The
reaction was carried out using FeCl3∙6H2O (5 mol%) in ClCH2CH2Cl (1 mL).
116
1.2.2 The reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and heteroaromatic aldehydes using FeCl3∙6H2O as
catalyst
After that, the synthesis of α-branched heteroarylamines have been
developed by the reaction of heteroaromatic aldehydes with 1,3,5-trimethoxybenzene
and tert-butyl carbamate (Table 4-5). The reaction of 1,3,5-trimethoxybenzene and
tert-butyl carbamate with furfural gave the N-Boc protected diarylmethylamine
III-6a in low yields (entries 1). While, the reaction of 2-pyridinecarbaldehyde with
1,3,5-trimethoxybenzene and tert-butyl carbamate at room temperature was
unsuccessful. Only starting material were recovered from the reaction mixture
(entry 2). However, heating the reaction mixture of 1,3,5-trimethoxybenzene with
2-pyridinecarbaldehyde and tert-butyl carbamate at 80 oC for 3 h afforded
the expected α-branched amine III-6b in moderate to good yield.
Table 4-5 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with
heteroaromatic aldehydes.a
III-1a III-2
HNOMe
OMeMeO
MeO
MeO OMe
HetHet-CHO
H2N O
O
toluene or ClCH2CH2Cl, rt
5 mol% FeCl3.6H2O
III-3
III-6
O
O
Entry R-CHO Products Toluene ClCH2CH2Cl
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
1 H
O
O
HN O
O
MeO
MeO OMeO
24 33
24 11
III-2k III-6a
117
Table 4-5 (continued).a
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (10 mol%) in solvent (1 mL) at room temperature. b Isolated yields.
c The
reaction was carried out in toluene (1.5 mL) at 80 oC.
d The reaction was carried out in
at 80 oC.
1.2.3 The reaction of 1,3,5-trimethoxybenzene with tert-butyl
carbamate and aliphatic aldehydes using FeCl3∙6H2O as
catalyst.
The reaction of 1,3,5-trimethoxybenzene with aliphatic aldehydes and
tert-butyl carbamate was then studied and the results are summarized in Table 4-6.
The reaction of 1,3,5-trimethoxybenzene and tert-butyl carbamate with long chain
aliphatic aldehydes gave the diarylalkanes III-7a to III-7c in moderate to high yields
(entries 1-3). The α-substituted aliphatic aldehydes, isobutyraldehyde and
2-ethylbutanal also proceed smoothly to afford the product III-7d to III-7e in high
yields (entry 4-5). For the β-substituted aliphatic aldehydes (entries 6), the product
III-7f was obtained in moderate to high yields. The reaction of 1,3,5-trimethoxy-
benzene and tert-butyl carbamate with cyclic carbaldehydes such as cyclopropane,
cyclopentane and cyclohexane carboxaldehydes led to the corresponding diaryl-
alkanes III-7g-i in moderate to high yields (entries 7-9). As the results, it should be
noted that the product yields in the case of aliphatic aldehydes depended on
the solvent effect. The reaction of aliphatic aldehyde in toluene gave the products in
excellent yields. Compared to aromatic aldehydes in ClCH2CH2Cl, the aliphatic
Entry R-CHO Products Toluene ClCH2CH2Cl
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
2 N
H
O
HN O
O
MeO
MeO OMeN
3 67c
3 87d
III-2l III-6b
118
aldehydes in ClCH2CH2Cl afforded lower yields of the corresponding α-branched
amines, probably due to the enol formation at the α-hydrogen of carbonyl group.
Table 4-6 Reaction of 1,3,5-trimethoxybenzene, tert-butyl carbamate with aliphatic
aldehydes.a
III-1a III-2
HNOMe
OMeMeO
MeO
MeO OMe
RR-CHO
H2N O
O
toluene or ClCH2CH2Cl, rt
5 mol% FeCl3.6H2O
III-3
III-7 R = alkyl
O
O
Entry R-CHO Products Toluene ClCH2CH2Cl
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
1 O
H
HN O
O
MeO
MeO OMe
2 96
2 69
III-2m III-7a
2 O
H
HN O
O
MeO
MeO OMe
4 96
4 94
III-2n III-7b
3
O
H
HN O
O
MeO
MeO OMe
1 91
1 95
III-2o III-7c
4
O
H
HN O
O
MeO
MeO OMe
1 98
1 99
III-2p III-7d
119
Table 4-6 (continued).a
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (10 mol%) in solvent (1 mL) at room temperature. b Isolated yields.
Entry R-CHO Products Toluene ClCH2CH2Cl
Time
(h)
Yieldb
(%)
Time
(h)
Yieldb
(%)
5 H
O
HN O
O
MeO
MeO OMe
4 81
4 80
III-2q III-7e
6 O
H
HN
O
OMeO
MeO OMe
4 98
4 64
III-2r III-7f
7
O
H
HN O
O
MeO
MeO OMe
2 83
2 64
III-2s III-7g
8 H
O
HN O
O
MeO
MeO OMe
1.5 90
2 68
III-2t III-7h
9 H
O
HN O
O
MeO OMe
MeO
2 96
2 63
III-2u III-7i
120
1.3 The aza-Friedel-Crafts reaction of various arenes, tert-butyl
carbamate with aromatic and aliphatic aldehydes in the presence of
FeCl3∙6H2O under optimized reaction condition.
The one-pot three-component aza-Friedel-Crafts reaction of an array of
arenes or heteroarenes with aldehydes, and tert-butyl carbamates was subsequently
investigated (Figure 4-4 and Table 4-7). The results presented in Table 4-7 showed
that the reactions led to selective formation of α-branched amines in low to high
yields depending on the arenes or heteroarenes substrates.
Ar-H
III-8 R = arylIII-10 R = alkyl
III-2III-1
R-CHOArAr
R+
III-9 R = arylIII-11 R = alkyl
+
Het-H
R = aryl or alkyl
+HN O
O
Ar H
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
Figure 4-4 The one-pot three-component aza-Friedel-Crafts reaction of arenes or
heteroarenes with aldehydes and tert-butyl carbamates.
1.3.1 The aza-Friedel-Crafts reaction of various electron-rich arenes,
tert-butyl carbamate with aromatic and aliphatic aldehydes
under optimized reaction condition.
Under optimized reaction conditions, the scope of the aza-Friedel-Crafts
alkylation of arenes with tert-butyl carbamate and aldehydes in both toluene and
dichloroethane as solvent were also studied and the results are outlined in Table 4-7.
The one-pot three-component aza-Friedel-Crafts reaction in toluene and
dichloroethane were successfully applied to other aromatic and heteroaromatic
compounds with benzaldehyde and tert-butyl carbamate to afford the functionalized
α-branched amines in low to good yields (2-72%, entries 1-17). From the results,
we can conclude that the reaction of the highest electron-rich arene, 1,2,4-trimethoxy-
benzene, gave the corresponding diarylmethylamine III-8a and triarylmethane III-9a
with comparable yield (entries 1-2). The formation of triarylmethane III-9a might be
obtained by addition of a second molecule of 1,2,4-trimethoxybenzene to the resulting
diarylmethyl amine III-8a. While the reaction of oxygen heteroaromatic arene
121
derivatives, 2-methylfuran with benzaldehyde and tert-butyl carbamates in toluene as
solvent gave the compound III-8b in good yields and a trace amount of
triarylmethane III-9b (entry 3). On the other hand, the reaction of 2-ethylfuran in
dichloroethane as solvent proceeded smoothly to afford triarylmethane III-10k in
70%. Gratifyingly, the less reactive nucleophile such as 2-methylthiophene and
2-ethylthiophene, also reactive with benzaldehyde and tert-butyl carbamate in
dichloroethane to provide diarylmethylamines III-8e to III-8f in good yields (entries
8-11). Under the same conditions, N-Boc pyrrole was also tested in the raction and
the desired α-branched amine adduct was observed in low yields (24-29%, entries
12-13). These might be explaned by the N-Boc protective group of pyrrole had steric
interactive and electronic effects which results in lower yields of the product.
It should be noted that no side product was obtained in these case. Notably, when
unprotected indole was employed as reactive nucleophile in the reaction mixture
under low reaction concentration and low temperature, the side product which derived
from bisarylation of aldehyde, was observed as a major product (entries 14-17).
Subsequently, the scope of arenes with tert-butyl carbamate and aliphatic
aldehyde were examined and the results are shown in entries 18 to 29. Under the same
aromatic aldehyde condition, all the case of arenes with a combination of tert-butyl
carbamate and aliphatic aldehyde, isobutyraldehyde, gave α-branched amine adducts
III-10a to III-10f in low to excellent yields. Interestingly, the chemical yields of
α-branched amines in the case of aliphatic aldehyde were higher than those of
aromatic aldehyde except in the case of thiophene (entries 24-27). These could be
due to the rate of keto-tautomerism of isobutyraldehyde was lower than the rate of
imine formation in the reaction media. Therefore, the electrophilicity aliphatic imines
derived from aliphatic aldehydes were reacted with a collection of arenes rather than
the less electrophilicity aromatic imines derived from aromatic aldehydes to afford the
desired α-branched amines in higher yields and trace amount of triarylmethane as a
side product. Moreover, the reaction of N-Boc protected pyrrole was occured
compound III-12a as a side product (entries 27-28).
122
Table 4-7 Reaction of various arenes, tert-butyl carbamate with benzaldehyde,
2-methylpropanal under the optimized reaction condition.a
Ar-H
III-8 R = arylIII-10 R = alkyl
III-2III-1
R-CHOArAr
R+
III-9 R = arylIII-11 R = alkyl
+
Het-H
R = aryl or alkyl
+HN O
O
Ar H
toluene or ClCH2CH2Cl, rt
III-3H2N O
O
FeCl3.6H2O (5 mol%)
Entry Ar-H Time
(h)
Products Yieldsb
(%)
1 OMe
MeO
OMe
24 HN O
O
MeO
OMe
MeO
67
OMe
MeO
OMe OMe
OMe
OMe
32
2 24 56c 44
c
III-1b III-8a III-9a
3
O
III-1c
2 HN O
O
O
72 O O
4
4 2 64c 36
c
III-8b III-9b
5 24 HN O
O
ONO2
66d
O O
NO2
4d
III-8c III-9c
6
O
2 HN O
O
O
65d
O O
17d
7 2 29c 70
c
III-1d III-8d III-9d
123
Table 4-7 (continued).a
Entry Ar-H Time
(h)
Products Yieldsb
(%)
8
S
3 HN O
O
S
22d S S
-d,e
9 3 57c 4
c
III-1e III-8e III-9e
10
S
2 HN O
O
S
9 S S
-e
11 2 27c -
c,e
III-1f III-8f III-9f
12 N
Boc
3 HN O
O
N
Boc
24d N N
Boc Boc
12
13 24 29c 13
III-1g III-8g III-9g
14
NH
0.5
HN O
O
HN
4f
HN NH
41f
15 2 5f 72
f
16 7 3g 27
g
17 0.28 2h 42
h
III-1h III-8h III-9h
18
OMe
MeO
OMe
24 HN O
O
MeO
OMe
MeO
63
OMe
MeO
OMe OMe
OMe
OMe
9
19 24 64c 25
c
III-1b III-10a III-11a
124
Table 4-7 (continued).a
Entry Ar-H Time
(h)
Products Yieldsb
(%)
20
O
24 HN O
O
O
80 OO
-e
21 24 89c -
c,e
III-1c III-10b III-11b
22 O
2 HN O
O
O
96 O O
3
23 2 98c 1
c
III-1d III-10c III-11c
24
S
1 HN O
O
S
6
S S
-e
25 4 37 -c,e
III-1e III-10d III-11d
26 S
2 HN O
O
S
12 S S
-e
27 2 13 -c,e
III-1f III-10e III-11e
28
N
Boc
24 HN O
O
N
Boc
15i
N N
Boc Boc
-e,i
29 24 42
-c,e,j
III-1g III-10f III-11f
a Reaction conditions: III-1a (1.0 mmol), III-2a (1.1 mmol), III-3 (1.0 mmol),
FeCl3∙6H2O (5 mol%) in solvent (1 mL) at room temperature. b Isolated yields.
c The
reaction was carried out using FeCl3∙6H2O (5 mol%) in ClCH2CH2Cl (1 mL).d The
reaction was carried out in toluene (1.5 mL). e No reaction based on TLC analysis.
f The reaction was carried out in toluene (15 mL) at 0
oC.
g The reaction was carried
125
out using FeCl3∙6H2O (10 mol%) in toluene (15 mL) at -40 oC to room temperature.
h The reaction was carried out in ClCH2CH2Cl (15 mL) at 0
oC.
i The reaction was
carried out in toluene (1.5 mL) and gave (syn or anti)-III-12a as minor product in 5%
(0.0123 g). j The reaction gave (syn or anti)-III-12a as minor product in 34% (0.0868 g).
On the basis of the literature information (Li et al., 2008; Thirupathi & Kim,
2010; Thirupathi, Neupane, & Lee, 2011; Jaratjaroonphong, Tuengpanya, &
Ruengsangtongkul, 2015) and our experimental results, a plausible explanation of
the mechanism is depicted in Figure 4-4. The first step is the formation of I, which is
formed by coordination of the aldehyde to FeCl3∙6H2O. Condensation of I with tert-
butyl carbamate gives the resulting activated N-Boc imine II. The nucleophilic
addition of 1,2,4-trimethoxybenzene III-1b attacks the resulting imine II, leading to
the formation of the desired amine III-8a. Further, the formation of triarylmethane
III-9a could be explained by addition of a second 1,2,4-trimethoxybenzene to
the reactive intermediate IV, which is generated by Fe(III) ion catalyzed carbamate
elimination of III-8a.
126
H R
OFeIII
H2N O
O
H R
N O
OFeIII
FeIII
R
MeO
OMe
MeOH
N O
OFeIII
HN
R
MeO
OMe
MeO
O
O
FeIII +
R
MeO
OMe
MeO
NHBocFeIII
OMe
OMe
MeO
H R
O
OMe
OMe
MeOR
MeO
OMe
MeO
OMe
OMe
MeO
I
II
IIIIII-8a
IV
III-3
III-1b
III-9aIII-1b
FeIII
Figure 4-5 Plausible reaction mechanism.
127
2. The Friedel-Crafts reaction of electron-rich arenes with N-Boc
diarylmethylcarbamate: Synthesis of the corresponding
unsymmetrical triarylmethanes
In previous work, the reaction of electron-rich arenes with a combination of
aldehydes and tert-butyl carbamate using FeCl3∙6H2O as catalyst leading to N-Boc
diarylmethylcarbamate or α-branched amine derivatives was successful. We then
studied the Friedel-Crafts reaction by using N-Boc diarylmethylcarbamates as an
alkylating agent for the efficient synthesis of unsymmetrical triarylmethanes (Figure
4-4).
Ar1 Ar2
HN O
O
Ar1
Ar3
Ar2
FeCl3.6H2O
solvent, rt
Ar3 H
-Branched amines UnsymmetricalTriarylmethanesor
N-Boc diarylmethylcarbamates
Figure 4-6 A model reaction for the synthesis of unsymmetrical triarylmethanes using
FeCl3∙6H2O as the catalyst.
2.1 Optimization of the reaction condition for Friedel-Crafts reaction of
2-methylfuran with N-Boc diarylmethylcarbamates
For initial optimization of the reaction conditions, tert-butyl phenyl(2,4,6-
trimethoxyphenyl)methylcarbamate (III-4a) or tert-butyl phenyl(2,4,5-trimethoxy-
phenyl)methylcarbamate (III-8a) with 2-methylfuran (III-1c) using FeCl3∙6H2O as
the catalyst at room temperature were chosen as model reaction for the synthesis of
unsymmetrical triarylmethanes III-13 (Figure 4-5).
128
Ar
HN O
O
O
catalyst (x mol%)
ClCH2CH2Cl, rt
Ar
III-4a or III-8a III-1c III-13
OO
III-9b III-1
OAr-H
Ar = 1,3,5-trimethoxybenzene, III-4a= 1,2,4-trimethoxybenzene, III-10a
III-13a, Ar = 1,3,5-trimethoxybenzeneIII-13b, Ar = 1,2,4-trimethoxybenzene
Figure 4-7 A model reaction for the synthesis of unsymmetrical triarylmethanes of
N-Boc diarylmethylcarbamate III-4a or III-8a and 2-methylfuran.
2.1.1 Reaction of 2-methylfuran with N-Boc diarylmethylcarbamate
in various catalyst
Preliminary investigation revealed that the species of catalyst had a
significant influence on the reaction of N-Boc diarylmethylcarbamate with 2-methyl-
furan. The results for the reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)-
methylcarbamate (III-4a) with 2-methylfuran in the presence of various Lewis acid
using dichloroethane as solvent at room temperature are summarized in Table 4-8.
One of the most efficient catalysts was FeCl3∙6H2O which can be catalyzed
the reaction to afford the desired unsymmetrical triarylmethane III-13a in moderate
yield (entry 12). Moreover, the undesired product III-9b and 1,3,5-trimethoxybenzene
which might be obtained via retro aza-Friedel-Crafts reaction of the starting material
III-4a were isolated in 22% and 33%, respectively. Meanwhile, I2 gives the desired
product in moderate yield. Again, the compounds III-9b and 1,3,5-trimethoxybenzene
were also found. When the less sterically N-Boc diarylmethyl carbamate, tert-butyl-
phenyl(2,4,5-trimethoxyphenyl)methylcarbamate (III-8a) was used as alkylating
agent to react with 2-methylfuran in the presence of FeCl3∙6H2O (10 mol%),
the reaction proceed smoothly to afford the desired product III-13a in high yield
(88%). Furthermore, no side product was obtained. Base on these results, FeCl3∙6H2O
was chosen as the Lewis acid catalyst for the synthesis of unsymmetrical
triarylmethanes III-13.
129
Table 4-8 Reaction of N-Boc diarylmethylcarbamates and 2-methylfuran in various
catalysts loading.a
Ar
HN O
O
O
catalyst (x mol%)
ClCH2CH2Cl, rt
Ar
III-4a or III-8a III-1c III-13
OO
III-9b III-1
OAr-H
Ar = 1,3,5-trimethoxybenzene, III-4a= 1,2,4-trimethoxybenzene, III-8a
III-13a, Ar = 1,3,5-trimethoxybenzeneIII-13b, Ar = 1,2,4-trimethoxybenzene
Entry Catalyst Mol % Time
(h)
Products Yields (%)b
III-13 III-9b III-1
1 I2 10 24 III-13a (41) 22 III-1a (3)
2 I2 20 24 III-13a (33) 34 III-1a (30)
3 I2 40 24 III-13a (25) 36 III-1a (29)
4 Montmorillonite 50 mg 24 III-13a (18) 8 III-1a (14)
5 Montmorillonite 100 mg 24 III-13a (28) 10 III-1a (10)
6 Bi(OTf)3 10 24 III-13a (34) 27 III-1a (10)
7 In(OTf)3 10 24 III-13a (20) 12 III-1a (9)
8 In(OTf)3 20 24 III-13a (27) 9 III-1a (14)
9 In(OTf)3 40 24 III-13a (37) 39 III-1a (35)
10 AlCl3∙6H2O 1.1 eq 24 III-13a (2) trace III-1a (3)
11 FeCl3 10 24 III-13a (12) trace III-1a (11)
12 FeCl3∙6H2O 10 24 III-13a (53) 22 III-1a (33)
13 FeCl3∙6H2O 10 1 III-13b (76) - III-1b (-)
a Reaction conditions: III-4a or III-8a (0.5 mmol), III-1c (0.5 mmol) in ClCH2CH2Cl
(2 mL) at room temperature. b Isolated yields.
130
On the basis of the literature information (Jaratjaroonphong, Tuengpanya, &
Ruengsangtongkul, 2015) and our experimental results, a plausible explanation of
the mechanism is depicted in Figure 4-8. The first step is the formation of I, which is
formed by coordination of carbonyl group of N-Boc protected diarylmethyl amine to
FeCl3∙6H2O. Then, elimination of carbamate group and generated benzylic
carbocation II. The nucleophilic addition of 2-methylfuran III-1c to the resulting
carbocation II, gave the formation of the desired unsymmetrical triarylmethane
III-13a. Further, the formation of side products III-9b and III-1a could be explained
by ortho-directing, methoxy group of 2,4,6-trimethoxyphenyl ring donated ion pair to
the aromatic system in the intermediate I and follow by replacement of hydrogen at
N-H position gave the oxonium ion III. Then, Fe(III) catalyzed retro aza-Friedel-
Crafts reaction of III gave 1,3,5-trimethoxybenzene and reactive imine IV which
could then reacted with 2-methylfuran gave α-branched amine intermediate V and
followed by the formation of triarylmethane III-9b via nucleophilic addition of
2-methylfuran to intermediate VII as showed in Figure 4-5.
131
HN O
O
MeO OMe
MeO
FeCl3 6H2O
HN O
O
MeO OMe
MeO
FeIII
MeO OMe
MeO
MeO OMe
MeOO
N O
O
MeO OMe
MeO
FeIII
H
OMe
MeO OMeH
N O
O
HN O
O
O
FeIII HN O
O
FeIII
O
O
O
O
III-4a
I II
III-13a
III
III-1a
III-9b
IV
V VI VII
OIII-1c
OIII-1c
OIII-1c
Figure 4-8 Plausible reaction mechanism.
132
2.2 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various N-Boc
diarylmethylcarbamates as alkylating agent with different arene
under optimized reaction condition
Following the optimization of the reaction conditions, the aza-Friedel-Crafts
alkylation of different arenes, including five-membered heteroaromatic system such
derivatives of furan, thiophene, pyrrole and indole with various N-Boc diarylmethyl-
carbamates in the presence of FeCl3∙6H2O (10 mol%) at room temperature were
carried out to extend the scope of the reaction and the results are shown in Figure 4-9
and Table 4-9 to 4-11.
Ar1/Het
HN O
O
Ar2
Ar1/Het
III-4 = ArIII-8 = Het
III-13
Ar2 Ar2
III-9 or III-15 III-1
Ar1/Het H10 mol% FeCl3
.6H2O
ClCH2CH2Cl, rt
III-1
R R R
R = H, NO2
Ar2 H
Figure 4-9 The synthesis of unsymmetrical triarylmethane derivatives using
FeCl3∙6H2O as the catalyst.
2.2.1 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4a with 2-methylfuran
From our methodology for the synthesis of α-branched amines,
the reaction of 1,3,5-trimethoxybenzene and a combination of benzaldehyde and
tert-butyl carbamate as starting material for in situ N-Boc imine preparation
in the presence of 5 mol% of FeCl3∙6H2O as catalyst, gave the formation of only
corresponding α-branched amine adduct III-4a. Therefore, we interested in the use of
these products as alkylating substrate for the C-C bond-forming reaction by reacting
with 2-methylfuran in dichloroethane using FeCl3∙6H2O (10 mol%) as catalyst.
The results presented in Table 4-9 showed that the reaction gave unsymmetrical
triarylmethane III-13a in 53% yield. However, compounds III-9b and III-1a were
also isolated as side products in 22% and 33% yields, respectively.
133
Table 4-9 Reaction of tert-butyl phenyl(2,4,6-trimethoxyphenyl)methyl carbamate
III-4a with different arene.a
HN O
O
MeO
MeO OMe
O
ClCH2CH2Cl, rt
MeO
MeO OMe
III-4a III-1c III-13a
OO
OMe
OMeMeO
III-9b
III-1a
10 mol% FeCl3.6H2O
O
Arene Time
(h)
Products Yields (%)b
III-13a III-9b III-1a
O
1c
24 O
MeO
MeO OMe
OO
OMe
OMeMeO
53 22 33
a Reaction conditions: III-4a (0.5 mmol), III-1c (0.5 mmol) in ClCH2CH2Cl (2 mL)
at room temperature. b Isolated yields.
2.2.2 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methyl-
carbamate III-8a with different arene
The scope of the reaction under the optimized conditions (Table 4-8, entry
12) was investigated by tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate
III-8a with other activated arenes in the presence of 10 mol% FeCl3∙6H2O in
dichloroethane at room temperature and the results are outlined in Table 4-10.
The reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate III-8a
with 2-methylfuran or 2-ethylfuran in dichloroethane at room temperature gave
the product III-13b and III-13c in high yields (76% and 95% yields, respectively)
(entries 1 and 2). The less reactive heteroaromatic areane, 2-methylthiophene reacted
with tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate III-8a under
134
the optimized condition at room temperature for 24 h to afford the corresponding
unsymmetrical triarylmethane III-13d in moderate yield (entry 3). Similarly, when
using 2-ethylthiophene as nucleophile was occurred unsymmetrical triarylmethane
adduct III-13e in comparable yield (entry 4). Under the same condition, when N-Boc
pyrrole was used as a nucleophile, the reaction showed steric and electronic effect that
was responsible in low yield of the desired product III-13f (33%, entry 5). As we
expected that unsymmetrical triarylmethane adduct III-14a derived from double
nucleophilic addition at C-2 and C-5 position of N-Boc pyrrole was obtaine as the side
product in 36% yield. While the reaction of N-H unprotected pyrrole, 2-ethylpyrrole,
gave unsymmetrical triarylmethane III-13g in 49% yield (entry 6). Interestingly,
the reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate III-8a with
reactive indole derivatives such as indole, 5-methoxy and 6-fluoroindole led to
selective formation of unsymmetrical triarylmethane in 93%, 96% and 80% yields,
respectively (entries 7-9).
To comparing the reactivity of heteroaromatic arenes such as furan,
thiophene, pyrrole and indole derivatives, we found that the nucleophilicity of indole
derivatives were higher reactivity than the other heteroarenes which could be reacted
with N-Boc protected diarylmethyl amines to give the resulting unsymmetrical
triarylmethanes in high to excellent yields. Moreover, indole containing fluoro and
methoxy substitutent on the 6 and 5 position, respectively, showed only slightly effect
on the yields of products. Considering the five-membered heteroaromatic arenes,
furan derivatives were more reactive than thiophene and pyrrole to give the desired
product in higher than yields another. Interestingly, the less reactive arenes such as
thiophene derivatives gave the yield of the desired unsymmetrical triarylmethanes
more than pyrrole derivatives. Therefore, indole derivatives are the most reactive
arenes, follow by furan, thiophene and pyrrole derivatives, respectively.
135
Table 4-10 Reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate
III-8a with different arene.a
HN O
O
MeO
MeO ClCH2CH2Cl, rt
III-10a III-1
10 mol% FeCl3.6H2O
OMe
Het-H
MeO
MeO
OMe
Het
III-13
Entry Het-H Time
(h)
Products Yields
(%)b
1 O
III-1c 1
OMeO
MeO
OMe
III-13b 76
2 O
III-1d 4 O
MeO
MeO
OMe
III-13c 95c
3 S
III-1e 24
SMeO
MeO
OMe
III-13d 60d
4 S
III-1f 24 S
MeO
MeO
OMe
III-13e 66c
136
Table 4-10 (continued).a
Entry Het-H Time
(h)
Products Yields
(%)b
5 N
Boc
III-1g 24
NMeO
MeO
OMe
Boc
III-13f 33c,e
6 NH
III-1i 1 NH
MeO
MeO
OMe
III-13g 49d
7 NH
III-1h 12
NH
MeO
OMe
MeO
III-13h 93
8 NH
MeO
III-1j 12
NH
MeO
OMe
MeO
MeO
III-13i 96d
9 NH
F III-1k 12
NH
MeO
OMe
MeO
F
III-13j 80c
a Reaction conditions: III-8a (0.5 mmol), III-1 (0.5 mmol), FeCl3∙6H2O (10 mol%) in
ClCH2CH2Cl (2 mL) at room temperature. b Isolated yields.
c The reaction was carried
out using III-8a (0.4 mmol), III-1 (0.4 mmol), FeCl3∙6H2O (10 mol%) in
ClCH2CH2Cl (2 mL) at room temperature. d The reaction was carried out using III-8a
(0.25 mmol), III-1 (0.25 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (2 mL) at
room temperature. e The reaction gave the mixture of syn-III-14a and anti-III-14a as
minor product which can not be separated.
137
2.2.3 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarba-
mate III-10b or tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)-
methylcarbamate III-10k with different arenes
We then explored the synthesis of unsymmetrical triarylmethanes
containing a biological active furan ring by Friedel-Crafts reaction of N-Boc
diarylmethylcarbamate III-8b and III-8c with a collection of heteroarenes in the
presence of FeCl3∙6H2O as catalyst and investigated the effect of nitro group as
substituent on the aromatic ring at the para position. The results are summarized in
Table 4-11. The results presented in Table 4-11 showed that all the reactions gave
selective formation of unsymmetrical triarylmethane derivatives III-13k-ab. Initially,
N-Boc diarylmethylcarbamate III-8b was treated with 2-ethylfuran to provide
the product III-13k in excellent yield (entry 1). Under the same condition, when
N-Boc diarylmethylcarbamate III-8c was used, the desired product III-13l was
isolated in lower yield (59%, entry 2). The reaction of furfuryl alcohol with N-Boc
diarylmethyl-carbamate III-8b also gave the desired product III-13m in 45% yield.
On the other hand, no reaction was observed, when N-Boc diarylmethylcarbamate III-
8c was used as alkylating agent. The reaction of less reactive nucleophile such as
2-methylthiophene and 2-ethylthiophene with N-Boc diarylmethylcarbamates III-8b
or III-8c in the presence of FeCl3∙6H2O (10 mol%) gave compounds III-8b and
III-8c in moderate to high yields (entries 5-8). Both the reaction of N-Boc pyrrole
with N-Boc diarylmethylcarbamate III-8b and III-8c provided the compounds
III-13s-t in moderate yields (entries 9-10). Meanwhile, 2-ethylpyrrole reacted with
N-Boc diarylmethylcarbamates III-8b or III-8c in similar conditions gave
the corresponding unsymmetrical triarylmethanes with 12% and 11% yields,
respectively (entries 11-12). In the case of indole derivatives such as indole,
5-methoxy and 6-fluoroindole reacted with with N-Boc diarylmethylcarbamate III-8b
smoothly to afford the desired products in 85%, 87% and 86% yields, respectively
(entries 13, 15 and 17). Futhermore, changing the N-Boc diarylmethylcarbamate
III-8b to N-Boc diarylmethylcarbamate III-8c to react with indole provided
the product III-13x in moderate yield (52%, entry 13). However, the reaction of
5-methoxyindole with N-Boc diarylmethylcarbamate III-8c in the presence of
FeCl3∙6H2O (20 mol%) under dichloroethane solution gave the desired product
138
III-13z in low yield (entry 16). Similarly, the reaction of 6-fluoroindole with N-Boc
diarylmethylcarbamate III-8c provided the desired product III-13ab in 24% yield
(entry 18).
Table 4-11 Reaction of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate
III-8b or tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methylcarba-
mate III-8c with different arene.a
III-8 III-1 III-13
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rt
HN O
O
O
Het
O
Het-H
R RR = H, III-10b
= NO2, III-10k
Entry Het-H
Products R Time
(h)
Yields (%)b
1
O III-1d
O
OR
H 1 III-13k (96)
2 NO2 24 III-13l (59)c
3
O
OH
III-1l
O
O
HO
R
H 24 III-13m (45)
4 NO2 24 III-13n (NR)d
5
S III-1e
S
OR
H 4 III-13o (86)
6 NO2 24 III-13p (71)
7
S III-1f
S
OR
H 4 III-13q (90)c
8 NO2 24 III-13r (74)c
139
Table 4-11 (continued).a
Entry Het-H
Products R Time
(h)
Yields (%)b
9 N
Boc
III-1g
NBoc
OR
H 24 III-13s (58)c
10 NO2 24 III-13t (56)d
11
NH
III-1i NH
OR
H 24 III-13u (12)
12 NO2 57 III-13v (11) e
13 NH
III-1h
NH
OR
H 24 III-13w (85)
14 NO2 24 III-13x (52)f
15
NH
MeO
III-1j
NH
O
MeO
R
H 1 III-13y (87)
16 NO2 27 III-13z (24)g
17
NH
F III-1k
NH
O
F
R
H 24 III-13aa (86)h
18 NO2 24 III-13ab (24)i
a Reaction conditions: III-8 (0.25 mmol), III-1 (0.25 mmol), FeCl3∙6H2O (10 mol%)
in ClCH2CH2Cl (2 mL) at room temperature. b Isolated yields.
c The reaction was
carried out using III-8 (0.25 mmol), III-1 (0.25 mmol), FeCl3∙6H2O (10 mol%) in
ClCH2CH2Cl (1 mL) at room temperature. d
The reaction was carried out using III-8
(0.2 mmol), III-1 (0.2 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (1 mL) at
room temperature. e
The reaction was carried out using FeCl3∙6H2O (30 mol%) at
room temperature to 70 oC.
f The reaction was carried out using III-8 (0.4 mmol), III-
140
1 (0.4 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (2 mL) at room temperature. g
The reaction was carried out using FeCl3∙6H2O (20 mol%). h The reaction was carried
out using III-8 (0.3 mmol), III-1 (0.3 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl
(2 mL) at room temperature. i The reaction was carried out using III-8 (0.5 mmol),
III-1 (0.5 mmol), FeCl3∙6H2O (10 mol%) in ClCH2CH2Cl (2 mL) at room
temperature.
2.3 FeCl3∙6H2O catalyzed Friedel-Crafts alkylation of various N-Boc
diarylmethylcarbamate as alkylating agent with indole under
optimized reaction condition
Base on the optimization conditions, the Friedel-Crafts reaction of wide
range a biologically active indole with various N-Boc diarylmethylcarbamate in the
presence of FeCl3∙6H2O (10 mol%) leading to the unsymmetrical triarylmethane
containing indole ring was then carried out. The results are shown in Table 4-12.
As the results, the reaction of tert-butyl phenyl(2,4,5-trimethoxyphenyl)-
methylcarbamate III-8a with indole in dichloroethane at room temperature for 12 h
proceeded smoothly to provide the product III-13h in excellent yield (93%, entry 1).
Under the same condition, when tert-butyl (5-methylfuran-2-yl)(phenyl)methyl-
carbamate III-8b was used as an alkylating agent, the desired product III-13w was
obtained in 85% (entry 2). Gratifyingly, the less reactive alkylating agent of
tert-butyl-(5-methyl-thiophen-2-yl)(phenyl)methylcarbamate also gave expected
product in excellent yield (94%, entry 3). The reaction of sterically alkylating agent,
tert-butyl 2-((tert-butoxycarbonyl-amino)(phenyl)methyl)-1H-pyrrole-1-carboxylate
with indole also afforded the corresponding unsymmetrical triarylmethane III-13ad in
moderate yield (60%, entry 4).
141
Table 4-12 Reaction of various N-Boc diarylmethylcarbamate as alkylating agent
with indole.a
III-8 III-1h III-13
10 mol% FeCl3.6H2O
ClCH2CH2Cl, rtAr
HN O
O
ArNH
NH
Entry III-8 Time
(h)
Products Yields
(%)b
1
HN
MeO
OMe
MeO
O
O
III-8a 12
NH
MeO
OMe
MeO
III-13h 93
2 HN
O
O
O
III-8b 24
NH
O
III-13w 85c
3 HN
O
O
S
III-8e 24
NH
S
III-13ac 94
4 HN
O
O
N
Boc
III-8g 24
NH
N
Boc
III-13ad 60
a Reaction conditions: III-8 (0.5 mmol), III-1h (0.5 mmol), FeCl3∙6H2O (10 mol%) in
ClCH2CH2Cl (2 mL) at room temperature. b Isolated yields.
c The reaction was carried
out using III-8 (0.25 mmol), III-h (0.25 mmol), FeCl3∙6H2O (10 mol%) in
ClCH2CH2Cl (2 mL) at room temperature.
142
Conclusions
1. The synthesis of α-branched amine derivatives using FeCl3∙6H2O as catalyst.
We have developed a simple, and efficient procedure for the preparation of
N-Boc protected α-branched amine derivatives through one-pot three-components
aza-Friedel-Crafts reactions of arenes with a combination of aldehydes, and tert-butyl
carbamate using FeCl3∙6H2O (5 mol%) as catalyst in toluene and dichloroethane at
room temperature. Mild reactions conditions low, catalyst loading, and one-step
synthesis are advantages of the present procedure.
III-1
Ar1-HHN
Ar1 Ar2/ Het/ R2or
Het-H
Ar2/ Het/ R2CHO
III-4 Ar = arylIII-6 Het = heteroylIII-7 R = alkyl
+
III-2
H2N O
O
toluene or ClCH2CH2Cl, rt
FeCl3.6H2O (10 mol%)
III-3
O
O
Figure 4-10 The synthesis of α-branched amine derivatives using FeCl3∙6H2O as
catalyst
2. The synthesis of unsymmetrical triarylmethane derivatives.
We have developed a simple and practical method for the synthesis of
unsymmetrical triarylmethanes via Friedel-Crafts reaction of electron-rich hetero-
aromatic arenes with various N-Boc diarylmethylcarbamates as alkylating agent using
FeCl3∙6H2O (10 mol%) as catalyst in dichloroethane at room temperature. Typically,
the corresponding unsymmetrical triarylmethanes were obtained in low to high yields.
The use of mild reaction conditions, low catalytic loading, less expensive, readily
available, and environmentally benign iron catalyst and high selective synthesis are
advantages of the present procedure.
143
Ar1 Ar2
HN O
O
Ar1
Ar3
Ar2FeCl3
.6H2O (10 mol%)
ClCH2CH2Cl, rt
Ar3 H
III-4 or III-8 III-1 III-13
Figure 4-11 The synthesis of unsymmetrical triaylmethane derivatives using
FeCl3∙6H2O as catalyst
Compound characterizations
All products were characterized by spectroscopic methods (NMR, IR, and HRMS)
Spectral data of α-branched amine derivatives
HN
O
OMeO
MeO OMe
Figure 4-12 Structure of tert-butyl[(2,4,6-trimethoxyphenyl)phenylmethyl]carbamate
III-4a
Compound III-4a: A white solid; m.p. 132-133 oC; Rf = 0.27 (2:8 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3): δ 7.26-7.24 (m, 4H, ArH), 7.17-7.16 (m, 1H,
ArH), 6.60 (d, J = 10.2 Hz, 1H, NH), 6.27 (d, J = 10.2 Hz, 1H, CHPh), 6.17 (s, 2H,
ArH), 3.83 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H, 3xCH3); 13
C NMR (100
MHz, CDCl3): δ 160.6 (C), 158.6 (C), 155.7 (C), 143.6 (C), 127.9 (CH), 126.1 (CH),
125.9 (CH), 111.2 (C), 91.2 (CH), 79.0 (C), 55.9 (OCH3), 55.4 (OCH3), 48.2 (CHPh),
28.6 (CH3); IR (film): νmax 3456 (N-H), 2975, 2939, 2840, 1713, 1593, 1494, 1455,
1419, 1365, 1234, 1205, 1154, 1127, 1042, 1017, 951 cm-1
; HRMS (ESI-TOF) calcd
for C21H27NO5Na [M+Na]+ 396.1787, found 396.1782.
144
HN
O
OMeO
MeOOMe F
Figure 4-13 Structure of tert-butyl (2-fluorophenyl)(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4b
Compound III-4b: A white solid; m.p. 128-129 oC; Rf = 0.28 (2:8 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3):δ 7.33 (t, J = 7.7 Hz, 1H, ArH), 7.15 (q,
J = 6.1 Hz, 1H, ArH), 7.03 (t, J = 7.4 Hz, 1H, ArH), 6.93 (t, J = 9.4 Hz, 1H, ArH),
6.77 (d, J = 9.9 Hz, 1H, NH), 6.14 (s, 2H, ArH), 6.07 (d, J = 9.9 Hz, 1H, CHPh), 3.81
(s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.46 (s, 9H, 3xCH3); 13
C NMR (100 MHz,
CDCl3): δ 160.7 (C), 160.5 (1J = 247.0 Hz, C-F), 158.7 (C), 155.1 (C), 130.0
(2J
= 14.0Hz, C-F), 128.2, (
3J
= 4.0 Hz, C-F), 127.9 (
3J
= 8.0 Hz, CH-F), 123.1
(4J
= 2.0 Hz, CH-F), 115.4 (
2J
= 22.0 Hz, C-F), 110.0 (C), 91.2 (CH), 79.2 (C), 55.9
(OCH3), 55.3 (OCH3), 44.0 (CHPh), 28.5 (CH3); IR (film): νmax 3457 (N-H), 2975,
2939, 1717, 1609, 1593, 1492, 1457, 1229, 1205, 1154, 1130, 1041, 757 cm-1
; HRMS
(ESI-TOF) calcd for C21H26FNO5 Na [M+Na]+ 414.1693, found 414.1687.
HN
O
OMeO
MeO OMe F
Figure 4-14 Structure of tert-butyl (4-fluorophenyl)(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4c
Compound III-4c: A white solid; m.p. 119-121 oC; Rf = 0.31 (2:8 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 8.1, 5.7 Hz, 2H, ArH), 6.92
(t, J = 8.7 Hz, 2H, ArH), 6.55 (d, J = 10.0 Hz, 1H, NH), 6.25 (d, J = 10.0 Hz, 1H,
CHPh), 6.17 (s, 2H, ArH), 3.83 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H,
3xCH3); 13
C NMR (100 MHz, CDCl3): δ 161.7 (1J = 242.0 Hz, C-F), 161.0 (C), 158.7
145
(C), 155.9 (C), 139.6 (4J = 2.0 Hz, C-F), 127.8 (
3J = 8.0 Hz, CH-F), 114.8
(2J = 21.0 Hz, CH-F), 111.2 (C), 91.5 (CH), 79.4 (C), 56.2 (OCH3), 55.6 (OCH3),
48.0 (CHPh), 28.8 (CH3); IR (film): νmax 3455 (N-H), 2975, 2939, 2841, 1712, 1609,
1493, 1457, 1366, 1221, 1205, 1155, 1126, 1042, 1016, 952, 814 cm-1
; HRMS (ESI-
TOF) calcd for C21H26FNO5Na [M+Na]+ 414.1693, found 414.1687.
HN
O
OMeO
MeO OMe Cl
Figure 4-15 Structure of tert-butyl (4-chlorophenyl)(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4d
Compound III-4d: A white solid; m.p. 114-115 oC; Rf = 0.36 (2:8 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3): δ 7.22-7.17 (m, 4H, ArH), 6.55 (d,
J = 10.0 Hz, 1H, NH), 6.22 (d, J = 10.0 Hz, 1H, CHPh), 6.16 (s, 2H, ArH), 3.82 (s,
3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H, 3xCH3); 13
C NMR (100 MHz,
CDCl3): δ 160.7 (C), 158.4 (C), 155.5 (C), 142.2 (C), 131.7 (C), 127.9 (CH), 127.4
(CH), 110.5 (C), 91.1 (2xCH), 79.2 (C), 55.8 (OCH3), 55.3 (OCH3), 47.7 (CHPh),
28.5 (CH3); IR (film): νmax 3455 (N-H), 2975, 2939, 2840, 1713, 1609, 1594, 1491,
1456, 1205, 1154, 1128, 1014, 750 cm-1
; HRMS (ESI-TOF) calcd for C21H27ClNO5
[M+H]+ 408.1578, found 408.1572.
HN
O
OMeO
MeO OMe Br
Figure 4-16 Structure of tert-butyl (4-bromophenyl)(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4e
146
Compound III-4e: A white solid; m.p. 133-135 oC; Rf = 0.33 (2:8 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 8.4 Hz, 2H, ArH), 7.13
(d, J = 8.4 Hz, 2H, ArH), 6.53 (d, J = 9.9 Hz, 1H, NH), 6.21 (d, J = 9.9 Hz, 1H,
CHPh), 6.16 (s, 2H, ArH), 3.83 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.48 (s, 9H,
3xCH3); 13
C NMR (100 MHz, CDCl3): δ 160.7 (C), 158.4 (C), 155.6 (C), 142.8 (C),
130.9 (CH), 127.9 (CH), 119.9 (C), 110.5 (C), 91.1 (CH), 79.3 (C), 55.9 (OCH3), 55.4
(OCH3), 47.8 (CHPh), 28.5 (CH3); IR (film): νmax 3453 (N-H), 2973, 2839, 1713,
1610, 1493, 1205, 1154, 1128, 1010, 952, 814 cm-1
; HRMS (ESI-TOF) calcd for
C21H26BrNO5Na [M+Na]+ 474.0892, found 474.0887.
HN
O
OMeO
MeO OMe NO2
Figure 4-17 Structure of tert-butyl (4-nitrophenyl)(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4f
Compound III-4f: A yellow solid; m.p. 161-163 oC; Rf = 0.21 (2:8 EtOAc/
hexane, 2 eluent); 1
H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.7 Hz, 2H, ArH), 7.42
(d, J = 8.7 Hz, 2H, ArH), 6.64 (d, J = 9.7 Hz, 1H, NH), 6.20 (d, J = 9.7 Hz, 1H,
CHPh), 6.16 (s, 2H, ArH), 3.83 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3), 1.49 (s, 9H,
3xCH3); 13
C NMR (100 MHz, CDCl3): δ 161.1 (C), 158.3 (C), 155.5 (C), 151.6 (C),
146.4 (C), 126.6 (CH), 123.1 (CH), 109.7 (C), 91.1 (CH), 79.6 (C), 55.8 (OCH3), 55.3
(OCH3), 48.0 (CHPh), 28.4 (CH3); IR (film): νmax 3450 (N-H), 2975, 2940, 2841,
1712, 1607, 1492, 1347, 1205, 1154, 1120, 1043 cm-1
; HRMS (ESI-TOF) calcd for
C21H27N2O7 [M+H]+ 419.1818, found 419.1815.
147
HN
O
OMeO
MeO OMe OMe
Figure 4-18 Structure of tert-butyl (4-methoxyphenyl)(2,4,6-trimethoxyphenyl)-
methylcarbamate III-4g
Compound III-4g: A white solid; m.p. 112-113 oC; Rf = 0.30 (2:8 EtOAc/
hexane, 2 eluent); 1
H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 8.6 Hz, 2H, ArH), 6.79
(d, J = 8.6 Hz, 2H, ArH), 6.55 (d, J = 10.2 Hz, 1H, NH), 6.27 (d, J =10.2 Hz, 1H,
CHPh), 6.17 (s, 2H, ArH), 3.82 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 3.77 (s, 3H,
OCH3), 1.48 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 160.4 (C), 158.5 (C),
158.0 (C), 155.6 (C), 135.7 (C), 127.1 (CH), 113.3 (CH), 111.1 (C), 91.2 (CH), 78.9
(C), 55.9 (OCH3), 55.3 (OCH3), 55.1 (OCH3), 47.8 (CHPh), 28.5 (CH3); IR (film):
νmax 3456 (N-H), 2973, 2938, 2838, 1712, 1609, 1593, 1510, 1495, 1465, 1365, 1246,
1205, 1154, 1126, 1038, 952, 813 cm-1
; HRMS (ESI-TOF) calcd for C22H29NO6Na
[M+Na]+ 426.1893, found 426.1887.
MeO
MeO OMe
HN O
O
CO2Me
Figure 4-19 Structure of methyl 4-((tert-butoxycarbonylamino)(2,4,6-trimethoxy-
phenyl)methyl)benzoateIII-4h
Compound III-4h: A white solid; m.p. 118-120 oC; Rf = 0.20 (2:8
EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.1 Hz, 2H, ArH), 7.31
(d, J = 8.1 Hz, 2H, ArH), 6.62 (d, J = 9.9 Hz, 1H, NH), 6.21 (d, J = 9.9 Hz, 1H,
CHPh), 6.16 (s, 2H, ArH), 3.89 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.77 (s, 6H,
2xOCH3), 1.48 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 166.9 (C), 160.7 (C),
158.2 (C), 155.4 (C), 149.0 (C), 129.1 (CH), 127.8 (C), 125.7 (CH), 110.2 (C), 91.0
148
(CH), 79.1 (C), 55.7 (OCH3), 55.1 (OCH3), 51.7 (OCH3), 48.0 (CHPh), 28.3 (CH3);
IR (film): νmax 3453 (N-H), 2970, 2840, 1717, 1610, 1493, 1456, 1350, 1279, 1205,
1154, 1119, 1018, 951, 764 cm-1
; HRMS (ESI-TOF) calcd for C23H29NO7Na
[M+Na]+ 454.1842, found 454.1841.
MeO
MeO OMe
HN O
O
H
O
Figure 4-20 Structure of tert-butyl (4-formylphenyl)(2,4,6-trimethoxyphenyl)methyl-
carbamate III-4j
Compound III-4j: A pale yellow oil; Rf = 0.38 (4:6 EtOAc/hexane);
1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H, CHO), 7.77 (d, J = 8.0 Hz, 2H, ArH),
7.41 (d, J = 8.0 Hz, 2H, ArH), 6.64 (d, J = 9.8 Hz, 1H, NH), 6.22 (d, J = 9.8 Hz, 1H,
CHPh), 6.16 (s, 2H, ArH), 3.82 (s, 3H, OCH3), 3.79 (s, 6H, 2xOCH3), 1.49 (s, 9H,
3xCH3); 13
C NMR (100 MHz, CDCl3): δ 192.0 (C), 160.9 (C), 158.3 (C), 155.5 (C),
151.1 (C), 134.6, (C), 129.5 (CH), 126.5 (CH), 110.2 (C), 91.1 (CH), 79.4 (C), 55.8
(OCH3), 55.3 (OCH3), 48.2 (CHPh), 28.4 (CH3); IR (film): νmax 3454 (N-H), 2974,
2939, 2840, 2735, 1715, 1704, 1607, 1495, 1456, 1206, 1043, 951, 819, 736 cm-1
;
HRMS (ESI-TOF) calcd for C22H27NO6Na [M+Na]+ 424.1736, found 424.1740.
HN
O
OMeO
MeO OMe
NHO
O
OMe
OMeMeO
Figure 4-21 Structure of tert-butyl 1,4-phenylenebis((2,4,6-trimethoxyphenyl)-
methylene)dicarbamatee III-5a
149
Compound III-5a: A white solid; m.p. 224-228 oC; Rf = 0.29 (4:6 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 7.10 (s, 4H, ArH), 6.54 (d, J = 8.2 Hz, 2H,
2xNH), 6.25 (dd, J = 10.2, 2.2 Hz, 2H, 2xCHPh), 3.80 (s, 6H, 2xOCH3), 3.76 (s, 6H,
2xOCH3), 3.75 (s, 6H, 2xOCH3), 1.47 (s, 9H, 3xCH3), 1.46 (s, 9H, 3xCH3); 13
C NMR
(100 MHz, CDCl3): δ 160.4 (C), 158.5 (C), 155.6 (C), 141.2 (C), 125.6, (CH), 111.1
(C), 91.1 (CH), 78.9 (C), 55.9 (OCH3), 55.3 (OCH3), 48.0 (CHPh), 28.6 (CH3); IR
(film): νmax 3457 (N-H), 2974, 2938, 2840, 1713, 1609, 1593, 1495, 1456, 1365,
1233, 1205, 1154, 1124, 1042, 951, 814 cm-1
; HRMS (ESI-TOF) calcd for
C36H48N2O10Na [M+Na]+ 691.3207, found 691.3203.
HN O
O
MeO
MeO OMeO
Figure 4-22 Structure of tert-butyl furan-2-yl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-6a
Compound III-6a: A white solid; m.p. 100-102 oC; Rf = 0.28 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 5.6 Hz, 1H, CH), 6.59
(d, J = 10.2 Hz, 1H, NH), 6.24 (br s, 1H, CH), 6.17 (s, 2H, ArH), 6.12 (br d,
J = 8.2 Hz, 1H, CHPh), 5.94 (br s, 1H, CH), 3.83 (s, 3H, OCH3), 3.81 (s, 6H,
2xOCH3), 1.48 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 160.8 (C), 158.8 (C),
155.8 (C), 155.3 (C), 141.2 (CH), 110.0 (CH), 108.4 (C), 105.0 (CH), 91.1 (CH), 79.2
(C), 55.9 (OCH3), 55.2 (OCH3), 43.5 (CHPh), 28.4 (CH3); IR (film): νmax 3456 (N-H),
2975, 2938, 2841, 1716, 1610, 1594, 1494, 1466, 1366, 1233, 1205, 1153, 1122,
1042, 1009, 952, 820 cm-1
; HRMS (ESI-TOF) calcd for C19H25NO6Na [M+Na]+
386.1580, found 386.1585.
150
HN O
O
MeO
MeO OMeN
Figure 4-23 Structure of tert-butyl pyridin-2-yl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-6b
Compound III-6b: A white solid; m.p. 124-126 oC; Rf = 0.28 (3:7 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 4.6 Hz, 1H, CH), 7.54
(t, J = 7.6 Hz, 1H, CH), 7.22 (d, J = 7.9 Hz, 1H, CH), 7.06 (br t, J = 5.9 Hz, 1H, CH),
6.63 (d, J = 9.7 Hz, 1H, NH), 6.30 (d, J = 9.7 Hz, 1H, CHPh), 6.15 (s, 2H, ArH), 3.81
(s, 3H, OCH3), 3.75 (s, 6H, 2xOCH3), 1.48 (s, 9H, 3xCH3); 13
C NMR (100 MHz,
CDCl3): δ 161.8 (C), 160.6 (C), 158.7 (C), 155.8 (C), 148.4 (CH), 135.8 (CH), 121.0
(CH), 120.7 (CH), 111.2 (C), 91.3 (CH), 78.9 (C), 55.9 (OCH3), 55.2 (OCH3), 49.6
(CHPh), 28.5 (CH3); IR (film): νmax 3455 (N-H), 2974, 2937, 2840, 1715, 1608, 1592,
1496, 1456, 1333, 1226, 1205, 1171, 1155, 1119, 1043, 1020, 951, 814, 770 cm-1
;
HRMS (ESI-TOF) calcd for C20H27N2O5 [M+H]+ 375.1920, found 375.1921.
HN
O
OMeO
MeO OMe
Figure 4-24 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)propylcarbamate
III-7a
Compound III-7a: A white solid; m.p. 85-87 oC; Rf = 0.30 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.14 (s, 2H, ArH), 5.81 (d, J = 10.1 Hz, 1H,
NH), 5.23 (q, J = 7.7 Hz, 1H, CHPh), 3.83 (s, 6H, 2xOCH3), 3.81 (s, 3H, OCH3),
1.82-1.68 (m, 2H, CH2CH3), 1.45 (s, 9H, 3xCH3), 0.83 (t, J = 7.4 Hz, 3H, CH2CH3);
13C NMR (100 MHz, CDCl3): δ 160.0 (C), 158.7 (C), 155.6 (C), 111.2 (C), 91.0
(CH), 78.5 (C), 55.8 (OCH3), 55.3 (OCH3), 47.2 (CHPh), 28.7 (CH2), 28.5 (CH3),
151
11.0 (CH3); IR (Film): νmax 3458 (N-H), 1713, 1610, 1592, 1497, 1456, 1364, 1230,
1205, 1171, 1155, 1138, 1060, 1042, 951, 814 cm-1
; HRMS (ESI-TOF) calcd for
C17H28NO5 [M+H]+ 326.1967, found 326.1971.
HN
O
OMeO
MeO OMe
Figure 4-25 Structure of tert-butyl 1-(2,4,6-trimethoxyphenyl)pentylcarbamate
III-7b
Compound III-7b: A white solid; m.p. 74-76 oC; Rf = 0.36 (2:8 EtOAc/
hexane): 1H- NMR (400 MHz, CDCl3): δ 6.13 (2H, s, ArH), 5.79 (d, J = 10.2 Hz, 1H,
NH), 5.30 (1H, q, J = 8.5 Hz, CHPh), 3.83 (s, 6H, 2xOCH3), 3.81 (s, 3H, OCH3),
1.76-1.64 (m, 2H,CH2), 1.44 (s, 9H, 3xCH3), 1.30-1.25 (m, 3H, CH2CH-H), 1.15-1.13
(1H, m, CH-H), 0.85 (t, J = 7.0 Hz, 3H, CH2CH3); 13
C NMR (100 MHz, CDCl3):
δ 159.9 (C), 158.5 (C), 155.4 (C), 111.4 (C), 90.9 (CH), 78.4 (C), 55.7 (OCH3), 55.2
(OCH3), 45.7 (CHPh), 35.5 (CH2), 28.5 (CH2), 28.4 (CH3), 22.5 (CH2), 14.0 (CH3);
IR (Film): νmax 3458 (N-H), 2958, 2935, 2860, 1713, 1610, 1593, 1496, 1456, 1365,
1205, 1172, 1154, 1138, 1041, 953, 814 cm-1
; HRMS (ESI-TOF) calcd for C19H32NO5
[M+H]+ 354.2280, found 354.2275.
HN
O
OMeO
MeO OMe
Figure 4-26 Structure of tert-butyl 3-phenyl-1-(2,4,6-trimethoxyphenyl)propyl-
carbamate III-7c
Compound III-7c: A colorless oil; Rf = 0.18 (1:9 EtOAc/hexane, 2 eluent);
1H NMR (400 MHz, CDCl3): δ 7.28-7.13 (m, 2H, ArH), 7.17-7.13 (m, 3H, ArH), 6.14
152
(s, 2H, ArH), 5.86 (d, J = 10.2 Hz, 1H, NH), 5.42 (q, J = 7.6 Hz, 1H, CHPh), 3.83 (s,
6H, 2xOCH3), 3.82 (s, 3H, OCH3), 2.73-2.65 (m, 1H, CH-H), 2.51-2.43 (m, 1H,
CH-H), 2.14-2.07 (m, 1H, CH-H), 2.02-1.94 (m, 1H, CH-H), 1.46 (s, 9H, 3xCH3);
13C NMR (100 MHz, CDCl3): δ 160.4 (C), 158.8 (C), 155.8 (C), 143.0 (C), 136.4
(CH), 128.6 (CH), 128.4 (CH), 125.7 (CH), 111.2 (C), 91.2 (CH), 79.0 (C), 56.1
(OCH3), 55.6 (OCH3), 46.2 (CH2), 37.8 (CHPh), 33.2 (CH2), 28.8 (CH3); IR (film):
νmax 3454 (N-H), 2969, 2939, 2835, 1172, 1609, 1592, 1495, 1455, 1365, 1260, 1204,
1151, 1119, 1043, 951, 814, 750 cm-1
; HRMS (ESI-TOF) calcd for C23H32NO5
[M+H]+ 402.2280, found 402.2275.
HN
O
OMeO
MeO OMe
Figure 4-27 Structure of tert-butyl 2-methyl-1-(2,4,6-trimethoxyphenyl)propyl-
carbamate III-7d
Compound III-7d: A white solid; m.p. 127-129 oC; Rf = 0.31 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.12 (s, 2H, ArH), 5.75 (d, J = 10.4 Hz, 1H,
NH), 4.97 (t, J = 10.2 Hz, 1H, CHPh), 3.81 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3),
2.05-1.98 (m, 1H, CHCH3), 1.42 (s, 9H, 3xCH3), 1.00 (d, J = 6.6 Hz, 3H, CHCH3),
0.69 (d, J = 6.6 Hz, 3H, CHCH3); 13
C NMR (100 MHz, CDCl3): δ 159.9 (C), 158.7
(C), 155.8 (C), 111.3 (C), 91.0 (CH), 78.4 (C), 55.8 (OCH3), 55.3 (OCH3), 51.8
(CHPh), 33.3 (CHCH3), 28.5 (CH3), 19.8 (CH3); IR (film): νmax 3458 (N-H), 2965,
2839, 1714, 1609, 1592, 1497, 1456, 1365, 1230, 1205, 1154, 1101, 1040, 1009 cm-1
;
HRMS (ESI-TOF) calcd for C18H30NO5 [M+H]+ 340.2124, found 340.2118.
153
HN O
O
MeO
MeO OMe
Figure 4-28 Structure of tert-butyl 2-ethyl-1-(2,4,6-trimethoxyphenyl)butylcarbamate
III-7e
Compound III-7e: A white solid; m.p. 82-84 oC; Rf = 0.32 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.13 (s, 2H, ArH), 5.66 (d, J = 10.4 Hz, 1H,
NH), 5.19 (t, J = 10.4 Hz, 1H, CHPh), 3.82 (s, 6H, 2xOCH3), 3.81 (s, 3H, OCH3),
1.88-1.66 (m, 2H, CH2CH3), 1.63-1.49 (m, 1H, CHCH3), 1.43 (s, 9H, 3xCH3),
1.17-1.13 (m, 2H, CH2CH3), 0.90 (t, J = 7.2 Hz, 3H, CH2CH3), 0.73 (d, J = 7.4 Hz,
3H, CH2CH3); 13
C NMR (100 MHz, CDCl3): δ 159.8 (C), 158.8 (C), 155.6 (C), 111.6
(C), 91.0 (CH), 78.3 (C), 55.8 (OCH3), 55.2 (OCH3), 48.2 (CHPh), 44.6 (CHCH3),
28.5 (CH3), 21.5 (CH2CH3), 21.2 (CH2CH3), 10.4 (CH2CH3), 10.3 21.5 (CH2CH3); IR
(film): νmax 3458 (N-H), 2964, 2938, 2876, 2839, 1715, 1610, 1497, 1457, 1365,
1220, 1205, 1155, 1040, 1009, 951, 876, 814 cm-1
.
HN
O
OMeO
MeO OMe
Figure 4-29 Structure of tert-butyl 3-methyl-1-(2,4,6-trimethoxyphenyl)butyl-
carbamate III-7f
Compound III-7f: A white solid; m.p. 91-93 oC; Rf = 0.30 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.13 (s, 2H, ArH), 5.72 (d, J = 10.2 Hz, 1H,
NH), 5.41 (q, J = 7.7 Hz, 1H, CHPh), 3.83 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3),
1.70-1.63 (m, 1H, CH-H), 1.57-1.48 (m, 1H, CH-H), 1.44 (m, 10H, CHCH3 and
3xCH3), 0.95 (d, J = 6.5 Hz, 3H, CH3), 0.90 (d, J = 6.5 Hz, 3H, CH3); 13
C NMR
(100 MHz, CDCl3): δ 159.9 (C), 158.4 (C), 155.3 (C), 111.8 (C), 90.9 (CH), 78.4 (C),
154
55.7 (OCH3), 55.2 (OCH3), 45.0 (CH2), 44.1 (CHPh), 28.5 (CH3), 25.3 (CH), 22.7
(CH3); IR (film): νmax 3458 (N-H), 2957, 2840, 1712, 1610, 1593, 1496, 1456, 1365,
1219, 1205, 1155, 1110, 1042, 951, 814, 764, 750 cm-1
; HRMS (ESI-TOF) calcd for
C19H32NO5 [M+H]+ 354.2280, found 354.2275.
MeO
MeO OMe
HN O
O
Figure 4-30 Structure of tert-butyl cyclopropyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-7g
Compound III-7g: A white solid; m.p. 105-107 oC; Rf = 0.28 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.16 (s, 2H, ArH), 5.95 (d, J = 10.2 Hz, 1H,
NH), 4.68 (t, J = 9.7 Hz, 1H, CHPh), 3.83 (s, 3H, OCH3), 3.81 (s, 6H, 2xOCH3), 1.44
(s, 9H, 3xCH3), 1.37-1.33 (m ,1H, CH-H), 0.56-0.52 (m, 1H, CH-H), 0.44-0.41 (m,
1H, CH-H), 0.35-0.33 (m, 1H, CH-H); 13
C NMR (100 MHz, CDCl3): δ 160.0 (C),
158.3 (C), 155.6 (C), 111.6 (C), 91.0 (CH), 78.5 (C), 55.8 (OCH3), 55.3 (OCH3), 49.9
(CHPh), 28.5 (CH3), 17.0 (CHCH2), 3.7 (CH2), 3.1 (CH2); IR (film): νmax 3460
(N-H), 1712, 1610, 1593, 1495, 1456, 1205, 1154, 1111, 1041, 1017, 957, 814 cm-1
;
HRMS (ESI-TOF) calcd for C18H27NO5Na [M+Na]+ 360.1787, found 360.1787.
MeO
MeO OMe
HN O
O
Figure 4-31 Structure of tert-butyl cyclopentyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-7h
Compound III-7h: A white solid; m.p. 116-118 oC; Rf = 0.36 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.13 (s, 2H, ArH), 5.79 (d, J = 10.4 Hz, 1H,
155
NH), 5.12 (t, J = 10.4 Hz, 1H, CHPh), 3.83 (s, 3H, OCH3), 3.81 (s, 6H, 2xOCH3),
2.38-2.32 (m, 1H, CHCH2), 1.76-1.68 (m, 2H, CH2), 1.61-1.56 (m, 1H, CH-H),
1.54-1.43 (m, 12H, 3xCH-H, 3xCH3), 1.27-1.20 (m, 1H, CH-H), 1.17-1.12 (m, 1H,
CH-H); 13
C NMR (100 MHz, CDCl3): δ 160.1 (C), 158.8 (C), 155.9 (C), 112.2 (C),
91.3 (CH), 78.6 (C), 56.0 (OCH3), 55.5 (OCH3), 50.0 (CHPh), 45.8 (CHCH2), 30.4
(CH2), 29.8 (CH2), 28.8 (CH3), 25.4 (2xCH2); IR (Film): νmax 3458 (N-H), 2954,
2868, 2839, 1712, 1609, 1592, 1497, 1455, 1365, 1230, 1204, 1163, 1152, 1117,
1040, 1011, 952, 814, 752 cm-1
; HRMS (ESI) calcd for C20H32NO5 [M+H]+
366.2280, found 366.2275.
HN
O
OMeO
MeO OMe
Figure 4-32 Structure of tert-butyl cyclohexyl(2,4,6-trimethoxyphenyl)methyl-
carbamate III-7i
Compound III-7i: A white solid; m.p. 138-140 oC; Rf = 0.39 (2:8 EtOAc/
hexane): 1H NMR (400 MHz, CDCl3): δ 6.12 (s, 2H, ArH), 5.74 (d, J = 10.3 Hz, 1H,
NH), 5.03 (t, J = 10.0 Hz, 1H, CHPh), 3.81 (s, 6H, 2xOCH3), 3.80 (s, 3H, OCH3),
1.94-1.91 (br m, 1H, CHCH2), 1.75-1.59 (br m, 4H, 2xCH2), 1.43 (s, 9H, 3xCH3),
1.26-1.04 (br m, 5H, CH-H), 0.97-0.91 (br m, 1H, CH-H); 13
C NMR (100 MHz,
CDCl3): δ 159.8 (C), 158.6 (C), 155.7 (C), 110.7 (C), 90.8 (CH), 78.3 (C), 55.7
(OCH3), 55.2 (OCH3), 50.6 (CHPh), 42.5 (CHCH2), 30.0 (CH2), 29.8 (CH2), 28.5
(CH3), 26.4 (CH2), 26.2 (2xCH2); IR (film): νmax 3458 (N-H), 2929, 2850, 1713, 1609,
1592, 1496, 1454, 1364, 1204, 1172, 1143, 1112, 1039, 1009, 951, 814, 750 cm-1
;
HRMS (ESI-TOF) calcd for C21H34NO5 [M+H]+
380.2437, found 380.2431.
156
HN
O
OMeO
MeO
OMe
Figure 4-33 Structure of tert-butyl phenyl(2,4,5-trimethoxyphenyl)methylcarbamate
III-8a
Compound III-8a: A white solid; m.p. 91-93 oC; Rf = 0.32 (2:8 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.29-7.18 (m, 5H, ArH), 6.82 (s, 1H, ArH),
6.53 (s, 1H, ArH), 6.00 (br d, J = 8.0 Hz, 1H, NH), 5.67 (br d, J = 5.8 Hz, 1H, CHPh),
3.88 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 1.46 (s, 9H, 3xCH3);
13C NMR (100 MHz, CDCl3): δ 155.7 (C), 151.6 (C), 149.3 (C), 143.3 (C), 142.8 (C),
128.5 (CH), 127.0 (CH), 126.8 (CH), 122.0 (C), 113.4 (CH), 98.8 (CH), 79.8 (C),
57.0 (OCH3), 56.7 (OCH3), 56.5 (OCH3), 55.3 (CHPh), 28.5 (CH3); IR (film): νmax
3368 (N-H), 2976, 2934, 2829, 1710, 1510, 1455, 1366, 1275, 1260, 1206, 1168,
1034, 863, 764, 750 cm-1
; HRMS (ESI-TOF) calcd for C21H27NO5Na [M+Na]+
396.1787, found 396.1781.
OMe
MeO
OMe
OMe
MeO OMe
Figure 4-34 Structure of 5,5'-(phenylmethylene)bis(1,2,4-trimethoxybenzene) III-9a
Compound III-9a: A white solid; m.p. 129-133 oC; Rf = 0.38 (4:6 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H, ArH), 7.18 (m, 1H, ArH),
7.07 (d, J = 7.6 Hz, 2H, ArH), 6.56 (s, 2H, ArH), 6.44 (s, 2H, ArH), 6.10 (s, 1H,
CHPh), 3.90 (s, 6H, 2xOCH3), 3.68 (s, 6H, 2xOCH3), 3.65 (s, 6H, 2xOCH3);
13C NMR (100 MHz, CDCl3): δ 151.9 (C), 148.4 (C), 144.6 (C), 143.1 (C), 129.3
(CH), 128.3 (CH), 126.1 (CH), 124.9 (C), 115.0 (CH), 98.8 (CH), 57.4 (OCH3), 57.0
157
(OCH3), 56.4 (OCH3), 42.9 (CHPh); IR (Film): νmax 2928, 2846, 1729, 1509, 1464,
1394, 1317, 1275, 1259, 1206, 1178, 1035, 764, 750 cm-1
; HRMS (ESI) calcd for
C25H28O6Na [M+Na]+ 447.1784, found: 447.1760.
HN
O
O
O
Figure 4-35 Structure of tert-butyl (5-methylfuran-2-yl)(phenyl)methylcarbamate
III-8b
Compound III-8b: A white solid; m.p. 73-75 oC; Rf = 0.63 (1:9 EtOAc/
hexane, 2 eluent); 1
H NMR (400 MHz, CDCl3): 7.38-7.28 (m ,5H, ArH), 5.99 (br s,
1H, NH), 5.90 (br s, 2H, 2xCH), 5.30 (br s, 1H, CHPh), 2.27 (s, 3H, CH3), 1.46 (br s,
9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 155.2 (C), 152.5 (C), 152.4 (C), 140.7
(C), 128.8 (CH), 127.2 (CH), 108.4 (CH), 106.4 (CH), 80.2 (C), 53.0 (CHPh), 28.7
(3xCH3), 13.9 (CH3); IR (film): νmax 3338 (N-H), 2978, 2925, 1706, 1496, 1455,
1367, 1243, 1168, 1046, 1021, 964, 879, 784, 700 cm-1
; HRMS (ESI-TOF) calcd for
C17H21NO3Na [M+Na]+ 310.1419, found 310.1418.
O O
Figure 4-36 Structure of 5,5'-(phenylmethylene)bis(2-methylfuran) III-9b
Compound III-9b: A yellow oil; Rf = 0.56 (1:9 EtOAc/hexane); 1
H NMR
(400 MHz, CDCl3): δ 7.35-7.28 (br m, 5H, ArH), 5.91 (br d, J = 4.3 Hz, 4H, 4xCH),
5.37 (s, 1H, CHPh), 2.28 (s, 6H, 2xCH3); 13
C NMR (100 MHz, CDCl3): δ 152.8 (C),
151.4 (C), 140.0 (C), 128.39 (CH), 128.36 (CH), 126.9 (CH), 108.1 (CH), 106.0
158
(CH), 45.1 (CHPh), 13.6 (CH3); IR (film): νmax 1603, 1561, 1494, 1452, 1218, 1022,
778 cm-1
; HRMS (ESI-TOF) calcd for C17H17O2 [M+H]+ 253.1229, found 253.1223.
HN
ONO2
O
O
Figure 4-37 Structure of tert-butyl (5-methylfuran-2-yl)(4-nitrophenyl)methyl-
carbamate III-8c
Compound III-8c: A yellow oil; Rf = 0.41 (1:9 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.22 (d, J = 8.5 Hz, 2H, 2xArH), 7.52 (d, J = 8.5 Hz, 1H,
2xArH), 6.01 (br s, 1H, NH), 5.93 (d, J = 10.0 Hz, 2xfuryl-H), 5.41 (br s, 1H, CHPh),
2.26 (s, 3H, CH3), 1.46 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 154.9 (C),
153.0 (2xC), 150.5 (C), 147.9 (C), 127.8 (2xCH), 123.8 (2xCH), 109.0 (CH), 106.5
(CH), 80.6 (C), 52.9 (CHPh), 28.4 (3xCH3), 13.5 (CH3); IR (film): νmax 3406 (N-H),
1715, 1521, 1349, 1244, 1166, 1022, 857, 788 cm-1
.
OO
NO2
Figure 4-38 Structure of 5,5'-((4-nitrophenyl)methylene)bis(2-methylfuran) III-9c
Compound III-9c: A yellow solid; m.p. 87-91 oC; Rf = 0.48 (1:9 EtOAc/
hexane); 1
H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.7 Hz, 2H, ArH), 7.43
(d, J = 8.7 Hz, 2H, ArH), 5.96 (br d, J = 3.0 Hz, 2H, 2xCH), 5.94 (br d, J = 3.0 Hz,
2H, 2xCH), 5.45 (s, 1H, CHPh), 2.27 (s, 6H, 2xCH3); 13
C NMR (100 MHz, CDCl3):
δ 152.5 (C), 151.4 (C), 147.9 (C), 147.5 (C), 129.7 (CH), 124.2 (CH), 109.3 (CH),
106.7 (CH), 45.3 (CHPh), 14.0 (CH3); IR (Film): max 2923, 1606, 1560, 1519, 1348,
159
1218, 1110, 1022, 950, 827, 781, 735 cm-1
; Compound is literature known, see:
[Chandrasekhar, S., Khatun, S., Rajesh, G. & Reddy, C. R. (2009). Tetrahedron Lett.,
50, 6693-6697].
HN
O
O
O
Figure 4-39 Structure of tert-butyl (5-ethylfuran-2-yl)(phenyl)methylcarbamate
III-8d
Compound III-8d: A yellow solid; m.p. 75-77 oC; Rf = 0.30 (1:9 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, ArH), 5.98 (br s, 1H, NH),
5.89 (br d, J = 3.1 Hz, 2H, 2xCH), 5.28 (br s, 1H, CHPh). 2.61 (q, J = 7.6 Hz, 2H,
CH2CH3), 1.45 (br s, 9H, 3xCH3), 1.20 (t, J = 7.6 Hz, 3H, CH2CH3); 13
C NMR
(100 MHz, CDCl3): δ 157.8 (C), 154.9 (C), 152.0 (C), 140.4 (C), 128.5 (CH), 127.5
(CH), 126.9 (CH), 107.9 (CH), 104.4 (CH), 79.9 (C), 52.8 (C), 28.4 (3xCH3), 21.4
(CH2), 12.0 (CH3): IR (film): νmax 3338 (N-H), 2976, 2935, 1705, 1496, 1455, 1367,
1246, 1168, 1046, 1013, 880, 751 cm-1
: HRMS (ESI-TOF) calcd for C18H23NO3Na
[M+Na]+ 324.1576, found 324.1579.
O O
Figure 4-40 Structure of 5,5'-(phenylmethylene)bis(2-ethylfuran) III-9d
Compound III-9d: A yellow oil; Rf = 0.58 (1:9 EtOAc/hexane); 1H NMR
(400 MHz, CDCl3): δ 7.37-7.28 (br m, 5H, ArH), 5.93 (br d, J = 2.7 Hz, 2H, 2xCH),
5.90 (br d, J = 2.7 Hz, 2H, 2xCH), 5.39 (s, 1H, CHPh), 2.64 (q, J = 7.6 Hz, 4H,
2xCH2), 1.23 (t, J = 7.6 Hz, 6H, 2xCH3); 13
C NMR (100 MHz, CDCl3): δ 157.4 (C),
160
153.0 (C), 140.4 (C), 128.6 (CH), 127.1 (CH), 108.2 (CH), 104.7 (CH), 45.4 (CHPh),
21.6 (CH2), 12.4 (CH3); IR (Film): νmax 2973, 2938, 1603, 1559, 1496, 1453, 1404,
1183, 1058, 1013, 975, 777, 731, 699 cm-1
: HRMS (ESI-TOF) calcd for C19H20O2Na
[M+Na]+ 303.1361, found 303.1292.
HN
S
O
O
Figure 4-41 Structure of tert-butyl (5-methylthiophen-2-yl)(phenyl)methylcarbamate
III-8e
Compound III-8d: A pale yellow solid; m.p. 105-109 oC; Rf = 0.39 (1:9
EtOAc/ hexane); 1
H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 5H, ArH), 6.57-6.55
(m, 2H, 2xCH), 6.02 (br s, 1H, NH), 5.21 (br s, 1H, CHPh), 2.42 (s, 3H, CH3), 1.44
(br s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 154.7 (C), 143.8 (C), 141.9 (C),
139.7 (C), 128.6 (CH), 127.6 (CH), 126.8 (CH), 125.3 (CH), 124.7 (CH), 80.0 (C),
54.6 (CH), 28.4 (3xCH3), 15.3 (CH3): IR (film): νmax 3357 (N-H), 2978, 2919, 1691,
1515, 1367, 1173, 1019, cm-1
; HRMS (ESI-TOF) calcd for C17H21NO2SNa [M+Na]+
326.1191, found 326.1190.
S S
Figure 4-42 Structure of 5,5'-(phenylmethylene)bis(2-methylthiophene) III-9e
Compound III-9e: A pale yellow oil; Rf = 0.59 (1:9 EtOAc/hexane);
1H NMR (400 MHz, CDCl3): δ 7.36-7.27 (m, 5H, ArH), 6.64 (br d, J = 3.4 Hz, 2H,
2xCH), 6.61 (br d, J = 3.4 Hz, 2H, 2xCH), 5.72 (s, 1H, CHPh), 2.46 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3): δ 145.3 (C), 143.9 (C), 139.1 (C), 128.5 (CH), 128.4
(CH), 127.0 (CH), 125.7 (CH), 124.6 (CH), 47.9 (CHPh), 15.4 (CH3); IR (film): νmax
161
1600, 1493, 1451, 1404, 1228, 1167, 1029, 796 cm-1
; Compound is literature known,
see: [Nair, V., Abhilash, K. G., & Vidya, N. (2005). Org. Lett., 7, 5857-5859].
HN
S
O
O
Figure 4-43 Structure of tert-butyl (5-ethylthiophen-2-yl)(phenyl)methylcarbamate
III-8f
Compound III-8f: A white solid; m.p. 77-81 oC; Rf = 0.42 (1:9 EtOAc/
hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 7.40-7.30 (m, 5H, ArH), 6.60
(s, 2H, CH), 6.05 (br s, 1H, NH), 5.26 (br s, 1H, CHPh), 2.80 (q, J = 7.5 Hz, 2H,
CH2CH3), 1.46 (br s, 9H, 3xCH3), 1.29 (t, J = 7.5 Hz, 3H, CH2CH3); 13
C NMR
(100 MHz, CDCl3): δ 154.4 (C), 146.9 (C), 143.0 (C), 141.4 (C), 128.1 (CH), 127.2
(CH), 126.4 (CH), 124.7 (CH), 122.4 (CH), 79.5 (C), 54.2 (CHPh), 27.9 (3xCH3),
23.1 (CH2), 15.4 (CH3); IR (film): νmax 3332 (N-H), 1702, 1494, 1455, 1366, 1246,
1166, 1016, 803, 753, 699 cm-1
: HRMS (ESI-TOF) calcd for C18H23NO2SNa
[M+Na]+ 340.1347, found 340.1346.
HN O
O
N
Boc
Figure 4-44 Structure of tert-butyl 2-((tert-butoxycarbonylamino)(phenyl)methyl)-
1H-pyrrole-1-carboxylate III-8g
Compound III-8g: A pale yellow oil; Rf = 0.37 (0.5:9.5 EtOAc/ hexane,
2 eluent); 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.6 Hz, 1H, NH), 7.30-7.13
(m, 5H, ArH), 6.40 (d, J = 8.6 Hz, 1H, CHPh), 6.25 (br s, 1H, CH), 6.16 (br t,
J = 3.2 Hz, 1H, CH), 5.78 (br s, 1H, CH), 1.49 (s, 9H, 3xCH3), 1.40 (s, 9H, 3xCH3);
162
13C NMR (100 MHz, CDCl3): δ 155.3 (C), 149.0 (C), 141.7 (C), 128.2 (CH), 127.0
(C), 126.6 (CH), 122.6 (CH), 114.3 (CH), 110.0 (CH), 84.2 (C), 79.6 (C), 52.4
(CHPh), 28.5 (3xCH3), 27.8 (3xCH3); IR (film): νmax 3433 (N-H), 1740, 1716, 1490,
1369, 1335, 1166, 1045, 847, 701 cm-1
: HRMS (ESI-TOF) calcd for C21H28N2O4Na
[M+Na]+ 395.1947, found 395.1946.
HN
HN
O
O
Figure 4-45 Structure of tert-butyl (1H-indol-3-yl)(phenyl)methylcarbamate III-8h
Compound III-8h: An orange solid; m.p. 131-135 oC; Rf = 0.22 (70:30:1
CH2Cl2/hexane/MeOH): 1H NMR (400 MHz, CDCl3): δ 8.08 (br s, 1H, NH), 7.55 (d,
J = 7.3 Hz, 1H, CH), 7.43-7.35 (m, 5H, ArH), 7.31-7.28 (m, 2H, CH), 7.23 (t,
J = 7.6 Hz, 1H, CH), 7.12 (t, J = 7.6 Hz, 1H, CH), 6.77 (br s, 1H, CH),), 6.24 (br d,
J = 7.2 Hz, 1H, NH), 5.25 (br s, 1H, CHPh), 1.48 (br s, 9H, 3xCH3); 13
C NMR
(100 MHz, CDCl3): δ 155.2 (C), 142.0 (C), 136.7 (C), 128.4 (CH), 127.1 (CH), 126.8
(CH), 125.9 (C), 123.2 (CH), 122.4 (CH), 119.8 (CH), 119.5 (CH), 118.0 (C), 111.3
(CH), 79.6 (C), 51.7 (CHPh), 28.4 (3xCH3); IR (film): νmax 3407, 3327, 1693, 1495,
1455, 1367, 1244, 1166, 1017, 879, 743 cm-1
; HRMS (ESI-TOF) calcd for
C20H22N2O2Na [M+Na]+ 345.1579, found 345.1577.
HN NH
Figure 4-46 Structure of 3,3'-(phenylmethylene)bis(1H-indole) III-9h
Compound III-9h: An orange solid; m.p. 93-97 oC; Rf = 0.22 (70:30:1
CH2Cl2/hexane/MeOH): 1H NMR (400 MHz, CDCl3): δ 7.96 (br s, 1H, NH),
163
7.42-7.36 (m, 6H, ArH), 7.32-7.30 (m, 2H, CH), 7.23-7.17 (m, 3H, CH), 7.02 (t,
J = 7.5 Hz, 1H, CH), 6.69 (br d, J = 1.5 Hz, 1H, CH), 5.91(s, 1H, CHPh); 13
C NMR
(100 MHz, CDCl3): δ 144.3 (C), 136.9 (C), 129.0 (CH), 128.5 (CH), 127.3 (CH),
126.5 (C), 123.9 (CH), 122.2 (CH), 120.2, 119.8 (CH), 119.5 (CH), 111.4 (C), 40.5
(CH3); IR (Film): νmax 3414, 1601, 1492, 1456, 1417, 1337, 1265, 1217, 1152, 1093,
1010, 793, 743 cm-1
; HRMS (ESI-TOF) calcd for C23H18N2Na [M+Na]+ 345.1368,
found 345.1360.
HN O
O
MeO
OMe
MeO
Figure 4-47 Structure of tert-butyl 2-methyl-1-(2,4,5-trimethoxyphenyl)propyl-
carbamate III-10a
Compound III-10a: A white solid; m.p. 104-106 oC; Rf = 0.24 (2:8
EtOAc/hexane): 1H NMR (400 MHz, CDCl3): δ 6.68 (s, 1H, ArH), 6.52 (s, 1H, ArH),
5.47 (d, J = 8.9 Hz, 1H, NH), 4.37 (t, J = 8.9 Hz, 1H, CHPh), 3.88 (s, 3H, OCH3),
3.83 (s, 6H, 2xOCH3), 1.82-1.78 (m, 1H, CHCH3), 1.43 (s, 9H, 3xCH3), 0.98 (d,
J = 6.6 Hz, 3H, CH3), 0.75 (d, J = 6.6 Hz, 3H, CH3); 13
C NMR (100 MHz, CDCl3):
δ 155.5 (C), 151.0 (C), 148.2 (C), 142.4 (C), 121.5 (C), 113.6 (CH), 97.7 (CH), 78.6
(C), 58.9 (CHPh), 56.5 (OCH3), 56.0 (OCH3), 32.9 (CHCH3), 20.1 (CH3), 19.2 (CH3);
IR (film): νmax 3453 (N-H), 3327, 1699, 1508, 1466, 1365, 1206, 1172, 1038, 861,
779 cm-1
; HRMS (ESI) calcd for C18H29NO5Na [M+Na]+ 362.1943, found 362.1945.
OMe
MeO
OMe OMe
OMe
OMe
Figure 4-48 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(1,2,4-trimethoxy-
benzene) III-11a
164
Compound III-11a: A brown oil; Rf = 0.31 (4:6 EtOAc/hexane): 1H NMR
(400 MHz, CDCl3): δ 6.96 (s, 2H, 2xArH), 6.49 (s, 2H, 2x ArH), 4.20 (d, J = 11.3 Hz,
1H, CHPh), 3.86 (s, 6H, 2xOCH3), 3.84 (s, 6H, 2xOCH3), 3.78 (s, 6H, 2xOCH3),
2.52-2.46 (m, 1H, CHCH3), 0.88 (d, J = 6.4 Hz, 6H, 2xCH3), 0.75 (d, J = 6.6 Hz, 3H,
CH3); 13
C NMR (100 MHz, CDCl3): δ 151.8 (C), 147.4 (C), 142.8 (C), 125.1 (C),
113.3 (2xCH), 98.3 (2xCH), 56.8 (2xOCH3), 56.7 (2xOCH3), 56.0 (2xOCH3), 45.1
(CHPh), 30.9 (CHCH3), 21.6 (2xCH3); IR (film): νmax 1515, 1464, 1396, 1314, 1207,
1179, 1127, 876, 817, 760 cm-1
; HRMS (ESI) (m/z) calcd for C22H30O6 [M]+
390.2042, found: 390.1951.
HN
O
O
O
Figure 4-49 Structure of tert-butyl 2-methyl-1-(5-methylfuran-2-yl)propylcarbamate
III-10b
Compound III-10b: A yellow oil; Rf = 0.55 (1:9 EtOAc/hexane): 1H NMR
(400 MHz, CDCl3): δ 6.01 (br d, J = 2.1 Hz, 1H, CH), 5.88 (br d, J = 2.1 Hz, 1H,
CH), 4.89 (br d , J = 7.9 Hz, 1H, NH), 4.49 (br t, J = 7.9 Hz, 1H, CHCHCH3), 2.27 (s,
3H, CH3), 2.10-2.05 (m, 1H, CHCH3), 1.46 (s, 9H, 3xCH3), 0.94 (d, J = 6.8 Hz, 3H,
CH3), 0.88 (d, J = 6.7 Hz, 3H, CH3); 13
C NMR (100 MHz, CDCl3): δ 155.4 (C), 152.6
(C), 151.0 (C), 106.9 (CH), 105.8 (CH), 79.3 (C), 54.4 (CHCHCH3), 32.3 (CHCH3),
28.4 (3xCH3), 19.1 (CHCH3), 18.4 (CHCH3), 13.5 (CH3); IR (film): νmax 3347 (N-H),
1705, 1499, 1390, 1366, 1240, 1171, 1020, 874, 782 cm-1
; HRMS (ESI-TOF) calcd
for C14H24NO3 [M+H]+ 254.1756, found 254.1751.
165
HN O
O
O
Figure 4-50 Structure of tert-butyl 1-(5-ethylfuran-2-yl)-2-methylpropylcarbamate
III-10c
Compound III-10c: A yellow oil; Rf = 0.44 (1:9 EtOAc/hexane): 1H NMR
(400 MHz, CDCl3): δ 5.98 (d, J = 2.9 Hz, 1H, CH), 5.84 (d, J = 2.9 Hz, 1H, CH), 4.94
(br d , J = 8.2 Hz, 1H, NH), 4.48 (br t, J = 8.2 Hz, 1H, CHCHCH3), 2.56 (q,
J = 7.6 Hz, 2H, CH2CH3), 2.07-2.00 (m, 1H, CHCH3), 1.42 (s, 9H, 3xCH3), 1.17 (t,
J = 7.6 Hz, 3H, CH2CH3), 0.89 (d, J = 6.8 Hz, 3H, CH3), 0.84 (d, J = 6.8 Hz, 3H,
CH3); 13
C NMR (100 MHz, CDCl3): δ 156.7 (C), 155.4 (C), 152.4 (C), 106.6 (CH),
104.1 (CH), 79.2 (C), 56.0 (CHCHCH3), 32.5 (CHCH3), 28.4 (3xCH3), 21.3
(CH2CH3), 19.1 (CHCH3), 18.4 (CHCH3), 12.2 (CH2CH3); IR (film): νmax 3459
(N-H), 1705, 1498, 1392, 1367, 1244, 1172, 1010, 874, 778 cm-1
; HRMS (ESI-TOF)
calcd for C15H25NO3Na [M+ Na]+ 290.1732, found 290.1738.
O O
Figure 4-51 Structure of 5,5'-(2-methylpropane-1,1-diyl)bis(2-ethylfuran) III-11c
Compound III-11c: A yellow oil; Rf = 0.76 (1:9 EtOAc/hexane): 1H NMR
(400 MHz, CDCl3): δ 6.00 (d, J = 3.0 Hz, 2H, 2xCH), 5.88 (d, J = 3.0 Hz, 2H, 2xCH),
3.73 (d, J = 7.8 Hz, 1H, CHCHCH3), 2.63 (q, J = 7.6 Hz, 4H, 2xCH2CH3), 2.35-2.27
(m, 1H, CHCH3), 1.22 (t, J = 7.6 Hz, 6H, 2xCH2CH3), 0.90 (d, J = 6.7 Hz, 6H,
2xCH3); IR (film): νmax 3459 (N-H), 1705, 1498, 1392, 1367, 1244, 1172, 1010, 874,
778 cm-1
.
166
HN O
O
S
Figure 4-52 Structure of tert-butyl 2-methyl-1-(5-methylthiophen-2-yl)propyl-
carbamate III-10d
Compound III-10d: A white solid; m.p. 68-70 oC; Rf = 0.42 (1:9 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 6.68 (br d, J = 2.7 Hz, 1H, CH), 6.59 (br d,
J = 2.7 Hz, 1H, CH), 4.80 (br s, 1H, NH), 4.68 (br s, 1H, CHCHCH3), 2.44 (s, 3H,
CH3), 2.04-1.99 (m, 1H, CHCH3), 1.44 (s, 9H, 3xCH3), 0.96 (d, J = 6.5 Hz, 3H, CH3),
0.94 (d, J = 6.5 Hz, 3H, CH3); 13
C NMR (100 MHz, CDCl3): δ 155.3 (C), 143.6 (C),
138.0 (C), 124.5 (CH), 124.0 (CH), 88.3 (C), 56.3 (CHCHCH3), 34.2 (CHCH3), 28.3
(3xCH3), 19.6 (CHCH3), 18.2 (CHCH3), 15.2 (CH3); IR (film): νmax 3446 (N-H),
1703, 1497, 1392, 1366, 1243, 1170, 1008, 873, 797 cm-1
; HRMS (ESI-TOF) calcd
for C14H23NO2SNa [M+Na]+ 292.1347, found 292.1345.
HN O
O
S
Figure 4-53 Structure of tert-butyl 1-(5-ethylthiophen-2-yl)-2-methylpropyl-
carbamate III-10e
Compound III-10e: A white solid; m.p. 62-64 oC; Rf = 0.44 (1:9 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 6.69 (br d, J = 2.8 Hz,1H, CH), 6.62 (br d,
J = 2.8 Hz,1H, CH), 4.78 (br s, 1H, NH), 4.70 (br s,1H, CHCHCH3), 2.80 (q,
J = 7.5 Hz, 2H, CH2CH3), 2.05-2.00 (m, 1H, CHCH3), 1.45 (s, 9H, 3xCH3), 0.96 (d,
J = 6.0 Hz, 3H, CH2CH3), 0.93 (d, J = 6.0 Hz, 3H, CH2CH3); 13
C NMR (100 MHz,
CDCl3): δ 155.4 (C), 145.9 (C), 143.3 (C), 123.9 (CH), 122.7 (CH), 79.5 (C), 56.4
(CHCHCH2), 34.3 (CHCH3), 28.4 (3xCH3), 23.5 (CH2CH3), 19.7 (CHCH3), 18.2
167
(CHCH3), 15.9 (CH2CH3); IR (film): νmax 3450 (N-H), 1702, 1496, 1392, 1366, 1244,
1170, 1008, 873, 803 cm-1
; HRMS (ESI-TOF) calcd for C15H25NO2SNa [M+Na]+
306.1504, found 306.1501.
HN O
O
N
Boc
Figure 4-54 Structure of tert-butyl 2-(1-(tert-butoxycarbonylamino)-2-methylpropyl)-
1H-pyrrole-1-carboxylate III-10f
Compound III-10f: A yellow oil; Rf = 0.33 (0.5:9.5 EtOAc/ hexane,
2 eluent); 1H NMR (400 MHz, CDCl3): δ 7.12 (br s, 1H, CH), 6.11 (br s, 1H, CH),
6.06 (br d, J = 3.0 Hz, 1H, CH), 5.72 (br s, 1H, NH), 4.80 (br t, J = 8.4 Hz, 3H,
CHCHCH3), 2.16-2.08 (m, 1H, CHCH3), 1.61 (s, 9H, 3xCH3), 1.44 (s, 9H, 3xCH3),
0.94 (d, J = 6.7 Hz, 3H, CHCH3), 0.77 (d, J = 6.7 Hz, 3H, CHCH3); 13
C NMR (100
MHz, CDCl3): δ 155.6 (C), 149.6 (C), 135.2 (C), 122.0 (CH), 113.5 (CH), 109.8
(CH), 83.9 (C), 78.8 (C), 55.1 (CHCHCH3), 31.8 (CHCH3), 28.4 (3xCH3), 28.0
(3xCH3), 20.3 (CHCH3), 18.6 (CHCH3); IR (film): νmax 3437 (N-H), 1733, 1716,
1494, 1393, 1369, 1330, 1252, 1164, 1012, 848, 773, 726 cm-1
; HRMS (ESI-TOF)
calcd for C18H30N2O4Na [M+Na]+ 361.2103, found 361.2105.
N
Boc
HN
HNO
O O
O* *
Figure 4-55 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonylamino)-
2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a
Compound (syn/anti)-III-12a: A yellow oil; Rf = 0.12 (0.5:9.5 EtOAc/
hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 5.99 (br s, 2H, 2xCH), 5.27 (br d,
J = 9.1 Hz, 2H, 2xNH), 4.88 (br t, J = 9.1 Hz, 2H, 2xCHCHCH3), 2.03-1.96 (m, 2H,
168
2xCHCH3), 1.67 (s, 9H, 3xCH3), 1.43 (s, 18H, 6xCH3), 0.92 (d, J = 6.4 Hz, 6H,
2xCHCH3), 0.82 (d, J = 6.4 Hz, 6H, 2xCHCH3); 13
C NMR (100 MHz, CDCl3):
δ 156.4 (2xC), 151.8 (C), 137.1 (2xC), 111.6 (2xCH), 86.1 (C), 79.5 (2xC), 55.2
(2xCHCHCH3), 32.9 (2xCHCH3), 28.7 (6xCH3), 28.1 (3xCH3), 20.4 (2xCHCH3),
18.6 (2xCHCH3); IR (film): νmax 3440 (N-H), 1738, 1716, 1489, 1369, 1252, 1168,
1118, 1066, 1012, 848, 773, 725 cm-1
; HRMS (ESI-TOF) calcd for C27H47N3O6Na
[M+Na]+ 532.3363, found 532.3361.
N
Boc
HN
HNO
O O
O* *
Figure 4-56 Structure of (syn/anti)-tert-butyl 2,5-bis(1-(tert-butoxycarbonylamino)-
2-methylpropyl)-1H-pyrrole-1-carboxylate III-12a
Compound III-12a: A yellow solid; m.p. 143-147 oC; Rf = 0.09 (0.5:9.5
EtOAc/ hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 5.98 (br d, J = 10.8 Hz, 2H,
2xCH), 5.22 (br d, J = 8.8 Hz, 2H, 2xNH), 4.95 (br t, J = 8.8 Hz, 2H, 2xCHCHCH3),
1.96-1.92 (m, 2H, 2xCHCH3), 1.66 (s, 9H, 3xCH3), 1.45 (s, 18H, 6xCH3), 0.87 (d,
J = 6.4 Hz, 6H, 2xCHCH3), 0.83 (d, J = 6.4 Hz, 6H, 2xCHCH3); 13
C NMR (100
MHz, CDCl3): δ 156.5 (2xC), 151.8 (C), 137.2 (2xC), 111.0 (2xCH), 85.8 (C), 79.6
(2xC), 55.2 (2xCHCHCH3), 32.9 (2xCHCH3), 28.7 (6xCH3), 28.1 (3xCH3), 20.2
(2xCHCH3), 18.6 (2xCHCH3); IR (film): νmax 3442 (N-H), 1738, 1716, 1489, 1369,
1252, 1168, 1118, 1066, 1012, 848, 773, 725 cm-1
; HRMS (ESI-TOF) calcd for
C27H47N3O6Na [M+Na]+ 532.3363, found 532.3360.
169
Spectral data of unsymmetrical triarylmethane derivatives
OMeO
MeO OMe
Figure 4-57 Structure of 2-methyl-5-(phenyl(2,4,6-trimethoxyphenyl)methyl)furan
III-13a
Compound III-13a: A white solid; m.p. 78-80 oC; Rf = 0.34 (0.5:9.5
EtOAc/hexane, 3 eluent); 1H NMR (400 MHz, CDCl3): δ 7.24-7.21 (m, 4H, 4xArH),
7.18-7.13 (m, 1H, ArH), 6.16 (s, 2H, 2xArH), 5.96 (s, 1H, CHPh), 5.87 (br d,
J = 2.6 Hz, 1H, furyl-H), 5.80 (br d, J = 2.6 Hz, 1H, furyl-H), 3.82 (s, 3H, OCH3),
3.66 (s, 6H, 2xOCH3), 2.26 (s, 3H, CH3); 13
C NMR (100 MHz, CDCl3): δ 160.2 (C),
159.2 (2xC), 155.2 (C), 149.9 (C), 143.1 (C), 128.5 (2xCH), 127.6 (2xCH), 125.6
(CH), 112.2 (C), 107.4 (CH), 106.0 (CH), 91.8 (2xCH), 55.9 (2xOCH3), 55.3 (OCH3),
39.7 (CHPh), 13.7 (CH3); IR (film): νmax 2938, 2838, 1606, 1590, 1494, 1455, 1417,
1223, 1204, 1149, 1116, 1059, 812, 699 cm-1
; HRMS (ESI) calcd for C21H22O4Na
[M+Na]+ 361.1416, found 361.1417.
OMe
OMeMeO
Figure 4-58 Structure of 1,3,5-trimethoxybenzene III-1a
Compound III-1a: A white solid; m.p. 52-54 oC; Rf = 0.46 (1:9 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 6.11 (s, 3H, 3xArH), 3.79 (s, 9H, 3xOCH3).
170
OMeO
MeO
OMe
Figure 4-59 Structure of 2-methyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)furan
III-13b
Compound III-13b: A brown solid; m.p. 58-60 oC; Rf = 0.42 (2:8 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.32-7.28 (m, 2H, 2xArH) , 7.24-7.18 (m,
3H, 3xArH), 6.64 (s, 1H, ArH), 6.57 (s, 1H, ArH), 5.89 (br d, J = 2.4 Hz, 1H,
furyl-H), 5.80 (s, 1H, CHPh), 5.76 (d, J = 2.4 Hz, 1H, furyl-H), 3.90 (s, 3H, OCH3),
3.76 (s, 3H, OCH3) , 3.74 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13
C NMR (100 MHz,
CDCl3): δ 155.1 (C), 151.2 (C), 148.5 (C), 143.1 (C), 142.3 (C), 128.6 (2xCH), 128.2
(2xCH), 126.3 (CH), 122.4 (C), 114.1 (CH), 108.8 (CH), 105.9 (CH), 98.1 (CH), 56.8
(OCH3), 56.7 (OCH3), 56.1 (OCH3), 43.1 (CHPh), 13.6 (CH3); IR (film): νmax 2936,
2848, 2832, 1610, 1599, 1561, 1509,1464, 1453, 1397, 1316, 1177, 1210, 1036, 876,
739, 701 cm-1
; HRMS (ESI-TOF) calcd for C21H22O4Na [M+Na]+ 361.1416, found
361.1412.
OMeO
MeO
OMe
Figure 4-60 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)furan
III-13c
Compound III-13c: A brown solid; m.p. 51-53 oC; Rf = 0.59 (2:8 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.32-7.29 (m, 2H, 2xArH), 7.25-7.19 (m, 3H,
3xArH), 6.65 (s, 1H, CH), 6.58 (s, 1H, CH), 5.92 (d, J = 2.8 Hz, 1H, furyl-H), 5.82 (s,
1H, CHPh), 5.78 (d, J = 2.8 Hz, 1H, furyl-H), 3.91 (s, 3H, OCH3), 3.76 (s, 3H,
171
OCH3), 3.75 (s, 3H, OCH3), 2.64 (q, J = 7.5 Hz, 2H, CH2CH3), 1.23 (t, J = 7.5 Hz,
3H, CH2CH3); 13
C NMR (100 MHz, CDCl3): δ 157.0 (C), 154.9 (C), 151.2 (C), 148.4
(C), 143.0 (C), 142.4 (C), 128.5 (2xCH), 128.1 (2xCH), 126.2 (CH), 122.4 (C), 114.8
(CH), 108.6 (CH), 104.4 (CH), 98.1 (CH), 56.7 (OCH3), 56.6 (OCH3), 56.1 (OCH3),
43.1 (CHPh), 21.4 (CH2CH3), 12.3 (CH2CH3); IR (film): νmax 2970, 2936, 2848, 2832,
1610, 1560, 1509, 1464, 1397, 1317, 1209, 1180, 1111, 1036, 982, 876, 739, 701
cm-1
; HRMS (ESI-TOF) calcd for C22H24O4Na [M+Na]+ 375.1572, found 375.1579.
SMeO
MeO
OMe
Figure 4-61 Structure of 2-methyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
thiophene III-13d
Compound III-13d: A white solid; m.p. 97-100 oC; Rf = 0.38 (3:7 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.32-7.22 (m, 5H, 5xArH), 6.69 (s, 1H, CH),
5.58 (br d, J = 3.0 Hz, 1H, thienyl-H), 6.56 (s,1H, CH), 6.46 (d, J = 3.0 Hz, 1H,
thienyl-H), 5.98 (s, 1H, CHPh), 3.91 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.73 (s, 3H,
OCH3), 2.44 (s, 3H, CH3); 13
C NMR (100 MHz, CDCl3): δ 151.2 (C), 148.6 (C),
145.7 (C), 144.2 (C), 143.1 (C), 138.6 (C), 128.7 (2xCH), 128.2 (2xCH), 126.4 (CH),
125.9 (CH), 124.5 (CH), 124.4 (C), 114.4 (CH), 98.2 (CH), 56.9 (OCH3), 56.8
(OCH3), 56.2 (OCH3), 44.5 (CHPh), 15.4 (CH3); IR (film): νmax 2933, 2848, 1608,
1600, 1509, 1463, 1453, 1316, 1396, 1247, 1207, 1178, 1103, 1036, 979, 740, 701
cm-1
; HRMS (ESI-TOF) calcd for C21H22O3SNa [M+Na]+ 377.1187, found 377.1190.
172
SMeO
MeO
OMe
Figure 4-62 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-
thiophene III-13e
Compound III-13e: A brown solid; m.p. 84-85 oC; Rf = 0.42 (2:8 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.34-7.25 (m, 5H, 5xArH), 6.74 (s, 1H, CH),
6.64 (d, J = 3.2 Hz, 1H, thienyl-H), 6.58 (s, 1H, CH), 6.52 (d, J = 3.2 Hz, 1H,
thienyl-H), 6.03 (s, 1H, CHPh), 3.92 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 2.82 (q, J = 7.5 Hz, 2H, CH2CH3), 1.31 (t, J = 7.5 Hz, 3H, CH2CH3);
13C NMR (100 MHz, CDCl3): δ 151.1 (C), 148.5 (C), 146.2 (C), 145.3 (C), 144.2 (C),
143.0 (C), 128.7 (2xCH), 128.1 (2xCH), 126.3 (CH), 125.7 (CH), 124.3 (C), 122.5
(CH), 114.2 (CH), 98.0 (CH), 56.8 (OCH3), 56.7 (OCH3), 56.1 (OCH3), 44.4 (CHPh),
23.5 (CH2CH3), 15.8 (CH2CH3); IR (film): νmax 2964, 2933, 2848, 2832, 1609, 1600,
1508, 1461, 1453, 1396, 1317, 1246, 1207, 1178, 1103, 1036, 979, 739, 701 cm-1
;
HRMS (ESI-TOF) calcd for C22H24O3SNa [M+Na]+ 391.1344, found 391.1346.
NMeO
MeO
OMe
Boc
Figure 4-63 Structure of tert-butyl 2-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-
pyrrole-1-carboxylate III-13f
Compound III-13f: A purple solid; m.p. 104-106 oC; Rf = 0.34 (2:8 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 7.33 (br dd, J = 2.6, 3.1 Hz, 1H, pyrrolyl-H),
7.28-7.19 (m, 3H, 3xArH), 7.06-7.05 (m, 2H, 2xArH), 6.55 (s, 1H, CH), 6.28 (m, 2H,
CH and pyrrolyl-H), 6.08 (t, J = 4.0 Hz, 1H, pyrrolyl-H), 5.58 (d, J = 1.1 Hz, 1H,
173
CHPh), 3.90 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 1.37 (s, 9H,
3xCH3); 13
C NMR (100 MHz, CDCl3): δ 152.2 (C), 150.4 (C), 149.2 (C), 144.8 (C),
143.8 (C), 137.6 (C), 129.7 (3x CH), 128.8 (2xCH), 126.8 (CH), 125.4 (C), 122.8
(CH), 115.8 (CH), 114.8 (CH), 110.2 (CH), 98.9 (CH), 84.1 (C), 57.3 (OCH3), 57.0
(OCH3), 56.6 (OCH3), 43.6 (CHPh), 27.8 (3xCH3); IR (film): νmax 2979, 2935, 2844,
2832, 1738, 1605, 1602, 1509, 1463, 1455, 1327, 1251, 1210, 1162, 1119, 1037, 852,
736, 702 cm-1
; HRMS (ESI-TOF) calcd for C25H29NO5Na [M+Na]+ 446.1943, found
446.1949.
NHMeO
MeO
OMe
Figure 4-64 Structure of 2-ethyl-5-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-
pyrrole III-13g
Compound III-13g: A brown oil; Rf = 0.65 (3:7 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 7.76 (br s, 1H, NH), 7.32-7.18 (m, 5H, 5xArH), 6.66 (s, 1H,
CH), 6.55 (s,1H, CH), 5.81 (br s, 1H, pyrrolyl-H), 5.70 (s, 1H, CHPh), 5.67 (br s, 1H,
pyrrolyl-H), 3.90 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 2.58 (q,
J = 7.6 Hz, 2H, CH2CH3), 1.21 (t, J = 7.6 Hz, 3H, CH2CH3); IR (film): νmax 3366,
2935, 2847, 1645, 1609, 1509, 1464, 1395, 1315, 1275, 1207, 1032, 933, 702 cm-1
.
NH
MeO
OMe
MeO
Figure 4-65 Structure of 3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-indole
III-13h
174
Compound III-13h: : A pink solid; m.p. 164-165 oC; Rf = 0.26 (2:8 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 8.08 (br s, 1H, NH), 7.35-7.25 (m, 7H,
5xArH and 2xindolyl-H), 7.20 (t, J = 7.5 Hz, 1H, indolyl-H), 7.03 (t, J = 7.5 Hz, 1H,
indolyl-H), 6.70 (s, 1H, CH), 6.64 (s, 1H, CH), 6.59 (s, 1H, indolyl-H), 6.10 (s, 1H,
CHPh), 3.94 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.64 (s, 3H, OCH3); 13
C NMR
(100 MHz, CDCl3): δ 151.3 (C), 148.1 (C), 144.3 (C), 142.9 (C), 136.8 (C), 128.8
(2xCH), 128.0 (2xCH), 127.0 (C), 125.9 (CH), 124.5 (C), 124.0 (CH), 122.1 (C),
121.8 (CH), 119.9 (CH), 119.5 (C), 119.1 (CH), 114.6 (CH), 111.0 (CH), 98.3 (CH),
56.9 (OCH3), 56.6 (OCH3), 56.1 (OCH3), 40.9 (CHPh); IR (film): νmax 3411, 3369,
2958, 2941, 2832, 1509, 1456, 1397, 1316, 1205, 1178, 1035, 742, 702 cm-1
;
Compound is literature known, see: [Thirupathi, P. & Kim, S. S. (2005). Eur. J. Org.
Chem., 1798–1808].
NH
MeO
OMe
MeO
MeO
Figure 4-66 Structure of 5-methoxy-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-
indole III-13i
Compound III-13i: A purple solid; m.p. 140-142 oC; Rf = 0.08 (3:7 EtOAc/
hexane, 3 eluent); 1H NMR (400 MHz, CDCl3): δ 7.87 (br s, 1H, NH), 7.30-7.19 (m,
6H, 5xArH and 1xindolyl-H), 6.83 (dd, J = 2.4, 8.7 Hz, 1H, indolyl-H), 6.68 (d,
J = 2.2 Hz, 1H, indolyl-H), 6.64 (s, 1H, indolyl-H), 6.59 (s, 2H, 2xArH), 5.32 (s, 1H,
CHPh), 3.91 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.62 (s, 3H,
OCH3); 13
C NMR (100 MHz, CDCl3): δ 153.8 (C), 151.5 (C), 148.3 (C), 144.3 (C),
132.1 (C), 129.0 (2xCH), 128.1 (2xCH), 127.8 (C), 127.8 (C), 126.0 (CH), 124.7
(CH), 124.6 (C), 119.7 (C), 114.7 (CH), 112.1 (CH), 111.6 (CH), 102.4 (CH), 98.6
(CH), 57.1 (OCH3), 56.8 (OCH3), 56.3 (OCH3), 55.9 (OCH3), 41.0 (CHPh); IR
(film): νmax 3354, 2936, 2830, 1583, 1508, 1485, 1453, 1438, 1396, 1319, 1265, 1205,
175
1172, 1109, 1031, 831, 734, 701 cm-1
; HRMS (ESI-TOF) calcd for C25H25NO4Na
[M+Na]+ 426.1681, found 426.1697.
NH
MeO
OMe
MeO
F
Figure 4-67 Structure of 6-fluoro-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-1H-
indole III-13j
Compound III-13j: A yellow oil; Rf = 0.33 (3:7 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.04 (br s, 1H, NH), 7.32-7.23 (m, 5H, 5xArH), 7.14 (dd,
J = 5.4, 8.6 Hz, 1H, indolyl-H), 7.01 (dd, J = 1.7, 9.6 Hz, 1H, indolyl-H), 6.76 (td,
J = 2.1, 9.3, 1H, indolyl-H), 6.62 (s, 1H, CH), 6.61 (s, 1H, CH), 6.55, (s, 1H,
indolyl-H), 6.02 (s, 1H, CHPh), 3.92 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.62 (s, 3H,
OCH3); 13
C- NMR (100 MHz, CDCl3): δ 160.1 (1J = 236.0 Hz, C-F), 151.5 (C), 148.4
(C), 144.1 (C), 143.1 (C), 136.8 (3J = 12.0 Hz, C-F), 128.9 (2xCH), 128.2 (2xCH),
126.1 (CH), 124.3 (CH), 123.9 (C), 120.9 (3J = 10 Hz, CH-F), 120.1 (C), 114.7 (CH),
108.1 (2J = 24 Hz, CH-F), 98.4 (CH), 97.4 (
2J = 26 Hz, CH-F), 57.1 (OCH3), 56.8
(OCH3), 56.3 (OCH3), 41.0 (CHPh); IR (film): νmax 3421, 3362, 2936, 2833, 1626,
1608, 1600, 1508, 1456, 1396, 1320, 1249, 1206, 1140, 1035, 952, 836, 804, 736, 702
cm-1
.
O
O
Figure 4-68 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)furan
III-13k
176
Compound III-13k: A yellow oil; Rf = 0.59 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 7.42-7.31 (m, 5H, 5xArH), 5.96 (br d, J = 3.4 Hz, 4H,
4xfuryl-H), 5.45 (s, 1H, CHPh), 2.69 (q, J = 7.5 Hz, 2H, CH2CH3), 2.33 (s, 3H, CH3),
1.28 (t, J = 7.5 Hz, 3H, CH2CH3); 13
C NMR (100 MHz, CDCl3): δ 157.2 (C), 153.0
(C), 152.7 (C), 151.4 (C), 140.1 (C), 128.4 (4xCH), 127.0 (CH), 108.2 (CH), 108.0
(CH), 106.1 (CH), 104.4 (CH), 45.2 (CHPh), 21.4 (CH2CH3), 13.6 (CH3), 12.2
(CH2CH3); IR (film): νmax 2973, 2922, 2880, 1603, 1558, 1496, 1453, 1219, 1184,
1075, 1058, 1021, 964, 954, 778, 731, 699 cm-1
; HRMS (ESI-TOF) calcd for
C18H18O2Na [M+Na]+ 289.1204, found 289.1205.
O
ONO2
Figure 4-69 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)furan
III-13l
Compound III-13l: A brown oil; Rf = 0.59 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.20 (d, J = 8.6 Hz, 2H, 2xArH), 7.43 (d, 2H, J = 8.6 Hz,
2xArH), 5.96 (d, J = 3.3 Hz, 2H, 2xfuryl-H), 5.94 (d, J = 4.1 Hz, 2H, 2xfuryl-H), 5.46
(s, 1H, CHPh), 2.62 (q, J = 7.5 Hz, 2H, CH2CH3), 2.27 (s, 3H, CH3), 1.22 (t,
J = 7.5 Hz, 3H, CH2CH3); 13
C NMR (100 MHz, CDCl3): δ 157.9 (C), 152.1 (C),
151.1 (C), 150.9 (C), 147.6 (C), 147.1 (C), 129.4 (2xCH), 123.8 (2xCH), 108.9 (CH),
108.7 (CH), 106.3 (CH), 104.7 (CH), 44.9 (CHPh), 21.4 (CH2CH3), 13.6 (CH3), 12.2
(CH2CH3); IR (film): νmax 2974, 2938, 2880, 1717, 1605, 1560, 1520, 1348, 1217,
1182, 1110, 1016, 860, 782, 735 cm-1
; HRMS (ESI-TOF) calcd for C18H17NO4Na
[M+Na]+ 334.1055, found 334.1053.
177
O
O
HO
Figure 4-70 Structure of (5-((5-methylfuran-2-yl)(phenyl)methyl)furan-2-yl)-
methanol III-13m
Compound III-13m: A yellow oil; Rf = 0.30 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, 5xArH), 6.25 (d, J = 3.0 Hz, 1H, furyl-H),
5.98 (d, J = 3.0 Hz, 1H, furyl-H), 5.91 (br s, 1H, furyl alcohol-H), 5.88 (br d,
J = 2.8 Hz, 1H, furyl alcohol-H), 5.40 (s, 1H, CHPh), 4.57 (s, 2H, CH2OH), 2.27 (s,
3H, CH3), 1.79 (s, 1H, OH); 13
C NMR (100 MHz, CDCl3): δ 155.0 (C), 153.5 (C),
152.4 (C), 151.7 (C), 139.7 (C), 128.6 (2xCH), 128.5 (2xCH), 127.2 (CH), 108.6
(CH), 108.4 (CH), 106.2 (CH), 57.7 (CH2), 45.3 (CHPh), 13.6 (CH3); IR (film): νmax
3367 (OH), 2924, 1599, 1496, 1368, 1217, 1164, 1022, 968, 783, 735, 700 cm-1
;
HRMS (ESI-TOF) calcd for C17H16O3Na [M+Na]+ 291.0997, found 291.0992.
S
O
Figure 4-71 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(phenyl)methyl)furan
III-13o
Compound III-13o: A brown oil; Rf = 0.64 (1:9 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 7.36-7.26 (m, 5H, 5xArH), 6.58 (br d, J = 3.2 Hz,1H,
thienyl-H), 6.57 (br d, J = 3.2 Hz, 1H, thienyl-H), 5.94 (br d, J = 2.9 Hz, 1H, furyl-H),
5.90 (br s, 1H, furyl-H), 5.52 (s,1H, CHPh), 2.44 (s, 3H, thienyl-CH3), 2.28 (s, 3H,
furyl-CH3); 13
C NMR (100 MHz, CDCl3): δ 154.4 (C), 151.5 (C), 143.2 (C), 142.0
(C), 139.0 (C), 128.5 (2xCH), 128.4 (2xCH), 127.0 (CH), 125.6 (CH), 124.6 (CH),
178
108.5 (CH), 106.1 (CH), 46.5(2xCHPh), 15.3 (thienyl-CH3), 13.6 (furyl-CH3); IR
(film): νmax 2920, 2858, 1717, 1634, 1600, 1560, 1494, 1452, 1219, 1167, 1022, 964,
787, 723, 699 cm-1
; HRMS (ESI-TOF) calcd for C17H16OSNa [M+Na]+ 291.0820,
found 291.0827.
S
ONO2
Figure 4-72 Structure of 2-methyl-5-((5-methylthiophen-2-yl)(4-nitrophenyl)methyl)-
furan III-13p
Compound III-13p: A brown solid; m.p. 152-154 oC; Rf = 0.33 (1:9
EtOAc/ hexane, 2 eluent); 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.6 Hz, 2H,
2xArH), 7.45 (d, J = 8.6 Hz, 2H, 2xArH), 6.61 (br s, 1H, thienyl-H), 6.58 (br d,
J = 3.4 Hz, 1H, thienyl-H), 5.98 (br d, J = 2.8 Hz, 1H, furyl-H), 5.94 (br s, 1H,
furyl-H), 5.60 (s,1H, CHPh), 2.45 (s, 3H, thienyl-CH3), 2.28 (s, 3H, furyl-CH3);
13C NMR (100 MHz, CDCl3): δ 150.3 (C), 150.2 (C), 149.3 (C), 141.0 (C), 139.8 (C),
129.2 (2xCH), 126.2 (CH), 124.8 (CH), 123.8 (2xCH), 109.1 (CH), 106.2 (CH), 46.1
(CHPh), 15.3 (thienyl-CH3), 13.6 (furyl-CH3), 26.3 (CH2), 26.1(2xCH2), 15.3 (CH3);
IR (film): νmax 2925, 2855, 1716, 1633, 1520, 1600, 1520, 1447, 1347, 1109, 839, 736
cm-1
; HRMS (ESI-TOF) calcd for C17H15NO3SNa [M+Na]+ 336.0670, found
336.0663.
S
O
Figure 4-73 Structure of 2-((5-ethylthiophen-2-yl)(phenyl)methyl)-5-methylfuran
III-13q
179
Compound III-13q: A yellow oil; Rf = 0.67 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 7.37-7.28 (m, 5H, 5xArH), 6.62 (d, J = 3.3 Hz, 1H, furyl-H),
6.60 (d, J = 3.3 Hz, 1H, furyl-H), 5.96 (d, J = 2.8 Hz, 1H, thienyl-H), 5.92 (br s, 1H,
thienyl-H), 5.53 (s, 1H, CHPh), 2.80 (q, J = 7.5 Hz, 2H, CH2CH3), 2.28 (s, 3H,
furyl-CH3), 1.29 (t, J = 7.5 Hz, 3H, CH2CH3); 13
C- NMR (100 MHz, CDCl3): δ 154.4
(C), 151.6 (C), 146.7 (C), 142.8 (C), 142.0 (C), 128.5 (2xCH), 128.4 (2xCH), 127.0
(CH), 125.4 (CH), 122.7 (CH), 108.5 (CH), 106.1 (CH), 46.5 (CHPh), 23.5
(CH2CH3), 15.8 (CH2CH3), 13.7 (CH3); IR (film): νmax 2966, 2924, 1634, 1494, 1452,
1219, 1022, 785, 699 cm-1
; HRMS (ESI-TOF) calcd for C18H18OSNa [M+Na]+
305.0976, found 304.2592.
S
ONO2
Figure 4-74 Structure of 2-((5-ethylthiophen-2-yl)(4-nitrophenyl)methyl)-5-methyl-
furan III-13r
Compound III-13r: A brown oil; Rf = 0.62 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.19 (d, J = 8.6 Hz, 2H, 2xArH), 7.45 (d, J = 8.6 Hz, 2H,
2xArH), 6.64 (d, J = 3.0 Hz, 1H, thienyl-H), 6.60 (d, J = 3.0 Hz, 1H, thienyl-H), 6.00
(d, J = 2.9 Hz, 1H, furyl-H), 5.94 (br s, 1H, furyl-H), 5.62 (s, 1H, CHPh), 2.81 (q,
J = 7.5 Hz, 2H, CH2CH3), 2.28 (s, 3H, furyl-CH3), 1.29 (t, 3H, J = 7.5 Hz, CH2CH3);
13C- NMR (100 MHz, CDCl3): δ 152.7 (C), 152.3 (C), 147.6 (C), 147.0 (C), 140.7
(C), 129.3 (2xCH), 126.0 (C), 123.8 (2xCH), 122.9 (CH), 109.2 (CH), 106.3 (CH),
46.2 (CHPh), 23.5 (CH2CH3), 15.8 (CH3), 13.7 (CH2CH3); IR (film): νmax 2970, 2931,
2874, 1717, 1640, 1598, 1520, 1446, 1347, 1266, 1218, 1109, 1022, 858, 839, 807,
737, 703 cm-1
; HRMS (ESI-TOF) calcd for C18H17NO3SNa [M+Na]+ 350.0827, found
350.0824.
180
NBoc
O
Figure 4-75 Structure of tert-butyl 2-((5-methylfuran-2-yl)(phenyl)methyl)-1H-
pyrrole-1-carboxylate III-13s
Compound III-13s: A yellow oil; Rf = 0.62 (1:9 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 7.33-7.25 (m, 4H, 4xArH), 7.16 (d, J = 7.4 Hz, 2H, 1xArH and
1xpyrrolyl-H), 6.10 (br t, J = 2.0 Hz, 1H, pyrrolyl-H), 6.02 (s, 1H, CHPh), 5.88 (brs,
1H, pyrrolyl-H), 5.71 (br d, J = 1.9 Hz, 1H, furyl-H), 5.64 (br d, J = 1.9 Hz, 1H,
furyl-H), 2.27 (s, 3H, furyl-CH3), 1.46 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3):
δ 154.8 (C), 151.0 (C), 149.4 (C), 141.2 (C), 134.9 (C), 128.8 (2xCH), 128.2 (2xCH),
126.7 (CH), 122.2 (CH), 114.5 (CH), 109.8 (CH), 108.3 (CH), 106.1 (CH), 83.9 (C),
44.5 (CHPh), 27.8 (3xCH3), 13.7 (CH3); IR (film): νmax 2980, 2922, 1743, 1561,
1453, 1488, 1405, 1370, 1331, 1161, 1117, 1063, 1022, 848, 778, 728, 699 cm-1
;
HRMS (ESI-TOF) calcd for C21H23NO3Na [M+Na]+ 360.1576, found 360.1574.
NBoc
ONO2
Figure 4-76 Structure of tert-butyl 2-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-
1H-pyrrole-1-carboxylate III-13t
Compound III-13t: A brown oil; Rf = 0.70 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.17 (d, J = 8.2 Hz, 2H, 2xArH), 7.33 (d, J = 8.2 Hz, 2H,
2xArH), 6.17 (s, 1H, CHPh), 6.14 (t, J = 3.2 Hz, 1H, pyrrolyl-H), 5.90 (br d,
J = 1.81 Hz, 1H, furyl-H), 5.79 (br s, 1H, furyl-H), 5.70 (br d, J = 2.7 Hz, 1H,
pyrrolyl-H), 2.27 (s, 3H, CH3), 1.46 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3):
δ 152.7 (C), 151.6 (C), 148.8 (C), 148.6 (C), 146.6 (C), 133.3 (C), 129.4 (2xCH),
123.3 (2xCH), 122.2 (CH), 114.5 (CH), 109.8 (CH), 108.7 (CH), 106.0 (CH), 83.9
181
(C), 44.0 (CHPh), 27.7 (3xCH3), 13.5 (CH3); IR (film): νmax 2924, 2851, 1740, 1522,
1370, 1347, 1157, 1120, 849, 733 cm-1
; HRMS (ESI-TOF) calcd for C21H22N2O5Na
[M+Na]+ 405.1426, found 405.1423.
NH
O
Figure 4-77 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(phenyl)methyl)-1H-pyrrole
III-13u
Compound III-13u: A brown oil; Rf = 0.50 (2:8 EtOAc/ hexane); IR (film):
νmax 3307, 2927, 1715, 1361, 1269, 1180, 735, 701 cm-1
.
NH
ONO2
Figure 4-78 Structure of 2-ethyl-5-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-
pyrrole III-13v
Compound III-13v: A brown oil; Rf = 0.37 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H, 2xArH), 7.82 (br s, 1H, NH), 7.40 (d,
J = 8.6 Hz, 2H, 2xArH), 6.00 (d, J = 2.9 Hz, 1H, furyl-H), 5.95 (br s, 1H, furyl-H),
6.85 (br s, 1H, pyrrolyl-H), 5.75 (br t, J = 2.7 Hz, 1H, pyrrolyl-H), 5.45 (s, 1H,
CHPh), 2.61 (q, J = 7.5 Hz, 2H, CH2CH3), 2.28 (s, 3H, furyl-CH3), 1.24 (t, 3H,
J = 7.5 Hz, CH2CH3); IR (film): νmax 3411 (N-H), 1702, 1497, 1452, 1364, 1245,
1168, 1009, 747 cm-1
; HRMS (ESI-TOF) calcd for C18H18N2O3Na [M+Na]+
333.1215, found 333.1214.
182
NH
O
Figure 4-79 Structure of 3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-indole III-13w
Compound III-13w: A red oil; Rf = 0.33 (1:9 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.02 (br s, 1H, NH), 7.43-7.25 (m, 7H, 5xArH and
2xindolyl-H), 7.20 (t, J = 7.4 Hz, 1H, indolyl-H), 7.06 (t, J = 7.4 Hz, 1H, indolyl-H),
6.80 (s, 1H, indolyl-H), 5.90 (br d, J = 2.5 Hz, 1H, furyl-H), 5.85 (d, J = 2.5 Hz, 1H,
furyl-H), 5.65 (s, 1H, CHPh), 2.29 (s, 3H, CH3); 13
C- NMR (100 MHz, CDCl3):
δ 155.1 (C), 151.2 (C), 142.2 (C), 136.6 (C), 128.6 (2xCH), 128.4 (2xCH), 126.9 (C),
126.6 (CH), 123.4 (CH), 122.1 (CH), 119.7 (CH), 119.5 (CH), 117.8 (C), 111.2 (CH),
108.2 (CH), 106.0 (CH), 42.8 (CH), 13.8 (CH3); IR (film): νmax 3417, 3059, 3027,
2921, 1602, 1561, 1494, 1456, 1416, 1338, 1218, 1095, 1021, 963, 783, 741, 700 cm-
1; HRMS (ESI-TOF) calcd for C20H17NONa [M+Na]
+ 310.1208, found 310.1209.
NH
ONO2
Figure 4-80 Structure of 3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-indole
III-13x
Compound III-13x: A yellow oil; Rf = 0.30 (3:7 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.18 (d, J = 8.4 Hz, 2H, 2xArH), 8.14 (s, 1H, NH), 7.41 (d,
J = 8.4 Hz, 2H, 2xArH), 7.35 (d, J = 7.9 Hz, 1H, indolyl-H), 7.22 (t, J = 7.4 Hz, 1H,
indolyl-H), 7.08 (t, J = 7.7 Hz, 1H, indolyl-H), 6.85 (s, 1H, indolyl-H), 5.93 (br s, 1H,
furyl-H), 5.90 (br d, J = 2.9 Hz, 1H, furyl-H), 5.73 (s, 1H, CHPh), 2.29 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3): δ 153.3 (C), 151.8 (C), 149.9 (C), 146.8 (C), 136.6 (C),
129.4 (2xCH), 126.4 (C), 123.7 (2xCH), 123.4 (CH), 122.5 (CH), 119.9 (CH), 119.4
183
(CH), 116.2 (C), 111.4 (CH), 108.8 (CH), 106.3 (CH), 42.6 (CHPh), 13.7 (CH3);
IR (film): νmax 3406, 3330, 2979, 2928, 1715, 1607, 1521, 1367, 1349, 1245, 1166,
1109, 1048, 1023, 858, 788, 715 cm-1
.
NH
O
MeO
Figure 4-81 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-
indole III-13y
Compound III-13y: A brown solid; m.p. 90-92 oC; Rf = 0.44 (3:7 EtOAc/
hexane); IR (film): νmax 3419, 2940, 2831, 1705, 1625, 1584, 1487, 1455, 1216, 1171,
1051, 1022, 787, 724, 700 cm-1
; HRMS (ESI-TOF) calcd for C21H19NO2Na [M+Na]+
340.1313, found 310.1209. 340.1314.
NH
O
MeO
NO2
Figure 4-82 Structure of 5-methoxy-3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-
1H-indole III-13z
Compound III-13z: A brown solid; m.p. 116-120 o
C; Rf = 0.09 (1:9 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H, 2xArH), 8.03 (br s,
1H, NH), 7.49 (d, J = 8.6 Hz, 2H, 2xArH), 7.29 (d, J = 7.6 Hz, 1H, indolyl-H), 6.87
(dd, J = 8.8, 2.2 Hz, 1H, indolyl-H), 6.81 (br s, 1H, indolyl-H), 6.76 (d, J = 2.1 Hz,
1H, indolyl-H), 5.92 (br s, 1H, furyl-H), 5.90 (br d, J = 3.0 Hz, 1H, furyl-H), 5.67 (s,
1H, CHPh), 3.76 (s, 3H, OCH3), 2.28 (s, 3H, CH3); 13
C NMR (100 MHz, CDCl3):
δ 154.1 (C), 153.1 (C), 151.8 (C), 149.8 (C), 131.6 (C), 129.3 (2xCH), 126.8 (C),
124.0 (CH), 123.6 (2xCH), 115.8 (C), 112.4 (CH), 112.0 (CH), 108.7 (CH), 106.2
184
(CH), 101.3 (CH), 55.8 (OCH3), 42.5 (CHPh), 13.6 (CH3); IR (film): νmax 3366,
2924, 2851, 1710, 1597, 1519, 1488 1347, 1214, 1172, 1025, 848, 731 cm-1
; HRMS
(ESI-TOF) calcd for C21H17N2O4+ [M
+-H] 361.1183, found 361.1174.
NH
O
F
Figure 4-83 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(phenyl)methyl)-1H-indole
III-13aa
Compound III-13aa: A red oil; Rf = 0.48 (2:8 EtOAc/ hexane); 1H NMR
(400 MHz, CDCl3): δ 8.00 (br s, 1H, NH), 7.34-7.27 (m, 6H, 5xArH and
1xindolyl-H), 7.04 (dd, J = 9.6, 1.7 Hz, 1H, indolyl-H), 6.82 (td, J = 9.2, 2.2 Hz, 1H,
indolyl-H), 6.77 (s, 1H, indolyl-H), 5.92 (br d, J = 2.6 Hz, 1H, furyl-H), 5.84 (d,
J = 2.6 Hz, 1H, furyl-H), 5.60 (s, 1H, CHPh), 2.29 (s, 3H, CH3); 13
C NMR (100 MHz,
CDCl3): δ 160.0 (1J = 263.0 Hz, C-F), 154.9 (C), 151.3 (C), 142.0 (C), 136.5
(4J = 13.0 Hz, C-F), 128.5 (2xCH), 128.4 (2xCH), 126.7 (CH), 123.6 (CH), 123.5 (C),
120.5 (3J = 10.0 Hz, C-F), 117.9 (C), 108.3 (
2J = 22.0 Hz, CH-F), 108.2 (CH), 106.1
(CH), 97.4 (2J = 22.0 Hz, CH-F), 42.8 (CHPh), 13.7 (CH3); IR (film): νmax 3426,
3063, 3028, 2922, 1627, 1559, 1497, 1456, 1342, 1251, 1217, 1140, 1022, 952, 837,
803, 738, 724, 700 cm-1
; HRMS (ESI-TOF) calcd for C20H16FNONa [M+Na]+
328.1114, found 328.1113.
NH
O
F
NO2
Figure 4-84 Structure of 6-fluoro-3-((5-methylfuran-2-yl)(4-nitrophenyl)methyl)-1H-
indole III-13ab
185
Compound III-13ab: A brown solid; m.p. 172-176 oC; Rf = 0.24 (1:9
EtOAc/ hexane, 3 eluent); 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H,
2xArH), 8.13 (br s, 1H, NH), 7.46 (d, J = 8.6 Hz, 2H, 2xArH), 7.23 (dd, J = 5.3, 8.7
Hz, 1H, indolyl-H), 7.08 (dd, J = 9.5, 2.1 Hz, 1H, indolyl-H), 6.83 (td, J = 8.4, 1.9 Hz,
1H, indolyl-H), 6.81 (br s, 1H, indolyl-H), 5.92 (br d, J = 2.1 Hz, 1H, furyl-H), 5.88
(d, J = 3.0 Hz, 1H, furyl-H), 5.68 (s, 1H, CHPh), 2.28 (s, 3H, CH3); IR (film): νmax
3342, 2924, 2853, 1714, 1626, 1598, 1520, 1450, 1347, 1216, 1141, 1108, 1015, 952,
848, 736 cm-1
; HRMS (ESI-TOF) calcd for C20H15FN2O3Na [M+Na]+ 373.0964,
found 373.0960.
NH
S
Figure 4-85 Structure of 3-((5-methylthiophen-2-yl)(phenyl)methyl)-1H-indole
III-13ac
Compound III-13ac: A red solid; m.p. 98-100 oC; Rf = 0.50 (50:50:1
CH2Cl2/hexane/MeOH); 1H NMR (400 MHz, CDCl3): δ 8.00 (br s, 1H, NH),
7.40-7.24 (m, 7H, 5xArH and 2xindolyl-H), 7.20 (t, J = 7.6 Hz, 1H, indolyl-H), 7.05
(t, J = 7.6 Hz, 1H, indolyl-H), 6.83 (s, 1H, indolyl-H), 6.58 (br s, 2H, 2xthienyl-H),
5.82 (s, 1H, CHPh), 2.44 (s, 3H, CH3); IR (film): νmax 3418, 2917, 2858, 1618, 1560,
1493, 1456, 1417, 1338, 1220, 1095, 800, 740, 700 cm-1
.
NH
N
Boc
Figure 4-86 Structure of tert-butyl 2-((1H-indol-3-yl)(phenyl)methyl)-1H-pyrrole-1-
carboxylate III-13ad
186
Compound III-13ad: A red solid; m.p. 78-82 oC; Rf = 0.34 (0.5:9.5 EtOAc/
hexane, 4 eluent); 1H NMR (400 MHz, CDCl3): δ 7.95 (br s, 1H, NH), 7.39-7.34 (m,
3H, 3xArH), 7.30-7.26 (m, 2H, 2xArH), 7.23-7.17 (m, 4H, 4xindolyl-H), 6.54 (br s,
1H, pyrrolyl-H), 6.26 (br s, 1H, pyrrolyl-H), 6.07 (t, J = 3.2 Hz, 1H, pyrrolyl-H), 5.68
(s, 1H, CHPh), 1.34 (s, 9H, 3xCH3); 13
C NMR (100 MHz, CDCl3): δ 149.7 (C), 143.5
(C), 136.9 (C), 136.6 (C), 128.8 (2xCH), 128.1 (2xCH), 127.0 (C), 126.2 (CH), 123.4
(CH), 122.0 (CH), 121.9 (CH), 119.8 (CH), 119.3 (CH), 114.7 (CH), 111.1 (CH),
119.8 (CH), 83.7 (C), 41.9 (CHPh), 27.7 (3xCH3); IR (film): νmax 3418, 2980, 1733,
1489, 1456, 1403, 1370, 1330, 1160, 1117, 1063, 1012, 847, 739 cm-1
; HRMS (ESI-
TOF) calcd for : C24H24N2O2Na [M+Na]+ 395.1735, found 395.1732.
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BIOGRAPHY
Name Miss Sureeporn Ruengsangtongkul
Date of birth March 23, 1989
Place of birth Chon Buri, Thailand
Present address 52/143, Village No. 5, Nongprue sub-district,
Banglamung district, Chon Buri province
Education
2009-2012 Bachelor of Science (B.Sc.),
Faculty of Science, Burapha University,
Chonburi, Thailand
2012-2015 Master of Science (M.Sc.),
Faculty of Science, Burapha University,
Chonburi, Thailand