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Bavishi, Abhay J., 2011, “Studies in Heterocyclic Moieties”, thesis PhD,

Saurashtra University

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“Studies In Heterocyclic Moieties”

A THESIS SUBMITTED TO

THE SAURASHTRA UNIVERSITY

IN THE FACULTY OF SCIENCE

FOR THE DEGREE OF

Doctor of Philosophy

IN

CHEMISTRY

BY

ABHAY J. BAVISHI

UNDER THE GUIDANCE OF

PROF. ANAMIK SHAH DEPARTMENT OF CHEMISTRY

(DST-FIST FUNDED AND UGC-SAP SPONSORED)

SAURASHTRA UNIVERSITY

RAJKOT – 360 005

GUJARAT (INDIA)

June- 2011

Statement under O. Ph. D. 7 of Saurashtra University The work included in the thesis is done by me under the supervision of

Prof. Anamik K. Shah and the contribution made thereof is my own

work.

Date:

Place: Abhay J. Bavishi

CERTIFICATE

This is to certify that the present work submitted for the Ph.D. degree of Saurashtra

University by Mr. Abhay J. Bavishi has been the result of work carried out under my

supervision and is a good contribution in the field of organic, heterocyclic and

synthetic medicinal chemistry.

Date:

Place: Prof. Anamik K. Shah

Acknowledgement

It is a moment of gratification and pride to look back with a sense of contentment at the

long traveled path, to be able to recapture some of the fine moments, to be able to think of the

infinite number of people, some who were with me from the beginning, some who joined me at

some stage during the journey, whose kindness, love and blessings has brought me to this day. I

wish to thank each one of them from the bottom of my heart.

Therefore first and foremost I would like to bow my head with utter respect to my

Parents who blessed me with their good wishes, relieving all types of stress and remaining always

with me and continuing to boost my spirit. The never ending process of unsurpassable devotion,

love and affection which showered upon me by my parents and my family who were ever

boosting me to go ahead to reach the goal. However I assured them to be worthy of whatever

they have done for me. I am gratified for their eternal love, trust and support. I bow my head

humbly before All Mighty God for making me much capable that I could adopt and finish this

task.

I would like to express my feelings of gratitude to Prof. P. H. Parsania, Professor and

Head, Department of Chemistry, Saurashtra University, Rajkot for providing adequate

infrastructure facilities.

I take this opportunity to express the deep sense of gratitude to my adored guide Prof.

Anamik Shah, who supported my aspirations with lot of love and encouragement. I consider

myself privilege to work under his generous guidance because I got the newer creative

dimensions, thinking analyzing capacity and positive attitude, which has always helped me in

making think simple and pragmatic too. I am always indebted to him.

I am very much grateful to Dr. Y.T.Naliapara for his valuable guidance during my entire

work.

I would like to convey my pleasant heartily thankfulness to my dearest friends Dr.

Shailesh, Ashish (Master), Hardevsinh (Bapu), Dr. Shrey, Dhairya, Vipul, Kaushik, Bhavesh,

Renish, Dr. Govind, Dr. Mahesh and Paresh for their time being help and moral support. I will

never forget their all kind concern, help, best wishes and that they have done for me.

I am also thankful to my team members Manisha, Jignesh, Dr. Rakshit, Hitesh,

Mrunal, Harshad, Vaibhav, Sachin, Dr. Nilay, Dr. Bharat, Ravi, Bhavin, Dilip, Pratik, Sabera,

Vishwa, Madhvi and Hetal for creating most healthy working atmosphere.

I would also like to thank my seniors for all their help, and support during my research

tenure. I heartily thank Dr. Dharmendra, Dr. Maitrey, Dr. Dhawal, Dr. Kuldip, Dr. Jitender,

Dr. Priti, Dr. Atul, Dr. Jyoti, Dr. Jalpa, Dr. Vaibhav, Dr. Naval, Dr. Raju and Dr. Kena for

their co-operation.

I was also blessed with some great colleagues whose presence has made this time a

memorable time for me and my work in the laboratory was really enjoyable due to them. I thank

Anil, Rakesh, Ashish, Amit, Ritesh, Piyush, Dipti, Lina, Suresh, Mehul, Rahul, Naimish, Vijay,

Meenaxi, Pankaj, Piyush, Vipul, Jignesh, Pooja.

I am also thankful to Prof. V. H. Shah, Prof. S. H. Baluja., Prof. H. S. Joshi, Dr. M. K.

Shah, Dr. U. C. Bhoya and Dr. R. C. Khunt.

I would also like to convey my pleasant regards and thankfulness towards, Kavita, Dr.

Hitarth and Dr. Kena for their constant care, support and encouragement.

I would also like to express my deep sense of gratitude to Dr. Ranjanben A. Shah and

Mr. Aditya A. Shah for their kind concern and moral support which made us feel at home. I

specifically thank Ranjan madam for all her help and expertise that she gave me when I had met

with a few accidents during this tenure.

I would also like to thank teaching and non-teaching staff members of Department of

Chemistry, Saurashtra University, Rajkot.

I am also grateful to Sophisticated Analytical Instrumentation Facility (SAIF), RSIC,

Punjab University, Chandigarh and CDRI, Lucknow and Alembic Research Centre, Alembic

Ltd., for 1H NMR, and 13C NMR, Dept. of Chemistry, Saurashtra University, Rajkot for IR,

Mass and Elemental analysis, TAACF, USA for providing facilities for carrying out biological

activity, “National Facility For drug discovery through new chemical entities development and

instrumentation support to small manufacturing pharma enterprises” for instrument support

and limited financial assistance.

Lastly I would like to thank each and every one of them who helped me directly or

indirectly during this wonderful and lots of experience gaining journey. I apologize if in any case

I am missing out any of the names as I am thankful to one and all.

Abhay J. Bavishi

CONTENTS

GENERAL REMARKS

ABBREVIATIONS USED

Chapter -1 Synthesis of (5-chloro-2-methoxyphenyl)(5-alkyl-3-(substituted) (phenyl/alkyl)-1H-

pyrazol-1-yl)methanones

1.1 Introduction 1

1.2 Literature review 1

1.3 Synthesis of functionalized pyrazoles using combinatorial chemistry approach 5

1.4 Pharmacological-significance of pyrazoles 8

1.5 Aim of current work 10

1.6 Reaction schemes 11

1.7 Plausible reaction mechanism 12

1.8 Experimental 13

1.9 Physical data 15

1.10 Spectral discussion 16

1.11 Analytical data 18

1.12 Results and discussion 23

1.13 Conclusion 23

1.14 Representative spectra 24

1.15 References 29

Chapter -2 Synthesis of 4-(3-(substituted)benzoyl-2-alkyl-5-(substituted)

alkyl-4-(substituted)phenyl-1H-pyrrol-1-yl)-2H-chromene-2-ones

2.1 Introduction 32


2.3 Pharmacology 42

2.4 Some drugs from pyrrole nucleus 42




2.8 Experimental 46





2.13 Conclusion 60


2.15 References 71

Chapter -3 Synthesis of 4-(dialkyl/alkyl)amino)-2-oxo-2H-chromene-3-

carbonitirles

3.1 Introduction 76


3.3 Pharmacology 86




3.7 Experimental 90





3.12 Conclusion 99


3.14 References

106

Chapter -4 Rapid synthesis of 5-(substituted)benzoyl-4-(1-phenyl, 3(substituted)phenyl-1H-pyrazole-4-

yl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonitriles

4.1 Introduction 111


4.3 Pharmacology 117

4.4 Some drugs from 1,4-dihydropyridine nucleus 118

4.5 Pyrazoles : a versatile synthon 118




4.9 Experimental 124





4.14 Conclusion 134


4.16 References

140

Chapter-5 Synthesis of 8-((substituted)amino)-10-methylchromeno[3,4-b] thieno[2,3-e][1,4]diazepin-6(12H)-ones

5.1 Introduction 145


5.3 Reported synthetic strategies for the piperazinyl derivetives of benzo- and

thienodiazepines

150

5.4 Pharmacology 157

5.5 Some drugs of diazepines 161



5.8 Experimental 165





5.13 Conclusion 177


5.15 References

187

BIOLOGICAL EVALUATION OF SYNTHESIZED COMPOUNDS

SUMMARY

CONFERENCES/SEMINARS/WORKSHOPS ATTENDED

PUBLICATIONS

General Remarks

Department of Chemistry, Saurashtra University, Rajkot – 360 005

GENERAL REMARKS 1. Melting points were recorded by open capillary method and are uncorrected.

2. Infrared spectra were recorded on Shimadzu FT IR-8400 (Diffuse reflectance

attachment) using KBr. Spectra were calibrated against the polystyrene

absorption at 1610 cm-1.

3. 1H & 13C NMR spectra were recorded on Bruker Avance II 400 spectrometer.

Making a solution of samples in DMSO d6 and CDCl3 solvents using

tetramethylsilane (TMS) as the internal standard unless otherwise mentioned,

and are given in the δ scale. The standard abbreviations s, d, t, q, m, dd, dt, br

s refer to singlet, doublet, triplet, quartet, multiplet, doublet of a doublet,

doublet of a triplet, AB quartet and broad singlet respectively.

4. Mass spectra were recorded on Shimadzu GC MS-QP 2010 spectrometer

operating at 70 eV using direct injection probe technique.

5. Analytical thin layer chromatography (TLC) was performed on Merck

precoated silica gel-G F254 aluminium plates. Visualization of the spots on

TLC plates was achieved either by exposure to iodine vapor or UV light.

6. The chemicals used for the synthesis of intermediates and end products were

purchased from Spectrochem, Sisco Research Laboratories (SRL), Thomas

Baker, Sd fine chemicals, Loba chemie and SU-Lab.

7. All the reactions were carried out in Samsung MW83Y Microwave Oven

which was locally modified for carrying out chemical reactions

8. All evaporation of solvents was carried out under reduced pressure on

Heidolph LABOROTA-400-efficient.

9. % Yield reported are isolated yields of material judged homogeneous by TLC

and before recrystallization.

10. The structures and names of all compounds given in the experimental section

and in physical data table were generated using ChemBio Draw Ultra 10.0.

11. Elemental analysis was carried out on Vario EL Carlo Erba 1108.

Abbreviations

Department of Chemistry, Saurashtra University, Rajkot-360005

ABBREVIATIONS

[bmim]BF4 1-butyl-3-methylimidazolium tetrafluoroborate [bmim]OH 1-Butyl-3-methylimidazolium hydroxide µm Micro meter AcOH Acetic Acid AIDS Acquired Immuno Deficiency Syndrome AlCl3 Aluminum chloride Ar Aromatic ArNHNH2 Phenyl Hydrazine ATP Adenosine triphosphate BF3 Boron trifluoride BiCl3 Bismuth chloride BP Boiling Point BuLi Butyllithium CDCl3 Deuterated chloroform CF3 Carbon trifluorideCNS Central Nervous System Conc. Concentrated CS2 Carbon disulphide CuI Cuprous IodideCuoAC Copper acetate DHP Dihydropyridine DIBAL Diisobutylaluminium hydride DMF Dimethyl Formamide DMSO Dimethyl Sulfoxide DNA Deoxyribonucleic acid EDDA ethylenediammonium diacetate EtoAc Ethyl acetate EtOH Ethanol EWG Electron Withdrawing Group FeCl3 Iron(III) chloride FT-IR Fourier Transform Infrared GABA Gama-amino butyric acid GC -MS Gas Chromatography Mass Spectra Hf(OTF)4 Hafnium trifluoromethanesulfonateHSAB Hard and soft (Lewis) acids and basesIC50 Inhibitory Concentration IR Infra Red

Abbreviations


K2CO3 Potassium Carbonate K3PO4 Potassium PhosphateKBr Potassium Bromide KMnO4 Potassium permanganate m Meta MAPK Mitogen-activated protein kinase MeOH Methanol MF Molecular Formula MHz Mega Hurtz MOM Methoxymethyl etherMP Melting Point mRNA Messenger Ribonucleic acid MS Mass Spectra MW Microwave MW Molecular Weight MWI Micro Wave Irradiation Na2CO3 Sodium Carbonate NaHCO3 Sodium Bicarbonate NaHSO4 Sodium hydrogen sulphate NCEs New Chemical Entities NEt3 N’tetramethyl ethylene diamine NH2NH2H2O Hydrazine Hydrazide NH4CN Ammonium Cyanide NH4OAc4 Ammonium Acetate nm Nano meter NMR Nuclear Magnetic Resonance O Ortho OEt2 Diethyl Ether P Para PAF anti platelet activating factor PBMC peripheral blood mononuclear cells PCl5 Phosphorus pentachloride Pd(OAc)4 Palladium tetraacetate POCl3 Phosphorous Oxychloride PPO polyphenol oxidase p-TsOH Para Toluene Sulphonic Acid QSAR Quantitative Structural Activity Relationship R&D Research and development R.T. Room Temperature Rf Retention Factor

Abbreviations


Rh2(O2CC3F7)4 Rhodium (II) heptafluorobutryate tetramer RNA Ribo Nucleic Acid t-BuOH Potassium Tertiary Butyl Alcohol t-BuOK Potassium Tertiary Butoxide TEA Triethyl amine TFA Trifluoroaceitic acid THF Tetrahydrofuran TiCl4 Titanium Tetrachloride TLC Thin Layer Chromatography TNFR Tumor necrosis factor R TNF-α Tumor necrosis factor ZnI2 Zinc Iodide

Sy

CCCynthesalkyl-

CCCHHHsis of -3-(su

pyr

HHHAAA(5-chl

ubstituazol-1

APPPTTT

loro-2uted) (1-yl) m

TTTEEERRR2-meth(phenymethan

RRR---hoxypyl/alknones

---111 phenylkyl)-1Hs

l)(5-H-

Chapter – 1 Synthesis of 1H-pyrazole derivatives

Department of Chemistry, Saurashtra University, Rajkot-360005 1

1.1 INRODUCTION

The chemistry of pyrazoles has been reviewed by Jarobe in 1967. Pyrazoles

have attracted attention of medicinal chemists for both with regard to heterocyclic

chemistry and the pharmacological activities associated with them. Pyrazole have

been studied extensively because of ready accessibility, diverse chemical reactivity,

broad spectrum of biological activity and varieties of industrial applications.

Pyrazole has three possible tautomeric structures. But 2-pyrazole consist a

unique class of nitrogen containing five member heterocycles.

As evident from the literature in recent years a significant portion of research

work in heterocyclic chemistry has been devoted to pyrazoles containing different

alkyl, aryl and heteroaryl groups as substituents.

1.2 LITERATURE REVIEW

Fluoride-mediated nucleophilic substitution reactions of 1-(4-methylsulfonyl

(or sulfonamido)-2-pyridyl)-5-chloro-4- cyano pyrazoles with various amines and

alcohols under mild conditions. The further reaction of novel pyrazoles provides the

5-alkyl amino and ether pyrazoles in moderate to high yields. 1



An efficient and divergent synthesis of fully substituted 1H-pyrazoles using

cyclopropyl oximes. Under Vilsmeier conditions (POCl3/DMF), substituted 1H-

pyrazoles were synthesized from 1-carbamoyl, 1-oximyl cyclopropanes via sequential

ring-opening, chlorovinylation, and intramolecular aza-cyclization. 2

A novel approach to the synthesis of pyrazole derivatives from

tosylhydrazones of α,β-unsaturated carbonyl compounds possessing a β-hydrogen

exploiting microwave (MW) activation coupled with solvent free reaction conditions.

The cycloaddition was studied on three ketones (trans-4-phenyl-3-buten-2-one, β-

ionone and trans-chalcone). The corresponding 3,5-disubstitued-1H-pyrazoles were

obtained in high yields and after short reaction times. 3

The cyclization of isocyanide with the oxime or BOC-protected hydrazones of

ethyl bromopyruvate furnished the pyrazole carboxy esters. 4

Regio-selective synthesis of 1,3,4,5-tetrasubstituted pyrazole derivatives from

the reaction of Baylis-Hillman adducts of alkyl vinyl ketone and hydrazine

derivatives. During the continuous studies on the chemical transformations of Baylis-

Hillman adducts including the synthesis of pyrazole. 5



Highly efficient and regioselective synthesis of 1-aryl-3,4-

substituted/annulated-5-(methylthio)-pyrazoles and 1-aryl-3-(methylthio)-4,5-

substituted/ annulated pyrazoles via cyclocondensation of arylhydrazines with either

α-oxoketene dithioacetals or α-oxodithioesters. 6

Synthesis of novel ketene N,S-acetals by the reaction of cyanoacetamide or

cyanothioacetamide with phenylisothiocyanate in the presence of potassium

hydroxide, followed by alkylation of the produced salts with methyl iodide. Further,

the reaction of ketene N,S-acetals with hydrazine afforded different substituted

pyrazoles in excellent yields. 7

Synthesid of 4-(3-phenylisoxazol-5-yl)morpholine derrivatives using ketene

dithioacetals. The reaction of substituted acetophenones with carbon disulfide in the

presence of base and followed by alkylation with methyl iodide afforded 4-

phenoxyphenyl-2,2- bis(methylthio)vinyl ketones, which were further reacts with

hydrazine hydrate to give substituted pyrazoles through in situ cyclization of the

resulting N,S-acetals. 8



Reaction of fluorosubstituted cyanoacetamide derivatives with

arylisothiocyanate in the presence of potassium hydroxide, yields novel fluorinated

ketene N,S-acetals by the followed by the alkylation with methyl iodide. The reaction

of fluorinated ketene N,S-acetals with hydrazine afforded different fluorosubstituted

pyrazole derivatives in good yield. 9

Two general protocols for the reaction of electron-deficient N-arylhydrazones

with nitroolefins allow a regioselective synthesis of 1,3,5-tri- and 1,3,4,5-

tetrasubstituted pyrazoles. Studies on the stereochemistry of the key pyrazolidine

intermediate suggest a stepwise cycloaddition mechanism.10

A series of 4-substituted 1H-pyrazole-5-carboxylates was prepared from the

cyclocondensation reaction of unsymmetrical enaminodiketones with tert-

butylhydrazine hydrochloride or carboxymethylhydrazine. The compounds were

obtained regiospecifically and in very good yields.11



A general two-step synthesis of substituted 3-aminoindazoles from 2-

bromobenzonitriles involves a palladium-catalyzed arylation of benzophenone

hydrazone followed by an acidic deprotection/cyclization sequence. This procedure

offers a general and efficient alternative to the typical SNAr reaction of hydrazine

with o-fluorobenzonitriles. 12

1.3 SYNTHESIS OF FUNCTIONALIZED PYRAZOLES USING COMBINATORIAL CHEMISTRY APPROACH

In recent decades, combinatorial chemistry tools have enabled the rapid

synthesis of a large number of heterocyclic small molecule libraries and it is

recognized now as a key element of early drug discovery.13 The main advantage of

the combinatorial technique is the speed at which diverse types of organic compounds

can be synthesized, formulated, and tested for a particular application. Moreover, in

combinatorial study the quantity of required material is less in comparison to

conventional methods, which makes it more suitable when the materials are

expensive.14

In 2009, Laborde E. et al15 have developed an efficient three-component, two-

step “catch and release” solid-phase synthesis of 3,4,5-trisubstituted pyrazoles. The

reaction involves a base-promoted condensation of a 2-sulfonyl acetonitrile derivative

1 with an isothiocyanate 2 and in situ immobilization of the resulting thiolate anion 3

on Merrifield resin. Reaction of the resin-bound sulfonyl intermediate 4 with

hydrazine, followed by release from the resin and intramoleculer cyclization, afforded



3,5-diamino-4-(arylsulfonyl)-1H-pyrazoles 5. However, this methodology has some

drawback such as; long reaction time, isolation of product and high reaction

temperature.

R1S

OOCN

Et3N, THF, 25 °C

R1S

OOCN

NH

SR2

THF, 60ºCCl

SO O

R1S

OOCN

NH

SR2

NH2NH2H2O,

THF, 60-70 °C

R1

NNH

HN

NH2

R2

1

2

3

4 5

R2-N=C=S

Recently, synthesis of structurally diverse and medicinally interesting series of

1, 4-dihydropyrano[2,3-c]pyrazoles via a three-component reaction using solution

phase synthesis in excellent yields has been reported. 16

The parallel solution-phase approach for syntehsizing more than 2200 7-

trifluoromethyl-substituted pyrazole[1,5-a]pyrimidine and 4,5,6,7-

tetrahydropyrazolo[1,5-a]pyrimidine carboxamides on a 50-100-mg scale. The

reactions were include assembly of the pyrazole[1,5-a]pyrimidine ring by

condensation of 5-aminopyrazole derivatives with the corresponding trifluoromethyl-

α-diketones. The libraries from libraries were then obtained in good yields and

purities using solution-phase acylation and reduction methodologies. Simple manual

techniques for parallel reactions using special CombiSyn synthesizers were coupled

with easy purification procedures (crystallization from the reaction mixtures) to give

high-purity final products. 17



A small combinatorial library had been synthesized containing pyrazolyl-

pyrazoles and pyrazole[1,5-a]pyrimidines by traditional organic synthesis and

parallel-liquid-phase combinatorial synthesis using α-S,S-acetal of ethyl cyanoacetate

as key synthon and hydrazine hydrate. 18

A library of 4-(5-Iodo-3-Methylpyrazolyl)Phenyl- sulfonamide derivatives

have been developed via solution-phase Suzuki coupling using Pd/C as a solid-

supported catalyst. 19

S NH2OO

NH2

9 steps

S NH2OO

NN

I

Synthesis of substituted pyrazole through in situ generation of polymer-bound

enaminones. The synthetic protocol makes use of commercially available aniline

cellulose, a low-cost and versatile biopolymer, under very mild conditions. This new

support allowed carrying out reactions in polar solvents under both conventional

heating and MW irradiation without degradation of the polymer. The reaction

between cellulose-bound enaminones and hydrazine to afford the target heterocycles

in high yields directly in solution is the key step. The support can be conveniently

recycled. 20



S NH2OO

NH2

9 steps

S NH2OO

NN

I

1.4 PHARMACOLOGICAL-SIGNIFICANCE OF PYRAZOLES

Pyrazoles belong to an important class of heterocycles due to their biological

and pharmacological activities21,22 such as

Anti-inflammatory,23

Herbicidal,24

Fungicidal,25

Bactericidal,26

Plant growth inhibitory,27

Antipyretic,28

Protein kinase inhibitory activities.29

Also, they are the key starting materials for the synthesis of commercial

aryl/hetero-arylazopyrazolone dyes.30,31 Many other authors have reported other

biological activities.31-57



1.4.1 SOME DRUGS FROM PYRAZOLES NUCLEUS 21-31

NN

Cl

COOH

Lonazolac

NN

(CH2)3N(CH3)2Fezolamine

NN

N

OO

OH

F

Pyrazole meva lonolactoneNN

OR

E-3710

NN NH

SHS

Pyrazoline-4-dithiocarbamic acid



1.5 AIM OF CURRENT WORK The structure of pyrazoles are of prime important in the Medicinal Chemistry

research as various drug molecules possess pyrazoles as the core moiety, exhibiting

pharmacological activities like anti-inflammatory, herbicidal, fungicidal, bactericidal,

plant growth inhibitory, antipyretic, etc

Thus, the opportunity to synthesize some new pyrazole entities possessing

chloro, and methoxy group in the benzene ring and to explore their biological activity

was the main rational behind initializing the work included in this chapter as the

presence of chloro and methoxy group may enhance the activity of newly synthesized

pyrazoles.



1.6 REACTION SCHEMES 1.6.1 PREPARATION OF BENZOYL ACETONES :

Reagents / Reaction Condition (a): Ethyl Acetate, C2H5ONa/ 0-5°C, 2 hours

1.6.2 PREPARATION OF ACETOACETANILIDE :

Reagents / Reaction Condition (b): Ethyl Aceto Acetate, MW 300W, 25-30 mins.

1.6.3 PREPARATION OF (5-CHLORO-2-METHOXYPHENYL)(5-ALKYL-3-(SUBSTITUTED) (PHENYL/ALKYL)-1H-PYRAZOL-1-YL)METHANONES :

STEP-I

OCH3

Cl

OCH3

O

OCH3

Cl

NHNH2

O

c

Reagents / Reaction Condition (c): Hydrazine Hydrate (99%), MW 300W, 2 min



STEP-II

Reagents / Reaction Condition (d): Ethanol, Con. HCl, reflux, 10 h

1.7 PLAUSIBLE REACTION MECHANISM

R NH

ONH2 R1

O

R2

O..

R2

O NH

OHR1

HN

OR

..N

NH

O R

OHR1HO

R2

..

H

NNH

O R

OH2R1HO

R2

..

NN

O R

R1HO

R2

..

H

NN

O R

R1H2O

R2NN

O R

R1

R2



1.8 EXPERIMENTAL 1.8.1 MATERIALS AND METHODS

Melting points were determined in open capillary tubes and are uncorrected.

Formation of the compounds was routinely checked by TLC on silica gel-G plates of

0.5 mm thickness and spots were located by iodine and UV. Formation of all

compounds was purified by using column chromatography. IR spectra were

recorded in Shimadzu FT-IR-8400 instrument using KBr method. Mass spectra

were recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe

technique. 1H NMR was determined in CDCl3/DMSO solution on a Bruker Ac 300

MHz spectrometer.

1.8.2 PREPARATION OF BENZOYL ACETONES :

A mixture of sodium ethoxide (0.2 mol), ethyl acetate (0.2 mol) were taken in

250 ml RBF then slowely add (0.05 mol) of aceto phenone to the mixture below 5°C.

After addition of acetophenone to it allow it for one day in freeze and pour it to ice

water mixture. Then acidify it by glacial acetic acid to get product.

After that filter the product and wash with chilled water to remove acidity and dry it.

1.8.3 PREPARATION OF ACETOACETANILIDES :

A mixture of amine (1 mmol) and ethyl acetoacetate (2.5-3.0 mmol) was taken

in a R.B.F. and placed in microwave oven and irradiated at 600W for 5-50 minutes.

The reaction was monitored by TLC. After the completion of reaction, product was

washed with petroleum ether (60-80°C) and the corresponding acetoacetylated

products were separated by filtration in 70-97% yield.



1.8.4 PREPARATION OF (5-CHLORO-2-METHOXYPHENYL)(5-ALKYL-3-

(SUBSTITUTED)(PHENYL/ALKYL)-1H-PYRAZOL-1-YL)

METHANONES :

STEP-I

Mixture of methyl-5-chloro-2-methoxy benzoate (0.01 mol) and hydrazine

hydrate (0.02 mol) was irradiated under microwave irradiation for 2 min at 300W.

After the completion of the reaction solid precipitates out, filtered and washed with

water to yield 91% product. M.P. 162°C.

STEP-II

Methyl 5-chloro-2-methoxybenzoate (0.01 mol), α-diketo compound (0.01

mol) was allowed to reflux for 10 h using ethanol (10 mL) as a solvent in presence of

catalytic amount of conc. HCl. Product precipitates out as a crystalline solid was

confirmed by TLC further washed with water and dried to yield desired compounds.

The physical constants of newly synthesized compounds are given in Table No.1



1.9 PHYSICAL DATA Physical data of (5-chloro-2-methoxyphenyl) (5-alkyl-3-(substituted) (phenyl/

alkyl)-1H-pyrazol-1-yl)methanones.

TABLE - 1

Sr. No. Code R1 R2 M.P. Rf 1 BAJ-401 CH3 C6H5 180-182 0.46

2 BAJ-402 CH3 4-F-C6H4 204-206 0.52

3 BAJ-403 CH3 2,4-di-Cl- C6H3 226-228 0.44

4 BAJ-404 CH3 NH-2,4-di-Me- C6H3 208-210 0.48

5 BAJ-405 CH3 NH-3-OMe-C6H4 196-198 0.50

6 BAJ-406 CH3 NH-4-Cl-C6H4 188-190 0.40

7 BAJ-407 CH3 NH-3-Cl-C6H4 210-212 0.44

8 BAJ-408 CH3 NH-3-F-C6H4 178-180 0.48

9 BAJ-409 CH3 NH-4-Br-C6H4 186-188 0.42

10 BAJ-410 CH3 NH-2-pyridyl 168-170 0.46

11 BAJ-411 CH3 NH-3-pyridyl 194-196 0.42

12 BAJ-412 CH3 CH3 206-208 0.54

13 BAJ-413 CH2-Cl O-CH2-CH3 178-180 0.50

14 BAJ-414 CH3 O-CH2-CH(CH3)2 166-168 0.48

15 BAJ-415 CH3 O-CH(CH3)2 218-220 0.40

16 BAJ-416 CH3 O-CH2-CH3 208-210 0.46

17 BAJ-417 CH3 O-CH3 178-180 0.44 Rf value was determined using solvent system = Ethyl Acetate : Hexane (2 : 3)



1.10 SPECTRAL DISCUSSION

1.10.1 IR SPECTRA

IR spectra of the synthesized compounds were recorded on Shimadzu FT-IR

8400 model using KBr method. Various functional groups present were identified by

characteristic frequency obtained for them.

The characteristic bands of (-C=N-) were obtained for stretching at 1650-1600

cm-1. The stretching vibrations (–C-O-C-) group showed in the finger print region of

1100-1050 cm-1 while (-C-Cl-) stretching signal was obtained at 800-750 cm-1. It

gives aromatic (-C-H-) stretching frequencies between 3200-3000 cm-1 and ring

skeleton (-C=C-) stretching at 1500-1350 cm-1 C-H stretching frequencies for methyl

and methylene group were obtained near 2950 - 2850 cm-1.

1.10.2 MASS SPECTRA

Mass spectra of the synthesized compounds were recorded on Shimadzu GC-

MS QP-2010 model using direct injection probe technique. The molecular ion peak

was found in agreement with molecular weight of the respective compound.

1.10.3 1H NMR SPECTRA

1H NMR spectra of the synthesized compounds were recorded on Bruker

Avance II 300 spectrometer by making a solution of samples in DMSO-d6 solvent

using tetramethylsilane (TMS) as the internal standard unless otherwise mentioned.

Numbers of protons and carbons identified from NMR spectrum and their chemical

shift (δ ppm) were in the agreement of the structure of the molecule. J values were

calculated to identify o, m and p coupling. In some cases, aromatic protons were

obtained as multiplet. Interpretation of representative spectra is discussed further in

this chapter.



1.10.4 13C NMR SPECTRA

13C NMR spectra of the synthesized compounds were recorded on Bruker



Types of carbons identified from NMR spectrum and their chemical shift (δ ppm)

were in the agreement of the structure of the molecule. Aliphatic carbon was observed

between 15-25, while methoxy carbon was observed between 55-60 δ ppm, aromatic

carbon was observed between 115-140 δ ppm, keto carbon was observed between

160-165 δ ppm.



1.11 ANALYTICAL DATA

(5-Chloro-2-methoxyphenyl)(5-methyl-3-phenyl-1H-pyrazol-1-yl)methanone

(BAJ-401)

Yield: 72%, IR (KBr, cm-1): 3070(aromatic -C-H stretching), 2987, 2943(aliphatic -

C-H stretching), 1670(-C=O stretching), 1635(-C=N stretching), 1535,

1481(Aromatic -C-C- stretching), 1184(-C-N stretching), 1109(-C-O-C- stretching),

806(C-Cl stretching), 694(-C-H oop bending disubstitued), 1H NMR (DMSO-d6) δ

ppm: 3H, s (2.14), 3H, s (3.87), 1H, d (7.23-7.26, J=9.0 Hz), 5H, m (7.57-7.72), 1H, s

(7.84), 1H. dd (8.05-8.08), 1H, d (8.28-8.31, J=9.0Hz), 13C: 22.12, 57.34, 90.45,

123.94, 124.92, 125.87, 126.20, 127.08, 127.92, 129.46, 130.93, 131.27, 131.72,

133.52, 134.37, 152.97, 157.71. MS m/z = 326 (M+), 328 (M+2); % Anal. Calcd. for

C18H15ClN2O2: C, 66.16; H, 4.63; Cl, 10.85; N, 8.57; O, 9.79.

(5-Chloro-2-methoxyphenyl)(3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-

yl)methanone (BAJ-402)

Yield: 75%, IR (KBr, cm-1): 3059(aromatic -C-H stretching), 2941(aliphatic –C-H

stretching), 1695 (-C=O stretching), 1637 (-C=N stretching), 1546 (aromatic -C-C-

stretching), 1184 (-C-N stretching), 1109(-C-O-C- stretching), 1049(-C-F stretching),

758(-C-Cl stretching), 725 (disubstituted), 688(monosubstituted); MS m/z = 344 (M+),

346 (M+2); % Anal. Calcd. for C18H14ClFN2O2: C, 62.71; H, 4.09; Cl, 10.28; F, 5.51;

N, 8.13; O, 9.28.

(5-Chloro-2-methoxyphenyl)(3-(2,4-dichlorophenyl)-5-methyl-1H-pyrazol-1-



stretching), 1697 (-C=O stretching), 1600(-C=N stretching), 1518(aromatic -C-C-

stretching), 1184(-C-N tretching), 1109(-C-O-C- stretching), 801(-C-Cl stretching),

748(disubstituted), 701 (monosubstituted),; MS m/z = 395 (M+), 397 (M+2); % Anal.

Calcd. for C18H13Cl3N2O2: C, 54.64; H, 3.31; Cl, 26.88; N, 7.08; O, 8.09.



(5-Chloro-2-methoxyphenyl)(3-((2,4-dimethylphenyl)amino)-5-methyl-1H-

pyrazol-1-yl)methanone(BAJ-404)

Yield: 74%, IR (KBr, cm-1): 3416(-N-H stretching), 3044(aromatic -C-H stretching),

2922 (aliphatic –CH- stretching), 1690(-C=O stretching), 1666-1599(-N-H bending),

1638(-C=N stretching), 1543(Aromatic -C-C- stretching), 1180 (-C-N stretching),

1112(-C-O-C- stretching), 782(-C-Cl stretching)754 (disubstituted),; MS m/z = 369

(M+), 371 (M+2); % Anal. Calcd. for C20H20ClN3O2: C, 64.95; H, 5.45; Cl, 9.59; N,

11.36; O, 8.65.

(5-Chloro-2-methoxyphenyl)(3-((3-methoxyphenyl)amino)-5-methyl-1H-pyrazol-

1-yl)methanone (BAJ-405)


2922 (aliphatic –C-H stretching), 1694(-C=O stretching), 1683(N-H bending), 1646 (-

C=N stretching), 1540(aromatic -C-C- stretching), 1188(-C-N stretching), 1114 (-C-

O-C- stretching), 784(-C-Cl stretching), 751 (disubstituted)701 (monosubstituted),;

MS m/z = 371 (M+), 373 (M+2); % Anal. Calcd. for C19H18ClN3O3: C, 61.38; H, 4.88;

Cl, 9.54; N, 11.30; O, 12.91.

(5-Chloro-2-methoxyphenyl)(3-((4-chlorophenyl)amino)-5-methyl-1H-pyrazol-1-

yl)methanone(BAJ-406)


2926 (aliphatic –C-H str.), 1688(-C=O stretching), 1666(-N-H bending),1641(-C=N

stretching), 1547 (aromatic -C-C- stretching), 1182(-C-N stretching), 1104(-C-O-C-

stretching), 778(-C-Cl stretching); 751 (disubstituted), 705 (mono substituted), MS

m/z = 376 (M+), 378 (M+2); % Anal. Calcd. for C18H15Cl2N3O2: C, 57.46; H, 4.02; Cl,

18.85; N, 11.17; O, 8.50.

(5-Chloro-2-methoxyphenyl)(3-((3-chlorophenyl)amino)-5-methyl-1H-pyrazol-1-



2945(aliphatic –C-H stretching), 1718(-C=O stretching), 1668(-N-H bending), 1606(-

C=N stretching), 1546, 1483(Aromatic -C-C- stretching), 1126(-C-N stretching),

1072(-C-O-C- stretching), 783(-C-Cl stretching), 769(disubstituted), 675(mono



substituted), 1H NMR (DMSO-d6) δ ppm: 3H, s (2.02), 3H, s (3.45), 1H, s (6.93), 1H,

m (7.10-7.13), 1H, d (7.22-7.25, 9.0Hz), 1H, t (7.31-7.37), 1H, d (7.44-7.47, 9.0 Hz),

1H, dd (7.55-7.59), 1H, d (7.73-7.74, 3.0 Hz), 1H, s (7.83), 1H, s (10.44), 13C: 17.46,

57.62, 90.52, 115.22, 118.42, 119.52, 123.94, 124.77, 125.56, 130.57, 131.33, 132.87,

133.94, 141.26, 156.68, 160.95. MS m/z = 376 (M+), 378 (M+2); % Anal. Calcd. for

C18H15Cl2N3O2: C, 57.46; H, 4.02; Cl, 18.85; N, 11.17; O, 8.50.

(5-Chloro-2-methoxyphenyl)(3-((4-fluorophenyl)amino)-5-methyl-1H-pyrazol-1-



2928 (aliphatic –C-H stretching), 1692(-C=O stretching), 1674(-N-H bending), 1648(-

C=N stretching), 1539(aromatic -C-C- stretching), 1184(-C-N stretching), 1112(-C-O-

C- stretching), 1091(C-F stretching), 763(-C-Cl stretching), 751 (disubstituted), 708

(mono substituted),; MS m/z = 359 (M+), 361 (M+2); % Anal. Calcd. for

C18H15ClFN3O2: C, 60.09; H, 4.20; Cl, 9.85; F, 5.28; N, 11.68; O, 8.89.

(3-((4-Bromophenyl)amino)-5-methyl-1H-pyrazol-1-yl)(5-chloro-2-

methoxyphenyl) methanone (BAJ-409)


2962(aliphatic –C-H stretching), 1695(-C=O stretching), 1672 (-N-H bending), 1641(-

C=N stretching), 1548(aromatic -C-C- stretching), 1186 (-C-N stretching), 1114 (-C-

O-C- stretching), 776 (-C-Cl stretching), 752(disubstituted), 686(monosubstituted),

579(C-Br stretching),; MS m/z = 420 (M+), 422 (M+2); % Anal. Calcd. for

C18H15BrClN3O2: C, 51.39; H, 3.59; Br, 18.99; Cl, 8.43; N, 9.99; O, 7.61.

(5-Chloro-2-methoxyphenyl)(5-methyl-3-(pyridin-2-ylamino)-1H-pyrazol-1-



2924(aliphatic –C-H stretching), 1691(-C=O stretching), 1669(-N-H bending), 1643(-


C- stretching), 774 (-C-Cl stretching), 754(disubstituted), ; MS m/z = 342 (M+), 344

(M+2); % Anal. Calcd. for C17H15ClN4O2: C, 59.57; H, 4.41; Cl, 10.34; N, 16.34; O,

9.34.



(5-Chloro-2-methoxyphenyl)(5-methyl-3-(pyridin-3-ylamino)-1H-pyrazol-1-



2921 (aliphatic -C-H stretching), 1691(-C=O stretching), 1664(-N-H bending), 1646(-


C- stretching), 768 (-C-Cl stretching), 756 (disubstituted), ; MS m/z = 342 (M+), 344

(M+2) ; % Anal. Calcd. for C17H15ClN4O2: C, 59.57; H, 4.41; Cl, 10.34; N, 16.34; O,

9.34.

(5-Chloro-2-methoxyphenyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone(BAJ-412)


stretching), 1688(-C=O stretching), 1640(-C=N stretching), 1546(aromatic -C-C-

stretching), 1181(-C-N stretching), 1115(-C-O-C- stretching), 765(-C-Cl stretching),

751(disubstituted) ; MS m/z = 264 (M+), 266 (M+2); % Anal. Calcd. for

C13H13ClN2O2: C, 58.99; H, 4.95; Cl, 13.39; N, 10.58; O, 12.09.

(5-Chloro-2-methoxyphenyl)(5-(chloromethyl)-3-ethoxy-1H-pyrazol-1-


Yield: 70%, IR (KBr, cm-1): 3064(aromatic -C-H stretching), 2926 (aliphatic –C-H

str.), 2891(-C-H stretching tertiary), 2857(aliphatic -CH2 stretching),1696 (-C=O

stretching), 1641 (-C=N stretching), 1540(aromatic -C-C- stretching), 1509,1455,

1366(CH bending), 1186 (-C-N stretching), 1109(-C-O-C- stretching), 762 (-C-Cl

stretching), 753(disubstituted); MS m/z = 329 (M+), 331 (M+2); % Anal. Calcd. for

C14H14Cl2N2O3: C, 51.08; H, 4.29; Cl, 21.54; N, 8.51; O, 14.58.

(5-Chloro-2-methoxyphenyl)(3-isobutoxy-5-methyl-1H-pyrazol-1-yl)methanone

(BAJ-414)


stretching), 2889(-C-H stretching tertiary), 2843(aliphatic -CH2- stretching), 1694(-

C=O stretching), 1638(-C=N stretching), 1541(aromatic -C-C- stretching),

1518,1445,1354 (C-H bending), 1182 (-C-N stretching), 1109(-C-O-C- stretching),

761(-C-Cl stretching), 755(disubstituted); MS m/z = 322 (M+), 324 (M+2); % Anal.

Calcd. for C16H19ClN2O3: C, 59.54; H, 5.93; Cl, 10.98; N, 8.68; O, 14.87.



(5-Chloro-2-methoxyphenyl)(3-isopropoxy-5-methyl-1H-pyrazol-1-yl)methanone

(BAJ-415)


stretching), 2899(-C-H stretching tertiary), 2828(aliphatic -CH2 stretching), 1696(-

C=O stretching), 1648(-C=N stretching), 1551(aromatic -C-C- stretching),

1529,1435,1343(C-H bending), 1180(-C-N stretching), 1113(-C-O-C- stretching), 770

(-C-Cl stretching), 759(disubstituted); MS m/z = 308 (M+), 310 (M+2); % Anal.

Calcd. for C15H17ClN2O3: C, 58.35; H, 5.55; Cl, 11.48; N, 9.07; O, 15.55.

(5-Chloro-2-methoxyphenyl)(3-ethoxy-5-methyl-1H-pyrazol-1-yl)methanone (BAJ-416) Yield: 68%, IR (KBr, cm-1): 3048(aromatic -C-H stretching), 2927(Aliphatic –C-H

stretching), 2836 (Aliphatic -CH2 stretching), 1695(-C=O stretching), 1650(-C=N

stretching), 1541(aromatic -C-C- stretching), 1190(-C-N stretching), 1458, 1356 (-C-

H bending), 1115(-C-O-C- stretching), 766 (-C-Cl stretching), 753(disubstituted);

MS m/z = 294(M+), 296 (M+2); % Anal. Calcd. for C14H15ClN2O3: C, 57.05; H, 5.13;

Cl, 12.03; N, 9.50; O, 16.29.

(5-Chloro-2-methoxyphenyl)(3-methoxy-5-methyl-1H-pyrazol-1-yl)methanone (BAJ-417) Yield: 72%, IR (KBr, cm-1): 3051(aaromatic -C-H stretching), 2927(aliphatic –C-H

stretching), 1694(-C=O stretching), 1648(-C=N stretching), 1536(aromatic -C-C-

stretching), 1186(-C-N stretching), 1109(-C-O-C- stretching), 767(-C-Cl stretching),

754(disubsituted); MS m/z = 280 (M+), 282 (M+2); % Anal. Calcd. for C13H13ClN2O3:

C, 55.62; H, 4.67; Cl, 12.63; N, 9.98; O, 17.10.



1.12 RESULTS AND DISCUSSION

Synthesis of substituted pyrazole has been carried out by the reaction of 5-

chloro-2-methoxybenzohydrazide and different α-diketo compounds. Total 17

comounds were synthesized and characterized using spectroscopic technique.

Synthesized compounds were explored by performing various biological activities.

1.13 CONCLUSION

Pyrazole derivatives of 5-chloro-2-methoxybenzohydrazide were prepared.

Presence of electron withdrawing groups in the core structure augment activities of

pyrazole moiety. The reaction was carried out using ethanol as solvent and catalytic

amount of Conc. HCl. The significance of present process is good yield and easy

work up method. The synthesized compounds were further explored for biological

screening.

CChapter – 1

Department

1.14 REP 1.14.1 IR S

1.14.2 MA

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PREENTA

Spectrum o

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24

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1.14.3 1H N

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NMR Spect

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try, Saurash

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CChapter – 1

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1.14.5 13C N

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NMR Spec

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CChapter – 1

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1.14.7 MA

1.14.8 1H N

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27

CChapter – 1

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1.14.9 Exp

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NMR Spect

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28



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456.

S

CCCSynth

(subst

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alkyltituted

HHHAAAPPPf 4-(3

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3-(subsubstitunyl-1Hmene-

TTTEEERRRstituteuted)aH-pyr-2-one

RRR---ed)benalkyl-4rrol-1-es

---222 nzoyl-4- -yl)-2H

-2-

H-

Chapter – 2 Synthesis N-substituted pyrrole derivatives


2.1 INTRODUCTION

Pyrrole is an important π-excessive aromatic heterocycle because this ring

system is incorporated in as a basic structural unit in porphyrins;porphin (heam) and

chlorin(chlorophyll) and corrins (vitamin B12). More over the presence of pyrrole

ring in system in porphobilinogen (intermediate in biosynthesis of porphyrins and

vitamin B12), biliverdin and bilirubin(pyrrole-based bile pigments) and

pyrrolnitrin(with antibiotic activity) has provided an impetus to the pyrrole chemistry.

Pyrrole has a planar pentagonal structure with four carbon atoms and nitrogen

sp2-hybridized. Each ring atom forms two sp2-sp2 σ -bonds to its neighbouring ring

atoms and one sp2-sσ -bond to a hydrogen atom. The remaining unhybridized p-

orbitals, one on each ring atom(with one electron on each carbon and two electron on

nitrogen), are perpendicular to the plane of σ -bondsand overlap to form a π-molecular

system with three bonding orbitals. The six π-electrons form an aromatic sextet which

is responsible for aromaticity and renders stability to the pyrrole ring. The Cα-N and

Cα-Cβ bonds are shroter than normal single bonds, where as Cα-Cβ bonds are normal



than normal double bonds. The molecular dimentions of the pyrrole reflect cyclic

delocalization with the environment of lone pair of electrons on the nitrogen atom.

Pyrrole is extremely weak base because the lone pair of electrons on the

nitrogen atom involved in the cyclic delocalization and is, therefore, less available for

protonation. Moreover, pyrrole is a weaker base than pyridine and even than aniline in

which lone pair on the nitrogen atom is involved in the resonance and not essentially

contributes to the aromatic sexlet. The protonation of pyrrole at nitrogen or C2 or C3

atom of the ring reduces its basicity and destroys its aromaticity. However, C- and N-

alkyl substituents enhance the basicity of pyrrole but the electron withdrawing

substituents on the ring make pyrrole a weaker base. 1-11


Pyrroles are generally synthesized by the cyclization reactions involving

nucleophilic-electrophilic interactions. This is the most widely used method and

involves the cyclizative condensation of α-aminoketones or α-amino-β-keto

esters(three atom fragment with nucleophilic nitrogen and electrophilic carbonyl

carbon) with β-diketones or β-ketoesters (two atom fragment with electrophilic

carbonyl carbon and a nucleophilic carbon) with the formation of N-C2 and C3-C4

bonds.

The reaction of α-aminoketones with alkynes proceeds with the nucleophilic

addition of amino group to the electrophilic carbon of alkyne with the formation of

enamine intermediate which on intramolecular cyclization provides pyrroles involving

nucleophilc(β-carbon of the enamine intermediate)-electrophilic (carbonyl carbon)

interaction with the formation of C3-C4 bond.12



The reaction of β-amino-α,β-unsaturated esters 91(three atom fragment) with

nitroalkenes(two atom fragment) provides substituted pyrrole involving (3+2)

cyclization with N-C2 and C3-C4 bonds.13

Base catalysed (3+2) cyclizative condensation of α-diketones with amines

substituted with electron withdrawing substituents at α, α’-positions results in the

corresponding pyrroles with the formation of C2-C3 and C4-C5 bonds.14

The reaction of β-ketoesters with α-haloketones or aldehydes in the presence

of ammonia or primary amine affords pyrroles involving (2+2+1) cyclization with the

formation of N-C2, C3-C4 and N-C5 bonds. (Hantzsch Synthesis). The reaction

proceeds via stabilized enamine intermediate which on C-alkylation and N-alkylation

by α-haloketone leads to the formation of corresponding pyrrole.



The condensation of aliphatic aldehydes or ketones with hydrazine under

strongly acidic conditions affords pyrroles involving (3+3) sigmatropic rearrangement

and cyclization. (Piloty-Robinson Synthesis). This reaction can also be applied for the

preparation of N-substituted pyrroles by condensing ketones with methyl hydrazine or

N,N’-dimethyl hydrazine.15

The reaction of benzoin with benzyl aryl ketones in the presence of

ammonium acetate results in the formation of polyaryl substituted pyrroles involving

(2+2+1) cyclization.16

The condensation of alkyl isocyanoacetates with aldehydes in 2:1 ratio

proceeds to involve an initial conjugated addition followed by an anionic cyclization

with the formation of C2-C3, C3-C4 and C4-C5 bonds.17

It is the most general method and involves (4+1)cyclizative condensation of

1,4-dikitones(enolizable) with ammonia or its derivatives with the formation of N-C2



and N-C5 bonds 1-6, 18-19. The reaction is considered to proceed with the successive

attacks of nucleophilic nitrogen on the carbonyl carbon and finally followed by

dehydration (aromatization) for which driving force is provided by the stability of the

resulting pyrrole.

Metal ion assisted amination of 1,4-dienes or diynes with primary amines

followed by cyclization provides N-substituted pyrroles.20-21

2-Acylaziridines undergo ring expansion reactions to provide pyrroles

involving ring-opened dipolar intermediates.22

Vinylazirines also undergo ring expansion reactions, but two isomeric pyrroles

are obtained depending on the reaction conditions. Thermal reactions involve a



nitrene intermediate, while photochemical reaction proceeds via a nitrile ylide

intermediate.23

The complex ring systems, formed by (3+2) cycloaddition of activated alkynes

substituted with electron-withdrawing substituents, with mesoionic heterocycles,

undergo extrusion reactions with the cleavage of larger ring leaving the pyrrole ring

system intact.24-26

E E +O

N+

R

O-

E = COOCH3

O

N R

OE

ENR

EE

E E +N

N+

R

R2R1

O-

E = COOCH3

NR

EE

R1R2

E E +S

N+

R

R1

O-

E = COOCH3

NR

EE

R1

-CO2

Ethyl-3-amino-5-phenyl-1H-pyrrol-2-carboxylate found to be a useful

intermediate in the sysnthesis of other nitrogen heterocycles.27 However Elliott and

co-workers28-29 have described that condensation of aldehyde with aminomalonate



gave 3-substituted enamine, which was cyclized in the presence of sodium methoxide

to give 3-amino-4-benzyl-1H-pyrrol-2-carboxylate.

Using a similar approach toward the synthesis of pyrrole, Ning Chen, et. al30

were failed to synthesize 2-substituted enamine intermediate from benzoyl acetonitrile

and diethyl aminomalonate using standard conditions such as azeotropic removal of

water,31 dehydration with molecular sieves or Lawis acid catalysis(TiCl432, BF3.OEt2)

CNPh

O

EtOOC

NH2

COOEt

NC

NEtOOC

EtOOC

PhH

NH

H2N

EtOOC Ph

Considering the lower electrophilicity of the aryl ketone compared to the

aldehyde, an alternative strategy for preparing enamine was examined. Since amines

are known to undergo substitution reactions with chloro- and alkylthio-substituted

olefins to yield enamines33, a similar approach was considered and the reaction of p-

toluenesulfonyl enol ester of α-cyano ketone with diethyl aminomalonate was

investigated. Tosylate was prepared by reacting benzoyl acetonitrile with p-

toluenesulfonic anhydride (1.2 equiv) in dichloromethane and triethylamine (1.5

equiv) in 99% yield. When a mixture of tosylate and diethyl aminomalonate

hydrochloride (1.2 equiv) were treated with an ethanolic solution of sodium ethoxide

(0.2 M, 3.5 equiv)34, the pyrrole was directly obtained without isolation of enamine.

Addition of the amine, cyclization and decarboxylation occurred in one-pot at room

temperature to give a 46% overall yield of from benzoyl acetonitrile.



In continuation with this study prior work at Saurashtra University on 1H-

pyrrole derrivatives clubed with substituted-1,3,4-Oxadiazoles, 1-[2,4-dimethyl-5-(5-

phenyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-3-yl]ethanone derivatives were synthesized.

The synthetic stretagy follows starting with acid catalysed cyclocondensation of ethyl

ester derivative of 3-amino-2-butenoic acid (generated insitu from ethylacetoacetate

upon oximenation followed by reduction) with acetylacetone to afford ethyl-3-acetyl-

2,4-dimethyl-1H-pyrrole-5-carboxylate, which was derivatized into corresponding

hydrazide derivative on treatment with hydrazine hydrate. The hydrazide derivative

on reaction with different aromatic and heteroaromatic acid, in the presence of

phosphorous oxychloride affords 1-[2,4-dimethyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-

1H-pyrrol-3-yl]ethanone derivatives.35-36

O

H3C

O

O

C2H5

1

O

H3C

O

O

NOH

H3C O

NH2CH3

CH3

O

O

O

H3C

ONH

OCH3

CH3

H2NHN

H3C

ONH

OCH3

CH3

ROH

OH3C

NH

OCH3

CH3O

NN

R

C2H5O

OC2H5

C2H5

A range of 2,5-disubstituted and 2,4,5-trisubstituted pyrroles can be

synthesized from dienyl azides at room temperature using ZnI2 or Rh2(O2CC3F7)4 as

catalysts.37



The CuI/N,N-dimethylglycine-catalyzed reaction of amines with γ-bromo-

substituted γ,δ-unsaturated ketones in the presence of K3PO4 and NH4OAc gave the

corresponding polysubstituted pyrroles in very good yields.38

Two methods for the regioselective synthesis of tetra- and trisubstituted N-H

pyrroles from starting vinyl azides have been developed: A thermal pyrrole formation

via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates

generated in situ from vinyl azides and a Cu(II)-catalyzed synthesis with ethyl

acetoacetate through a 1,4-addition. 39

NH

Rtoluene, 100°C, 2-5 hR

R1

N3+

O OOR1

An operationally simple, practical, and economical Paal-Knorr pyrrole

condensation of 2,5-dimethoxytetrahydrofuran with various amines and sulfonamines

in water in the presence of a catalytic amount of iron(III) chloride allows the synthesis

of N-substituted pyrroles under very mild reaction conditions in good to excellent

yields. 40



A new and efficient three-component reaction between dialkyl

acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals

afforded polysubstituted pyrrole derivatives in high yields. The reactions were

performed in dichloromethane at room temperature and under neutral conditions. 41

A three-component reactions of arylacyl bromides, amines, and dialkyl

acetylenedicarboxylate in the presence of iron(III) chloride as a catalyst at room

temperature afforded polysubstituted pyrroles in high yields. 42

A new and efficient three-component reaction between dialkyl

acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals

afforded polysubstituted pyrrole derivatives in high yields. The reactions were

performed in dichloromethane at room temperature and under neutral conditions. 43



2.3 PHARMACOLOGY

Pyrrole has its own pharmaceutical importance and various activities of

pyrrole include:

Selective Mono Amine Oxidase type A Inhibitors 44-57

Antitubercular activities 58-66

HIV-1 intigrase Inhibitors 67-69

Antiproliferative activity 70-71

Glycogen Synthase Kinase-3(GSK-3) Inhibitors 72-79

Analgesic and Antiinflammatory activity 80-81

Bactericidal activities 82-86

Fungicides and Plant Growth Regulators 87-89

Action on the Cardiovascular System 90-94

Neuronal L-type Calcium channel activator 95

2.4 SOME DRUGS FROM PYRROLE NUCLEUS 44-95 .



2.5 AIM OF CURRENT WORK

In continuation with our study on pyrrole derrivatives reveals that pyrrole

moiety contacting heterocyclic molecules exhibits significance biological potential.

Thus to synthesize novel pyrrole derivatives we utilized 4-amino coumarin, nitro

methane, substituted aldehydes and α-diketo compounds in presence of lewis acid to

afford of 4-(3-(substituted)benzoyl-2-alkyl-5-(substituted) alkyl-4-(substituted)

phenyl-1H-pyrrol-1-yl)-2H-chromene-2-ones.



2.6 REACTION SCHEMES 2.6.1 PREPARATION OF BENZOYL ACETONES :

Reagents / Reaction Condition (a): Ethyl Acetate, C2H5ONa/ 0-5°C, 2 hours.

2.6.2 PREPARATION OF 4-AMINO COUMARIN :

Reagents / Reaction Condition (b): Ammonium Acetate, MW 300W, 10-15 min.

2.6.3 PREPARATION OF 4-(3-(SUBSTITUTED)BENZOYL-2-ALKYL-5-

(SUBSTITUTED)ALKYL-4-(SUBSTITUTED)PHENYL-1H-PYRROL-1-

YL)-2H-CHROMENE-2-ONES/QUINOLIN-2(1H)-ONES

+ R1 R2

O O

+ N+

O-

ON

R3

O

R1

OO

R2

R3-CHO +

O O

NH2

c

R1= CH3, CH2Cl, etc.R2= H, 4-F, 2,4-di ClR3= substituted phenyl, thiophene, etc.

Reagents / Reaction Condition (c): Ammonium Acetate, MW 300W, 2 min.




R1

NH O

R2

R ..

R3

NO2

HNHR1

NOOH

R

R2H

R3

..

N

R2R3H

NH OH

OHR

R1






0.5 mm thickness and spots were located by iodine and UV. IR spectra were recorded

in Shimadzu FT-IR-8400 instrument using KBr method. Mass spectra were recorded

on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe technique. 1H

NMR was determined in CDCl3/DMSO solution on a Bruker Ac 400 MHz

spectrometer.

2.8.2 PREPARATION OF BENZOYL ACETONES:

A mixture of Sodium Ethoxide (0.2 mol), Ethyl acetate (0.2 mol) were taken

in 250 ml RBF then slowely add (0.05 mol) of aceto phenone to the mixture below

5°C. After addition of acetophenone to it allow it for one day in freeze and pour it to

ice water mixture. Then acidify it by glacial acetic acid to get product.

After that filter the product and wash with chilled water to remove acidity and dry it.

2.8.3 PREPARATION OF 4-AMINO COUMARIN

A mixture of 4-hydroxy coumarin (1.0 mmol) and ammonium acetate (3.0

mmol) was taken in a R.B.F. and placed in microwave oven and irradiated at 300W

for 10-15 minutes. After observation of TLC, the reaction was allowed to cool and the

product was allowed to stir in 20ml 10% NaHCO3 solution for 1 h, filtered and

washed with water further recrystallized from methanol to yield 35%., 4-amino

coumarin with m.p. 230–232°C. (ARKIVOC, (10), 2010, 62-76)

.

2.8.4 PREPARATON OF SUBSTITUTED PYRROLE

To a stirred solution of 4-amino coumarin (1.5 mmol), aromatic aldehyde (1

mmol) and α-diketo compound (1 mmol) in nitromethane (1 ml) was added anhydrous

ZnCl2 (0.1 mmol) and the mixture was heated to reflux slowly for 2-3 h and cooled

down to room temperature, followed by addition of 5 ml methanol and allowed to



reflux for 1 h and cooled down to room temperature, after confirmation from TLC

obtain desired compound was filtered and washed with methanol to yield crystalline

solid. In some compounds if solid do not precipitates out, the excess solvent was

removed under vacuum, and to the residue was added petroleum ether and allowed to

crystallize the product at room temperature and isolated in 60-80% yield.


2.9 PHYSICAL DATA Physical data of 4-(3-(substituted)benzoyl-2-alkyl-5-(substituted)

alkyl-4-(substituted)phenyl-1H-pyrrol-1-yl)-2H-chromene-2-ones

TABLE – 1 Sr. No. Code R1 R2 R3 M.P. Rf

1 BAJ-201 CH3 C6H5 C6H5 180-182 0.50

2 BAJ-202 CH3 4-F-C6H4 C6H5 204-206 0.49

3 BAJ-203 CH3 2,4-di-Cl- C6H3 C6H5 226-228 0.47

4 BAJ-204 CH3 O-CH(CH3)2 C6H5 208-210 0.43

5 BAJ-205 CH3 O-CH2-

CH(CH3)2 C6H5 196-198 0.44

6 BAJ-206 CH3 C6H5 3-Br-C6H4 188-190 0.45

7 BAJ-207 CH3 4-F-C6H4 3-Br-C6H4 210-212 0.44

8 BAJ-208 CH3 2,4-di-Cl- C6H3 3-Br-C6H4 178-180 0.48

9 BAJ-209 CH3 O-CH(CH3)2 3-Br-C6H4 186-188 0.43

10 BAJ-210 CH3 O-CH2-

CH(CH3)2 3-Br-C6H4 168-170 0.48

11 BAJ-211 CH3 C6H5 C6H4-3-O-C6H5 194-196 0.45

12 BAJ-212 CH3 4-F-C6H4 C6H4-3-O-C6H5 206-208 0.39



13 BAJ-213 CH3 2,4-di-Cl- C6H3 C6H4-3-O-C6H5 178-180 0.48

14 BAJ-216 CH3 CH3 C6H5 166-168 0.47

15 BAJ-217 CH3 CH3 3-Br-C6H4 218-220 0.48

16 BAJ-218 CH3 CH3 C6H4-3-O-C6H5 208-210 0.44

17 BAJ-219 CH3 C6H5 2-Thiophenyl 178-180 0.48

18 BAJ-220 CH3 4-F-C6H4 2-Thiophenyl 212-214 0.50

19 BAJ-221 CH3 2,4-di-Cl- C6H3 2-Thiophenyl 202-204 0.40

20 BAJ-222 CH3 CH3 2-Thiophenyl 182-184 0.44

21 BAJ-225 CH3 C6H5 4-F-C6H4 176-178 0.48

22 BAJ-226 CH3 4-F-C6H4 4-F-C6H4 218-220 0.42

23 BAJ-227 CH3 2,4-di-Cl- C6H3 4-F-C6H4 192-194 0.47

24 BAJ-228 CH3 O-CH(CH3)2 4-F-C6H4 188-190 0.46

25 BAJ-229 CH3 O-CH2-

CH(CH3)2 4-F-C6H4 178-180 0.44

26 BAJ-231 CH3 C6H5 4-Me-C6H4 212-214 0.48

27 BAJ-232 CH3 4-F-C6H4 4-Me-C6H4 202-204 0.40

28 BAJ-233 CH3 2,4-di-Cl- C6H3 4-Me-C6H4 182-184 0.42

29 BAJ-234 CH3 CH3 4-Me-C6H4 176-178 0.45

30 BAJ-237 CH2-Cl O-CH2-CH3 C6H5 218-220 0.49

31 BAJ-238 CH2-Cl O-CH2-CH3 3-Br-C6H4 192-194 0.52

32 BAJ-239 CH2-Cl O-CH2-CH3 C6H4-3-O-C6H5 188-190 0.48

33 BAJ-240 CH2-Cl O-CH2-CH3 4-F-C6H4 222-224 0.55

34 BAJ-241 CH2-Cl O-CH2-CH3 4-Me-C6H4 196-198 0.44

Rf value was determined using solvent system = Ethyl Acetate : Hexane (4 : 1)




2.10.1 IR SPECTRA


8400 model using KBr pallet method. Various functional groups present were

identified by characteristic frequency obtained for them.

The characteristic bands of (-C=O) were obtained for stretching at 1650-1750


1100-1050 cm-1. (-C-N-) stretching was observed at 1400-1350 cm-1. It gives

aromatic (-C-H-) stretching frequencies between 3200-3000 and ring skeleton (-

C=C-) stretching at 1500-1350 cm-1 C-H stretching frequencies for methyl and

methylene group were obtained near 2950 - 2850 cm-1.

2.10.2 MASS SPECTRA








Numbers of protons and carbons identified from 1H NMR spectrum and their

chemical shift (δ ppm) were in the agreement of the structure of the molecule. J

values were calculated to identify o, m and p coupling. In some cases, aromatic

protons were obtained as multiplet. Interpretation of representative spectra is

discussed further in this chapter.








were in the agreement of the structure of the molecule. Aliphatic carbon was

observed between 15-25 δ ppm and alkene carbon at 100-102 δ ppm. Aromatic

carbon was observed between 115-140 δ ppm while aliphatic keto carbon was

observed at 158-160 and aromatic keto carbon was observed at 190-195 δ ppm.

Aromatic carbon attached to hetero atom was observed at 155-157 δ ppm.




4-(3-Acetyl-2-methyl-4-phenyl-1H-pyrrol-1-yl)-2H-chromen-2-one (BAJ-201)

IR (cm-1): 3082,3014 (aromatic -C-H stretching), 2974,2901 (aliphatic -C-H

stretching), 1708(-C=O stretching), 1353 (-C-N stretching), 1021(-C-O-C stretching),

981 (-C-H bending) , MS: m/z = 343 (M+), % Anal. Calcd. for C22H17NO3: C, 76.95;

H, 4.99; N, 4.08; O, 13.98.

4-(3-(4-Fluorobenzoyl)-2-methyl-4-phenyl-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-202)

IR (cm-1): 3189,3086 (aromatic -C-H stretching), 2908,(aliphatic -C-H stretching),

1691(-C=O Stretching), 1315(-C-N stretching), 1042(-C-F stretching), 1003(-C-O-C

stretching), 717(-C-H bending monosubstituted), MS: m/z = 423 (M+), 424 (M+1); %

Anal. Calcd. for C27H18FNO3: C, 76.59; H, 4.28; F, 4.49; N, 3.31; O, 11.34.

4-(3-(2,4-Dichlorobenzoyl)-2-methyl-4-phenyl-1H-pyrrol-1-yl)-2H-chromen-2-

one (BAJ-203)

IR (cm-1): 3032,3024 (aromatic -C-H stretching), 2984 (aliphatic -C-H stretching),

1690(-C=O Stretching), 1361(-C-N stretching), 1048(-C-O-C stretching), 756(-C-Cl

stretching), 699(-C-H bending m-disubstituted), MS: m/z = 474 (M+), 476 (M+2); %

Anal. Calcd. for C27H17Cl2NO3: C, 68.37; H, 3.61; Cl, 14.95; N, 2.95; O, 10.12.

Isopropyl-2-methyl-1-(2-oxo-2H-chromen-4-yl)-4-phenyl-1H-pyrrole-3-

carboxylate (BAJ-204)

IR (cm-1): 3062,3034 (aromatic- C-H stretching), 2984,2901 (aliphatic -C-H

stretching), 2894(aliphatic -CH stretching), 1693(-C=O stretching), 1263 (-C-N

stretching), 1095(-C-O-C stretching), 1082 (-C-H bending), MS: m/z = 387 (M+); %

Anal. Calcd. for C24H21NO4: C, 74.40; H, 5.46; N, 3.62; O, 16.52.

Isobutyl-2-methyl-1-(2-oxo-2H-chromen-4-yl)-4-phenyl-1H-pyrrole-3-



stretching), 2823 (aliphatic -CH2 stretching), 1669(-C=O stretching), 1428,1382 (-C-



H bending), 1262 (-C- N stretching), 1088 (-C-H bending), 1005(-C-O-C stretching),

981 (-C-H bending), MS: m/z = 401 (M+); % Anal. Calcd. for C25H23NO4: C, 74.79;

H, 5.77; N, 3.49; O, 15.94.

4-(3-Benzoyl-4-(3-bromophenyl)-2-methyl-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-206)



702 (-C-H bending monosubstituted), 542 (-C-Br stretching), MS: m/z = 484 (M+),

486 (M+2), % Anal. Calcd. for C27H18BrNO3: C, 66.95; H, 3.75; Br, 16.50; N, 2.89;

O, 9.91.

4-(4-(3-Bromophenyl)-3-(4-fluorobenzoyl)-2-methyl-1H-pyrrol-1-yl)-2H-

chromen-2-one (BAJ-207)

IR (cm-1): 3189, 3064(aromatic -C-H stretching), 2941(aliphatic -C-H stretching),

1658(-C=O Stretching), 1585, 1500(-C=C- ring strain), 1309(-C-N stretching), 1124(-

C-O-C stretching), 1010(-C-F stretching), 711(-C-H bending monosubstituted), 597(-

C-Br stretching), 1H NMR (DMSO-d6) δ ppm: 3H, s (2.20), 1H s (5.03), 1H, d (7.06-

7.08, J=8.0 Hz), 2H, m (7.11-7.18), 5H, m (7.25-7.38), 1H, d (7.49-7.50 , J=4.0 Hz ),

1H,m (7.56-7.60), 1H, s (8.05), 1H, m (8.33-8.35, J=8.0 Hz), 13C: 18.60, 101.42,

111.76, 112.71, 116.62, 121.43,122.84, 123.57, 126.45, 127.30, 128.96, 129.20,

129.25, 129.82, 130.41, 130.47, 131.57, 138.87, 139.69, 141.60, 147.41, 147.91,

152.15, 160.25, 191.49. MS: m/z = 502 (M+), 504 (M+2); % Anal. Calcd. for

C27H17BrFNO3: C, 64.56; H, 3.41; Br, 15.91; F, 3.78; N, 2.79; O, 9.56.

4-(4-(3-Bromophenyl)-3-(2,4-dichlorobenzoyl)-2-methyl-1H-pyrrol-1-yl)-2H-


IR (cm-1): 3036,3012 (Aromatic -C-H stretching), 2956 (Aliphatic -C-H stretching),


stretching), 713 (-C-H bending monosubstituted), 653(-C-H bending m-disubstituted),

532(-C-Br stretching) MS: m/z = 553 (M+), 555 (M+2); % Anal. Calcd. for

C27H16BrCl2NO3: C, 58.62; H, 2.92; Br, 14.44; Cl, 12.82; N, 2.53; O, 8.68.



Isopropyl-4-(3-Bromophenyl)-2-methyl-1-(2-oxo-2H-chromen-4-yl)-1H-pyrrole-

3-carboxylate (BAJ-209)

IR (cm-1): 3026,3043 (aromatic -C-H stretching), 2948,2910 (aliphatic -CH3


722 (-C-H bending monosubstituted), 582(-C-Br stretching), MS: m/z = 466 (M+),

468 (M+2); % Anal. Calcd. for C24H20BrNO4: C, 61.81; H, 4.32; Br, 17.13; N, 3.00; O,

13.72.

Isobutyl-4-(3-bromophenyl)-2-methyl-1-(2-oxo-2H-chromen-4-yl)-1H-pyrrole-3-


IR (cm-1): 3052,3023 (Aromatic -C-H stretching), 2998,2924 (Aliphatic -CH3

stretching), 2854 (Aliphatic -CH2 Stretching), 1698(-C=O stretching), 1423,1397 (-C-

H bending), 1223(-C-N stretching), 988(-C-O-C stretching), 718(-C-H bending

monosubstituted), 591(-C-Br stretching), MS: m/z = 480 (M+), 482 (M+2); % Anal.

Calcd. for C25H22BrNO4: C, 62.51; H, 4.62; Br, 16.63; N, 2.92; O, 13.32.

4-(3-Benzoyl-2-methyl-4-(3-phenoxyphenyl)-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-211)

IR (cm-1): 3078,3021 (Aromatic -C-H stretching), 2944,2909 (Aliphatic -C-H

stretching), 1660(-C=O stretching), 1332(-C-N stretching), 1023(-C-O-C stretching),

984(-C-H bending) , 739(-C-H bending monosubstituted), MS: m/z = 497 (M+), %


4-(3-(4-Fluorobenzoyl)-2-methyl-4-(3-phenoxyphenyl)-1H-pyrrol-1-yl)-2H-


IR (cm-1): 3198,3068 (Aromatic -C-H stretching), 2964,(Aliphatic -C-H stretching),




4-(3-(2,4-Dichlorobenzoyl)-2-methyl-4-(3-phenoxyphenyl)-1H-pyrrol-1-yl)-2H-






C-O-C stretching), 754(-C-Cl stretching), 734(-C-H stretching monosubstituted),

673(-C-H bending m-disubstituted), 1H NMR (DMSO-d6) δ ppm: 3H, s (2.25), 1H, s

(5.05), 1H, m (6.73-6.75), 1H, s (6.83), 2H, d (6.91-6.93, J= 8Hz), 2H, t (6.95-7.00),

1H, t (7.05-7.09), 1H, t (7.14-7.17), 1H, dd (7.23-7.25), 4H, m (7.28-7.34), 1H, d

(7.40-7.41, J=1.8), 1H, t (7.53-7.57), 1H, s (7.70), 1H, d (8.25-8.27, J=8.0 Hz), 13C:

18.52, 101.77, 112.00, 112.79, 116.46, 116.55, 118.01, 118.10, 122.41, 122.57,

122.67, 123.29, 126.91, 128.82, 129.00, 129.20, 129.23, 130.61, 131.19, 134.95,

139.31, 141.38, 146.80, 147.08, 152.13, 156.27, 156,46, 160.55, 192.14. MS: m/z =

566 (M+), 568 (M+2); % Anal. Calcd. for C33H21Cl2NO4: C, 69.97; H, 3.74; Cl, 12.52;

N, 2.47; O, 11.30.

4-(3-Acetyl-2-methyl-4-phenyl-1H-pyrrol-1-yl)-2H-chromen-2-one (BAJ-216)



934 (-C-H bending) , MS: m/z = 343 (M+), % Anal. Calcd. for C22H17NO3: C, 76.95;

H, 4.99; N, 4.08; O, 13.98.

4-(3-Acetyl-4-(3-bromophenyl)-2-methyl-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-217)

IR (cm-1): 3066(aromatic -C-H stretching), 2970(aliphatic -C-H stretching), 1660(-

C=O stretching), 1598, 1566, 1502(-C=C- ring strain), 1354(-C-N stretching), 1056(-

C-O-C stretching), 759(-C-H bending monosubstituted), 601(-C-Br stretching), 1H

NMR (DMSO-d6) δ ppm: 3H, s (2.20), 3H, s (2.58), 1H,s (5.15), 1H, t (7.13-7.17),

4H, m (7.25-7.36), 1H, s(7.48), 1H, t (7.52-7.56), 1H, s (7.72), 1H, d (8.25-8.27, J=8.

08 Hz), 13C: 19.01, 29.67, 100.86, 111.29, 112.83, 116.52, 121.91, 122.42, 123.30,

126,34, 129.36, 129.70, 130.24, 131.20, 141.64, 144.92, 147.16, 152.07, 160.85,

197.23. MS: m/z = 422 (M+), 424 (M+2); % Anal. Calcd. for C22H16BrNO3: C, 62.57;

H, 3.82; Br, 18.92; N, 3.32; O, 11.37.

4-(3-Acetyl-2-methyl-4-(3-phenoxyphenyl)-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-218)

IR (cm-1): 3087,3034 (Aromatic -C-H stretching), 2989,2923 (Aliphatic -C-H




932(-C-H bending) , 732(-C-H bending monosubstituted), MS: m/z = 435 (M+); %


4-(3-Benzoyl-2-methyl-4-(thiophen-2-yl)-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-219)



981 (-C-H bending), 866 (-C-S stretching) MS: m/z = 411 (M+), % Anal. Calcd. for

C25H17NO3S: C, 72.97; H, 4.16; N, 3.40; O, 11.66; S, 7.79.

4-(3-Benzoyl-2-methyl-4-(thiophen-2-yl)-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-220)



C-O-C stretching), 1025(-C-F stretching), 848(-C-S stretching), 748(-C-H bending

monosubstituted), 1H NMR (DMSO-d6) δ ppm: 3H, s (2.05), 1H, s (5.41), 1H, d

(6.77-6.78, J=3.24 Hz), 1H, m (6.81-6.83), 1H, dd (7.08-7.10), 2H, m (7.12-7.18),

2H, m (7.31-7.37), 1H, m (7.56-7.60), 2H, m (7.65-7.70), 1H, s (7.90), 1H, dd (8.29-

8.32), 13C: 18.34, 99.29, 112.28,113.03, 115.16,115.38, 116.6, 122.69, 123.28,

123.40, 123.59, 126.35, 130.54, 130.63, 131.32, 135.79, 135.82, 140.89, 142.34,

148.97, 152.13, 160.60, 163.06, 165.57, 194.95. MS: m/z = 429 (M+), 430 (M+1); %

Anal. Calcd. for C25H16FNO3S: C, 69.92; H, 3.76; F, 4.42; N, 3.26; O, 11.18; S, 7.47.

4-(3-(2,4-Dichlorobenzoyl)-2-methyl-4-(thiophen-2-yl)-1H-pyrrol-1-yl)-2H-



1696(-C=O Stretching), 1325(-C-N stretching), 1034(-C-O-C stretching), 849(-C-S

streching), 746(-C-Cl stretching), 659(-C-H bending m-disubstituted), MS: m/z = 480

(M+), 482 (M+2); % Anal. Calcd. for C25H15Cl2NO3S: C, 62.51; H, 3.15; Cl, 14.76; N,

2.92; O, 9.99; S, 6.68.

4-(3-Acetyl-2-methyl-4-(thiophen-2-yl)-1H-pyrrol-1-yl)-2H-chromen-2-one (BAJ-

222)





954 (-C-H bending), 856(-C-S stretching), MS: m/z = 349 (M+), % Anal. Calcd. for

C20H15NO3S: C, 68.75; H, 4.33; N, 4.01; O, 13.74; S, 9.18.

4-(3-Benzoyl-4-(4-fluorophenyl)-2-methyl-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-225)





4-(3-(4-Fluorobenzoyl)-4-(4-fluorophenyl)-2-methyl-1H-pyrrol-1-yl)-2H-





Anal. Calcd. for C27H17F2NO3: C, 73.46; H, 3.88; F, 8.61; N, 3.17; O, 10.87.

4-(3-(2,4-Dichlorobenzoyl)-4-(4-fluorophenyl)-2-methyl-1H-pyrrol-1-yl)-2H-



1675(-C=O Stretching), 1384(-C-N stretching), 1073(-C-O-C stretching), 1015(-C-F

stretching), 795(-C-Cl stretching), 710(-C-H bending monosubstituted), 679(-C-H

bending m-disubstituted), MS: m/z = 492, (M+), 494 (M+2); % Anal. Calcd. for

C27H16Cl2FNO3: C, 65.87; H, 3.28; Cl, 14.40; F, 3.86; N, 2.85; O, 9.75.

Isopropyl-4-(4-Fluorophenyl)-2-methyl-1-(2-oxo-2H-chromen-4-yl)-1H-pyrrole-

3-carboxylate (BAJ-228)


stretching), 2887(aliphatic -CH stretching), 1693(-C=O stretching), 1263 (-C-N

stretching), 1095(-C-O-C stretching), 1082 (-C-H bending), 1036(-C-F stretching),

730(-C-H bending monosubstituted), MS: m/z = 405 (M+), 406 (M+1); % Anal.

Calcd. for C24H20FNO4: C, 71.10; H, 4.97; F, 4.69; N, 3.45; O, 15.79.



Isobutyl-4-(4-Fluorophenyl)-2-methyl-1-(2-oxo-2H-chromen-4-yl)-1H-pyrrole-3-



stretching), 2817 (aliphatic -CH2 Stretching), 1634(-C=O stretching), 1428,1382 (-C-

H bending), 1235 (-C- N stretching), 1102(-C-F stretching), 1074 (-C-H bending),

1005(-C-O-C stretching), 981 (-C-H bending), 730(-C-H bending monosubstituted),

MS: m/z = 419 (M+), 420 (M+1); % Anal. Calcd. for C25H22FNO4: C, 71.59; H, 5.29;

F, 4.53; N, 3.34; O, 15.26.

4-(3-Benzoyl-2-methyl-4-(p-tolyl)-1H-pyrrol-1-yl)-2H-chromen-2-one (BAJ-231)


1691(-C=O Stretching), 1315(-C-N stretching), 1003(-C-O-C stretching), MS: m/z =

419 (M+); % Anal. Calcd. for C28H21NO3: C, 80.17; H, 5.05; N, 3.34; O, 11.44.

4-(3-(4-Fluorobenzoyl)-2-methyl-4-(p-tolyl)-1H-pyrrol-1-yl)-2H-chromen-2-one

(BAJ-232)





4-(3-(2,4-Dichlorobenzoyl)-2-methyl-4-(p-tolyl)-1H-pyrrol-1-yl)-2H-chromen-2-

one (BAJ-233)



stretching), 685(-C-H bending m-disubstituted), MS: m/z = 488 (M+), 490 (M+2); %

Anal. Calcd. for C28H19Cl2NO3: C, 68.86; H, 3.92; Cl, 14.52; N, 2.87; O, 9.83.

4-(3-Acetyl-2-methyl-4-(p-tolyl)-1H-pyrrol-1-yl)-2H-chromen-2-one (BAJ-234)



738(-C-H bending monosubstituted), MS: m/z = 357 (M+), % Anal. Calcd. for

C23H19NO3: C, 77.29; H, 5.36; N, 3.92; O, 13.43.



Ethyl-2-(chloromethyl)-1-(2-oxo-2H-chromen-4-yl)-4-phenyl-1H-pyrrole-3-



stretching), 2849(aliphatic -CH2 stretching), 1669(-C=O stretching), 1428,1382 (-C-

H bending), 1234 (-C-N stretching), 1103(-C-O-C stretching), 1053(-C-H bending),

772(-C-Cl stretching), MS: m/z = 407 (M+), 409 (M+2); % Anal. Calcd. for

C23H18ClNO4: C, 67.73; H, 4.45; Cl, 8.69; N, 3.43; O, 15.69.

Ethyl-4-(3-bromophenyl)-2-(chloromethyl)-1-(2-oxo-2H-chromen-4-yl)-1H-

pyrrole-3-carboxylate (BAJ-238)



H bending), 1229 (-C-N stretching), 1099(-C-O-C stretching), 1042(-C-H bending),

743(-C-Cl stretching), 589(-C-Br stretching), MS: m/z = 486 (M+), 488 (M+2); %

Anal. Calcd. for C23H17BrClNO4: C, 56.75; H, 3.52; Br, 16.42; Cl, 7.28; N, 2.88; O,

13.15.

Ethyl-2-(chloromethyl)-1-(2-oxo-2H-chromen-4-yl)-4-(3-phenoxyphenyl)-1H-



stretching), 2812(aliphatic -CH2 stretching), 1658(-C=O stretching), 1425,1386 (-C-

H bending), 1239(-C-N stretching), 1104(-C-O-C stretching), 751(-C-Cl stretching),

711(-C-H bending monosubstituted), 574(-C-Br stretching), MS: m/z = 499 (M+), 501

(M+2); % Anal. Calcd. for C29H22ClNO5: C, 69.67; H, 4.44; Cl, 7.09; N, 2.80; O,

16.00.

Ethyl-2-(chloromethyl)-4-(4-fluorophenyl)-1-(2-oxo-2H-chromen-4-yl)-1H-




H bending), 1236 (-C-N stretching), 1093(-C-O-C stretching), 1015(-C-F stretching),

752(-C-Cl stretching), 717(-C-H bending monosubstituted), MS: m/z = 425 (M+),



427 (M+2); % Anal. Calcd. for C23H17ClFNO4: C, 64.87; H, 4.02; Cl, 8.33; F, 4.46; N,

3.29; O, 15.03.

Ethyl-2-(chloromethyl)-1-(2-oxo-2H-chromen-4-yl)-4-(p-tolyl)-1H-pyrrole-3-


IR (cm-1): 3094,3022 (aromatic -C-H stretching), 2974,2953(aliphatic -C-H


H bending), 1253 (-C-N stretching), 1012(-C-O-C stretching), 749(-C-Cl stretching),

711(-C-H bending monosubstituted), MS: m/z = 421 (M+), 423 (M+2); % Anal.

Calcd. for C24H20ClNO4: C, 68.33; H, 4.78; Cl, 8.40; N, 3.32; O, 15.17.




According to the Grob and Cameisch, pyrroles can be obtained from Michael

reaction of β-enamino ketones or esters and nitroalkenes followed by cyclization.96

However, only little has been explored in thisfield and reported only for aliphatic

nitroalkenes.97 Moreover, in this method it is a prerequisite to prepare nitroalkenes

from aldehyde and nitroalkanes, and β-enaminocarbonyl derivatives from β-

dicarbonyl and amines beforehand. Consequently, there are opportunities for further

improvement of this reaction. Present study reveals simultaneous one pot synthesis of

β-keto-enamines from 1,3-dicarbonyl compounds and nitrostyrene from readily

available starting materials in the presence of a suitable catalyst, and these two

component undergo Michael reaction, to tandem synthesis of functionalized pyrroles.

2.13 CONCLUSION

In summary, we have successfully developed a novel, operationally simple,

economical, and environmentally friendly one-pot four-component coupling reaction

to synthesis functionalized pyrroles by employing 1,3-dicarbonyl compounds,

aromatic aldehyde, amines, and nitro alkanes. Considering these advantages and

experimental simplicity, this one-pot catalytic transformation clearly represents an

appealing methodology for the synthesis of highly functionalized pyrroles. Further

study in this area is going on in our laboratory to improve the yield, mechanism, and

possible applications of this reaction.

CChapter – 2

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2.14 RE 2.14.1 IR S

2.14.2 MA

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EPRESEN

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NTATIVE

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RA

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2.14.3 1H N

2.14.4 Exp

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AJ-207

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2.14.5 13C N

2.14.6 IR S

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AJ-207

Synthesis N-

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CChapter – 2

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2.14.7 MA

2.14.8 1H N

H

Cl

C

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H3C

OO

Cl

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um of BAJ-

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O

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-213

AJ-213

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2.14.9 Exp

2.14.10 13C

H3

Cl

C

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C NMR Spe

N

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C

OO

l

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NMR Spect

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BAJ-213

Synthesis N-

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AJ-213

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65

CChapter – 2

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2.14.11 IR

2.14.12 MA

t of Chemist

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ASS Spectr

H3

H3C

try, Saurash

of BAJ-217

rum of BAJ

N

O

3C

OO

C

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7

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Br

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H3C

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H3C

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66

Br

CChapter – 2

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2.14.13 1H

2.14.14 Exp

O

H3C

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H3C

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panded 1H

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try, Saurash

ectrum of B

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Br

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BAJ-217

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sity, Rajkot-

BAJ-217

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CChapter – 2

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2.14.15 13C

2.14.16 IR

O

H3C

O

H3C

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Spectrum

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ectrum of B

of BAJ-222

Br

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BAJ-217

20

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CChapter – 2

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2.14.18 1H

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J-220

BAJ-220

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69

CChapter – 2

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2.14.19 Exp

2.14.20 13C

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try, Saurash

H NMR Spe

ectrum of B

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ctrum of B

BAJ-220

Synthesis N-

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BAJ-220

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70



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Van Embden J., Grosset J., Cole S.; Lancet, 1994, 344, 293.

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63. Pearson, M., Jereb, J., Frieden, T., Crawford, J., Davis, B., Dooley, S., Jarvis,

W.; Ann. Intern. Med., 1992, 117, 191.

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W.; Agents Chemother., 1993, 37, 183.

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67. (a) Esposito, D., Craigie, R.; Adv. Virus Res., 1999, 52, 319. (b) Asante-Appiah

E., Skalka A.; Adv. Virus Res., 1999, 52, 351. (c). Pommier Y., Neamati N.;

Adv. Virus Res., 1999, 52, 427.

68. (a) Hazuda, D., Felock, P., Witmar, M., Wolfe, A., Stillmock, K., Grobler, J.,

Espeseth, A., Gabryelski, L., Schleif W., Blau C., Miller M.; Science, 2000, 287,

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Clark, D., Medina, J.; W09962513 (c) Toshio, F., Tomokazu, Y.; W099-

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71, 7005.

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36(19), 2739.

Sy

CCCynthe

CCCHHHsis of 2H-ch

HHHAAAPPP4-(diahrome

PPPTTT

alkyl/aene-3-

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o

hy

hy

rh

ca

sy

p

C

co

co

to

is

al

b

g

v

hi

le

bi

in

Chapter – 3

Department o

.1 INRO

The c

f dicoumar

ydroxycoum

ydrooxycoum

hodenticides

aroinostatic,

ystem depr

sychotropic

Coumarin der

oumarin bas

oumarins wh

Coum

onka bean (

solated in 18

Coum

ll of which c

e subdivided

-pyrones, of

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igh levels in

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n higher pla

3

of Chemistry,

ODUCTION

chemistry of

ol. A num

marins have

marin are

s(long acting

, antitubercu

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and antiferti

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sed structure

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marin is class

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f which the

ass of compo

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, Saurashtra

N

f 4-hydroxyc

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ssessing a 4-

e possess div

present in co

their class n

dorata Willd

sified as a m

benzene rin

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the plant kin

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Coumarin is

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the discover

lly active 4

ly earlier 4

as well a

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oxycoumarin

position (I) o

o as hydroxy

r name of th

rin itself wa

f compound

zopyrones ca

and the benzo

ns comprise

y are found

0 ppm), cass

in fruits (e.

umarins occu

Umbellifera

ves

76

ry

4-

4-

as

al

us

ic,

n.

of

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as

ds,

an

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a

at

ia

g.

ur

ae.

Chapter – 3 Synthesis of2-oxo-2H-chromene-3-carbonitirle derivatives

Department of Chemistry, Saurashtra University, Rajkot-360 005 77

Although distributed throughout all parts of the plant, the coumarins occur at the

highest levels in the fruits, followed by the roots, stems and leaves. Environmental

conditions and seasonal changes can influence the occurrence in diverse parts of the

plant. Recently six new minor coumarins have been isolated from the fruits and the

stem bark of Calophyllum dispar (Clusiaceae). The genus Calophyllum, which

comprises 200 species, is widely distributed in the tropical rain forest where several

species are used in folk medicine.


Coumarin and his derivatives were synthesized by many researchers using different

methods. Perkin1 synthesized coumarin and then several methods are reported for the

synthesis of 4-Hydroxy coumarins and their 4-Hydroxy substituted derivatives

namely:

1 Anschutz method 2

2 Pauli Lockemann synthesis 3

3 Sonn's synthesis 4

4 Mentzer's synthesis 5

5 Robertson synthesis 6

6 Ziegler and Junek method 7

7 Garden's method 8

8 Shah, Bose and Shah's method 9

9 Kaneyuki method 10

10 Resplandy's method 11

11 Jain, Rohatagi and Sheshadri's method 12

12 Shah, Bhatt and Thakor's method 13

Shah et al. 9-13 have prepared 4-Hydroxy coumarin derivatives in good yield by

condensation of different phenols with malonic acid in the presence of zinc chloride

and phosphorous oxychloride. The method is useful as single step preparation of 4-

Hydroxy coumarin derivatives substituted in benzenoid part.



Pechmann Coumarin Synthesis

Recently many researchers14-45 have reported synthetic strategies for 4-

Hydroxy coumarin.

The employment of hydrophobic ionic liquids dramatically enhanced the

activity of metal triflates in Friedel-Crafts alkenylations of aromatic compounds with

various alkyl-and aryl-substitutedalkynes.46

Arylpropionic acid methyl esters having a MOM-protected hydroxy group at

the ortho position underwent hydroarylation with various arylboronic acids in MeOH

at ambient temperature in the presence of a catalytic amount of CuOAc, resulting in

the formation of 4-arylcoumarins in high yields after the acidic workup.47

The basic ionic liquid 1-Butyl-3-methylimidazolium hydroxide, [bmim]OH,

efficiently catalyzes the Knoevenagel condensation of various aliphatic and aromatic

aldehydes and ketones with active methylenes at room temperature without

requirement of any organic solvent. 48



A facile, convenient, efficient and high yielding synthesis of a combinatorial

library of 3-aroylcoumarins has been developed by the condensation of easily

available aroylketene dithioacetals and 2-Hydroxybenzaldehydes in the presence of

catalytic amount of piperidine in THF reflux.49

The ionic liquid 1-Butyl-3-methylimidazonium tetrafluoroborate [bmim]BF4

was used for Ethylenediammonium diacetate (EDDA)-catalyzed Knoevenagel

condensation between aldehydes or ketones with active methylene compounds.

Catalyst and solvent were recyclable.50

A new carbamoyl Baker-Venkataraman rearrangement allows a general

synthesis of substituted 4-Hydroxycoumarins in good overall yields. Intermediate

arylketones are efficiently prepared via a Directed ortho Metalation - Negishi cross

coupling protocol from arylcarbamates. The overall sequence provides a regiospecific

anionic Friedel-Crafts complement for the construction of ortho-acyl phenols and

coumarins.51



An Efficient and Practical Procedure for the Synthesis of 4-Substituted Coumarins.52

Coumarin syntheses via Pechmann condensation in Lewis acidic

chloroaluminate ionicliquid.53

3.2.1 Reported synthetic strategy for the 4-arylaminocoumarin

The 4-arylamino coumarins are reported in literature.54 The reaction of various

amines, such as primary aromatic, arylaliphatic and aliphatic amine with either 4-

hydroxy or 4-chlorocoumarins results in the formation of N-substituted-4-amino

coumarins.

Apparently it is found that 4-aminocourmarin is prepared by direct method by

removing acidic hydroxyl group with amino group in one step only, but alternate

route is to convert the hydroxyl group into chloro group and then convert it into

amino group by appropriate reagent for substitution (Scheme-2.1).

O O

OH

O O

HNR

O O

Cl R=H, Alkyl or Aryl

The conversion of 4-hydroxy coumarin can also be afforded by a direct one

step method using appropriate arylamine using solvents, without solvents under

conventional heating or by using microwave assisted synthetic strategy.

Anschutz54 reported the synthesis of 4-anilino coumarin during his pioneering

work, by heating 4-hydroxy coumarin directly with aniline.



Zagorevskii55 reported that the action of liquor ammonia on 4-chloro coumarin

in the presence of copper powder exclusively afforded the 4-aminocoumarin. In

another method, 4-chlorocoumarin when treated with concentrated ammonium

hydroxide in dioxane for 40 hours at room temperature afforded 4-aminocoumarin (1)

in 25% yield and o-hydroxyphenylpropionamide (2) (52% yield)56-58 due to opening

of the lactone ring. However, only the desired 4-aminocoumarins were obtained in

some cases.59-61

O O

NH2

OH

NH2

O(1) 4-aminocoumarin (2) o-hydroxyphenylpropionamide

High electron density appears around the chlorine substituent and low electron

density at the neighboring carbon atom at C4 is the reason that the chlorine atom is

readily and quantitatively exchanged for nitrogen atom of amines and amino acids.62

It was also found that refluxing coumarin in an excess of amine, in the

presence or absence of a solvent, yielded a mixture of the corresponding phenol and

4-arylamino coumarin.58

It was recently reported that refluxing coumarin in glacial acetic acid with an

excess of primary amine prevented lactone ring opening with increased yield.63 Only

the disadvantage of this method is long reaction time (10-20 h). The reaction of

coumarins with secondary amines was reported to fail.63 All known methods require

considerable excess of the amine, e.g. amine : coumarin molar ratios from 10:1 to

20:1 and, hence, large quantity of amine wasted.

Ivanov 64 and co-worker have prepared 4- arylamino coumarin without any

solvent in molar ratio of 1:1.2 under microwave irradiation with 90-98% yield.



Checchi and Vettori65 prepared 4-aminocoumarin-3-sulphonamide and its

derivatives. Sulphonation of 4-hydroxycoumarin in absence of any solvent, with an

excess of chlorosulphonic acid yielded 3-sulphonic acid, which was converted to its

potassium salt and on further chlorination with phosphorous oxychloride, afforded 4-

chlorocoumarin sulphochloride. The treatment of either ammonia or primary aliphatic

and aromatic amines led to the formation of 4-aminocoumarin-3-sulphonamide and its

derivatives.

4-Arylaminocoumarins were prepared by treatment of an ethanolic solution of

4-hydroxycoumarin and o-aminobenzaldehyde under refluxe condition, which on

further intramolecular cyclization afforded cromeno[4,3-b]quinoline.66 This gives way

for another method for synthesis of 3, 4-fused system on coumarin nucleus.

Asherson et al. 67 heated dicoumarol and 4-hydroxycoumarin with aniline to

yield 4-arylaminocoumarin. Which was further validated by Conlin et al.68 while they

heated dicoumarol and 4-hydroxycoumarin with aniline, benzylamine and

cyclohexylamine under reflux to yield corresponding anil of 4-hydroxycoumarin.

Bhatt and Thakor 69 prepared 4-anilinocoumarins by direct condensation of 4-

hydroxycoumarins with different amines, thus opening the single step route of such

arylaminocoumarin derivatives.

Joshi 70 and Berghaus 71 have also independently reported the synthesis of 4-

amino benzopyrans as intermediate products during annelation.

Reddy et al.72 carried out condensation reaction of 4-hydroxycoumarin and 2-

aminothiophenol in dimethylsulfoxide. This cyclized product was desulfurized with

Raney-Nickel to give 4-arylaminocoumarin.



Hamdi et al. 73 reported that heating 1, 2-phenylenediamine with the 4-

hydroxycoumarin in ethanol, two products were obtained, one was N-(2-

aminophenyl)-3-hydroxy-3-(2-hydroxyphenyl) acrylamide (3) and another was 4-[(2-

aminophenyl) amino]-2H-chromen-2-one (4). While 1, 4-phenylenediamine was

refluxed in xylene with 4-hydroxycoumarin, it also gave two products, one was 4-[(4-

aminophenyl) amino]-2H-chromen-2-one (5) and another was the dimer (6).

O O

HNNH2

OH

OH

O

NHNH2

(3) N-(2-aminophenyl)-3-hydroxy-3-(2-hydroxyphenyl)acrylamide

(4) 4-((2-aminophenyl)amino)-2H-chromen-2-one

O O

HN

NH2

OO

HN NH

OO

(5) 4-((4-aminophenyl)amino)-2H-chromen-2-one

(6) Dimer

3.2.2 3-CYANO COUMARIN

3-cyano-4-methyl coumarin also found their way into the the preparation of

methine dyes.74 Variety of dyes was synthesized by reacting the 3-cyano-4-methyl

coumarin with different dye intermediates. Very recently, 4-cyano couamrin

derivatives found their application in photochemical polymerization, dye lasers and

electroluminescent elements.75



Hence Khellins were utilized as analgesic,hypnotics and antihistaminics.

And in this study it was found that compounds i.e 3-cyano-5,8-dimethoxy-4-methyl-

6,7-furanocoumarin has more intense neuroplegic properties than khellin. Specifically

these compounds relax the autonomous system i.e neurovegetative dystonias,

depressive states such as anxiety, hyperemotional, hypernervousness. In combination

with barbiturates, these derivatives are indicative in profound depressive states with

loss of muscular tonus, obstinate insomnias, extraordinary pains (urethral lithiasis). In

combination with antihistaminics they show gangliolegic power. being more precise,

active against asthma, common and obstinate coughs, five day fevers of whooping

cough.

Moreover, another method for synthesis of 4-alkyl-3-cyano-coumarin

derivatives were reported which deviates from the classical way. Alkylation of

various 3-substituted coumarins were carried out and it was observed that cyano

group at third position efficiently promoted 4-methylation76 and in continuation of

this, alkylation was carried out by diazo ethene, 2-diazopropane, etc to give diverse 4-

alkyl 3-cyano coumarins77

4-Methyl-3-(terazol-yl) coumarin is already known in the literature, where it

was shown that these compounds did not show any antiallergic activity, but in the

compounds of type (XX) showed substantial antiallergic activity. These compounds

are preapred by reacting the substituted cyano coumarin with ammonium azide in

inert organic solvent such as DMF at a temperature above room temperature. The

ammonium azide is formed in-situ by reacting sodium azide with ammonium

chloride.78



O-hydroxy acetophenones were transformed into 3-cyano-4-methylcoumarins

by means of condensation with ethyl cyanoacetate in the presence of piperidine or

ammonium acetate as a catalyst. Further, 4-styryl derivatives were obtained by

condensation of the 3-cyano-4-methylcoumarins with different aromatic and

heterocyclic aldehydes.79

Condensation of 4-chloro-2-oxo-2H-chromene-3-carbonitrile with selected

heteroarylamines in acetonitrile contg. a catalytic amt. of triethylamine, followed by

intramol. cyclization, gave the new coumarin derivatives.80

Reactions of 4-chloro-3-nitrocoumarin with a variety of nucleophiles produced

a no. of novel substituted coumarins. Hard and borderline nucleophiles exclusively

substitute chlorine in position 4, while soft nucleophiles substitute the nitro group in

position 3 (except for iodide). This result of the nucleophilic substitution rationalized

in terms of the HSAB model. 81



3.3 PHARMACOLOGY

Numerous biological activities have been associated with simple coumarin and its

analogues. Among them, antimicrobial, antiviral, anticancer, enzyme inhibition, anti-

inflammatory, antioxidant, anticoagulant and effect on central nervous system are

most prominent. Coumarin nucleus possesses diversified biological activities that can

be briefly summarized as under:

1 Antimicrobial and Molluscicidal 82-84

2 Antiviral 85-87

3 Anticancer 88-90

4 As Enzyme Inhibition 91-93

5 Antioxidant 94-97

6 Anti-inflammatory 98-100

7 Anticoagulant and Cardiovascular 101-103

8 Effect on Central Nervous System 104-105

4-Hydroxycoumarin is a versatile scaffold and is being consistently used as a building

block in organic chemistry as well as in heterocyclic chemistry for the synthesis of

different heterocyclic. The synthetic versatility of 4-Hydroxy coumarin has led to the

extensive use of this compound in organic synthesis. 4-Hydroxy coumarin shows

diversified chemical reactivity.




Various biological importances of Coumarin derivatives prompted us to

synthesize some novel 3-cyano functionalized coumarin derivatives.

To synthesize desired compounds we utilized 4-chloro-3-formyl coumarin.

The current work is aimed for preparing novel 3-cyano coumarin derivatives from 3-

formyl coumarin derivatives in presence of hydroxyl amine hydrochloride under the

reaction conditions such that instead of formation of 2H-[1] benzopyran [3,4-

d]isoxazoles-2-one. Since cyano coumarin is a privilege structure, the possibility of

diverse pharmacological activities is expected from compounds synthesized in this

chapter.



3.5 REACTION SCHEMES 3.5.1 PREPARATION OF 4-(DIALKYL/ALKYL)AMINO)-2-OXO-2H-

CHROMENE-3-CARBONITIRLES STEP-I: PREPARATION OF 4-CHLORO-3-FORMYL COUMARIN :

Reagents / Reaction Condition (a): DMF, POCl3, 0-5°C, 2 h, heat 60°C, 1 h.

STEP-II: PREPARATION OF 4-CHLORO-3-CYANO COUMARIN:

Reagents / Reaction Condition (b): hydroxyl amine hydrochloride, sodium acetate,

acetic acid, 60°C, stirr.

STEP-III: PREPARATION OF 4-(DIALKYL/ALKYL)AMINO)-2-OXO-2H-

CHROMENE-3-CARBONITIRLES

Reagents / Reaction Condition (c): DMF, K2CO3, 0-5°C, substituted primary/sec.

amine.







in Shimadzu FT-IR-8400 instrument using KBr method. Mass spectra were recorded

on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe technique. 1H

NMR was determined in CDCl3/DMSO solution on a Bruker Ac 400 MHz

spectrometer.

3.7.2 STEP-I: PREPARATION OF 4-CHLORO-3-FORMYL COUMARIN:

To a stirred mixture of 4-hydroxycoumarin (0.06 mol) in anhydrous DMF (0.6

mol) were added dropwise POCl3 (0.18 mol) at –10°C to –5°C. The reaction mixture

was then stirred for 1 h at room temperature and heated and stirred for 2 h at 60°C.

After the reaction completed, the mixture was poured onto crushed ice under vigorous

stirring. After storing the mixture overnight at 0°C the pale yellow solid was collected

by filtration and washed successively with Na2CO3 (5%) and water, and then was air–

dried. Recrystallization from acetone gave 85% of 4-chloro-3-formyl coumarin as a

pale yellow powder with m.p. 115–120 °C. (ARKIVOC, (6), 2001, 122-128)

3.7.2 STEP-II: PREPARATION OF 4-CHLORO-3-CYANO COUMARIN: To a 20 mL solution of 4-chloro-3-formyl coumarin (0.01 mol) in glacial

acetic acid was added sodium acetate (0.01mol) and hydroxyl amine hydrochloride

(0.01 mol) and the solution was allowed to stirr at 60°C for 2 h. After completion of

the reaction monitored the solid was filtered and washed with water (25 ml).

Crystallization of compound from DMF:IPA (80:20) under 0-5°C yields 45% of 4-

chloro-3-cyano coumarin as a light green crystals m.p. 198–200 °C. (Journal of

Heterocyclic Chemistry 45(1), 2008, 295-297)



3.7.3 STEP-III: PREPARATION OF 4-(DIALKYL/ALKYL)AMINO)-2-OXO-

2H-CHROMENE-3-CARBONITIRLES

4-chloro-3-cyano coumarin (0.01 mol) was dissolved in 10 mL DMF and

allowed to stir between 0-5°C followed by addition of 2.0 g of K2CO3, and allowed to

stir for 10 min. Primary/secondary amine (0.1 mol) was carefully added to the

solution so that the temperature do not rise 10°C. Allow it to stir for 30 min and

slowly raise to room temperature. After completion of the reaction, was poured into

crushed ice, filtered and washed with water. Crystallization from chloroform gives 4-

(dialkyl/alkyl)amino)-2-oxo-2H-chromene-3-carbonitirles. Yield 68-86%




3.8 PHYSICAL DATA

Physical data of 4-(dialkyl/alkyl)amino)-2-oxo-2H-chromene-3-carbonitriles

Table-I

Sr. No. Code R M.P. Rf

1 BAJ-101

126-128 0.40

2 BAJ-102

134-136 0.43

3 BAJ-103

136-138 0.43

4 BAJ-104

142-144 0.42

5 BAJ-105

158-160 0.44

6 BAJ-106

144-146 0.43

7 BAJ-107 N-(CH(CH3)2)2 136-138 0.47

8 BAJ-108 N-(CH2CH3)2 148-150 0.42

9 BAJ-109 N-((CH2)3-CH3)2 162-164 0.44

10 BAJ-110 N-CH2-CH3 176-178 0.46

11 BAJ-111

144-146 0.50

12 BAJ-112 NH-CH3 142-144 0.48

13 BAJ-113

148-150 0.52

N

NNCH3

NN

NN

NNH3C

NO

N

CH3

N

O



14 BAJ-114

164-166 0.44

15 BAJ-115 NH-(CH2)3-CH3 154-156 0.48

16 BAJ-116 NH-CH2-CH(CH3)2 148-150 0.38

17 BAJ-117

166-168 0.42

18 BAJ-118

148-150 0.48



3.9.1 IR SPECTRA


8400 model using KBr pallet method. Various functional groups present were

identified by characteristic frequency obtained for them.

The characteristic bands of (-C≡N) were obtained for stretching at 2200-2100


1100-1050 cm-1. (-C-N-) stretching was observed at 1400-1350 cm-1. Characteristic

band of (-CH2-) group was observed between1500-1450 cm-1. It gives aromatic (-C-

H-) stretching frequencies between 3200-3000 and ring skeleton (-C=C-) stretching

at 1500-1350 cm-1 C-H stretching frequencies for methyl and methylene group were

obtained near 2950 - 2850 cm-1.

3.9.2 MASS SPECTRA




N

NHN

N

CH3





Avance II 400 spectrometer by making a solution of samples in CDCl3 solvent using

tetramethylsilane (TMS) as the internal standard unless otherwise mentioned.








Avance II 300 spectrometer by making a solution of samples in CDCl3 solvent using

tetramethylsilane (TMS) as the internal standard unless otherwise mentioned. Types

of carbons identified from NMR spectrum and their chemical shift (δ ppm) were in

the agreement of the structure of the molecule. Aliphatic carbon was observed

between 15-25 δ ppm, methylene carbon was observed between 60-65 δ ppm and

alkene carbon at 100-105 δ ppm. Aromatic carbon was observed between 115-140 δ

ppm while aliphatic keto carbon was observed at 158-160 δ ppm. Carbon attached to

hetero atom was observed at 155-157 δ ppm.




2-Oxo-4-(piperidin-1-yl)-2H-chromene-3-carbonitrile (BAJ-101)

Yield: 68% IR (cm-1): 3126(aromatic -C-H stretching), 2839(aliphatic -CH2

stretching), 2198(-C-N stretching), 1710(-C=O stretching), 1599, 1545, 1516(-C=C-

ring strain), 1448, 1354(-C-H bending), 1292(-C-N stretching tertiary amine), 1053(-

C-O-C stretching), 1H NMR (CDCl3) δ ppm: 6H, s (1.77), 3H,d (3.27-3.29 J=8.0

Hz), 2H, m (7.25-7.31), 1H,m (7.48-7.52), 1H, dd (7.75-7.77 J=8.0 HZ), 13C: 24.14,

26.48, 54.40, 104.87, 117.56, 118.68, 123.76, 125.34, 131.84, 145.74, 153.23, 159.57,

161.85. MS: m/z = 254 (M+),; % Anal. Calcd. for C15H14N2O2: C, 70.85; H, 5.55; N,

11.02; O, 12.58.

4-(4-Methylpiperazin-1-yl)-2-oxo-2H-chromene-3-carbonitrile (BAJ-102)

Yield: 76% IR (cm-1): 3190, 3161 (aromatic -C-H stretching), 2978 (aliphatic –CH-

stretching), 2833 (aliphatic -CH2 stretching), 2152(-C-N stretching), 1718 (-C=O

stretching), 1517(-C=C- ring strain), 1419,1354 (-C-H bending), 1323(-C-N stretching

tertiary amine), 1012(-C-O-C stretching) MS= m/z = 269 (M+),; % Anal. Calcd. for

C15H15N3O2: C, 66.90; H, 5.61; N, 15.60; O, 11.88.

2-Oxo-4-(4-phenylpiperazin-1-yl)-2H-chromene-3-carbonitrile (BAJ-103)

Yield: 88% IR (cm-1): 3043, 3021 (aromatic -C-H stretching), 2820 (Aliphatic -CH2

stretching), 2140(-C-N stretching), 1720(-C=O stretching), 1523(-C=C- ring strain),

1419,1364 (-C-H bending), MS: m/z = 331 (M+),; % Anal. Calcd. for C20H17N3O2: C,

72.49; H, 5.17; N, 12.68; O, 9.66.

4-(4-Benzylpiperazin-1-yl)-2-oxo-2H-chromene-3-carbonitrile (BAJ-104)

Yield: 72% IR (cm-1): 3051,3014 (aromatic -C-H stretching), 2879 (aliphatic -CH2

stretching), 2131(-C-N stretching), 1725(-C=O stretching), 1519(-C=C- ring strain),

1415,1346(-C-H bending), 1326(-C-N stretching tertiary amine), 1033(-C-O-C

stretching) MS: m/z = 345 (M+),; % Anal. Calcd. for C21H19N3O2: C, 73.03; H, 5.54;

N, 12.17; O, 9.26.



4-(4-Ethylpiperazin-1-yl)-2-oxo-2H-chromene-3-carbonitrile (BAJ-105)

Yield : 69% IR (cm-1): 3097, 3012 (aromatic -C-H stretching), 2978 (aliphatic –CH-

stretching), 2901 (aliphatic -CH2 stretching), 2129(-C-N stretching), 1706(-C=O


tertiary amine), 1029(-C-O-C stretching) MS: m/z = 283 (M+),; % Anal. Calcd. for

C14H14N2O2: C, 69.41; H, 5.82; N, 11.56; O, 13.21.

4-Morpholino-2-oxo-2H-chromene-3-carbonitrile (BAJ-106)

Yield : 86% IR (cm-1): 3015, 3011 (aromatic -C-H stretching), 2945 (aliphatic –CH-


stretching), 1527(-C=C- ring strain), 1435 (-C-H bending), 1318(-C-N stretching

tertiary amine), 1007 (-C-O-C stretching). MS: m/z = 256 (M+),; % Anal. Calcd. for

C14H12N2O3: C, 65.62; H, 4.72; N, 10.93; O, 18.73.

4-(Diisopropylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-107)

Yield : 75% IR(cm-1): 3115, 3041 (aromatic -C-H stretching), 2935 (aliphatic –CH-

stretching), 2135(-C-N stretching), 1711 (-C=O stretching), 1560(-C=C- ring strain),

1425,1326 (-C-H bending), 1329(-C-N stretching tertiary amine), 1092 (-C-H

bending), 1026(-C-O-C stretching) MS: m/z = 270 (M+),; % Anal. Calcd. for

C16H18N2O2: C, 71.09; H, 6.71; N, 10.36; O, 11.84.

4-(Diethylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-108)

Yield: 78% IR (cm-1): 3126, 3016(aromatic -C-H stretching), 2839(aliphatic -CH2

stretching), 2200(-C-N stretching), 1662(-C=O stretching), 1595, 1508(-C=C- ring

strain), 1446, 1357(-C-H bending), 1325(-C-N stretching tertiary amine), 1097(-C-O-

C stretching), 1H NMR (CDCl3) δ ppm: 6H, t (1.17-1.20), 4H, q (3.47-3.53), 1H,m

(7.23-7.27), 1H, d (7.32-7.34, J=8.0 Hz), 1H, m (7.49-7.53), 1H, m (7.70-7.72), 13C:

13.76, 47.47, 108.71, 117.48, 119.35, 123.73, 126.04, 131.94, 144.63, 153.34, 159.61,

160.45. MS: m/z = 242 (M+),; % Anal. Calcd. for C14H14N2O2: C, 69.41; H, 5.82; N,

11.56; O, 13.21.

4-(Dibutylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-109)

Yield : 78% IR (cm-1): 3110, 3051 (aromatic -C-H stretching), 2978 (aliphatic -CH3

stretching), 2833(aliphatic -CH2 stretching), 2129(-C-N stretching), 1726(-C=O



stretching), 1522(-C=C- ring strain),1439,1364 (-C-H bending), 1314(-C-N stretching

tertiary amine), 1017(-C-O-C stretching), MS: m/z = 298 (M+),; % Anal. Calcd. for

C18H22N2O2: C, 72.46; H, 7.43; N, 9.39; O, 10.72.

4-(Ethylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-110)

Yield : 69% IR (cm-1): 3435(-N-H stretching), 3190,3051 (aromatic -C-H stretching),

2978 (aliphatic -CH stretching) , 2843 (aliphatic -CH2 stretching), 2119(-C-N

stretching), 1704 (-C=O stretching), 1616,1572 (-N-H bending), 1519(-C=C- ring

strain),1439,1384 (-C-H bending), 1244, (-C-N stretching secondary amine), 1020(C-

O-C stretching), MS: m/z: 214 (M+),; % Anal. Calcd. for C12H10N2O2: C, 67.28; H,

4.71; N, 13.08; O, 14.94.

4-(2-Methylpiperidin-1-yl)-2-oxo-2H-chromene-3-carbonitrile (BAJ-111)

Yield: 82% IR (cm-1): 3090, 3052 (aromatic -C-H stretching), 2988 (aliphatic –CH-

stretching), 2853 (Aliphatic -CH2 stretching), 2116(-C-N stretching), 1726 (-C=O


tertiary amine), 1081 (-C-H bending), 1011(-C-O-C stretching), MS: m/z = 268

(M+),; % Anal. Calcd. for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44; O, 11.93.

4-(Methylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-112)

Yield : 76% IR (cm-1): 3435(N-H stretching), 3190,3062 (aromatic -C-H stretching),

2998 (aliphatic –CH stretching), 2863 (aliphatic -CH2 stretching), 2126(-C-N

stretching), 1706 (-C=O stretching) 1616,1542 (-N-H bending), 1231, (-C-N

stretching secondary amine), 1024(-C-O-C stretching), MS: m/z = 200 (M+),; % Anal.

Calcd. for C11H8N2O2: C, 66.00; H, 4.03; N, 13.99; O, 15.98.

2-Oxo-4-(2-oxo-2,3-dihydro-1H-pyrrol-1-yl)-2H-chromene-3-carbonitrile (BAJ-

113)

Yield : 83% IR (cm-1): 3090, 3072 (aromatic -C-H stretching), 2998 (aliphatic -CH

stretching), 2873 (Aliphatic -CH2 stretching), 2115(-C-N stretching), 1742 (-C=O

stretching), 1489,1372 (-C-H bending), 1008(-C-O-C stretching), MS: m/z = 252


2-Oxo-4-(1H-pyrrol-1-yl)-2H-chromene-3-carbonitrile (BAJ-114)



Yield : 68% IR (cm-1): 3090,3072 (aromatic -C-H stretching), 2129(-C-N

stretching),1714 (-C=O stretching), 1518 (-C=C- ring strain), 1332(-C-N stretching

tertiary amine), 1258 (-C-H bending), 1031(-C-O-C stretching), MS: m/z = 236 (M+),;

% Anal. Calcd. for C14H8N2O2: C, 71.18; H, 3.41; N, 11.86; O, 13.55.

4-(Butylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-115)

Yield : 86% IR (cm-1): 3415(-N-H stretching), 3091, 3071 (aromatic -C-H

stretching), 2978 (aliphatic -CH stretching), 2872 (aliphatic -CH2 stretching), 2133(-

C-N stretching),1719 (-C=O stretching), 1616,1531 (-N-H bending), 1522(-C=C- ring

strain), 1488,1371 (-C-H bending), 1244, (-C-N stretching secondary amine), 1019(-

C-O-C stretching), MS: m/z = 242 (M+),; % Anal. Calcd. for C14H14N2O2: C, 69.41;

H, 5.82; N, 11.56; O, 13.21.

4-(Isobutylamino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-116)


stretching), 2988 (aliphatic -CH stretching), 2883 (aliphatic -CH2 stretching), 2123(-

C-N stretching),1736 (-C=O stretching), 1636,1522 (-N-H bending), 1479,1382(-C-H

bending), 1229, (-C-N stretching secondary amine), 1082(-C-H bending), 1012(-C-O-

C stretching), MS: m/z = 242 (M+),; % Anal. Calcd. for C14H14N2O2: C, 69.41; H,

5.82; N, 11.56; O, 13.21.

2-Oxo-4-(piperazin-1-yl)-2H-chromene-3-carbonitrile (BAJ-117)


stretching), 2988 (aliphatic -CH stretching), 2883 (aliphatic -CH2 stretching), 2116(C-

N stretching), 1722(-C=O stretching), 1636,1542 (-N-H bending), 1479,1382(-C-H

bending), 1219(-C-N stretching secondary amine), 1027(-C-O-C stretching), MS: m/z

= 255 (M+),; % Anal. Calcd. for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46; O, 12.54.

4-(Ethyl(phenyl)amino)-2-oxo-2H-chromene-3-carbonitrile (BAJ-118)

Yield : 82% IR (cm-1): 3091, 3082 (aromatic -C-H stretching), 2997(aliphatic -CH


stretching), 1499,1371(-C-H bending), 1028(-C-O-C stretching), MS: m/z = 290





Current chapter describes synthesis of 18 novel compounds characterized by

various spectroscopic data. The reaction of 4-chloro-3-formyl coumarin with

hydroxyl amine hydrochloride in presence of sodium acetate and acetic acid as a

solvent afforded target synthon, which on further reaction with primary/secondary

amines in presence of base yielded novel 3-cyano functionalize cumarin derivatives.

The yield of these compounds varies from 68-86 %.

3.12 CONCLUSION

The synthetic methodology adopted led to considerable inprovement in the

reaction product. The reaction product was obsereved as a 3-cyano derivative of

coumarin. the reaction of 4-chloro-3-formyl coumarin with hydroxyl amine

hdrochloride in the presence of sodium acetate and acetic acid afforded 4-chloro-3-

cyano coumarin. The reaction is facile, easy to worup procedure and convinient to

synthesize this class of molecules for biological interest.

However in presence of sodium acetate and ethanol under reflux condition the

reaction of 4-chloro-3-formyl coumarin with hydroxyl amine hdrochloride yields 2H-

[1] benzopyran [3,4-d] isoxazoles-2-one as reported in the prior art. 106

D

3 3

3

Chapter – 3

Department o

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1999, 54, 554.

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1999, 260, 682.

93. Wang, X., Ng, B.; Plant Med., 2001, 67, 669.

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95. Kaneko, T., Baba, N., Matsuo, M.; Cytotechnology, 2001, 35, 43

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2001, 24, 777.

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R.; J. Nat. Prod., 2001, 64, 861.

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Carotti, A.; Bioorg. & Med. Chem., 2003, 11, 123.



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Puglisi, G.; Drug Dev. Res., 2002, 57, 115.

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Lett., 2003, 13, 175.

106. Mulwad V.V., Hegde A.S.; Indian Journal of Chemistry, 2009, 48B, 1558.

R

CCCRapid

4-(1-pyd

CCCHHHsynth

-phenyyrazol

dihydr

HHHAAAPPPhesis oyl, 3(sle-4-y

ropyri

PPPTTT

of 5-(susubsti

yl)-2,6dine-3

TTTEEERRRubstitituted)6-dime3-carb

RRR---tuted))phenethyl-1bonitr

-444 benzo

nyl-1H1,4-riles

oyl-H-

Chapter – 4 Rapid synthesis of Dihydropyridine derivatives


4.1 INRODUCTION

Dihydropyridines are the largest and most studied class of drugs calcium

channel blocker. In addition to their proven clinical utilities in cardiovascular

medicine, dihydropyridines are employed extensively as biological tools for the study

of voltage-activated calcium channel.

Many 1,4-dihydropyridine derivatives have been synthesized and developed as

calcium channel antagonists which inhibit smooth and cardiac muscle contractions

blocking the influx of Ca+2 through calcium channels and antihypertensive action .


Recently much effort has been expended to develop more efficient methods

for the preparation of 1,4-DHPs such as using microwave1, metal triflates as catalyst2,

reaction in ionic liquid3, p-TSA4, HY-Zeolite5, and HClO4 -SiO26. 1,4-DHPs are

synthesized by the Hantszch method, which involves cyclocondensation of aldehyde,

β-ketoester, and ammonia either in acetic acid at room temperature or refluxing in

alcohol for a long time.

Joshi et al.7 has used molecular iodine as a catalyst for the preparation of 1,4-

dihydropyridine. Molecular iodine8-11 has attracted attention as an inexpensive, non

toxic, readily available catalyst for various organic transformations to afford the

corresponding products in excellent yields with high selectivity. It has been used as a

mild Lewis acid in the dehydration of tertiaryalcohols to alkenes, in the formation of

ethers, as well as β-keto enol ethers,12-14 for esterification,15 transesterification,16

acetylation9 and benzothiophene17 formation, but there are only a few reports about its

use for the synthesis of 1,4-DHPs. Its use for the synthesis of 1,4-DHPs.18-19



Xin Ying Zhang et al.20 developed an efficient and green method for the

synthesis of 1, 4-dihydropyridine derivatives mediated in an ionic liquid,

[bmim][BF4], through a four-component condensation process of aldehydes, 1, 3-

dione, Meldrum’s acid and ammonium acetate.

R CHOO O

O

OO

O

NH4OAC

[bmim][BF4]

NH

RO

O

By this investigation they showed that not only aromatic aldehydes, but also

heterocyclic and aliphatic aldehydes could undergo the above reaction effectively to

afford the corresponding products in good yields.

Furthermore, 1, 3-cyclohexanedione and an acyclic 1, 3-dione, pentane-2, 4-

dione were also tried in place of 5, 5-dimethyl-1, 3-cyclohexanedione for this multi-

component condensation process, respectively and it also gives the good results in

preparation of DHP.



Nandkishor et al.21 found that L-Proline has been found as an effective catalyst

for the one pot synthesis of polyhydroquinoline derivatives via four component

Hantzsch reaction. This method provides several advantages such as being

environmentally benign, possessing high yields with increased variations of the

substituents in the product and preparative simplicity.

CHO

R

O

O

O

OC2H5

O

NH4OACL-proline(Cat)

Ethanol,ref lux

NH

O

OC2H5

O

Many MCR for synthesis of DHP and it’s aza analog dihydropyridines are

revieved by several authors.22 The multicomponent reaction often affords the target

compounds in good yields and this experimental method remains the most widely

used protocol to access to 1,4-DHP differently substituted in position 4. Some

modified procedures have later been proposed and they involve the use of preformed

Knoevenagel adducts between the aldehyde and the keto ester or the use of preformed

enaminoesters (represented in the E form to clarify the scheme).



The Unsymmetric23-27 3-cyano-5-carboxy ester 1,4-diydrpyridine was

prepared by condensation of aldehyde, 3-aminocrotononitrile with alkyl 3-

aminocrotonate.

CHO

R H3C

NH2

CN H3C

NH2

COOR1

NH

NC

H3C

COOR1

CH3

H

R

The other methods for the preparation28 of unsymmetric cyano 1,4-

dihydropyridine are reported as under.

Two different routes of synthesis in single step are reported29 for 3-cyano

ethoxycarbonyl-2,6-dimethyl-4-(2-trifluromethyl phenyl)-1,4-dihydropyridine.Firstly,

the condensation of aldehyde with ethyl-3-aminocrotonate and 2-cyanoethyl-3-

oxobutanoate. In another method, the condensation of ethyl-2-(2-triflouromethyl

phenyl benzylidene ) acetoacetate was carried out with 2-cyanoethyl(2Z)-3-aminobut-

2-enoate.



CHOCF3

H3C

NH2

COOC2H5

O

O

OCN

NH

CF3H3CH2COOC COOCH2CH2CN

CH3H3C

CF3

O

C2H5OOCH3C

NH2

COOCH2CH2CN

Bossert et al.30 have prepared anti-inflammatory agents such as 2-amino-3-

benzoyl cyano-1,4-dihydropyridine.

Scoane et al.31 reported a facile method for synthesis of 3,5-dicyano-2,6-

diphenyl-1,4-dihydropyridine(compound-1).When 3,5-dicyano-6-aminopyran was

reacted with ammonium acetate in acetic acid gave the. While 3-cyano-5-carethoxy-6-

aminopyran afforded to give fully aromatized pyridine.



Berson et al.32 reported earlier for first time the synthesis of a quinoline

containing unsymmetrical compound 4-(4-quinolyl)-2,6-dimethyl-3-carbethylxy-5-

acetyl-1,4-dihydropyridne.

Bossert et al.33 also put in their efforts to preparing coronary dilator and

antihypertensive 1,4-dihydropyridines containing a quinoline group at C4 position.

Ethyl 2-amino-4-(4-quinolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate have

been prepared by the cyclization of 1,3-cyclohexanedione with aldehyde and CH3-

CH2-CH2-C(NH)-NH2.

Other unsymmetric 2,6-diamino-4-(4-quinolyl)-1,4-dihydropyridine was

synthesized by a different route.34



Sachio et al.35 prepared antihypertensive 1,4-dihydropyridine containing a

benzo furazanyl moiety at C4 Position.

Ozbey et al.36 synthesized some 1,4-dihydropyridine derivatives containing

the flavones ring system.

4.3 PHARMACOLOGY

1,4-DHPs posses different pharmacological activities such as antitumor,37

vasodilator,38 coronary vasodilator and cardiopathic,39 antimayocardiac ischemic,

antiulcer,40 antiallergic,41 antiinflammatory42 and antiarrhythmic,43 PAF antagonist,44

Adenosine A3 receptor antagonist45 and MDR reversal activity.46

In particular, DHP-CA (calcium channel antagonist DHP) are extensively used

for the treatment of hypertension,47 subarachnoid hemorrhage,48-49 myocardial

infarction50-53 and stable54-55 and unstable angina56-57 even though recently their

therapeutic efficacy in myocardial infarction and angina has been questioned.58 This

class of compounds is also under clinical evaluation for the treatment of heart

failure,59 ischemic brain damage62 nephropathies and atherosclerosis.61



4.4 SOME DRUGS FROM 1,4-DIHYDROPYRIDINES NUCLEUS 37-41

4.5 PYRAZOLS : A VERSATILE SYNTHON

Pyrazole refers both to the class of simple aromatic ring organic compounds of

the heterocyclic series characterized by a five-membered ring structure composed of

three carbon atoms and two nitrogen atoms in adjacent positions and to the



unsubstituted parent compound. Being so composed and having pharmacological

effects on humans, they are classified as alkaloids, although they are rare in nature.

The synthesis of pyrazoles remains of great interest owing to the wide

applications in pharmaceutical and agrochemical industry due to their herbicidal,

fungicidal, insecticidal, analgesic, antipyretic and anti-inflammatory properties62-63.

Some methods have been developed in recent years, though the most important

method is the reaction between hydrazones and β-dicarbonyl compounds64 This

reaction involves the double condensation of 1, 3-diketones or α, β-unsaturated

ketones with hydrazine or its derivatives.65-66 However, the appealing generality of

this method is somewhat vitiated by the severe reaction conditions or the multistep

sequences usually required to access the starting materials.67 Thus, continuous efforts

have been devoted to the development of more general and versatile synthetic

methodologies for this class of compound.68

The application of Vilsmeier–Haack (VH) reagent (POCl3 / DMF) for

formylation of a variety of both aromatic and heteroaromatic substrates is well

documented.69 Besides this, the reagent has also been extensively used for effecting

various chemical transformations from other classes of compounds. Many of these

reactions have led to novel and convenient routes for the synthesis of various

heterocyclic compounds.70 A notable example that finds significant application in

heterocyclic chemistry is the synthesis of 4-formylpyrazoles from the double

formylation of hydrazones with Vilsmeier-Haack (VH) reagent.71-72 These



observations, coupled with the recent developments on the simple synthesis of

pyrazole derivatives,73 especially 4-functionalized 1,3-diphenylpyrazoles as

antibacterial, anti-inflammatory,74-75 antiparasitic76 and antidiabetic77 drugs,

prompted chemistry research to undertake the synthesis of pyrazole-4-carboxldehyde

derivatives using Vilsmeier-Haack (VH).78-79 The study is particularly aimed at

developing a one-pot synthesis of pyrazole-4-carboxaldehyde oximes starting from

acetophenone phenylhydrazones.




The aim of current work was to prepare the dihydropyridine which have a

hybrid ‘motif’ where at C3- position possess a cyano group, while at C5 position

various benzophenone groups are present. This will ultimately give structural and

molecular diversity of unsymmetric nature.



4.7 REACTION SCHEMES 4.7.1 PREPARATION OF PYRAZOLE ALDEHYDES: STEP – 1

Reagents / Reaction Condition (a): Glacial acetic acid, Ethanol / Reflux, 5-6 hours.

STEP – 2

Reagents / Reaction Condition (b): DMF – POCl3 / 70-80°C, 5-6 hours.

4.7.2 PREPARATION OF ASYMMETRIC 1,4-DIHYDROPYRIDINES:

Reagents/ Reaction Condition (c): α-diketo comounds, Glacial Acetic acid / 60-70°C,

1 h







in Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were

recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe

technique. 1H NMR was determined in CDCl3/DMSO solution on a Bruker Ac 400

MHz spectrometer. Elemental analysis of the all the synthesized compounds was

carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are in

agreements with the structures assigned.

4.9.2 PREPARATION OF PYRAZOLE ALDEHYDE : PREPARATION OF PYRAZOLE ALDEHYDE: GENERAL METHOD

STEP – 1: PREPARATON OF ACETOPHENONE PHENYL HYDRAZONES.

Appropriately substituted Acetophenone (0.1 mol) was dissolved in 50 ml of

ethanol into 250 ml R.B.F. Phenyl hydrazine (0.1 mol) was added to above flask

along with 3-4 drops of glacial acetic acid. The reaction mixture was stirred for 1

hours at room temperature. The progress and the completion of reaction was

monitored by TLC using ethyl acetate : hexane (6 :4 ) as a mobile phase. After the

completion of the reaction, the reaction mixture was kept to room temperature for 1 h

and the crystalline product was filtered, washed with ethanol and dried at room

temperature to give substituted acetone phenyl hydrazone in good yield which was

pure enough to use as such for the next step. The Physical constants of newly

synthesized compounds were compared with the standard data. 80

STEP – 2 PREPARATION OF PYRAZOLE ALDEHYDES

Dimethylformamide (0.32 mol) was transferred into 25 ml flat bottom flak.

Phosphorous oxychloride (0.032 mol) was added under controlled rate under stirring

so that temperature does not rise above 5°C. After complete addition, the mixture



was raised to temperature and allow it to stir for 10-15 min. Freshly prepared

acetophenone hydrazone 0.03 mole was added to above mixture and the content was

heated on water bath for 5-6 hours. The progress and the completion of reaction was

monitored by TLC using toluene: ethyl acetate (6: 4) as a mobile phase. After the

completion of the reaction, mixture was cooled to room temperature and the content

of the flask was poured on crushed ice to isolate the product. The separated product

was filtered and washed with 1L cold water to remove complete acidity. It was

further dried at 65°C and recrystallized from the mixture of DMF-Methanol to give

crystalline pyrazole aldehyde in good yield. The Physical constants of newly

synthesized compounds were compared with the standard data. 80

4.9.3 PREPARATION OF 5-CYANO-4-(1-PHENYL, 3(SUBSTITUTED)

PHENYL-1H-PYRAZOL-4-YL)-2,6-DIMETHYL-1,4-

DIHYDROPYRIDINE-3-CARBOXYLATES.

A mixture of pyrazole aldehyde (0.01 mol), and α-diketo compound (0.01

mol) in 10 ml glacial CH3COOH was added 3-amino crotononitrile (0.01 mol) under

stirring condition at 60-70°C. Addition of 3-amino crotononitrile was performed at a

very slow rate to avoid generation of unnecessary impurities. The reaction was

continued for 1 h. The solid precipitates were filtered and washed with glacial acetic

acid and further washed with hexane to yield desired compounds.

The Physical constants of newly synthesized compounds are given in Table No.1



4.10 PHYSICAL DATA

4.10.1 Physical data of 5-Cyano-4-(1-phenyl, 3(Substituted)phenyl-

1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3-

carboxylates.

NN R

NH

CH3H3C

CNR1

O

TABLE – 1

Code

Substitution

MP OC

Rf Value

R R1BAJ-501 C6H5 CH3 220-222 0.50 BAJ-502 C6H5 CH2-Cl 198-200 0.49 BAJ-503 C6H5 C6H5 178-200 0.47 BAJ-504 C6H5 4-F-C6H4 186-188 0.43 BAJ-505 C6H5 2,4-di-Cl- C6H3 202-204 0.44 BAJ-506 2-OMe-C6H4 CH3 166-168 0.45 BAJ-507 2-OMe-C6H4 CH2-Cl 208-210 0.44 BAJ-508 2-OMe-C6H4 C6H5 222-224 0.48 BAJ-509 2-OMe-C6H4 4-F-C6H4 238-240 0.43 BAJ-510 2-OMe-C6H4 2,4-di-Cl- C6H3 214-216 0.48 BAJ-511 2-OH- C6H5 CH3 228-230 0.45 BAJ-512 2-OH-C6H4 CH2-Cl 232-234 0.39 BAJ-513 2-OH-C6H4 C6H5 218-220 0.48 BAJ-514 2-OH-C6H4 4-F-C6H4 214-216 0.47 BAJ-515 2-OH-C6H4 2,4-di-Cl- C6H3 196-198 0.48





4.11.1 IR SPECTRA




The characteristic bands of -OH groups were obtained for streching at 3400-

3650 cm-1 and those for bending were obtained at 1050-1250 cm-1.The stretching

vibrations N-H group showed in the region of 3200 to 3500 cm-1 with a deformation

due to in plane bending at 1650-1580 cm-1. It gives aromatic C-H stretching

frequencies between 3000-3200 cm-1 and bending vibration near 1300-1500 cm-1

respectively. C-H stretching frequencies for methyl and methylene group were

obtained near 2950 cm-1 to 2850 cm-1. Characteristic frequency of C-N stretching

showed near 2100-2300 cm-1 and bending vibration near 1250-1400 cm-1.

4.11.2 MASS SPECTRA




Fragmentation pattern can be observed to be particular for these compounds and the

characteristic peaks obtained for each compound.

















were in the agreement of the structure of the molecule. Aliphatic carbon was

observed between 15-25 δ ppm and aliphatic keto carbon at 30-40 δ ppm, while

aliphatic carbon attached to hetero group was observed at 60-65 δ ppm. Aromatic

carbon was observed between 115-140 δ ppm while aliphatic keto carbon was

observed at 158-160 and aromatic keto carbon was observed at 190-195 δ ppm.

Aromatic carbon attached to hetero atom was observed at 155-157 δ ppm.




5-Acetyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3-

carbonitrile (BAJ-501)

Yield: 79% IR (cm-1): 3489,3367 (-N-H stretching), 3198(aromatic -C-H stretching),

2974 (aliphatic –CH stretching), 2875(-C-H stretching tertiary), 2260,2332(-C-N

stretching), 1707(-C=O stretching), 1660-1587(-N-H bending), 1519,1435,1356(-C-

H bending), 1291(-C-N stretching), MS: m/z = 394 (M+); % Anal. Calcd. for

C25H22N4O: C, 76.12; H, 5.62; N, 14.20; O, 4.06.

5-(2-Chloroacetyl)-4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-

dihydropyridine-3-carbonitrile (BAJ-502)

Yield : 79 % IR (cm-1): 3469,3307(-N-H stretching), 3191(aromatic -C-H stretching),

2984 (aliphatic -CH stretching), 2891(-C-H stretching tertiary), 2857(aliphatic -CH2

stretching), 2250,2312(-C-N stretching), 1727(-C=O stretching), 1650-1577(-N-H

bending), 1509,1455, 1366(-CH bending), 1279(-C-N stretching), 749(-C-Cl

stretching), MS: m/z = 428 (M+), 430 (M+2) % Anal. Calcd. for C25H21ClN4O: C,

70.01; H, 4.93; Cl, 8.27; N, 13.06; O, 3.73.

5-Benzoyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3-

carbonitrile (BAJ-503)


2984 (aliphatic-CH stretching), 2884(-C-H stretching tertiary), 2262,2342(-C-N

stretching), 1707(-C=O stretching), 1662-1587(-N-H bending), 1380(-C-H bending),

1288(-C-N stretching), MS: m/z = 456 (M+); % Anal. Calcd. for C30H24N4O: C,

78.92; H, 5.30; N, 12.27; O, 3.50.

4-(1,3-Diphenyl-1H-pyrazol-4-yl)-5-(4-fluorobenzoyl)-2,6-dimethyl-1,4-



2954 (aliphatic -CH stretching), 2894(-C-H stretching tertiary), 2240,2342 (-C-N

stretching), 1717(-C=O stretching), 1669-1581 (-N-H bending), 1396 (-C-H bending)

,1272 (-C-N stretching), 1107(-C-F stretching) 689 (monosubstituted) MS: m/z = 474



(M+), 475 (M+1); % Anal. Calcd. for C30H23FN4O: C, 75.93; H, 4.89; F, 4.00; N,

11.81; O, 3.37.

5-(2,4-Dichlorobenzoyl)-4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-


Yield : 81 % IR (cm-1): 3489,3367 (-N-H stretching), 3198 (aromatic -C-H

stretching), 2974 (aliphatic –CH stretching), 2888(-C-H stretching tertiary),

2260,2332 (-C-N stretching), 1707(-C=O stretching), 1660-1587 (-N-H bending),

1356 (-C-H bending) , 1282(-C-N stretching), 801(-C-Cl stretching), 744

(disubstituted), MS: m/z = 525 (M+), 527 (M+2); % Anal. Calcd. for C30H22Cl2N4O: C,

68.58; H, 4.22; Cl, 13.49; N, 10.66; O, 3.05.

5-Acetyl-4-(3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-


Yield : 83 % IR (cm-1): 3253(-N-H stretching), 3132(aromatic -C-H stretching), 2918

(aliphatic -CH stretching), 2841(-C-H stretching tertiary), 2196(-C-N stretching),

1712(-C=O stretching), 1658-1537(-N-H bending), 1597, 1537(-C=C- ring strain),

1454,1411,1350 (-C-H bending), 1247(-C-N stretching), 1159(-C-O-C stretching),

692(monosubstituted), 1H NMR (DMSO-d6) δ ppm: 6H, s (1.84), 3H, s (3.34), 3H, s

(3.72), 2H, m (7.08-6.99), 1H, s (4.33), 2H, m (7.08-6.98), 1H, d (7.24-7.21, J=7.2),

1H, t (7.32-7.27), 1H, t (7.42-7.38), 2H, t (7.52-7.48), 2H. d (7.89-7.87, J=7.8), 1H, s

(8.52), 1H, s (9.11), 13C: 17.62, 31.37, 55.03, 82.08, 110.65, 117.74, 119.39, 121.63,

126.05, 126.94, 129.53, 129.94, 131.61, 139.37, 146.14, 149.19, 157.00, 191.10.

MS: m/z = 424 (M+); % Anal. Calcd. for C26H24N4O2: C, 73.56; H, 5.70; N, 13.20; O,

7.54.

5-(2-Chloroacetyl)-4-(3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-

dimethyl-1,4-dihydropyridine-3-carbonitrile (BAJ-507)


2934 (aliphatic -CH3 stretching), 2889(-C-H stretching tertiary), 2843 (aliphatic -CH2

stretching), 2261,2331 (-C-N stretching), 1717(-C=O), 1661-1577 (-N-H bending),

1518,1445,1354 (-C-H bending), 1283(-C-N stretching), 1187(-C-O-C stretching),

722(-C-Cl stretching), 689(monosubstituted), MS: m/z = 458. (M+), 460 (M+2); %

Anal. Calcd. for C26H23ClN4O2: C, 68.04; H, 5.05; Cl, 7.72; N, 12.21; O, 6.97.



5-Benzoyl-4-(3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-


Yield : 69 % IR (cm-1): 3509,3357(-N-H stretching), 3190(aromatic -C-H

stretching), 2984 (aliphatic -CH3 stretching), 2898(-CH stretching tertiary), 2261,2330

(-C-N stretching), 1717(-C=O stretching), 1661-1589 (-N-H bending),

1518,1434,1354 (-C-H bending),`1281 (-C-N stretching), 1193(-C-O-C stretching),

689 (monosubstituted), MS: m/z = 486 (M+); % Anal. Calcd. for C31H26N4O2: C,

76.52; H, 5.39; N, 11.51; O, 6.58.

5-(4-Fluorobenzoyl)-4-(3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-


Yield : 78 % IR (cm-1): 3479,3368(-N-H stretching), 3188(aromatic -C-H

stretching), 2978 (aliphatic -CH stretching), 2887 (-CH stretching tertiary), 2250,2342


1529,1425,1346 (-C-H bending) ,1272 (-C-N streching), 1186(-C-O-C stretching),

1109(-C-F stretching), 689 (monosubstituted), MS: m/z = 504 (M+), 505 (M+1); %

Anal. Calcd. for C31H25FN4O2: C, 73.79; H, 4.99; F, 3.77; N, 11.10; O, 6.34.

5-(2,4-Dichlorobenzoyl)-4-(3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-

dimethyl-1,4-dihydropyridine-3-carbonitrile) (BAJ-510)

Yield : 79 % IR (cm-1): 3489,3389(-N-H stretching), 3159(Aromatic -C-H

stretching), 2979 (aliphatic -CH stretching), 2879(-CH stretching tertiary), 2288,2332


1529,1455,1356 (-C-H bending) ,1282 (-C-N stretching), 1180(-C-O-C stretching),

791(-C-Cl stretching), 749 (disubstituted), 687 (monosubstituted), MS: m/z = 555

(M+), 557 (M+2); % Anal. Calcd. for C31H24Cl2N4O2: C, 67.03; H, 4.36; Cl, 12.77; N,

10.09; O, 5.76.

5-Acetyl-4-(3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-


Yield : 89 % IR (cm-1): 3612(O-H stretching), 3583,3566(-N-H stretching),

3198(aromatic -C-H stretching), 2974 (aliphatic -CH stretching), 2897(-C-H stretching

tertiary), 2245(-C-N stretching), 1707(-C=O stretching), 1660-1587 (-N-H bending),

1519,1435,1356 (-C-H bending), 1240 (-C-N stretching), 1107(O-H bending),



744(disubstituted), 688(monosubstituted), 1H NMR (DMSO-d6) δ ppm: 6H, s (1.86),

3H, s (3.38), 1H, s (4.48), 1H, t( 6.87-6.84, J=7.2), 1H. d (6.93-6.91, J=7.8), 2H, t

(7.23-7.19), 1H, t (7.32-7.27), 2H, t (7.93-7.87), 1H , s (8.51), 1H d (9.14-9.10), 1H, s

(9.61), 13C: 17.67, 21.11, 26.82, 31.28, 82.02, 107.47, 115.28, 115.77, 116.25, 117.75,

118.38, 119.56, 119.79, 126.04, 126.32, 127.00, 128.00, 128.88, 129.56, 129.91,

131.10, 131.45, 138.62, 139.40, 154.78, 146.34, 149.74, 154.85, 155.48, 193.18. MS:

m/z = 410 (M+); % Anal. Calcd. for C25H22N4O2: C, 73.15; H, 5.40; N, 13.65; O, 7.80.

5-(2-Chloroacetyl)-4-(3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-


Yield : 81 % IR (cm-1): 3609(O-H stretching), 3459,3377 (-N-H stretching), 3058

(aromatic -C-H stretching), 2976 (aliphatic -C-H stretching), 2899(-C-H stretching

tertiary), 2828(aliphatic -CH2 stretching), 2261,2322 (-C-N stretching), 1727(-C=O

stretching), 1689-1588 (-N-H bending), 1539,1435,1343(-C-H bending), 1273(-C-N

bending), 1234,1101(O-H bending), 738(disubstituted), 679 (monosubstituted), MS:

m/z = 444 (M+), 446 (M+2); % Anal. Calcd. for C25H21ClN4O2 C, 67.49; H, 4.76; Cl,

7.97; N, 12.59; O, 7.19.

5-Benzoyl-4-(3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-


Yield : 78 % IR (cm-1): 3611(OH stretching), 3479,3347(-N-H stretching),

3108(romatic -C-H stretching), 2974(aliphatic -C-H stretching), 2897(-C-H stretching

tertiary), 2260,2332(-C-N stretching), 1707(-C=O stretching), 1660-1587 (-N-H

bending), 1519,1435,1356 (-C-H bending) ,1282(-C-N stretching), 1240,1107(-OH

bending), 788(-C-Cl stretching), 744 (disubstituted), 688(monosubstituted, MS: m/z =

472 (M+); % Anal. Calcd. for C30H24N4O2: C, 76.25; H, 5.12; N, 11.86; O, 6.77.

5-(4-Fluorobenzoyl)-4-(3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-



3118(aromatic -C-H stretching), 2984 (aliphatic -C-H stretching), 2887 (-C-H

stretching tertiary), 2261,2342 (-C-N stretching), 1717(-C=O stretching), 1661-1581

(-N-H bending), 1518,1445,1346 (-C-H bending) ,1281 (-C-N stretching), 1241,1117

(-OH bending), 1108(-C-F stretching). 689 (monosubstituted), MS: m/z = 490 (M+),



491 (M+1); % Anal. Calcd. for C30H23FN4O2: C, 73.46; H, 4.73; F, 3.87; N, 11.42; O,

6.52.

5-(2,4-Dichlorobenzoyl)-4-(3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-



3101(aromatic -C-H stretching), 2970 (aliphatic -C-H stretching), 2890 (-C-H

stretching tertiary), 2261,2322 (-C-N stretching), 1707(-C=O stretching), 1669-

1586(-N-H bending), 1509,1425,1326(-C-H bending) ,1283(-C-N bending),

1241,1117(-OH bending),799(-C-Cl stretching), 745(disubstituted), 685

(monosubstituted), MS: m/z = 541 (M+), 543 (M+2); % Anal. Calcd. for

C30H22Cl2N4O2: C, 66.55; H, 4.10; Cl, 13.10; N, 10.35; O, 5.91.




This chapter deals with the preparation of asymmetric dihydropyridine by

three component reaction by modifying general conventional methodologies. Ethyl

acetoacetate/Methyl acetoacetate, methyl 3-aminocrotonate and Pyrazole aldehydes

have been employed to synthesize these DHPs. Under normal conditions, the DHPs

were prepared by refluxing the aldehydes, 3-aminocrotononitrile and Methyl

acetyoacetate/Ethyl acetoacetate more than 10 hrs.

4.14 CONCLUSION

In this chapter, along with yield optimization of the 1,4-Dihydropyridines,

simple, easy and fast method was adopted. Exploration of unreported compounds and

their biological activity was the aim behind the work done in this chapter.

Ch

D

4 4

4

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4.16 REFERENCES

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C. W. Rees; E. F. V. Scriven, Eds.; Pergamon Press: Oxford, 1996, 1.

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80. Thakrar S,; Ph.D. Thesis, Saurashtra University 2010.

CCCSynth

met

CCCHHHhesis othylche][1,4

HHHAAAPPPof 8-((hrome4]diaz

PPPTTT

(substeno[3,zepin-

TTTEEERRRtituted,4-b] t6(12H

RRR---d)aminthienoH)-one

---555 no)-10o[2,3-es

0-

Chapter – 5 Synthesis of diazepine derivatives


5.1 INRODUCTION

The clinical importance and commercial success associated with the 1,4-

benzodiazepine class of central nervous system (CNS)-active agents and the utility of

1,4-diazepines as peptidomimetic scaffolds have led to their recognition by the

medicinal chemistry community as privileged structures. This ring system has

demonstrated considerable utility in drug design, with derivatives demonstrating a

wide range of biological activities.

On the other hand, examples of the serendipitous discovery of new drugs

based on an almost random screening of chemicals synthesized in the laboratory are

striking. Since 1960, when chlordiazepoxide (Librium) entered in the market, efforts

to discover new biologically active compounds with limited side effects in

benzodiazepines are going on which are reflected by the important number of

publication focused in this subject.1-5

Among all types of benzodiazepines (1,2-,1,3-, 1,4-, 1,5-, 2,3-, & 2,4- ) only

1,4- and 1,5-benodiazepines have found wide applications in medicines, during one of

the most important classes of the therapeutic agents with wide spread biological

activities6 including hypnotics, sedatives, anxiolytics and antianxiety etc., effect range

from their well-documented anticonvulsive or tranquilizing properties, through

pesticidal7 or antitumor8 action and to their more recently described peptidomimetic

activity. 9

The cyclic amidines represent an important functional group in medicinal

chemistry and can be found in many natural products or FDA-approved drugs, e.g. the

antipsychotic clozapine and loxapine. Moreover, substituted amidines are useful

intermediates in the synthesis of many heterocyclic compounds. 10 The most common

and convergent strategies for amidine synthesis are based on the addition of amines to

activated amide intermediates, e.g. imido ester, 11 imidoyl chloride12 or o-triflated

imidate. 13 In 1969, Fryer et al reported a one-step method for the preparation of

cyclic amidines from amides using titanium tetrachloride complex. 14 Clozapine was

originally synthesized in 1960s by Sandoz-Wander Ltd based upon a structural

similarity to the tricyclic antidepressant, but it showed unexpectedly a high

antipsychotic activity that lead to a new class of antipsychotic drug useful in the

treatment of schizophrenia.



Diazepine derivatives constitute an important class of heterocyclic compounds

which possess a wide range of therapeutic and pharmacological properties.

Derivatives of benzodiazepines are widely used as anticonvulsant, antianxiety,

analgesic, sedative, anti-depressive, and hypnotic agents15, 16 as well as anti-

inflammatory agents. 17 In the last decade, the area of biological interest of 1,5-

benzodiazepines has been extended to several diseases such as cancer, viral infection

and cardiovascular disorders.18,19 In addition, 1,5-benzodiazepines are key

intermediates for the synthesis of various fused ring systems such as triazolo-,

oxadiazolo-, oxazino- or furanobenzodiazepines.20-23 Besides, benzodiazepine

derivatives are also of commercial importance as dyes for acrylic fibers in

photography. 24

From the standpoint of biological activity, fused heteroaromatic systems are

often of much greater interest than the constituent monocyclic compounds. Recently,

the thienodiazepine system has been studied extensively. They have been tested

clinically as an anxiolytic and hypnotic.25 Recently, there has been considerable

interest in hetero[1,4]diazepine with an additional ring fused to the seven-member

ring, structurally analogues to the a-face-fused 1,4-benzodiazepines.


Sayed et al 26 has synthesized 5,7-dimethyl-5H-benzo[2,3][1,4]diazepino[6,5-

c]quinolin-6(13H)-one (2) by the reaction of 3-acetyl-4-hydroxy-1-methylquinolin-

2(1H)-one and o-phenylenediamine.

Ghosh and Khan27 report the reaction of 3-formylchromones with o-

phenylenediamine. The benzo[b]chromeno[2,3-e][1,4]diazepin-13(6H)-one was

prepared in two step as shown below.



o-Phenylenediamine undergoes 1,2-addition to the nitrile functions of 3-

nitrilechromone to form intermediate amidines, which on further cyclization and

subsequent air oxidation afforded 6-amino-7-oxo-7H-[l]benzopyrano[2,3-b]-

[1,5]benzocliazepines. 28

Reaction of 4-chloro-3-(l-chlorovinyl)-6-methyl-2H-pyran-2-one with o-

phenylenediamine gives pyranobenzodiazepine in the presence of Et3N in 98% EtOH

under reflux condition. 29

4-hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one were treated with carbon

disulfide in dimethyl sulfoxide in the presence of a catalytic amount of pyridine to

yield the novel condensed benzodiazepin-2-thione. In this case, ring closure

exclusively proceeded by intramolecular nucleophilic attack of the double bond of the

pyrone moiety on the isothiocyanate intermediate and not through nitrogen, which

would give benzoimidazole-2-thione derivatives.30



The reaction 3-nitro-4-chlorocoumarin with anthranilic acid gave 3-nitro-4-(2-

carboxyphenyl)coumarin. Which was hydrogenated in alcohol over Pd/BaSO4 under

the usual conditions to give 3-amino-4-(2-carboxyphenyl)coumarin; the latter was

cyclized to benzo[e]chromeno[3,4-b][1,4]diazepin-6(13H)-one by refluxing in

concentrated hydrochloric or glacial acetic acid.31

The reaction of 3-nitro-4-chlorocoumarin with anthranilic acid was used to

synthesize N-(3-nitro-4-coumarinyl)-anthranilic acid, from which, through the acid

chloride, obtained a number of amides, which were reduced to N-(3-amino-4-

coumarinyl)anthranilic acid amides. The latter are cyclized under the influence of

hydrochloric acid to 6,7,8,13-tetrahydro[l]benzopyrano-[4,3-b][l,4]benzodiazepine-

6,8-dione (Scheme 5.7), which was also obtained from N-(3-amino-4-

coumarinyl)anthranilic acid by its thermolysis or treatment with hydrochloric acid.32



O O

ClNO2

+H2N

HO2C

O O

HNNO2

HO2C

O O

HNNO2

ClOC

O O

HNNO2

R1RNOC

O O

HNNH2

R1RNOC

O

HNNH

O

O

SOCl2

HNRR1

[H]H+

Scheme 5.7

4-Azido-3-coumarincarbaldehydes are useful starting materials for syntheses

of a variety of 3,4-disubstituted coumarins as well as heterocyclic [c]-fused

coumarins, e. g. isoxazoles, pyrazoles and 1,5-diazepines, under mild conditions.33

The reaction of 4-Azido-3-coumarincarbaldehydes with o-phenylenediamine to

afford benzo[e]chromeno[3,4-b][1,4]diazepin-6(13H)-one.

4-Chloro-3-coumarincarbaldehyde or 4-azido-3-coumarincarbaldehyde were

converted into 1,4-benzodiazepines by nucleophilic substitution with diamines and

subsequent cyclization with good yields.34



O O

OH

O O

Cl

O O

N3

O O

HN N

YX

X

YH2N

H2N R

R

X

YH2N

H2N R

acetone-water

NaN3 +

DMF

Et3N/EtOH, reflux

R=H, CH3; X=C, N; Y=C, N

OO

POCl3

DMF

The 6-formylfurocoumarin derivative were reacted with o-phenylene-diamine

in EtOH and the resulting imines which underwent intramolecular cyclocondensation

reaction using acetic acid gave the corresponding benzodiazepine derivative.35

OO O

CHOOH

O

O

H2N

H2N

OO O

OH

O

O N

H2N

OO OO

O HN N

AcOHreflux

(25)

+

5.3 REPORTED SYNTHETIC STRATEGIES FOR THE PIPERAZINYL DERIVETIVES OF BENZO- AND THIENODIAZEPINES

Different synthetic pathways are generally used to convert lactams or

aminoesters into the amidine group. The diazepines were synthesized by reacting the

corresponding diazepinone derivatives with an appropriate amine in the presence of

TiCl4 and anisole according to modified Fryer’s method.36 The diazepinones were also

converted into the corresponding thiones that after reaction with an amine gave the

desired amidine. Oxa- and thiazepine analogues were obtained following another

approach. Lactams were treated with an excess of phosphorus oxychloride in



refluxing toluene to give iminochlorides which directly reacted with an excess of the

desire amine to give the appropriate amidines.

The tricyclic ring has been differently modified during 1980s. Replacement of

the central heteroatom NH was made by classical isosteric substitution (O, S, and

CH2). This modification generates products with a strong central depressant activity.

37, 38 The partial replacement of nitrogen atom in the seven member rings provided a

potent alternative to clozapine, fluperlapine.39 The compound was synthesized from

the amide converted to the iminochloride which was treated with N-methylpiperazine.

An alternative approach was an intramolecular dehydration of amide.

Bioisoteric replacement of the distal benzene rings is largely intended to

improve the pharmacological profile and/or the bioavailability, but mainly to reduce

toxicological problems. Thiophene rings have been incorporated in different tricyclic

nuclei. The introduction of a heterocycle in the tricyclic structure generally provides



two chemical series according to the lactam position (-[1,4]- and -[1,5]- analogues). In

these series of compounds, a lot of benzodiazepine analogues have mainly been

synthesized.

Thieno[2,3-b][1,5]benzodiazepines

Such compounds were synthesized by condensation of halogenonitrobenzene

(2-fluoronitro, 2,5-difluoronitrobenzene) with thiophene amino ester (ethyl-2-amino-

5-methylthiophene-3-carboxylate). The nitroanilinothiophene derivative was then

reduced by catalytic hydrogenation to the orthophenelynediamine analogue. The

cyclization by means of NaH in DMSO afforded the corresponding lactam which was

condensed with N-methylpiperazine using Fryer's Procedure (Scheme 5.13).36


The key intermediate thieno[3,4-b][1,4]benzodiazepinone was prepared using

several methods.40 The anthranilamide was obtained from an appropriate substituted

isatoic anhydride and 3-amino-4-ethoxytheophene. The enol ether-like moiety is acid

labile and subject to nucleophilic attack. Indeed, intramolecular cyclization was

operated with polyphosphoric acid. The amidine was obtained following the Fryer's

procedure.36 Thieno[3,4-b][1,4]benzodiaze-pines have a neuroleptic/antidepressant

mixed action profile similar to their [1,5] isomer41 but are less potent.



NH

O S

O

O

H2N

EtO

R+

DMSO RHN

S

NH2EtO

O

PPA

NH

NH

S

OR

NH

N

S

NR

N

MNP

TiCl4,toluene


The appropriate substituted o-phenylenediamine was condensed with methyl

tetrahydro-4-oxo-thiophene-3-carboxylate to give the tetrahydrolactam which was

then oxidized in the corresponding aromatic thiophene derivative and then compound

reacted with N-methylpiprazine.41 Corresponding benzoxa- and benzothiazepines

were also described as potent antispychotics. 41,42 Amidines were prepared using

pentachloride in toluene to form the iminochlorides which reacted with N-

methylpiperazine.

Tieno[3,2-b][1,5]- and Tieno[3,2-b][1,4]benzodiazepines

The synthetic pathways for preparing these derivatives were similar to those

used for thieno[2,3-b][1,5] isomer. Aminothiophene carboxylate was treated with

halogenonitrobenzene in DMSO in the presence of potassium carbonate as basic



catalyst.43 The activity determined by hypothermia in mice, conditioned avoidance

response procedure and catalepsy was increased when the phenyl ring was substituted

with a halogen at position 7.

Glamkowski et al synthesized the tetracyclic 1H-quinobenzodiazepines

bearing a pendant N-methylpiperazine substituent.43 The key step involves a Bischler-

Napieralski type cyclization of the ureas. This was achieved by refluxing in

phosphorus oxychloride to affect a cyclodehydration to form the seven-membered

central ring.

Another tetracyclic bezo[c]pyrrolo[1,2,3-ef][1,5]benzodiazepine derivatives

were synthesized by cyclization of (7-aminoindolin-1-yl)benzamide or benzoic acid.

The resulting tetracyclic lactams were treated with N-methylpiperazine in the

presence of titanium tetrachloride to provide piperazinyl derivatives which were

tested for potential antipsychotic activity.44

Tetracyclic 12-Amino-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (46)

derivatives have been synthesized as shown below and they have been tested for the

treatment of schizophrenia, Alzheimer’s disease.45



NO2F

SH2N

NC

+HN

NO2

SNC

K2CO3

DMF

NH

N

S

NH2

NH

N

S

N

NMP

N

1. NaSO3, DMF2. Conc. HCl,

MeOH

R R1 R

R1

R1RR1R

R = H, Cl, F, CH3, CF3, etc R1 = H, Cl, F, CH3, OCH3, etc

A series of 4-(4-methylpiperazin-1-yl)theino[2,3-b][1,5]benzoxazepines has

been synthesized from 4-bromo-2-methylthiiophene or ethyl 2-amino-4,5-dimethyl-3-

thiophencarboxylate. Preparation of the key intermediate thieno[2,3-b][1,5]benzoxa-

zepine-4(5H)-ones were carried out by treatment of 2-bromo-N-(2-hydroxyphenyl)-3-

thiophencarboxamides with potassium carbonate in DMSO.46

NH2OH

SBr

EtOOC+

OH

SBr

K2CO3

DMSO

O

HN

S

O

O

N

S

N

2. NMP

N

R

RR

R = H, Cl, CH3, OCH3, etc

NH

ORpyridine

toluene

1. POCl3

The benzodiazepines olanzapine and clozapine are nowadays manufactured by

a three-step process with a final yield below 50%. An approach to environmentally-

friendly intensive processes consists in the development of multifunctional solid

catalyst able to catalyze multistep reactions. The bifunctional metal acid solid catalyst

was prepared and able to carry out hydrogenation-cyclisation-amination reactions in a



cascade process. The catalytic system was illustrated for the synthesis of these

important antipsychotics.47



5.4 PHARMACOLOGY

The synthesis of a new class of anellated 1,4-benzodiazepines with anti-psychotic

activity was exemplified by preparation of 10-fluoro-3-methy1-7-(2-thieny1)-

1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine. The influence of

variations of the fluoro-substitution pattern and variations of the fused ring system on

the biological activity of the structural analogues was evaluated.48

3-Acetyl coumarins when allowed react with isatin gave corresponding 3-(3’-

hydroxy-2’-oxoindolo)acetylcoumarins, which on dehydration afforded the

corresponding α,β-unsaturated ketones. Which on Cyclocondensation with substituted

o-phenylenediamines resulted in novel 4-(2-oxo-2H-chromen-3-yl)-1,5-dihydro

spiro[benzo[b][1,4]diazepine-2,3'-indolin]-2'-one. Structures of all the compounds

have been screened for their antimicrobial activity and antianxiety activity in mice.49

Nakanishi et al 50 reports the synthesis and pharmacological activity of

tetrazolo, oxadiazolo and imidazothienodiazepines derivatives. Some of them were

found as minor tranquilizers.



SN

N

R1

NN

N

R2

X

SN

N

R1

N

R2

X

SN

N

R1

ON

R2

X

O

R1 = H, alkyl, etc; R2 = H, alkyl, etc; X = H, CF3, halogen, alkoxy group

Tricyclic ring systems possessing a dibenzo structure joined to a central seven-

membered heterocyclic ring with a basic side chain frequently show effects on the

central nervous system. During the last 40 years, a number of dibenzepines have been

introduced. Some of these are powerful antipsychotic agents: clotiapine, metiapine,

and loxapine are classical neuroleptics showing a similar pattern of pharmacological

activities to the phenothiazines, while amoxapine has antidepressant properties and

perlapine is a hypnotic agent.37 Clozapine is an exception, since it was the first

example of a new class of tricyclic neuroleptics with a novel activity pattern,

producing minimal extrapyramidal side effects (EPS) in man.51 Fluperlapine is the

newest drug with a clozapine-like activity: it is in clinical trial and resembles

clozapine qualitatively and quantitatively.39,52

Chakrabarti et al [53] described the synthesis and pharmacological evaluation

of a series of pyrazolo[l,5]benzodiazepines. Some of the 4-piperazinyl-2,10-dihydro-

pyrazolo[3,4-b][1,5]benzodiazepine derivatives demonstrated potent anxiolytic

activity. Compounds and were more active than the clinically effective anxiolytic

chlordiazepoxide in releasing conflict-suppressed behavior. This study shows a



dissociation of the anxiolytic and antidopaminergic activities found in the thieno- and

dibenzodiazepine derivatives flumezapine and clozapine, respectively.

Chakrabarti et al 54 described the synthesis and biological evalution of

[1,2,3]triazolo[4,5-b][1,5], imidazolo[4,5-b][1,5], and pyrido[2,3-b]

[1,5]benzodiazepines in their another paper. The antidopaminergic and anticholinergic

activities of the compounds have been examined by the respective in vitro

[3H]spiperone and [3H]QNB receptor binding assay. The neuroleptic potential has

been further evaluated in terms of their ability to produce hypothermia and catalepsy

in mice and a conditioned avoidance response in rats. Only compounds from the

triazolobenzodiazepine series show antipsychotic potential. The lack of activity in the

imidazolo- and pyridobenzodiazepine series indicates that the basicity of the

heteroarene moiety may be determinant for activity.

Novel 4-arylpiperazin-1-yl-substituted 2,3-dihydro-1H-1,4- and 1H-1,5-benzo

diazepines and their aza-analogues were synthesized as debenzoclozapine derivatives

for evaluation as potential D4-ligands. While Ki values of some of the compounds



came within the range of clozapine, they showed an impressively greater selectivity

over other dopamine receptor subtypes, especially D2. For the most promising

compounds, intrinsic activity and binding properties to serotonin 5-HT1A and 5-HT2

were also determined.55

NH

NN

N

Cl

NH

NN

N

NH

NN

N

N

NN

N

NH

NN

N

Sasikumar et al 56 reports the acylated and aroylated hydrazinoclozapines

which were found highly potent dopamine D1 antagonists that show remarkable

selectivity over other dopamine receptors. The most potent compound in this series

was the 2,6-dimethoxybenzhydrazide 33 with a D1 Ki of 1.6 nM and 212-fold

selectivity over D2 receptor.



5.5 SOME DRUGS FROM DIAZEPINE NUCLEUS 37-56

S

N

NN

N

Br

H3C

Cl

BrotizolamSedetive-Hypnotic

HN

N

S

O

BentazepamAnxiolytic

NN

NN

S

Br

Cl

CiclotizolamGABAA receptor agonist

S

N

N

H3C

OH3C

Cl

ClotiazepamAnxiolytic

S

N

NC2H5

Cl

NN

EtizolamShort-term treatment ofanxiety or panic attacks

NH

N

S

N

N

Olanzapineatypical antipsychotic

NH

NN

N

Clozapineatypical antipsychoticused in the treatment

of schizophrenia

Cl

O

NN

N

Cl

Loxapinetypical antipsychotic

O

NN

NH

Cl

Amoxapineantidepreassant

S

N

Clotiapineatypical antipsychotic

N

N

Cl

S

NN

N

Cl

Quetiapineatypical antipsychotic

O

HO

NN

N

MirtazapineTetracyclic antidepreassant

S

N

Metitepineantagonist at various serotonin

& dopamine reseptorused as anantipsychotic

N

N

S




Thienodiazepines have been the object of intense studies since the early 1960s

because of their value in psychotherapy. An impressive number of synthetic routes

have thus been described. Recently the attention has been concentrated on the

synthesis of analogs having heterocycles in place of the benzene ring and on

compounds having additional fused heterocyclic rings.

Our target was the synthesis of new compounds possessing 7-membered rings

with two heteroatom a 1,4-diazepines having fused heterocyclic ring of coumarin and

thiophene and cyclic secondary amine as a side chain. Substituted 8-amino-10-methyl

chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6(12H)-one hydrochlorides treated with

cyclic secondary amine (N-methyl, N-ethyl, N-phenyl and N-benzylpiperazine,

piperidine, morpholine, pyrrrolidine, 2-methylpiperidine and piperazine) in DMSO

and toluene at reflux condition to give title compounds. The products were

characterized by FT-IR, mass spectra, 1H NMR and elemental analysis. The newly

synthesized compounds were subjected to various biological activities viz.,

antimicrobial, antimycobacterial, anticancer and antiviral.



5.7 REACTION SCHEMES 5.7.1 Preparation of 4-chloro-3-nitrocoumarins

5.7.2 Preparation of 2-amino-5-methylthiophene-3-carbonitrile

5.7.3 Preparation of 5-methyl-2-((3-nitro-coumarin-4-yl)amino)thiophene-3-

carbonitriles

5.7.4 Preparation of 8-amino-10-methylcoumarino[3,4-b]thieno[2,3-e]

[1,4]diazepine hydrochlorides



5.7.5 Preparation of 10-methyl-8-((substituted)amino)chromeno[3,4-b]thieno

[2,3-e][1,4]diazepin-6(12H)-ones






0.5 mm thickness and spots were located by iodine. IR spectra were recorded

Shimadzu FT-IR-8400 instrument using KBr method. Mass spectra were recorded on

Shimadzu GC-MS-QP-2010 model using Direct Injection Probe technique. 1H NMR

was determined in DMSO-d6 solution on a Bruker Ac 400 MHz spectrometer.

Elemental analysis of the all the synthesized compounds was carried out on Elemental

Vario EL III Carlo Erba 1108 model and the results are in agreements with the

structures assigned.

5.8.2 Preparation of 4-chloro-3-nitrocoumarins

According to the previously published procedure57, 4-hydroxycoumarin was

nitrated in glacial AcOH with 72% HNO3 to afford 4-hydroxy-3-nitrocoumarin.

Starting compound 4-choro-3-nitrocoumarin was prepared from 4-hydroxy-3-

nitrocoumarin following the method of Kaljaj et al. 58 The preparation was carried out

in the following manner: N,N-dimethylformamide (DMF, 0.1 mol) was cooled to 10

ºC in an ice bath. With stirring, POCl3 (0.1 mol) was added dropwise, and the

obtained mixture was stirred for an additional 15 min. Then, the ice bath was removed

and the reaction was left to proceed at room temperature for a further 15 min. Finally,

the solution of 4-hydroxy-3-nitrocoumarin (0.1 mol) in DMF (50 mL) was added

dropwise. After 15 minutes of stirring, the reaction was stopped by adding cold water

(60 mL). The precipitated solid was collected by filtration and washed with saturated

sodium-bicarbonate solution and water.

5.8.3 Preparation of 2-amino-5-methylthiophene-3-carbonitrile

A mixture of sulfur (0.1 mol), propionaldehyde (0.12 mol) and DMF (20 mL)

was placed in a 100 mL flask and cooled in an ice bath. Triethylamine (0.06 mol) was

added drop wise over 30 minutes to the stirred reaction mixture and the temperature

was maintained between 5-10 °C. The pot was warmed to 15-20 °C, and stirred at 15-



20 °C over 50 minutes. A solution of malononitrile (0.1 mol) in DMF (15 mL) was

added drop wise at a temperature of 15-20 °C. After the addition was complete, the

mixture was stirred at 15-20 °C for 45 minutes. After checking TLC for malanonitrile

the mixture was poured onto ice/water (180 mL) while stirring. A solid precipitate

was collected by filtration, washed thoroughly with water, and dried overnight, to

give 2-amino-5-methylthiophene-3-carbonitrile.

5.8.4 Preparation of 5-methyl-2-((substituted-3-nitrocoumarin-4-yl)amino)thio

-phene-3-carbonitriles

A mixture of 4-chloro-3-nitrocoumarin (0.01 mol), 2-Amino-5-methyl-

thiophene-3-carbonitrile (0.01 mol) and methanol (15 mL) place in 100 mL flat

bottom flask with magnetic needle. Triethylamine (0.011 mol) was added drop wise

with stirring at room temperature and the resultant mixture was heated under reflux

condition for 3-4 hours. After the completion of the reaction as monitored by TLC for

both starting material, the reaction mixture was allow to cooled at room temperature

and the formed solid was then filtered by vacuum filtration, washed with cold

methanol and dried to give title product which was then used for next step without

any purification.

5.8.5 Preparation of 8-amino-10-methyl(substituted)coumarino[3,4-b]thieno

[2,3-e][1,4]diazepine hydrochlorides

To a 100 mL round bottom flask placed 5-methyl-2-((3-nitro-2-oxo-2H-

chromen-4-yl) amino) thiophene-3-carbonitriles (0.01 mol) and 95 % ethanol (20 mL)

and a solution of stannous chloride dihydrate (0.03) in conc. hydrochloric acid (20

mL) was added slowly with stirring at room temperature and the resultant mixture

was reflux for 4-5 hours. After completion of reaction as monitored by TLC, the

reaction mixture was allowed to cool to 20-25 °C. The formed solid was collected by

filtration, washed with ethanol (10 mL) and then with water (10 mL), dried and

crystallized from ethanol to afford the desired product.



5.8.6 Preparation of 10-methyl-8-((substituted)amino)chromeno[3,4-b]thieno

[2,3-e][1,4]diazepin-6(12H)-ones

To a 50 mL round bottom flask placed 8-amino-10-methylchromeno[3,4-

b]thieno[2,3-e][1,4]diazepin-6(12H)-one hydrochlorides (0.01 mol) and it was reflux

in a mixture of appropriate secondary amine (9 mL), DMSO (15 mL) and toluene (15

mL) for 6 to 8 hours. After completion of reaction as monitored by TLC, the reaction

mixture was allowed to cool and the solvent evaporated under reduce pressure at 80

°C. The residue was poured on to ice-water to formed solid, it was collected by

filtration, washed with water (10 mL), dried and crystallized from chloroform to

afford the desired products.



5.9 PHYSICAL DATA Physical Data of 10-methyl-8-((substituted)amino)chromeno[3,4-b]thieno [2,3-

e][1,4]diazepin-6(12H)-ones

Code R NR1R2M. P.

°C

Yield %Rf

BAJ-301 7-CH3 212-214 54 0.42

BAJ-302 7, 8-CH3 244-246 57 0.41

BAJ-303 8-CH3 110-112 52 0.44

BAJ-304 7, 8-CH3 138-140 58 0.45

BAJ-305 8-CH3 130-132 50 0.47

BAJ-306 7, 8-CH3 254-256 56 0.46

BAJ-307 8-CH3 244-246 60 0.43

BAJ-308 7, 8-CH3 260-262 66 0.48

BAJ-309 8-CH3 252-254 53 0.51

BAJ-310 7, 8-CH3 140-142 55 0.53

BAJ-311 8-CH3 218-220 48 0.54

BAJ-312 7, 8-CH3 202-204 53 0.57

BAJ-313 8-CH3 216-218 57 0.50

BAJ-314 7, 8-CH3 180-182 52 0.52

BAJ-315 8-CH3 222-224 47 0.44

BAJ-316 7, 8-CH3 110-112 50 0.41

BAJ-317 8-CH3 140-142 42 0.46

BAJ-318 7, 8-CH3 148-150 41 0.48

Rf value was determined using solvent system = Chloroform: Methanol (8:2)

N

N

N

N

N

N

Ph

N

N

Ph

N

O

N

N

NH

N

N




5.10.1 IR SPECTRA




For chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6(12H)-one derivatives, a

characteristic band of secondary amine group was observed in the range of 3348-3213

cm-1. Confirmatory band for carbonyl group of coumarin ring was observed at 1707-

1676 cm-1. The coumarin moiety showed the ring skeleton vibrations at 1624-1604,

1599-1569, 1568-1520 and 1471-1440 cm-1. The ether (C-O-C) was observed at

1087-1058 cm-1.

5.10.2 MASS SPECTRA








Numbers of protons and carbons identified from NMR spectrum and their chemical

shift (δ ppm) were in the agreement of the structure of the molecule. J values were

calculated to identify o, m and p coupling. In some cases, aromatic protons were

obtained as multiplet. Interpretation of representative spectra is discussed further in

this chapter.







Methyl carbon observed between 11.66-20.92 δ ppm, all type of methylene carbons

were observed at 24.25-66.05 δ ppm and aromatic carbon observed between 113.99-

148.23 δ ppm while cyclic keto carbon was observed at 148.01-150.18 δ ppm. The

aromatic carbon attached with secondary amino (C-NH-C) group was observed at

149.44-158.71 δ ppm and aromatic carbon attached with tertiary nitrogen atom was

observed at 160.41-160.98 δ ppm. The methylene groups were also identified by

DEPT 135 spectrum.




4,10-dimethyl-8-(4-methylpiperazin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diaze-

pin-6(12H)-one (BAJ-301)

Yield: 54%; IR (cm-1): 3235 (-N-H stretching of secondary amine), 3034 (-C-H

stretching of aromatic ring), 2954 (-C-H asymmetrical stretching of CH3 group), 2849

(-C-H symmetrical stretching of CH3 group), 1681 (-C=O stretching of coumarin

ring), 1624, 1573, 1539, 1500 (-C=C stretching of aromatic ring), 1368 (-C-H

asymmetrical deformation of -CH3 group), 1312 (-C-H symmetrical deformation of

CH3 group), 1252 (-C-N vibration of amine), 1069 (-C-O-C stretching of coumarin

ring); MS: m/z 394; Anal. Calcd. for C21H22N4O2S: C, 63.94; H, 5.62; N, 14.20.

3,4,10-trimethyl-8-(4-methylpiperazin-1-yl)chromeno[3,4-b]thieno[2,3-e]

[1,4]diazepin-6(12H)-one (BAJ-302)




ring), 1604, 1587, 1556 and 1440 (-C=C- stretching of aromatic ring), 1373 (--C-H



ring); 1H NMR (DMSO-d6) δ ppm: 2.28 (s, 6H), 2.32 (s, 3H), 2.33 (s, 3H), 2.38 (s,

4H), 3.47 (s, 4H), 6.34 (s, 1H), 7.06-7.08 (d, 1H, J = 8.2 Hz), 7.68-7.70 (d, 1H, J =

8.28 Hz), 7.87 (s, 1H); 13C NMR δ ppm: 11.27, 15.08, 19.70, 45.66, 46.14, 54.41,

114.17, 118.65, 120.52, 120.61, 121.86, 123.14, 124.95, 130.52, 138.45, 144.73,

148.22, 149.98, 158.41, 160.37; MS: m/z 408; Anal. Calcd. for C22H24N4O2S: C,

64.68; H, 5.92; N, 13.71.

8-(4-ethylpiperazin-1-yl)-4,10-dimethylchromeno[3,4-b]thieno[2,3-e][1,4]diaze-





ring), 1608, 1578, 1550 and 1441 (-C=C- stretching of aromatic ring), 1382 (-C-H



asymmetrical deformation of -CH3 group), 1340(-C-H symmetrical deformation of



8-(4-ethylpiperazin-1-yl)-3,4,10-trimethylchromeno[3,4-b]thieno[2,3-e][1,4]diaze-





ring), 1605, 1582, 1545, 1464 (-C=C- stretching of aromatic ring), 1386 (-C-H



ring); MS: m/z 422; Anal. Calcd. for C23H26N4O2S: C, 65.38; H,6.20; N, 13.26.

8-(4-benzylpiperazin-1-yl)-4,10-dimethylchromeno[3,4-b]thieno[2,3-e][1,4]diaze-


Yield: 50%; IR (cm-1): 3274 (-N-H stretching of secondary amine), 3072 and 3005 (-

C-H stretching of aromatic ring), 2964 (-C-H asymmetrical stretching of CH3 group),

2878 (-C-H symmetrical stretching of CH3 group), 1689 (-C=O stretching of

coumarin ring), 1624, 1569, 1555, 1462 (-C=C- stretching of aromatic ring), 1376 (-

C-H asymmetrical deformation of -CH3 group), 1314 (-C-H symmetrical deformation

of CH3 group), 1250 (-C-N vibration of amine), 1070 (-C-O-C stretching of coumarin


8-(4-benzylpiperazin-1-yl)-3,4,10-trimethylchromeno[3,4-b]thieno[2,3-e][1,4]di-

azepin-6(12H)-one (BAJ-306)










8-(4-phenylpiperazin-1-yl)-4,10-dimethylchromeno[3,4-b]thieno[2,3-e][1,4]diaze-





ring), 1629, 1599, 1568 and 1521 (-C=C- stretching of aromatic ring), 1375 (C-H




4H), 6.41 (s, 1H), 6.80-6.83 (t, 1H), 6.94-6.96 (d, 2H, J = 8.24 Hz), 7.14-7.18 (t, 1H),

7.21-7.25 (t, 2H), 7.27-7.29 (d, 1H, J = 7.32 Hz), 7.81-7.83 (d, 1H, J = 7.92 Hz); 13C

NMR δ ppm: 15.10, 15.36, 46.23, 48.54, 115.77, 116.26, 119.35 119.63, 120.43,

121.37, 121.83, 123.14, 124.84, 128.72, 130.59, 130.72, 144.63, 148.41, 150.37,

150.75, 158.62, 160.17; MS: m/z 456; Anal. Calcd. for C26H24N4O2S: C, 68.40; H,

5.30; N, 12.27.

8-(4-phenylpiperazin-1-yl)-3,4,10-trimethylchromeno[3,4-b]thieno[2,3-e][1,4]di-









4,10-dimethyl-8-(piperidin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-

6(12H) -one (BAJ-309)










3,4,10-trimethyl-8-(piperidin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6-

(12H)-one (BAJ-310)








4,10-dimethyl-8-morpholinochromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6(12H)-

one (BAJ-311)



2854 (C-H symmetrical stretching of CH3 group), 1703 (-C=O stretching of coumarin

ring), 1610, 1583, 1564 and 1519 (-C=C- stretching of aromatic ring), 1431 (-C-H




4H), 6.35 (s, 1H), 7.14-7.18 (t, 1H), 7.27-7.29 (d, 1H, J = 7.28 Hz), 7.80-7.82 (d, 1H,

J = 7.92 Hz), 7.94 (s, 1H); 13C NMR δ ppm: 15.06, 15.34, 46.93, 66.04, 116.24,

119.63 120.28, 121.41, 121.73, 123.13, 124.82, 130.57, 130.73, 144.55, 148.40,

150.33, 158.76, 160.15; MS: m/z 381; Anal. Calcd. for C20H19N3O3S: C, 62.97; H,

5.02; N, 11.02.

3,4,10-trimethyl-8-morpholinochromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6(12H)-

one (BAJ-312)










4,10-dimethyl-8-(pyrrolidin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6-

(12H)-one (BAJ-313)



(-C-H symmetrical stretching of CH3 group), 1688(-C=O stretching of coumarin ring),

1615, 1561, 1520, 1503 (-C=C- stretching of aromatic ring), 1416 (-C-H




3,4,10-trimethyl-8-(pyrrolidin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6-

(12H)-one (BAJ-314)



2854 (-C-H symmetrical stretching of CH3 group), 1699 (-C=O stretching of

coumarin ring), 1627, 1583, 1546 and 1519 (-C=C stretching of aromatic ring), 1371

(-C-H asymmetrical deformation of -CH3 group), 1294 (-C-H symmetrical

deformation of CH3 group), 1271 (-C-N vibration of amine),1062 (-C-O-C stretching

of coumarin ring); MS: m/z 379; Anal. Calcd. for C21H21N3O2S: C, 66.47; H, 5.58; N,

11.07.

4,10-dimethyl-8-(piperazin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6-

(12H)-one (BAJ-315)










3,4,10-trimethyl-8-(piperazin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6-

(12H)-one (BAJ-316)








4,10-dimethyl-8-(2-methylpiperidin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]diaze-


Yield: 42%; IR (cm-1): 3289 (--N-H stretching of secondary amine), 3009 (-C-H







3,4,10-trimethyl-8-(2-methylpiperidin-1-yl)chromeno[3,4-b]thieno[2,3-e][1,4]di-












This chapter deals with synthesis of substituted 10-methyl-8-((substi-

tuted)amino)chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6(12H)-ones from 8-amino-

10-methylchromeno[3,4-b]thieno[2,3-e][1,4]diazepin-6(12H)-one hydrochloride. The

synthesis was done by using two different 8-amino-10-methylchromeno[3,4-

b]thieno[2,3-e][1,4]diazepin-6(12H)-one hydrochloride and nine different cyclic

secondary amine. Total 18 compounds were synthesized and characterized using

spectroscopic technique.

5.13 CONCLUSION

In conclusion, the synthesis of title compounds has been done by using 3.0

mole equivalent secondary amine and DMSO/toluene as solvents mixture at 100 °C.

Most of the piperazinyl derivatives were easily synthesized and purified in chloroform

to get crystalline products. Synthesized compounds were explored for performing

various biological activities.

Ch

D

55

5

hapter – 5

Department o

5.14 REPR.14.1 IR spe

.14.2 Mass s

of Chemistry,

REENTATectrum of B

spectrum of

, Saurashtra

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f BAJ-302

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.14.3 1H NM

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6



5.15 REFERENCES

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183.

Bisy

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ationpou

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f

Biological Evaluation of Synthesized Compounds …


INTRODUCTION The present chapter deals with the preliminary biological screening results of some

synthesized compounds during the course of invention. In the current chapter,

biological aspects of anti tubercular screening were described along with the activity

protocols and activity data obtained by preliminary screening In vitro. Finally on the

screening results conclusion is also narrated.

The ant tubercular screening of all the synthesized compounds was carried out at

Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF),

Alabama, USA.

PROCEDURE FOR THE RESAZURIN MIC ASSAY The resazurin MIC assay, developed by Collins and Franzblau (1997), is a

colorimetric assay used to test compounds for antimycobacterial activity. A color

change from blue to pink is observed when growth occurs. Compounds are initially

tested at a single point concentration of 10 μg/ml against Mycobacteruim tuberculosis

H37Rv (H37Rv), obtained from Colorado State University, Fort Collins, CO. If

compounds are active at the 10 μg/ml level, they are further tested in an MIC assay at

8 concentrations in a dose range between 10 to 0.078 μg/ml.

Receipt and Preparation of Test Compounds

Upon receipt, test compounds are logged into the inventory spreadsheet and placed in

a -20ºC freezer. The day of the experiment, one vial from each compound is

reconstituted using the supplier’s recommended solvent to achieve a stock

concentration of 3.2 mg/ml.

Inoculum Preparation

H37Rv is grown in Middlebrook 7H9 broth medium (7H9 medium) supplemented

with 0.2% (v/v) glycerol, 10% (v/v) ADC (albumin, dextrose, catalase), and 0.05%

(v/v) Tween 80. The bacteria are inoculated in 50 ml of 7H9 medium in 1 liter roller

bottles that are placed on a roller bottle apparatus in an ambient 37oC incubator.



When the cells reach an OD600 of 0.150 (equivalent to ~1.5 x 107 CFU/ml), they are

diluted 200-fold in 7H9 medium.

Single Point Concentration Procedure

The procedure is the same as that used for the MIC procedure described below, but

only the first 2 fold dilution is made that reduces the stock solution to 1.6 mg/ml. An

additional 1:10 dilution is made in water (see Step 3 below) which reduces the stock

solution further to 0.16 mg/ml. Addition of 6.25 μl of the 1:10 dilution to the wells in

a final volume of 100 μl will give rise to a concentration equivalent to 10 μg/ml (see

Step 2 below).

MIC Procedure

1. 20 μl of the 3.2 mg/ml test compound is added to a 96-well microtiter plate.

2. 2-fold dilutions are made by the addition of 20 μl of diluent.

Expected final Test Compound = 3.2 mg/ml

dose level (μg/ml) Dilute 1:2

10 1st dilution of 8 = 1.6 mg/ml Dilute 1:2

5 2nd dilution of 8 = 0.8 mg/ml Dilute 1:2

2.5 3rd dilution of 8 = 0.4 mg/ml Dilute 1:2

1.25 4th dilution of 8 = 0.2 mg/ml Dilute 1:2




0.078 8th dilution of 8 = 0.0125 mg/ml

3. Each dilution is further diluted 1:10 in sterile water (10 μl of dilution to 90 μl

of sterile water). Note: The additional 10-fold dilution in water is required

when DMSO is used as solvent to minimize toxicity to the bacteria. For

uniformity in the assay procedure, this dilution step is used even if water or

other solvents are used.

4. 6.25 μl of each dilution is transferred to duplicate 96-well test plates.



5. 93.75 μl of the cell suspension (~ 104 bacteria) in 7H9 medium is added to the

test plates.

6. Positive, negative, sterility and resazurin controls are tested.

a. Positive controls include: rifampicin and isoniazid

b. Negative controls include:

i. cell culture with solvent and water

ii. cell culture only

c. Sterility controls include:

i. media only

ii. media with solvent and water

d. Resazurin control includes one plate containing the diluted compounds

with resazurin only. No bacterial suspension is added. This control

plate is needed to verify whether the compound reacts with resazurin

that could possibly elicit fluorescence.

7. The 96 well test plates are incubated in an ambient 37ºC incubator for 6 days.

8. After the 6 day incubation, 5 μl of a 0.05% sterile resazurin solution is added

to each well of the 96-well plate. The plates are placed in an ambient 37ºC

incubator for 2 days.

9. After the 2 day incubation, a visual evaluation and fluorimetric read-out is

performed. The results are expressed as μg/ml (visual evaluation) and as IC50

and IC90 (fluoremetric readout)



TABLE-1 – IC50 VALUE OF NEWLY SYNTHESIZED COMPOUNDS

Compound ID Structure Solvent Results (µg/mL)

BAJ-201 DMSO >10

BAJ-202 DMSO >10

BAJ-203 DMSO >10

BAJ-204 DMSO >10

BAJ-205 DMSO >10

BAJ-206 DMSO >10

BAJ-207 DMSO >10

BAJ-208 DMSO >10

BAJ-209 DMSO >10



BAJ-210 DMSO >10

BAJ-211 DMSO >10

BAJ-212 DMSO >10

BAJ-213 DMSO >10

BAJ-216 DMSO >10

BAJ-217 DMSO >10

BAJ-218 DMSO >10

BAJ-219 DMSO >10

BAJ-220 DMSO >10



BAJ-221 DMSO >10

BAJ-222 DMSO >10

BAJ-225 DMSO >10

BAJ-226 DMSO >10

BAJ-227 DMSO >10

BAJ-228 DMSO >10

BAJ-229 DMSO >10

BAJ-231 DMSO >10



BAJ-232 DMSO >10

BAJ-233 DMSO >10

BAJ-234 DMSO >10

BAJ-237 DMSO >10

BAJ-238 DMSO >10

BAJ-239 DMSO >10

BAJ-240 N

O

OO

O

Cl

H3C

F

DMSO >10

BAJ-241 DMSO >10

BAJ-301 DMSO >10



BAJ-301

DMSO >10

BAJ-302

DMSO >10

BAJ-303

DMSO >10

BAJ-304

DMSO >10

BAJ-305

DMSO >10

BAJ-306

DMSO >10

BAJ-307

DMSO >10



BAJ-308

DMSO >10

BAJ-309

DMSO >10

BAJ-310

DMSO >10

BAJ-311

DMSO >10

BAJ-312

DMSO >10

BAJ-313

DMSO >10

BAJ-315

DMSO >10



BAJ-316

DMSO >10

BAJ-317

DMSO >10

BAJ-318

DMSO >10

Rifampin DMSO 0.0125

Isoniazid DMSO 0.063

Reference: Collins, L. A. and S. G. Franzblau. Microplate Alamar Blue Assay versus BACTEC

460 System for High-Throughput Screening of Compounds against Mycobacterium

tuberculosis and Mycobacterium avium. Antimicrobial Agents and Chemotherapy,

41:1004-1009 (1997).

Conclusion: In all 52 novel compounds were screened for Antitubercular Activity. All compounds

show MIC value >10 µg/mL and therefore it is necessary to study further other

biological activities.

Summary of the work done in this thesis


The work represented in the thesis entitled “Studies In Heterocyclic Moieties”

is divided into five chapters which can be summarized as under.

Chapter-1 deals with the synthesis of pyrazole derivatives using 5-chloro-2-

methoxybenzohydrazide and different α-diketo compounds in presence of Con. HCl

as catalysts. Good yield and easy work up is the main significance of this method.

The chapter represents 17 compounds including reaction mechanism, IR, 1H NMR, 13C NMR, Mass spectral and other Physical data to support the structure elucidation.

Chapter-2 covers synthesis of functionalized pyrrole derivatives. In this chapter we

have developed a novel, rapid and efficient methodology for the synthesis of highly

functionalized pyrroles. This process involves one pot four component coupling

reaction of 1,3-dicarbonyl compounds, aromatic aldehyde, amines, and nitro alkanes.

Considering these advantages and experimental simplicity, this one-pot catalytic

transformation clearly represents an appealing methodology for the synthesis of

highly functionalized pyrroles. The main advantage of this process is economical,

environmental friendly and less time consuming. Total 34 compounds are included in

this chapter along with reaction mechanism, IR, 1H NMR, 13C NMR, Mass spectral

and other Physical data to support the structure elucidation.

Chapter-3 represents 18 compounds of 3-cyano-4-(alkyl/dialkyl amino)coumarin

derivatives. Insertion of the cyano group to the 3rd position is a result of modification

in the prior art method of synthesizing isoxazoles. The process delivers high yield

and purity and the presence of cyano group is in the interest of biological activity. The

chapter covers reaction mechanism, IR, 1H NMR, 13C NMR, DEPT, Mass spectral

and other Physical data to support the structure elucidation.

Chapter-4 is an effort to modify well-known Hantzsch synthesis of

Dihydropyridines. A successful method was developed by changing the temperature

and solvent condition for rapid synthesis of various DHP’s without using the

microwave irradiation so as further development of this method may prove to be

commercially viable as the class of Dihydropyridine represents many drugs in this

Summary of the work done in this thesis


current era. Total 15 synthesized compounds are presented in this chapter.

Compounds were characterized by spectral analysis.

Chapter-5 involves the synthesis of chromeno[3,4-b]thieno[2,3-e][1,4]diazepin-

6(12H)-ones and its piperazinyl derivatives. The previously synthesized 5-methyl-2-

((3-nitro-2-oxo-2H-chromen-4-yl)amino)thiophene-3-carbonitriles were reduced and

cyclised by SnCl22H2O/HCl to produce chromenothienodiazepinones, which were

treated with various cyclic secondary amine to afforded 18 novel compounds. The

chapter covers IR, 1H NMR, 13C NMR, DEPT, Mass spectral and other Physical data

to support the structure elucidation.

Biological Activity: The anti tubercular screening done on several newly synthesized

molecules.

In all compounds were screened. Unfortunately compounds were not shown to the

posses moderate activity.

In entire thesis, total 102 compounds were prepared during this work. Biological

screening of some of the compounds is performed while remaining compounds are

under study.

Conferences/Seminars/Workshops Attended

CONFERENCES/SEMINARS/WORKSHOPS ATTENDED

ISCB Conference “International conference on Bridging gaps in discovery and development: Chemical & Biological science for affordable health, wellness & sustainbility” at Department of Chemistry, Saurashtra University, Rajkot on 4-7th February-2011

ISCB Conference “International conference on chemical biology for discovery: perspectives and Challenges” at CDRI, Lucknow on 15-18th Jan., 2010.

ISCB Conference “Interplay of Chemical and Biological Sciences: Impact

on Health and Environment” at Delhi University, on 26th February - 1st

March 2009.

“International Seminar on Recent Developments in Structure and Ligandbased Drug Design” jointly organized by Schrodinger LLC, USA; National Facility for Drug Discovery through New Chemicals Entities Development & Instrumentation support to Small Manufacturing Pharma Enterprises and DSTFIST, UGC-SAP & DST-DPRP Funded Department of Chemistry, Saurashtra University, Rajkot on 23rd, December, 2009.

“National seminar on Alternative Synthetic Strategies for Drugs & Drug Intermediates” at Institute of Pharmacy, Nirma University, Ahmedabad on 13th November, 2009.

“Two Days National Workshop on Patents & Intellectual Property Rights Related Updates” Sponsored by TIFAC & GUJCOST and Organized by DST-FIST, UGC-SAP & DST-DPRP Funded Department of Chemistry, Saurashtra University, Rajkot on 19-20th September, 2009.

DST-FIST, UGC (SAP) supported and GUJCOST Sponsored “National Conference on Selected Topics in Spectroscopy and Stereochemistry” organized by the Department of Chemistry, Saurashtra University, Rajkot on 18-20th March, 2009.

National seminar on “Recent Advances in Chemical Sciences & an Approach to Green Chemistry”, Rajkot on October, 2006.

National workshop on “E-resources in Chemical Synthsis and Natural Products”, Rajkot on March, 2006.

Conferences/Seminars/Workshops Attended

Poster presented at the International Conference:

Synthesis of Nucleoside Reverse Transcriptase Inhibitors: Bis (2 – Propyl) – 7 – [2 – (Phosphonomethoxy) ethyl] – 2 – amino – 6 – chloropurine (7 – isomer) & Bis (2 – Propyl) – 9 – [2 – (Phosphonomethoxy) ethyl] – 2 – amino – 6 – chloropurine (9 – isomer)

Abhay Bavishi, Shrey Parekh, Bhavin Marvania, Ravi Chhaniyara, Anamik Shah*,

Presented at 13th ISCB International conference at Department of Chemistry, Delhi University, Delhi on 26th February‐1st March, 2010.

Synthesis And Antimicrobial Activity of some fused Bicyclic Heterocycles

Abhay Bavishi, and Nikhil Vekariya*

Presented at 14th ISCB International conference at CDRI, Lucknow on 15‐18th Jan., 2010.

Synthesis and biological evaluation of 4‐Styrylcoumarin derivatives as inhibitors of TNF‐α and IL‐6 with anti‐tubercular activity

Abhay Bavishi. Kuldip Upadhyay, Anamik Shah*

Presented at 15th ISCB International conference at Saurashtra University, Rajkot on 4‐7th Feb., 2011.

PPublications

Department

PUBL

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3. Syn

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LICATIO

nthesis and

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organic & Me

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o-2H-chromirya Bhavsar,

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organic & Me

efficient a

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ON LIST

biological e

TNF-α and Iy, Abhay Bav

Bhavsar, Mah

edicinal Chem

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ol-1-yl) met

of multidru

oma cells inhairya Bhavsa

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and rapid sy

ridines usin, Abhay Bav

ha Parmar, M

(Accepted).

sisted rapid

microbial ag

Abhay Bavi

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evaluation o

IL-6 with avishi, Shailesh

hesh Savant,

mistry Letters

novel be

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ug resistan

vitro. ar, Mahesh Sa

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rnal of Medic

nti-HIV Ac

cetamide Ddi, Shrey Par

ardev Vala, M

mistry Letters.

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ng glacial acvishi, Dhairya

Mahesh Savan

d Synthesis

gent.

ishi, Shrey Pa

Nilay Pandya

sity, Rajkot-

of 4-Styrylc

nti-tubercuh Thakrar, As

Manisha Par

doi:10.1016/j

enzofuran-2

nd studies o

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avant, Shailesh

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Manisha Parm

doi:10.1016/

f highly fun

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nt, Nilay Pan

of novel 1,

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j.bmcl.2011.0

2-yl(4,5-dihy

on the antip

man MDR1

h Thakrar, Ab

ndya, Juliana

try, Volume 4

-1,3-benzo[d

using MTT h Savant, Sha

mar, Roberta L

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nctionalize

as solvent. Shrey Parekh,

ndya and An

5-benzodia

a Bhavsar, Ha

mik Shah* Jo

derivatives a

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dlakha, Anam

02.016

hyro-3,5-sub

proliferative

1-gene tran

bhay Bavishi

Serly, Joseph

46, Issue 5, M

[d]thiazol-2-

method. ailesh Thakra

Loddo, Anam

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Hardev Val

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May 2011,

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mik Shah*

mmetric

a, Ashish

Synthetic

rivatives

la, Ashish

eterocyclic

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