Metal Triflate Mediated Synthesis of Selected Biologically ...shodhganga.inflibnet.ac.in/bitstream/10603/26392/1... · The thesis entitled “Metal triflate mediated synthesis of

Metal Triflate Mediated Synthesis of Selected

Biologically Active Heterocyclic Compounds

THESIS

Submitted in partial fulfillment of the

requirements for the degree of

DOCTOR OF PHILOSOPHY

by

V. Kameswara Rao

Under the supervision of

Dr. Anil Kumar

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE, PILANI

PILANI - 333031 (RAJASTHAN) INDIA

February 2014

Dedicated to My Parents and Family

i

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE

PILANI (RAJASTHAN)

CERTIFICATE

This is to certify that the thesis entitled “Metal Triflate Mediated Synthesis of Selected

Biologically Active Heterocyclic Compounds” submitted by Mr. V. Kameswara Rao ID

No 2008PHXF416P for the award of Ph. D. Degree of the Institute embodies the original

work done by him under my supervision.

Signature in full of the Supervisor:

Name in capital block letters: Dr. ANIL KUMAR

Designation: Associate Professor

Date:

TABLE OF CONTENTS

Page No

Certificate i

Acknowledgements ii

Abstract iv

List of tables v

List of figures vi

List of abbreviations and symbols vii

Chapter 1: Yb(OTf)3–Catalyzed Synthesis of Tetrahydroindazolones, Flavonones

and Quinolinones in [bmim][BF4] Ionic Liquid

1.1 Introduction 1

1.1.1 Ytterbium triflate catalyzed organic reactions 1

1.1.2 Ionic liquids 4

1.1.3 Metal triflate catalyzed organic reactions in ionic liquid 5

PART-A: Synthesis of Tetrahydroindazolones and their Biological

Evaluation

8

1.2 Literature methods for the synthesis of tetrahydroindazolones 8

1.3 Results and discussion 9

1.3.1 Chemistry 9

1.3.2 Biological activity 16

1.3.2.1 c-Src kinase inhibitory activity 16

1.3.2.2 Molecular modeling 17

1.3.2.3 Anti-cancer activity 18

1.4 Conclusions 19

1.5 Experimental 19

1.5.1 General 19

1.5.2 Representative procedure for the synthesis of 63aaa 20

1.5.3 Analytical data 20

1.5.4 Procedure for c-Src kinase activity assay 30

1.5.5 Procedure for cell culture 31

1.5.6 Procedure for molecular modeling 31

PART-B: Synthesis of Flavanone and Dihydroquinolinones using

Yb(OTf)3 in Ionic Liquid

32

1.6 Literature method for synthesis of flavanone and quinolinones 33


1.8 Conclusions 41

1.9 Experimental 41

1.9.1 Representative procedure for the isomerization 41


1.9.3 General procedure for recovery and reuse of catalyst 45

1.10 References 46

Chapter 2: Microwave–Assisted Synthesis of 2,3-Diarylnaphthofurans and

Quinolines

2.1 Introduction 52

PART-A: Synthesis of 2,3-Diarylnaphthofurans 56

2.2 Literature methods for synthesis of naphthofuran and benzofuran 56


2.4 Conclusions 69

2.5 Experimental 69

2.5.1 General information 69

2.5.2 Representative procedure for the synthesis of 49a 69



PART-B: Synthesis of Quinolines 78

2.6 Literature methods for synthesis of substituted quinolines 78


2.8 Conclusions 87

2.9 Experimental 87

2.9.1 General information 87



2.10 References 94

Chapter 3: Cu(OTf)2 Catalyzed Synthesis of 1,3,5-Triarylpyrazoles and Bis(5-

methyl-2-furyl)methanes

3.1 Introduction 99

PART-A: Synthesis of and Anti‒cancer Activities 103

1,3,5-Triarylpyrazoles

3.2 Literature methods for the synthesis of 1,3,5-triarylpyrazoles 103


3.3.1 Chemistry 106

3.3.2 Biological evaluation 113

3.3.2.1 Anti‒cancer activity 113

3.4 Conclusions 114

3.5 Experimental 114

3.5.1 General 114

3.5.2 Representative procedure for synthesis of 38 and 39 114


3.5.4 Anti-cancer assay protocol 124

3.5.4.1 Procedure for cell culture 124

3.5.4.2 Procedure for cell proliferation assay 124

PART-B: Synthesis of Bis(5-methyl-2-furyl)methanes 126

3.6 Literature methods for synthesis of bis(5-methyl-2-

furyl)methanes

126


3.8 Conclusions 134


3.9.1 General 134



3.9.4 Representative procedure for the synthesis of 42a from 43a 135


3.9.6 References 139

Chapter 4: Silica‒supported Yb(OTf)3 Catalyzed Synthesis of 3-Substituted Indole

4.1 Introduction 143

4.1.2 Silica‒supported catalysis 143

4.1.3 3-Substituted indoles 147

4.2 Literature methods for synthesis of 3-aminoalkylated indoles 147


4.3.1 Chemistry 149

4.3.2 Biological activity 153

4.3.2.1 c-Src kinase inhibitory activity 153

4.3.2.2 Molecular modeling 154

4.3.2.3 Anti‒cancer activity 155

4.3.2.4 Anti‒bacterial activity 156

4.4 Conclusions 158


4.5.1 General 158



4.5.4 Procedure for c‒Src kinase assay 164

4.5.5 Procedure for molecular modeling 165

4.5.6 Procedure for anti-cancer activities 165

4.5.6.1 Procedure for cell culture 165

4.5.6.2 Procedure for cell proliferation assay 165

4.5.7 Procedure for anti‒bacterial assay 166

4.6 References 167

Chapter 5: Conclusions

5.1 General conclusions 170

5.2 Specific conclusions 171

5.3 Future scope of the research work 173

Appendices

List of publications A-1

List of papers presented in conference A-2

Brief biography of the candidate A-3

Brief biography of the supervisor A-4

ii

ACKNOWLEDGEMENTS

I take this opportunity to put my gratitude and thanks on record to all those who were of

great help and support to me in their own special ways during the journey of my doctoral

studies.

At first I would thank my research supervisor Prof. Anil Kumar whose dedicated

guidance, scientific temperament and pursuit to excellence has been a great source of

motivation for me. I deeply thank him for his encouragement that carried me on through

difficult times and for his insights and suggestions that helped to shape my research skills.

His inspiring guidance and constant motivation have helped me to understand better and

remain optimistic during the course of my study. Although this eulogy is insufficient, I

preserve an everlasting gratitude to him.

I put forward my thanks to Prof. B. N. Jain, Vice-chancellor, Prof. L. K. Maheshwari,

(Former Vice-Chancellor) and Prof. G. Raghurama, Director, Birla Institute of

Technology & Science, Pilani (BITS Pilani), Pilani Campus, for allowing me to pursue

my research work successfully. I am immensely thankful to Deputy Directors and Deans

of BITS Pilani for providing necessary facilities and financial support.

I also express my sincere gratitude to Prof. S. K. Verma (Dean, ARD, BITS Pilani), Prof.

Ravi Prakash and Prof. A. K. Das (Former Dean, ARD, BITS Pilani) for their constant

support, timely help and encouragement. I sincerely thank Prof. Hemant R Jadhav

(Associate Dean, ARD, BITS Pilani) for his cooperation and constant guidance during

each phase of my research work. I also express my thanks to the office staff of ARD,

whose secretarial assistance helped me in submitting the various evaluation documents in

time.

I am grateful to the members of my Doctoral Advisory Committee, Prof. Dalip Kumar

and Dr. Bharti Khungar for their great cooperation in refining my thesis. I am thankful to

Prof. Keykavous Parang, Chapman University, School of Pharmacy, USA, and Prof.

Jitendra Panwar, Department of Biological Sciences, BITS Pilani campus, in extending

their support for biological screening and valuable suggestions. I would like to thank Dr.

Rakesh Tiwari, Dr. Bhupender Chhikara and Dr. Amir N. Shirazi from University of

Rhode Island, Kingston, USA for their generous help in this work. I would also like to

thank Prof. Amitabh Jha, Department of Chemistry, Acadia University, Canada for giving

me opportunity to visit his lab and his valuable guidance during my six months period of

stay at Acadia University.

iii

I am thankful to all the respectable faculty members of the Department of Chemistry,

BITS Pilani for their generous help and support along with fruitful discussions during the

different stages of my doctoral study. Thanks are also to all the office staff of the

Department for their help during my work. My sincere thanks to Dr. M. Ishwara Bhatt,

Librarian, BITS Pilani and other staff of library for their support and help rendered while

utilizing the library services.

I always had a hearty inspiration from my seniors and labmates Dr. Sudershan Rao, Mr.

Manoj Kumar, Mr. Kasi Pericherla, Mr. Ganesh, Mrs. Poonam, Ms. Sunita, Ms. Pankaj,

Ms. Pinku, Mr. Hitesh, Ms. Khima, Mr. Shiv, Mr. Nitesh and Ms. Saroj including all the

research scholars. I extend my heartfelt thanks to Dr. Ajay, Mr. Nagarjun Reddy, Mr.

Nagesh, Mr. Vijith, Mr. Basavanna Gowda, Mr. Murthy, Mr. Sharath, Mr. Jitu, Mr. Vadi,

Mr. Muthu, Ms. Anjali, Ms. Danhu and Mr. Naveen for helping me in this work. A

special thanks to my friends Mr. Rajan Pandey, Ms. Ruchika, Ms. Priya, Mr. Harsh and

Mr. Ishan for their help and charming company.

Words are inadequate to express my reverence for my parents (Shri V. Kanakeswara Rao

and V. Jayamma) for their love, inspirations, support, and never-ending blessings. I

express my heartfelt thanks to my brothers Mr. V. Durga Rao, V. Ravi Kumar and V.

Chandra Mouli & their family for their love, motivation and accepting my decision in

letting me pursue things with enormous encouragement. Without their love,

encouragement, co-operation and sacrifice, successful achievement of this work would

have only remained a dream.

My thanks are duly acknowledged to DST, BITS Pilani and CSIR for their valuable

support in the form of Project Fellow and Senior Research Fellowship (SRF) during my

research tenure.

V. Kameswara Rao

iv

ABSTRACT

The thesis entitled “Metal triflate mediated synthesis of selected biologically active heterocyclic compounds”

deals with the synthesis of some selected bioactive heterocyclic compounds using metal triflates as catalyst

under mild reaction conditions. The synthesized compounds have been evaluated for c-Src kinase inhibition,

anti-cancer activities and/or anti-microbial activities. The thesis is divided in four chapters.

The first chapter of thesis describes the use of ytterbium triflate immobilized in [bmim][BF4] ionic liquids in

the synthesis of tetrahydroindazolones 67, flavanone 74 and dihydroquinolinones 81. The chapter is divided in

two parts. In part-A, an environmentally benign regioselective synthesis of tetrahydroindazolones was

developed by three-component condensation reaction of 1,3-diketones 60, aryl hydrazines 62 and aryl

benzaldehydes 61 using Yb(OTf)3 as a catalyst in [bmim][BF4] ionic liquid. An array of 33 compounds was

prepared in good yields (48–88%) and evaluated for inhibition of cell proliferation of HT-29, SK-OV-3, and

c-Src kinase inhibitory activity. Compounds 67ada and 67aaj has shown moderate c-Src kinase inhibition

with IC50 values of 35.1 and 50.7 μM respectively while compound 67bab inhibited cell proliferations of SK-

OV-3 and HT-29 cells by 62% and 58%, respectively at 50 μM. In part-B of the chapter, an efficient and

environmentally benign method was developed for the synthesis of 2-arylchroman-4-one (flavanone) 74 and

2-aryl-2,3-dihydroquinolin-4(1H)-ones (dihydroquinolinone) 81 by the isomerization of 2ꞌ-hydroxychalcone

and 2ꞌ-aminochalcone using Yb(OTf)3 as Lewis acid catalyst in [bmim][BF4] ionic liquid.

The second chapter of thesis briefly describes metal triflate catalyzed organic reaction under microwave

irradiation. In part-A, microwave-assisted and In(OTf)3-mediated hydroarylation of β-naphthols 42 and

alkynes 44 gave α-hydroxy styrenes (vinylnaphthols) 49, which were further treated with Pd(OAc)2 and aryl

iodide 47 to give 2,3-diarylnaphthofurans in moderate to good (36-72%) yield. In part-B, a microwave

assisted and Yb(OTf)3 catalyzed method was developed for the synthesis of quinolines involving three

component reaction of aryl aldehydes 14, aryl amines 21 and aryl alkynes 28 in [bmim][BF4] ionic liquid. A

series of compounds were synthesized in good yields (69–93%) under mild reaction condition and the catalyst

was recycled and reused.

The third chapter of the thesis focuses on the exploration of Cu(OTf)2 as catalysts in organic reactions. In part-

A of the chapter a simple, efficient, and environment friendly protocol was developed for the synthesis of

1,3,5-triarylpyrazole using Cu(OTf)2 in [bimm][PF6] ionic liquid. The reaction protocol gave 1,3,5-

triarylpyrazoles in good to high yields (71-82%) via a one-pot addition–cyclocondensation between

hydrazines and chalcones, and oxidative aromatization without requirement for an additional oxidizing

reagent. The catalyst can be reused up to four cycles without much loss in the catalytic activity. The pyrazoles

(38a-o) and pyrazolines (39a-n) were evaluated for anti-proliferative activity in SK-OV-3, HT-29, and HeLa

human cancer cells lines. Among all compounds, 39b inhibited cell proliferation of HeLa cells by 80% at a

concentration of 50 μM. In part-B, a facile and efficient one-pot three-component synthesis of bis(5-methyl-2-

furyl)methanes has been achieved via the reaction of 2-methylfuran 40 with aliphatic and aromatic

aldehydes/ketones 41 in the presence of Cu(OTf)2 under solvent-free conditions. The bis(5-methyl-2-

furyl)methanes 42 were obtained in moderate to good yields (34–75%) and the catalyst was recycled up to

four successive cycles without much loss in catalytic activity.

The chapter four of the thesis describes application of silica-supported Yb(OTf)3 for synthesis of 3-substituted

indoles. A one pot three-component coupling reaction of aldehyde 34, N-methyl aniline 44 and indole 33

using Yb(OTf)3-SiO2 as a catalyst gave good yields (51-88%) of 3-substituted indoles 45. All the synthesized

compounds were evaluated for inhibition of cell proliferation (HT-29 and SK-OV-3) and c-Src kinase as well

as anti-bacterial activity. The compounds 45o, 45p and 45q inhibited cell proliferation of SK-OV-3 and HT-

29 cells by 70-77% at a concentration of 50 M. Compound 45d and 45l showed the inhibition of c-Src kinase

with IC50 values of 50.6 μM and 58.3 μM, respectively. Compound 45b and 45r showed good antibacterial

activity against both Gram positive and Gram negative strains.

v

LIST OF TABLE

No Title Page No

1.1 Optimization of reaction conditions for the model reaction 63aaa 10

1.2 Synthesized 2-substituted THI’s 63aaa-bba 11-12

1.3 c-Src kinase inhibitory activity of substituted THI’s 63aaabba 16

1.4 Yields of 74a by different catalysts in [bmim][BF4]. 35

1.5 Effect of solvent on yield of 74a 36

1.6 Synthesis of flavanones 74 37

1.7 Synthesis of dihydroquinolinones 81. 40

2.1 Optimization of hydroarylation conditions for 49a 59

2.2 Synthesis of 1-vinylnaphthols 49a-f 60

2.3 Optimization of Heck-oxyarylation condition for 50a 62

2.4 Synthesis of 2,3-diarylnaphthofurans 50a-n 63

2.5 Optimization of the reaction conditions 54a 82

2.6 Synthesis of substituted quinolines using Yb(OTf)3 in ionic liquid under MW 84

3.1 Optimization of reaction conditions for the synthesis of 38a 107

3.2 Synthesized 1,3,5-triarylpyrazoles 38a-o 110

3.3 Synthesized 1,3,5-triarylpyrazolines 39a-n 111

3.4 Optimization of reaction conditions for the synthesis of bis(furyl)methanes 129

3.5 Cu(OTf)2-promoted synthesis of bis(furyl)methanes 42a-n 131-132

4.1 Optimization of reaction condition to prepare 45a 150

4.2 Synthesis of different 3-substituted indoles 45a-r 152

4.3 c-Src kinase inhibitory activity of 3-substituted indoles 45ar 154

4.4 Zone of inhibition and MIC values of 45a-r against Gram-positive and Gram-

negative bacteria 157

vi

LIST OF FIGURES

Figure No. Caption Page No.

1.1 Chemical structures of different ionic liquids 4

1.2 Chemical structures of lead compounds containing THI’s scaffolds 8

1.3 NMR spectrum of THI 63ada (1H & 13C) 12-13

1.4 ORTEP view of molecular structure THI’s 63aac and 63aca 14

1.5 Structural relativity of THI to Combrestatin A-4 15

1.6 Molecular modeling of THI’s 17

1.7 Anti-cancer activities of THI’s 63aaabba 18

1.8 The structural categories of flavonoids and bioactive quinolinone 32

1.9 NMR spectrum of 74a (1H & 13C) 38

1.10 NMR spectrum of 81c (1H & 13C) 39

2.1 Structure of bioactive benzofuran and naphthofuran compounds 56

2.2 Retrosynthetic analysis of 1,2-diarylnaphthofurans 58

2.3 NMR spectrum of 49a (1H & 13C) 60-61

2.4 NMR spectrum of 50a (1H & 13C) 64-65

2.5 NMR spectrum of 52 (1H & 13C) 66

2.6 NMR spectrum of 53 (1H & 13C) 67

2.7 ORTEP diagram of 58 68

2.8 Structures of bioactive quinoline compounds 78

2.9 Synthesis of quinoline derivatives by different synthetic route 79

2.10 NMR spectrum of 54p (1H & 13C) 85

3.1 Chemical structure of drug molecules contain pyrazole moiety 103



3.4 Anti-cancer activities of 51a-o and 50a-n 113


4.1 Chemical structures of Aplysinopsin and Gramine derivatives 147

4.2 NMR spectrum of 45b (1H & 13C) 151

4.3 Molecular modeling of 45d 155

4.4 Anti-cancer activities of 3-substituted indoles 45a-r 156

CHAPTER - I

Yb(OTf)3–Catalyzed Synthesis of

Tetrahydroindazolones

Flavonones and Quinolinones in

[bmim][BF4] Ionic Liquid

Chapter-I

1

1.1 Introduction

Lanthanide triflates can act as strong Lewis acid compared to the lanthanide halides because of the

strong electron withdrawing nature of the triflates group. It is having hard character and has strong

affinity towards carbonyl oxygen. The most characteristic feature of lanthanide triflates [Ln(OTf)3]

is that they are stable in water and can act as Lewis acid catalyst in aqueous media.1,2

Kobayashi

group firstly explored the rare earth triflouromethanesulponate complexes and substituted

traditional Lewis acids in diverse of organic transformations in aqueous media.3,4

Not only

Ln(OTf)3 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu),5 but also scandium (Sc),

yttrium (Y), were shown to be water-compatible Lewis acids.6-11

In past three decades, there has

been a growing interest in metal triflates catalyzed organic transformations because of their unique

reactivity, water tolerance and recyclability.12

Among these metal triflates, Yb(OTf)3 has received

special attention of organic chemist due to its high reactivity. A brief overview of some recent

Yb(OTf)3 catalyzed reations is given below.

1.1.1 Ytterbium triflate catalyzed organic reactions

Ytterbium triflate is probably one of the most exploited lanthanide triflate for a variety of such

organic transformations such as Aldol reaction,1,13

allylation reactions, Mannich-type reactions,14,15

Diels-Alder reactions,16,17

Fredal-Craft alkylation,18

acylation,19

protection, deprotection

reactions,20-22

oxidation reactions,23

total synthesis,24

and natural product synthesis.25

Yb(III) has

showed high Lewis acidity due to its small ionic radii.

Kumar et al.26

developed a straight forward method for the synthesis of 1-amidomethyl

imidazo[1,2-a]pyridines 4 using Yb(OTf)3 as catalyst (Scheme 1.1). The 3-substituted imidazo[1,2-

a]pyridines were achieved by a three-component reaction of aldehydes 2, acetamide 3, and

imidazo[1,2-a]pyridines 1 in moderate to good yield under mild reaction condition and the catalyst

was recycled.

Scheme 1.1 Yb(OTf)3 catalyzed synthesis of 1-amidomethyl imidazo[1,2-a]pyridines

Chapter-I

2

Jha et al.27

developed a tandem multicomponent approach for the synthesis of N-arylmethyl-6-

amino-2,4-diarylquinolines 8 from 1,4-phenylenediamines 5, aryl aldehydes 6, and arylacetylenes 7

using Yb(OTf)3 as catalyst (Scheme 1.2). The reported methodolgy provided easy access to novel

6-aminoquinoline derivatives via tandem Povarov reaction, 1,2-dihydroquinoline oxidation and

imine reduction.

Scheme 1.2 Yb(OTf)3 catalyzed synthesis of N-arylmethyl-6-amino-2,4-diarylquinolines

Chan et al.28

developed a method to synthesize indenols 11 by Yb(OTf)3 assisted Friedel-Crafts

alkylation/hydroarylation of propargylic alcohols 9 with phenols 10 in good yield (Scheme 1.3).

Scheme 1.3 Yb(OTf)3 catalyzed synthesis of indenols

Kobayashi et al.29

described the reaction of silyl enol ethers 13 with aldehydes 12 for the synthesis

of 2-(hydroxy(phenyl)methyl)cyclohexanone derivatives 14 (Scheme 1.4) in aqueous media using

catalytic amount of Yb(OTf)3 as catalyst in high yields.

Scheme 1.4 Yb(OTf)3 catalyzed synthesis of 2-(hydroxy(phenyl)methyl)cyclohexanone derivatives.

Chapter-I

3

Sello et al.30

reported four component Ugi-reaction of amine 15, aldehyde 16, isocyanide 18 and

carboxylic acid 17 using Yb(OTf)3 as Lewis acid to give α-acylamino carboxamide 19 in good to

excellent yield (Scheme 1.5). The catalyst was reused and recycled up to four times.

Scheme 1.5 Yb(OTf)3 catalyzed four component Ugi-reaction

Reutrakul et al.31

reported synthesis of (1-alkyl-1-aryl)methylphenylsulfones 22 from the reaction

of α-amido sulfones 21 with aryl compounds 20 using Yb(OTf)3 as catalyst (Scheme 1.6). The

reaction proceeded smoothly with the activated aromatic compounds at ambient temperature. The

advantage of the procedure is that one can avoid the usage of corrosive acids.

Scheme 1.6 Yb(OTf)3 catalyzed synthesis of (1-alkyl-1-aryl)methyl phenylsulfones

Barrett et al.32

reported Yb(OTf)3 as catalyst in the application of penicillin to cephalosporin

conversion (Scheme 1.7). The sulfinyl chloride was converted into the desired product 23 in

presence of Yb(OTf)3 at ambient temperature and further steps lead to synthesis of cephalosporin

25.

Scheme 1.7 Synthesis of Cephalosporin

Chapter-I

4

1.1.2 Ionic liquids

Ionic liquids are generally defined as liquids composed entirely of ions and having a melting point

below boiling point of water (Figure 1.1).33,34

The first publication using ionic liquids as solvent in

organic synthesis appeared in 1985.35,36

Chauvin et al and Wilkes et al.37

in 1990 explained

transition metal catalyst can be used as homogeneous system in ionic liquids. Over the past few

years ionic liquids have received a great attention for catalyst immobilization for large number of

reactions and successfully proved it can be immobilized polar catalyst also and further it can be

recovered and reused. The ionic liquids have unique chemical and physical properties,38-42

some of

the useful properties of ionic liquids are stated below.

1) They are designer solvents, because their melting point, viscosity, density, hydrophobicity

can be varied.

2) They are non-volatile in nature as compared to organic solvents.

3) All the reagents can bring into homogeneous system.

4) The acidic and basic properties can be tuned.

5) They have good thermal, chemical stability along with non-coordinating nature.

6) They have negligible vapour pressure

Figure 1.1 Chemical structures of different ionic liquids

Ionic liquids have received recognition as green media in organic synthesis and have contributed to

improve reaction condition and simple isolation process. The ionic liquids are one of the alternative

sources for volatile organic solvents. Moreover the reuse of solvent from the reaction media has

shown excellent results. Various reactions have been reported with the immobilization of metal

triflates in ionic liquids, with enhanced catalytic reactivity.47

After the reaction, both the solvent and

catalyst were easily recovered and reused. A brief overview of some recent literature for the

immobilization of metal triflates in ionic liquids is given below.

Chapter-I

5

1.1.3 Metal triflate catalyzed organic reactions in ionic liquids

Su et al.43

reported synthesis of dibenzoxanthenes 34 from 2-naphthol 32 and arylaldehydes 33

using Yb(OTf)3 in [Bmim][BF4] ionic liquid. The product formation was enhanced in presence of

ionic liquid as solvent. This method provides greener approach to prepare dibenzoxanthenes in

shorter reactions time, with high yields (Scheme 1.8).

Scheme 1.8 Yb(OTf)3 catalyzed synthesis of dibenzoxanthenes

Song et al.44

demonstrated the synthesis of prop-1-ene-1,1-diyldibenzenes 37 using Sc(OTf)3 in

[Bmim][SbF6] ionic liquid (Scheme 1.9). It is worthy to mention that replacing the ionic liquid with

other solvents diminished the yields of Friedel‒Craft alkenylation product.

Scheme 1.9 Synthesis of prop-1-ene-1,1-diyldibenzenes using Sc(OTf)3 and [Bmim][SbF6]

Chauhan et al.45

synthesized 1,3-oxathiolanes 40 in ionic liquids using Yb(OTf)3 as a catalyst

(Scheme 1.10). The 1,3-oxathiolanes were achieved from the reaction of carbonyl compounds 38

with 2-mercaptoethanol 39 with high yield and the catalyst can be easily recovered and reused in

this reaction. The catalytic activity of metal triflates dramatically increased in presence of ionic

liquid as solvent.

Scheme 1.10 Yb(OTf)3–catalyzed 1,3-oxathiolanes 3 from carbonyl compounds in ionic liquid

Chapter-I

6

Xiao et al.46

demonstrated Cu(OTf)2 catalyzed Friedel–Crafts acylations in [bmim][BF4] ionic

liquid (Scheme 1.11). The regioselectivitiy of acetylation and reaction rate dramatically increased

in ionic liquid compared with conventional solvent conditions.

Scheme 1.11 Cu(OTf)2 catalyzed Friedel–Crafts acylation in [bmim][BF4]

Laali et al.47

reported that metal triflates immobilized in imidazolium ionic liquids were efficient

systems for propargylation of arenes and hetero arenes (Scheme 1.12). The final product 46 and 48

were achieved in high yield from the reaction of propargylic alcohols 44 and corresponding aryl

arenes 45 and hetero arenes 47, respectively. Further they demonstrated no appreciable decrease in

product after reuse of the IL.

Scheme 1.12 M(OTf)3 catalyzed propargylation of arenes and heteroarenes in ionic liquids

Lee et al.48

explored intramolecular Friedel–Crafts alkenylation reaction of aryl phenyl propiolates

49 and phenyl propinamide catalyzed by Hf(OTf)4 in a mixture of [bmim][SbF6] and

methylcyclohexane. 4-Phenylcoumarins 50 and 2-(1H)-quinolinones were obtained in moderate to

good yields (Scheme 1.13).

Chapter-I

7

Scheme 1.13 Hf(OTf)4 catalyzed synthesis of 4-phenylcoumarins and 2(1H)-quinolinones

Multi-component reactions (MCRs) have emerged as a powerful synthetic strategy in organic and

medicinal chemistry to generate structurally diverse libraries of drug-like molecules.49

MCRs offer

significant advantages over conventional linear-type syntheses, such as being rapid and one-pot

reactions without the need to generate and purify intermediates.

Chapter-I

8

Part A: Synthesis of Tetrahydroindazolones and their Biological

Evaluation

Tetrahydroindazolones (THI’s) have broad spectrum of biological and pharmacological activities.50

Compounds with indazoles and indazolones scaffolds have been reported to exhibit herbicidal, anti-

inflammatory,51

anticancer,52

and antituberculosis53-55

activities. A tetrahydroindazolone scaffold

containing SNX-2122 (Figure 1.2) 51 is a heat-shock protein 90 (HSP-90) inhibitor52

and it

exhibits potent antiproliferative activities against HER2-dependent breast cancer cells.56

Tetrahydroindazole-based compound 52 is a potent inhibitor of Mycobacterium tuberculosis

(MTB).

Figure 1.2 Chemical structures of lead compounds containing tetrahydroindazolone scaffolds (51)

SNX-2122 HSP90 inhibitor; (52) MTB inhibitor

1.2 Literature methods for the synthesis of tetrahydroindazolones

The most common method for the synthesis of THI’s is a simple condensation of arylhydrazines

with 2-acylcyclohexane-1,3-diones.57-60

Park et al.59

developed a strategy for the regioselective

synthesis of N-alkyl-3-substituted tetrahydroindazolones 57 using Boc-protected alkylhydrazines

54, dimedone 53 and arylaldehydes 56 (Scheme 1.14). The procedure provides an advantage of

synthesizing two regiomers in good yield.

Scheme 1.14 Synthesis of N-alkyl-3-substituted tetrahydroindazolones

Chapter-I

9

Petrova et al.57

synthesized substituted tetrahydroindazole derivatives 57 using arylhydrazines,

dimedone 58 to give appropriate phenylhydrazone 59, which on reacting with arylaldehyde 56 gave

desired product (Scheme 1.15).

Scheme 1.15 Synthesis of tetrahydroindazolones

Nagakura et al.61

synthesized and isolated regioisomeric mixtures of tetrahydroindazole, further it

was purified by column chromatography with low yields. There are very few methods for the

synthesis of 2-substituted THI’s and separation of 2-substituted THI’s from a mixture of isomers is

challenging and, therefore, these compounds have not been much explored for biological activity.

Therefore, there is need for an eco-friendly and green catalysts which can be recycled at the end of

reactions and give good yield.

1.3 Results and discussion

1.3.1 Chemistry

Protocol standardization experiment was conducted with 5,5-dimethylcyclohexane-1,3-dione (60),

4–chlorobenzaldehyde (61), and 3,4-dichlorophenylhydrazine (62) in ethanol at room temperature

in presence of Yb(OTf)3 (20 mol%), the product 63aaa (R1 = Me, X = C, R

2 = 3,4-Cl2C6H3, R

3 = 4-

ClC6H4) was obtained in 20% yield (Scheme 1.16).

Scheme 1.16 Synthesis of substituted tetrahydroindazolones

Further optimization of reaction condition was carried out by changing solvents, catalysts, and

catalyst loading. As shown in Table 1.1, the use of 20 mol% Yb(OTf)3 in [bmim][BF4] gave the

desired product 63aaa in high yield 88% (entry 4). When Yb(OTf)3 was changed with other metal

Chapter-I

10

triflates such as Sc(OTf)3, Zn(OTf)2, Cu(OTf)2 or AgOTf the yield of 63aaa was moderate to good

(Table 1.1, entries 7-10). The catalytic order Yb(OTf)3 > Zn(OTf)2 > Sc(OTf)3 > Cu(OTf)2 >

AgOTf was established for the synthesis of 63aaa based on isolated yield in [bmim][BF4]. There

was not much increase in yield of 63aaa on changing the amount of Yb(OTf)3 from 20 mol% to 40

mol% (Table 1.1, entries 4-6). However, reducing the amount of Yb(OTf)3 decreased yield of

63aaa 75% to 51%. It should be noted that no product formation was observed in solvent free

conditions; however 45% of 63aaa was formed in the absence of Yb(OTf)3. It is worthy to mention

that under these conditions we obtained only 2-substituted tetrahydroindazolones (THI’s).

Table 1.1 Optimization of reaction conditions for the model reaction 63aaa

entry Catalyst Moles (%) Solvent Yield (%)a

1 Yb(OTf)3 0 [bmim][BF4] 45

2 Yb(OTf)3 10 - NPb

3 Yb(OTf)3 10 [bmim][BF4] 51

4 Yb(OTf)3 20 [bmim][BF4] 88

5 Yb(OTf)3 30 [bmim][BF4] 90

6 Yb(OTf)3 40 [bmim][BF4] 89

7 Zn(OTf)2 20 [bmim][BF4] 70

8 Ag(OTf) 20 [bmim][BF4] 50

9 Sc(OTf)3 20 [bmim][BF4] 60

10 Cu(OTf)2 20 [bmim][BF4] 56

11 Yb(OTf)3 20 [bmim][PF6] 65

12 Mont. K-10 20 Ethanol 20

13 pTSA 20 Ethanol 20

14 Yb(OTf)3 20 Ethanol 20

15 Yb(OTf)3 20 Toluene NA

16 Yb(OTf)3 20 THF NA

aIsolatedyield, b

No product formed

Chapter-I

11

The structure of the compound 63aaa was confirmed by 1H NMR,

13C NMR and mass data. In

1H

NMR three singlet were observed at δ 2.81, 2.42 and 1.16 ppm for C7-CH2, C5-CH2, and C6-(CH3)2,

respectively along with other aromatic protons. Under the optimized reaction conditions, various

arylhydrazines, arylaldehydes, and 1,3-diones were reacted in one-pot to afford the corresponding

2-substituted THI’s 63aaa-bba (Table 1.2). Various substituents such as nitro, halo, hydroxyl,

methoxy, alkyl on arylaldehydes and arylhydrazines were well tolerated (Scheme 1.16). The yield

of the products was good to excellent (48-88%).

Table 1.2 Synthesized 2-substituted THI’s 63aaa-bba.

Compound R1 X R

2 R3 Yield (%)

a

63aaa CH3 CH2 3,4-Cl2C6H3 4-ClC6H4 88

63aab CH3 CH2 3,4-Cl2C6H3 4-NO2C6H4 85

63aac CH3 CH2 3,4-Cl2C6H3 C4H3S 73

63aad CH3 CH2 3,4-Cl2C6H3 4-CH3C6H4 83

63aae CH3 CH2 3,4-Cl2C6H3 3-OH,4-OMeC6H3 65

63aaf CH3 CH2 3,4-Cl2C6H3 4-OHC6H4 70

63aag CH3 CH2 3,4-Cl2C6H3 C4H4N 80

63aah CH3 CH2 3,4-Cl2C6H3 4-OMeC6H4 74

63aai CH3 CH2 3,4-Cl2C6H3 C6H5 75

63aaj CH3 CH2 3,4-Cl2C6H3 3-ClC6H4 82

63baa H CH2 3,4-Cl2C6H3 4-ClC6H4 82

63bab H CH2 3,4-Cl2C6H3 C4H3S 71

63bac H CH2 3,4-Cl2C6H3 4-CH3C6H4 78

63bad H CH2 3,4-Cl2C6H3 2-FC6H4 77

63bae H CH2 3,4-Cl2C6H3 4-OMeC6H4 70

63baf H CH2 3,4-Cl2C6H3 C6H5 72

63bag H CH2 3,4-Cl2C6H3 4-OHC6H4 65

63bah H CH2 3,4-Cl2C6H3 3-OH,4-OMeC6H3 60

63bai H CH2 3,4-Cl2C6H3 4-NO2C6H4 84

63bba H CH2 3-Cl, 4-CH3C6H3 3-OMeC6H4 77

63aba CH3 CH2 3-Cl, 4-CH3C6H3 4-ClC6H4 81

63abb CH3 CH2 3-Cl, 4-CH3C6H3 C5H4N 69

63abc CH3 CH2 3-Cl, 4-CH3C6H3 C4H4N 54

Chapter-I

12

The chemical structures of all synthesized compounds were elucidated by 1H NMR,

13C NMR, and

mass spectral data. For example, a representative 1H and

13C NMR spectra for compound 63ada are

shown in Figure 1.3. In 1H NMR five singlet peaks were observed at δ 3.81, 2.81, 2.42, 1.30 and

1.16 ppm for OCH3, C7-CH2, C5-CH2, C-(CH3)3 and C6-(CH3)2 respectively, along with other

aromatic protons. A peak appeared at δ 193.59, 55.24, 31.24 and 28.50 for C=O, OCH3, C-(CH3)3

and C6-(CH3)2 in 13

C NMR respectively, along with other carbons.

Figure 1.3a 1H NMR spectrum of THI 63ada

63aca CH3 CH2 C6H11 C4H3S 78

63acb CH3 CH2 C6H11 4-NO2C6H4 80

63acc CH3 O C6H11 4-ClC6H4 50

63bca H CH2 C6H11 3-ClC6H4 76

63bcb H CH2 C6H11 4-CH3C6H4 76

63ada CH3 CH2 4-(CH3)3CC6H4 4-OMeC6H4 77

63adb CH3 CH2 4-(CH3)3CC6H4 3,4-(OMe)2C6H3 81

63adc CH3 CH2 4-(CH3)3CC6H4 4-ClC6H4 77

63add CH3 O 4-(CH3)3CC6H4 4-ClC6H4 48

63ade CH3 CH2 4-(CH3)3CC6H4 4-CH3C6H4 79

aIsolated yield

Chapter-I

13

Figure 1.3b 13

C NMR spectrum of THI 63ada

The regioselective formation of N-2-substituted THI’s indicates that hydrazine first attacks at

carbonyl group of diketone. Based on the product formation, the reaction is believed to proceed

through the formation of hydrazone followed by attack of aldehyde to give aldol product, which

undergoes nucleophilic addition as shown in Scheme 1.17. It appears that ionic liquid helps in

stabilization of charged intermediate generated by coordination of Yb(OTf)3 to aldehydes and

diones. Furthermore, the acidic C-2 proton of imidazolium ionic liquid also facilitates the

enolization of dione.

Chapter-I

14

Scheme 1.17 Plausible mechanism for synthesis of THI’s

Furthemore, regioselective formation of 2-substituted THI’s was confirmed by X-ray

crystalographic data for compound 63aac (CCDC 848784) and 63aca (CCDC 850178). The

ORTEP view for compound 63aac and 63aca (Figure 1.4) clearly shows that 3,4-dichlorophenyl

and cyclohexyl group are at N-2 position in 63aac and 63aca, respectively.

Figure 1.4 ORTEP view of molecular structure of compound (a) 63aac and (b) 63aca

Combretastatin A-4 (CA4) (Figure 1.5) 64 is a potent anti-proliferative agent which acts through

interaction with microtubules. Analogues of CA4 and several other derivatives where cis-double

bond was replaced with a tetrazole, thiazole, imidazole, or oxazole rings have been synthesized and

studied for evaluating anticancer activities and establishing structure-activity relationships.62,63,64

THI’s have also been previously reported possessing antitumor activity.65

The synthesized THI’s

have structural resemblance to the tetrazole, triazole, imidazole, or oxazole derivatives of CA4 that

a b

Chapter-I

15

were shown to exhibit potent cytotoxicity and anti-tumor activity.62,66

We hypothesized that

incorporation of crucial structural features of CA4 and THI’s may generate lead compounds with

anticancer properties (Figure 1.5).

Phenylpyrazolopyrimidine 66 derivatives, such as PP1 and PP267

have been reported as inhibitors

of the Src family of tyrosine kinases (SFKs) that play prominent roles in multiple signal

transduction pathways, involving cell growth and differentiation. The nine members of non receptor

SKFs (Src, Yes, Lck, Fyn, Lyn, Fgr, Hck, Blk, and Yrk) share a great deal of structural homology

and are present in the cytoplasm.68

The expression of Src tyrosine kinase, the prototype of SFKs, is

frequently elevated in a number of epithelial tumors compared with the adjacent normal tissues. Src

reduces cancer cell adhesions and facilitates their motility,69

thus it is a key modulator of cancer cell

invasion and metastasis.70,71

Heterocyclic THI’s have some structural similarity with

phenylpyrazolopyrimidine derivatives (Figure 1.5), and were investigated to determine whether

they can mimic PP1 and PP2.

Figure 1.5 Structural relativity of THI to Combrestatin A-4 and phenylpyrazolopyrimidines

In search of small molecules as anticancer agents and/or c-Src kinase inhibitors,72-74

the synthesized

THI derivatives were evaluated for c-Src kinase inhibition and anti-cancer activities.

Chapter-I

16

1.3.2 Biological activity

1.3.2.1 c-Src kinase inhibitory activities

Synthesized substituted THI’s were evaluated for c-Src kinase inhibitory activity. The results of Src

kinase inhibitory activity of compounds (63aaa61bba) is shown in Table 1.3. Among all the

compounds, 63aai, 63aaj, 63baf, 63bba, 63aba, and 63aca showed modest c-Src kinase inhibition

with IC50 values in the range of 35-77 µM. The highest Src kinase inhibitory activities were

observed for compounds 63aca and 63aaj with IC50 values 35.1 and 50.7 M, respectively, among

all the compounds.

Table 1.3 c-Src kinase inhibitory activity of substituted THI’s 63aaabba

Compound IC50 (µM) Compound IC50 (µM)

63aaa 86.0 63bai 150

63aab 150 63bba 82.7

63aac 150 63aba 131.8

63aad 150 63abb 74.3

63aae 150 63abc 150

63aaf 66.6 63aca 77.3

63aag 150 63acb 150

63aah 94.1 63acc 150

63aai 62.1 63bca 58.4

63aaj 50.7 63bcb 57.7

63baa 81.0 63ada 35.1

63bab 150 63adb 150

63bac 150 63adc 150

63bad 150 63add 150

63bae 150 63ade 150

63baf 65.8 Staurosporine 0.6

63bag 150 PP2 0.5

63bah 150

Chapter-I

17

1.3.2.2 Molecular modeling

Molecular modeling and energy minimization of compounds 63aca and 63aaj was used to explore

and compare the binding mode of these compounds with PP1 within the ATP-binding site of the

enzyme (Figure 1.6). The compounds and side chains of amino acids are rendered in stick styles.

Compounds are in the lowest energy conformers predicted. The Figure is drawn using the Accelrys

visualization system. The backbone tetrahydroindazolone in 63aca and 63aaj and

pyrazolopyrimidine in PP1 occupied a similar pocket in ATP-binding site of Src. The modeling

studies indicated that 3,4-dichlorophenyl and 4-(tert)butylphenyl at R2 position in 63aaj and 63aca,

respectively, occupy and fit the hydrophobic binding pocket similar to tolyl group of PP1 with

slightly different orientations of phenyl groups (Figure 1.6). The 4-methoxyphenyl and 3-

chlorophenyl at R3 position of 63ada and 63aaj, respectively, are oriented far from the large cavity

that is formed from side chains of helix αC and helix D, where the triphosphate group of ATP

usually binds similar to that of t-butyl group of PP1, thus suggesting that substitution at R3 position

of THI’s does not generate any advantageous in Src kinase inhibition through interactions with

adjacent amino acids in the ATP binding site.

These data suggest that further structural modifications in tetrahydroindazolone scaffold is required

to convert them to more potent Src kinase inhibitors such as phenylpyrazolopyrimidine derivatives

PP1 and PP2.

Figure 1.6 Comparison of structural complexes of Src kinase with different THI’s derivatives

63ada (yellow), PP1 (blue), and 63aaj (red) based on molecular modeling.

Chapter-I

18

1.3.2.3 Anti‒cancer activity

All the synthesized compounds 63aaabba were evaluated for their effect on proliferation of

ovarian adenocarcinoma cells (SK-OV-3) and colon adenocarcinoma (HT-29), two human cancer

cells lines that over express c-Src.75

Doxorubicin (Dox) and DMSO were used as positive and

negative controls, respectively. The results for cell proliferation at 50 µM after 72 h for compound

63aaabba are shown in (Figure 1.7). The results are shown as the percentage of the control

DMSO that has no compound (set at 100%). All the experiments were performed in triplicate. All

the compounds were more active against HT-29 cells than SK-OV-3 cells.

Compounds 63baf, 63acb, and 63adb inhibited the cell proliferation of HT-29 cells by 65-72%

while they were not effective against SK-OV-3. Compounds 63bab, 63bac, and 63aba showed 48-

62% and 49-58% inhibition in the cell proliferation of HT-29 and SK-OV-3 cells, respectively. The

presence of C4H3S- substituent as R3 or 3,4-dichlorophenyl or tolyl as R

2 is critical for maximum

anti-proliferative activity as seen in compounds 63bab and 63bac.

Figure 1.7 Inhibition of HT-29 and SK-OV-3 cell proliferation by compounds 63aaabba (50 µM)

after 72 h incubation.

Poor correlation between inhibition of c-Src kinase and the cell proliferation could be due to the

differential cellular uptake and alternative mechanisms in anti-proliferative activities of the

compounds.

0

20

40

60

80

100

120

140

160

180

DM

SO

DO

X

63

aaa

63

aab

63

aac

63

aad

63

aae

63

aaf

63

aag

63

aah

63

aai

63

aaj

63

baa

63

bab

63

bac

63

bad

63

bae

63

baf

63

bag

63

bah

63

bai

63

bb

a

63

aba

63

abb

63

abc

63

aca

63

acb

63

acc

63

bca

63

bcb

63

ada

63

adb

63

adc

63

add

63

ade

HT-29 SK-OV-3

Chapter-I

19

1.4 Conclusions

In conclusion, an eco-friendly and regioselective method was developed for the synthesis of 2-

substituted THI’s by one-pot three-component coupling reaction of benzaldehydes, arylhydrazines,

and 1,3-diones using Yb(OTf)3 as a catalyst in ionic liquid. The synthesized compounds were

evaluated for c-Src kinase inhibitory activity and compound 63aca showed moderate inhibition of

c-Src kinase with IC50 value of 35.1 µM. Compounds 63bab and 63bac consistently inhibited the

cell proliferation of SK-OV-3 and HT-29 cells by 49-62% at a concentration of 50 μM. Further

structure-activity relationship studies are required for optimizing the c-Src kinase inhibition and

anti-proliferative activities of THI’s.

1.5 Experimental

1.5.1 General

Melting points were determined in open capillary tubes on a MPA120-Automated Melting Point

apparatus and are uncorrected. NMR spectra were recorded on a Bruker Heaven Avance 11400 and

Varian (500 MHz) spectrometers using CDCl3 and DMSO-d6 as solvents and the chemical shifts are

expressed in ppm. Data are reported as follows: chemical shifts, multiplicity (s = singlet, d =

doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet), coupling constants (Hz),

and integration. The IR spectra were recorded using KBr pellets on Shimadzu Prestige-21 FTIR

spectrophotometer and max is expressed in cm-1

. Mass spectra were recorded on a QSTAR® ELITE

LX/MS/MS mass spectrometer from Applied Biosystem. Metal triflates, diketones, hydrazines, 2ꞌ-

hydroxyacetophenones, 2ꞌ-aminoacetophenones and aldehydes were purchased from Sigma-

Aldrich. All other reagents and solvents were purchased from S. D. Fine, India and used without

further purification unless otherwise specified. The products were purified by column

chromatography using silica gel (60-120 mesh, S. D. Fine, India). The purity of the products was

determined on silica-coated aluminum plates (Merck). 2'-Hydroxychalcone and 2'-aminochalcones

were prepared using the appropriate aldehyde and the corresponding ortho-substituted

acetophenones.76

The ionic liquid, [bmim][BF4] was prepared from 1-methylimidazole by minor

modification of literature procedure.77

Chapter-I

20

1.5.2 Representative procedure for synthesis of 63aaa

(3,4-Dichlorophenyl)hydrazine. HCl (1.0 mmol) and 5,5-dimethylcyclohexane-1,3-dione (1.0

mmol) were mixed at 90 °C in presence of Yb(OTf)3 (20 mol%) in [bmim] [BF4] ionic liquid

followed by addition of 4-chlorobenzaldehyde (1.2 mmol) to the reaction mixture with vigorous

stirring at 100 °C. After completion of reaction as indicated by TLC the product was isolated using

hexane: ethyl acetate (50%) and purified through column chromatography to afford 63aaa in good

yield (88%).

1.5.3 Analytical data for the synthesized compounds

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-3-(4

ꞌꞌ-chlorophenyl)-6,7-dihydro-6,6-dimethyl-2H-indazol-4(5H)-one

(63aaa)

M.p.: 147 – 149 °C. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 2.46

Hz, 1H), 7.37 – 7.26 (m, 3H), 7.31 – 7.27 (m, 2H), 6.91 (dd, J =

8.65, 2.48 Hz, 1H), 2.81 (s, 2H), 2.42 (s, 2H), 1.16 (s, 6H). 13

C NMR

(125 MHz, CDCl3) δ 193.43, 157.04, 142.13, 138.10, 136.05,

133.34, 132.39, 131.59, 130.52, 128.76, 127.15, 126.02, 124.20,

116.29, 53.68, 37.10, 34.85, 28.42. ESI-MS (m/z): calcd. for

C21H17Cl3N2O 418.0406, found 419.0464 [M + H] +

.

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-6,6-dimethyl-3-(4

ꞌꞌ-nitrophenyl)-2H-indazol-4(5H)-one

(63aab)


Hz, 2H), 7.56 – 7.54 (d, J = 2.48 Hz, 3H), 7.32 (s, 1H), 6.91 (d, J =

8.0 Hz, 1H), 2.84 (s, 2H), 2.45 (s, 2H), 1.18 (s, 6H). 13

C NMR (100

MHz, CDCl3) δ 193.49, 157.27, 148.25, 140.69, 137.68, 134.08,

133.00, 131.44, 130.77, 127.21, 124.18, 123.55, 116.90, 53.62,

37.04, 34.95, 28.43. ESI-MS (m/z): calcd. for C21H17Cl2N3O3

429.0647, found 430.0687 [M + H]+.

Chapter-I

21

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-6,6-dimethyl-3-(thiophen-2-yl)-2H-indazol-4(5H)-one

(63aac)


Hz, 1H), 7.49 (d, J = 4.0 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.12 (d, J =

8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 2.80 (s, 2H), 2.45 (s, 2H), 1.16

(s, 6H). 13

C NMR (100 MHz, CDCl3) δ 193.18, 156.90, 138.43,

137.55, 133.23, 133.01, 132.06, 130.63, 129.37, 129.03, 128.03, 127.45, 125.17, 116.12, 53.79,

31.17, 34.73, 28.42. ESI-MS (m/z): calcd. for C21H17Cl2N3O3 429.0647, found 430.0687 [M + H]+.

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-6,6-dimethyl-3-p-tolyl-2H-indazol-4(5H)-one (63aad)

M.p.: 148 – 150 °C. 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.32

(d, J = 8.0 Hz, 1H), 7.24 (d, J = 4.0 Hz, 2H), 7.18 (d, J = 4.0 Hz,

2H), 6.94 (d, J = 8.0 Hz, 1H), 2.81 (s, 2H), 2.42 (s, 2H), 1.16 (s,

6H). 13

C NMR (100 MHz, CDCl3) δ 193.33, 156.94, 140.03, 138.52,

136.12, 133.07, 131.96, 130.34, 130.18, 129.16, 127.09, 124.59,

124.29, 116.10, 53.75, 37.19, 34.82, 28.46, 21.50. ESI-MS (m/z): calcd. for C22H20Cl2N2O

398.0953, found 399.1037 [M + H]+.

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-3-(4

ꞌꞌ-hydroxy-3-methoxyphenyl)-6,6-dimethyl-2H-

indazol-4(5H)-one (63aae)

M.p.: 219 – 221 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H),

7.51 (s, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.00 – 6.98 (m, 2H), 6.80 (d, J

= 8.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 3.79 (s, 3H), 2.80 (s, 2H),

2.42 (s, 2H), 1.16 (s, 6H). 13

C NMR (125 MHz, DMSO-d6) δ 194.74,

157.61, 147.36, 144.57, 138.93, 132.57, 127.61, 124.29, 118.90,

115.97, 115.34, 114.08, 56.38, 37.43, 35.23, 28.76. ESI-MS (m/z): calcd. for C22H20Cl2N2O3

430.0851, found 431.0922 [M + H]+.

Chapter-I

22

2-(3ꞌ,4


ꞌꞌ-hydroxyphenyl)-6,6-dimethyl-2H-indazol-4(5H)-

one (63aaf)


Hz, 1H), 7.32 (d, J = 8.66 Hz, 1H), 7.14 (d, J = 8.46 Hz, 2H,), 6.95

(dd, J = 8.66, 2.46 Hz, 1H), 6.77 (d, J = 8.50 Hz), 2.79 (s, 2H), 2.42

(s, 2H), 1.15 (s, 6H). 13

C NMR (125 MHz, CDCl3) δ 193.33, 158.17,

157.17, 144.17, 138.35, 133.03, 131.68, 130.43, 127.09, 124.32,

123.63, 122.13, 115.69, 53.70, 37.06, 34.93, 28.39, 19.30. ESI-MS (m/z): calcd. for C21H18Cl2N2O2

400.0745, found 401.0802 [M + H]+.

2-(3ꞌ,4

ꞌ-dichlorophenyl)-3-(2

ꞌꞌ-fluorophenyl)-6,7-dihydro-6,6-dimethyl-2H-indazol-4(5H)-one

(63aag)

M.p.: 146 – 148 °C. 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.48 (m,

1H), 7.50 – 7.43 (m, 1H), 7.39 (t, J = 12.0 Hz, 1H), 7.35 (d, J = 8.0

Hz, 1H), 7.22 (t, J = 12.0 Hz, 1H), 7.09 (t, J = 12.0 Hz, 1H), 7.01 (d,

J = 4.0 Hz, 1H), 2.83 (s, 2H), 2.42 (s, 2H), 1.16 (s, 6H). ESI-MS

(m/z): calcd. for C21H17Cl2FN2O 402.0702, found 403.0769 [M + H]+.

2-(3ꞌ,4


ꞌꞌ-methoxyphenyl)-6,6-dimethyl-2H-indazol-4(5H)-

one (63aah)


(d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz,

1H), 6.89 (d, J = 8.0 Hz, 2H), 3.83, (s, 3H), 2.80 (s, 2H), 2.42 (s,

2H), 1.16 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ 193.42, 160.65,

156.97, 143.49, 138.58, 133.12, 131.96, 131.77, 130.38, 127.14,

124.29, 119.61, 115.87, 113.90, 53.31, 53.76, 32.70, 28.46. ESI-MS (m/z): calcd. for

C22H20Cl2N2O2 414.0902, found 415.0993 [M + H]+.

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-6,6-dimethyl-3-phenyl-2H-indazol-4(5H)-one (63aai)


– 7.31 (m, 6H), 6.94 (d, J = 8.0 Hz, 1H), 2.82 (s, 2H), 2.43 (s, 2H),

1.17 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ 193.38, 156.96, 143.46,

138.38, 133.13, 132.09, 130.27, 130.21, 129.85, 127.67, 124.19,


Chapter-I

23

C21H18Cl2N2O 384.0796, found 385.0993 [M + H]+.

2-(3ꞌ,4



(63aaj)


Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.97 – 6.94 (m, 4H), 6.85 (d, J =

4.0 Hz, 1H), 3.77 (s, 3H), 2.81 (s, 2H), 2.42 (s, 2H), 1.17 (s, 6H). 13

C

NMR (100 MHz, CDCl3) δ 193.33, 159.30, 156.92, 143.22, 138.44,

132.04, 130.36, 129.49, 128.86, 126.97, 124.10, 122.49, 116.29,

115.80, 115.71, 55.39, 53.77, 37.17, 34.84, 28.47. ESI-MS (m/z): calcd. for C20H16Cl2N2O

370.064, found 371.0781 [M + H]+.

2-(3ꞌ,4



(63baa)

M.p.: 141 – 143 °C. 1H NMR (400 MHz, , CDCl3) δ 7.60 – 7.52 (m,

2H, ), 7.41 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 4.0 Hz, 1H), 7.13 (d, J =

12.0 Hz, 1H), 2.84 (t, J = 8.0 Hz, 2H), 2.52 – 2.43 (m, 2H), 2.06 (t, J

= 8.0 Hz, 2H). 13

C NMR (100 MHz, CDCl3) δ 196.28, 160.86,

157.81, 150.29, 146.02, 142.46, 132.56, 132.52, 133.97, 133.97,

131.60, 131.44, 128.72, 127.89, 126.10, 63.83, 23.47, 22.98. ESI-MS (m/z): calcd. for

C19H13Cl3N2O 390.0093, found 391.0170 [M + H]+.

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-3-(thiophen-2-yl)-2H-indazol-4(5H)-one (63bab)


3H), 7.44 (d, J = 4.0 Hz, 1H), 7.30 (d, J = 4.0 Hz, 1H), 7.09 – 7.07

(m, 1H), 2.85 (t, J = 12.0 Hz, 2H), 2.51 – 2.47 (m, 2H), 2.07 (t, J =

8.0 Hz, 2H). 13

C NMR (100 MHz, CDCl3) δ 193.51, 157.63, 138.96,

137.43, 132.51, 131.53, 130.71, 128.61, 127.60, 127.59, 126.87,

117.10, 55.32, 23.18, 23.15. ESI-MS (m/z): calcd. for C17H12Cl2N2OS 362.0047, found 363.0165

[M + H]+.

Chapter-I

24

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-3-p-tolyl-2H-indazol-4(5H)-one (63bac)


Hz, 1H,), 7.24 (d, J = 8.66 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.09 (d,

J = 8.01 Hz, 2H), 6.84 (dd, J = 9.42, 0.77 Hz, 1H), 2.87 (t, J = 6.15

Hz, 2H), 2.50 – 2.42 (m, 2H), 2.29 (s, 3H), 2.22 – 1.93 (m, 2H). 13

C

NMR (125 MHz, CDCl3) δ 193.78, 157.66, 143.85, 139.98, 138.46,

133.05, 131.97, 130.04, 128.98, 127.12, 124.70, 124.26, 117.15,

39.80, 23.42, 23.31, 21.48. ESI-MS (m/z): calcd. for C20H16Cl2N2O 370.064, found 371.0781

[M + H]+.

2-(3ꞌ,4


ꞌ-fluorophenyl)-6,7-dihydro-2H-indazol-4(5H)-one (63bad)

M.p.: 121 – 123 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J =

8.0 Hz,), 7.54 – 7.50 (m, 2H), 7.42 (t, J = 12.0 Hz, 2H), 7.27 – 7.22

(m, 2H), 7.17 (d, J = 4.0 Hz, 1H), 2.90 (t, J = 12.0 Hz, 2H), 2.52 –

2.45 (m, 2H), 2.09 (t, J = 8.0 Hz). 13

C NMR (100 MHz, DMSO-d6) δ

193.50, 160.44, 158.40, 157.68, 138.66, 137.12, 132.81, 131.93,

131.48, 126.79, 124.95, 118.55, 116.65, 116.54, 116.29, 116.13, 58.30, 23.31, 22.98. ESI-MS (m/z):

calcd. for C19H13Cl2FN2O 374.0389, found 375.0526 [M + H]+.

2-(3ꞌ,4


ꞌꞌ-methoxyphenyl)-2H-indazol-4(5H)-one (63bae)


8.0 Hz, 1H), 7.58 (s, 1H), 7.25 (d, J = 4.0 Hz, 2H), 7.12 – 7.10 (m,

1H), 6.93 (d, J = 4.0 Hz, 2H), 3.31 (s, 3H), 2.86 (t, J = 12.0 Hz,

2H), 2.49 – 2.43 (m, 2H), 2.07 (t, J = 8.0 Hz, 2H). 13

C NMR (100

MHz, DMSO-d6) δ 193.49, 160.46, 157.50, 143.58, 139.10, 132.22,

131.83, 131.27, 131.11, 127.86, 126.00, 120.11, 116.95,

114.07, 55.66, 23.33, 23.19. ESI-MS (m/z): calcd. for C20H16Cl2N2O2 386.0589, found 387.0704 [M

+ H]+.

Chapter-I

25

2-(3ꞌ,4

ꞌ-Dichlorophenyl)-6,7-dihydro-3-phenyl-2H-indazol-4(5H)-one (63baf)


8.0 Hz, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.41 – 7.36 (m, 3H), 7.32 –

7.28 (m, 2H), 7.13 (d, J = 4.0 Hz, 1H), 2.88 (t, J = 12.0 Hz, 2H),

2.49 – 2.44 (m, 2H), 2.08 (t, J = 12.0 Hz, 2H). 13

C NMR (100 MHz,

DMSO-d6) δ 193.53, 157.53, 143.54, 138.87, 131.78, 131.27,

131.22, 130.66, 129.96, 128.61, 128.31, 125.99, 117.27, 55.49, 22.33, 23.14. ESI-MS (m/z):

Calcd. for C19H14Cl2N2O 356.0483, found 357.0648 [M + H]+.

2-(3ꞌ,4


ꞌꞌ-hydroxyphenyl)-2H-indazol-4(5H)-one (63bag)


Hz, 1H), 7.28 (d, J = 8.65 Hz, 1H), 7.08 (d, J = 8.62 Hz, 2H), 6.89

(dd, J = 8.65, 2.46 Hz, 1H), 6.71 (d, J = 8.64 Hz, 2H), 5.35 (s, 1H),

2.86 (t, J = 6.27 Hz, 2H), 2.57 – 2.31 (m, 2H), 2.19 – 2.01 (m, 2H).

13C NMR (125 MHz, CDCl3) δ 194.79, 158.45, 157.83, 144.44,

138.29, 131.67, 124.38, 118.15, 116.53, 115.34, 39.57, 23.18, 23.15.

ESI-MS (m/z): calcd. for C19H14Cl2N2O2 372.0432, found 373.0530 [M + H]+.

2-(3ꞌ,4


ꞌꞌ-hydroxy-4-methoxyphenyl)-2H-indazol-4(5H)-one

(63bah)

M.p.: 186 –188 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.49 – 9.45

(m, 1H), 7.65 – 7.58 (m, 1H), 7.18 – 7.12 (m, 1H), 7.06 – 6.95 (m,

2H), 6.84 (d, J = 4.0 Hz, 2H), 3.65 (s, 3H), 2.89 – 2.86 (m, 2H), 2.50

– 2.47 (m, 2H), 2.07 (t, J = 8.0 Hz 2H). 13

C NMR (125 MHz,

DMSO-d6) δ 193.46, 157.46, 148.34, 148.30, 147.91, 147.41,

144.03, 139.29, 131.72, 131.20, 130.98, 127.78, 125.96, 123.93,

123.83, 118.71, 115.57, 55.87, 39.32, 23.39, 23.14. ESI-MS (m/z): calcd. for C20H16Cl2N2O3

402.0538, found 403.0572 [M + H]+.

Chapter-I

26

2-(3,4-Dichlorophenyl)-6,7-dihydro-3-(4-nitrophenyl)-2H-indazol-4(5H)-one (63bai)

M.p.: 238 – 240 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.28 – 8.18

(m, 2H,), 7.69 – 7.59 (m, 4H), 7.18 – 7.08 (m, 1H), 2.90 (t, J = 12.0

Hz, 2H), 2.49 – 2.47 (m, 2H), 2.13 – 2.09 (m, 2H). 13

C NMR (100

MHz, DMSO-d6) δ 193.75, 164.11, 157.73, 148.21, 141.28, 138.38,

134.83, 132.37, 131.78, 131.46, 128.13, 126.20, 123.61, 117.84,

31.13, 23.22, 23.11. ESI-MS (m/z): calcd. for C19H13Cl2N3O3

401.0334, found 402.0406 [M + H]+.

2-(3-Chloro-4-methylphenyl)-6,7-dihydro-3-(3-methoxyphenyl)-2H-indazol-4(5H)-one

(63bba)


(m, 3H), 7.03 – 6.94 (m, 3H), 6.78 (d, J = 4.0 Hz, 1H), 3.67 (s, 3H),

2.86 (t, 2H), 2.49 (m, 2H), 2.29 (s, 3H), 2.08 (s, 2H). 13

C NMR (100

MHz, DMSO-d6) δ 193.50, 159.04, 157.17, 143.08, 138.17, 136.11,

133.55, 131.71, 129.78, 129.63, 126.14, 124.51, 122.72, 117.04, 116.48, 115.34, 55.35, 23.37,

23.15, 19.61. ESI-MS (m/z): calcd. for C21H19ClN2O2 366.1135, found 367.1250 [M + H]+.

2-(3ꞌ-Chloro-4

ꞌ-methylphenyl)-3-(4

ꞌꞌ-chlorophenyl)-6,7-dihydro-6,6-dimethyl-2H-indazol-

4(5H)-one (63aba)

M.p.: 146 –148 °C. 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.35 (m,

3H), 7.35 (d, J = 3.0 Hz), 7.17 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 4.0

Hz, 1H), 2.85 (s, 2H), 2.41 (s, 2H), 2.23 (s, 3H), 1.20 (s, 6H). 13

C

NMR (100 MHz, CDCl3) δ 193.55, 156.73, 137.68, 136.48, 135.70,

134.69, 131.68, 130.97, 128.71, 126.25, 126.01, 125.18, 123.49,

115.0, 53.70, 37.13, 34.87, 28.44, 19.75. ESI-MS (m/z): calcd. for C23H23ClN2O 398.0953,

found 399.1090 [M + H]+ and 799.1941 [2M + H]

+.

2-(3ꞌ-Chloro-4

ꞌ-methylphenyl)-6,7-dihydro-6,6-dimethyl-3-(pyridin-4

ꞌꞌ-yl)-2H-indazol-4(5H)-

one (63abb)


Hz, 2H,), 7.39 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 4.0 Hz,

1H), 6.87 (d, J = 8.0 Hz, 1H), 2.84 (s, 2H), 2.44 (s, 2H), 2.38, (s,

3H), 1.17 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ 195.93, 149.79,

Chapter-I

27

147.41, 145.24, 136.97, 131.11, 125.96, 124.52, 123.39, 119.40, 116.54, 110.19, 106.01, 105.01,

53.69, 37.08, 34.95, 28.44, 19.81. ESI-MS (m/z): calcd. for C21H20ClN3O 365.1295, found

366.1370 [M + H]+ and 731.2720 [2M + H]

+.

2-(3ꞌ-Chloro-4

ꞌ-methylphenyl)-6,7-dihydro-6,6-dimethyl-3-(1H-pyrrol-2

ꞌꞌ-yl)-2H-indazol-

4(5H)-one (63abc)

Pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.41

– 7.35 (m, 3H), 7. 33 – 7.27 (m, 3H), 2.84 (s, 2H), 2.47 (s, 2H),

2.29, (s, 3H), 1.19 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ 194.32,

135.63, 139.07, 133.40, 131.40, 130.52, 129.13, 126.75, 125.99,

118.65, 52.87, 36.80, 35.25, 28.45, 17.99. ESI-MS (m/z): calcd. for C20H20ClN3O 353.1295, found

354.1376 [M + H]+.

2-Cyclohexyl-6,7-dihydro-6,6-dimethyl-3-(thiophen-2ꞌ-yl)-2H-indazol-4(5H)-one (63aca)


Hz, 1H,), 7.35 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 4.26 –

4.21 (m, 1H), 2.73 (s, 2H), 2.35 (s, 2H), 2.04 – 2.01 (m, 2H), 1.93 –

1.86 (m, 4H), 1.69 – 1.62 (m, 2H), 1.31 – 1.27 (m, 2H), 1.11 (s, 6H).

13C NMR (100 MHz, CDCl3) δ 193.14, 155.31, 135.59, 128.41,

127.93, 127.26, 115.17, 58.09, 53.60, 37.25, 34.86, 33.15, 28.48, 25.43, 24.99. ESI-MS (m/z):

calcd. for C19H24N2OS 328.1609, found 329.1695 [M + H]+ and 657.3304 [2M + H]

+.

2-Cyclohexyl-6,7-dihydro-6,6-dimethyl-3-(4ꞌ-nitrophenyl)-2H-indazol-4(5H)-one (63acb)


Hz, 2H,), 7.57 (d, J = 8.0 Hz, 2H), 3.92 – 3.88 (m, 1H), 2.76 (s,

2H,), 2.35 (s, 2H), 2.06 – 2.00 (m, 2H), 1.89 – 1.83 (m, 4H,), 1.66 –

1.58 (m, 2H), 1.27 – 1.24 (m, 2H), 1.12 (s, 6H). 13

C NMR (100

MHz, CDCl3) δ 193.46, 155.57, 148.24, 140.14, 135.37, 130.96,

123.63, 115.07, 58.32, 53.38, 37.10, 35.03, 33.09, 28.47, 25.35,

24.85. ESI-MS (m/z): calcd. for C21H25N3O3 367.1896, found 368.2003 [M + H]+ and 735.3910

[2M + H]+.

Chapter-I

28

3-(4ꞌ-Chlorophenyl)-2-cyclohexyl-6,6-dimethyl-[1,3]dioxino[4,5-c]pyrazol-4(2H)-one (63acc)


(m, 2H), 7.69 – 7.61 (m, 2H), 3.26 – 3.20 (m, 1H), 1.97 – 1.93 (m,

2H), 1.73 – 1.68 (m, 2H), 1.60 – 1.56 (m, 2H), 1.55 (s, 6H), 1.29 –

1.24 (m, 4H). 13

C NMR (100 MHz, DMSO-d6) δ 193.30, 155.85,

140.81, 133.41, 131.14, 130.71, 130.12, 129.75, 128.67, 115.88,

57.60, 39.43, 32.99, 25.25, 25.11, 23.58, 23.20. ESI-MS (m/z): calcd. for C19H21ClN2O3 360.1241,

found 361.1321 [M + H]+.

3-(3-Chlorophenyl)-2-cyclohexyl-6,7-dihydro-2H-indazol-4(5H)-one (63bca)


(m, 3H,), 7.34 (d, J = 8.0 Hz, 1H), 3.86 – 3.83 (m, 1H), 2.79 – 2.76

(m, 2H), 2.49 – 2.46 (m, 2H), 2.35 (t, J = 12 Hz, 2H), 2.07 – 2.00 (m,

2H), 1.86 – 1.72 (m, 6H), 1.17 – 1.13 (m, 2H). 13

C NMR (100 MHz,

DMSO-d6) δ 193.30, 155.85, 140.81, 133.41, 131.14, 130.71,

130.12, 129.75, 128.67, 115.88, 57.60, 39.43, 32.99, 25.25, 25.11, 23.58, 23.20. ESI-MS (m/z):

calcd. for C19H21ClN2O 328.1342, found 329.1509 [M + H]+.

2-Cyclohexyl-6,7-dihydro-3-p-tolyl-2H-indazol-4(5H)-one (63bcb)

M.p.: 178 – 180 °C. 1H NMR (500 MHz, CDCl3) δ 7.21 – 7. 18 (m,

4H,), 3.94 – 3.89 (m, 1H), 2.80 (t, J = 6.2 Hz, 2H), 2.37 – 2.35 (m,

4H), 2.05 (q, J = 6.05 Hz, 2H), 1.99 – 1.92 (m, 2H), 1.78 – 1.75 (m,

4H), 1.62 – 1.49 (m, 2H), 1.15 (s, 3H). 13

C NMR (125 MHz, CDCl3)

δ 193.82, 156.05, 143.12, 139.34, 129.51, 129.17, 125.86, 115.60,

39.56, 33.03, 25.54, 25.42, 24.97, 23.63, 23.46, 21.47. ESI- MS

(m/z): calcd. for C20H24N2O 308.1889, found 309.1991 [M + H]+ and 617.3867 [2M + H]

+.

2-(4ꞌ-tert-butylphenyl)-6,7-dihydro-3-(4

ꞌꞌ-methoxyphenyl)-6,6-dimethyl-2H-indazol-4(5H)-one

(63ada)


Hz, 2H,), 7.32 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 6.0 Hz, 2H), 6.85 (d,

J = 8.0 Hz, 2H), 3.82 (s, 3H), 2.81 (s, 2H), 2.42 (s, 2H), 1.30 (s, 9H),

1.16 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ 193.59, 160.19, 156.41,

151.06, 143.11, 136.79, 131.88, 125.88, 124.91, 120.41, 115.25,

Chapter-I

29

113.50, 55.24, 53.84, 32.27, 34.84, 34.65, 32.24, 28.50. ESI-MS (m/z): calcd. for C26H30N2O2

402.2307, found 403.2349 [M + H]+

and 805.4574 [2M + H]+.

2-(4ꞌ-tert-Butylphenyl)-6,7-dihydro-3-(2

ꞌꞌ,4

ꞌꞌ-dimethoxyphenyl)-6,6-dimethyl-2H-indazol-

4(5H)-one (63adb)

M.p.: 135 – 137 °C. 1H NMR (400 MHz, CDCl3) δ δ 7.33 (d, J = 8.0

Hz, 1H), 7.27 (d, J = 6.9 Hz, 2H), 7.16 (d, J = 4.0 Hz, 2H), 7.03 (d, J

= 8 Hz, 1H), 6.95 (s, 1H), 3.83 (s, 3H), 3.30 (s, 3H), 2.81 (s, 2H),

2.39 (s, 2H), 1.27 (s, 9H), 1.16 (s, 6H). 13


δ 193.44, 162.28, 157.71, 156.33, 133.16, 124.42, 123.70, 118.54,

116.17, 110.75, 104.76, 99.03, 53.63, 55.36, 54.89, 37.27, 34.89, 34.58, 31.25. ESI- MS (m/z):

calcd. for C27H32N2O3 432.2413, found 433.2561 [M + H]+, 865.4797 [2M + H]

+ and 887.4720

[2M –H + Na]+.

2-(4ꞌ-tert-Butylphenyl)-6,7-dihydro-3-(2

ꞌꞌ,4

ꞌꞌ-dimethoxyphenyl)-6,6-dimethyl-2H-indazol-

4(5H)-one (63adc)


Hz, 2H,), 7.33 – 7.31 (m, 4H), 7.26 (d, J = 8.0 Hz, 2H), 2.82 (s, 2H),

2.42 (s, 2H), 1.30 (s, 9H), 1.17 (s, 6H). 13

C NMR (100 MHz,

CDCl3) δ 207.65, 156.52, 151.47, 145.67, 140.06, 135.44, 131.77,

128.37, 126.72, 126.05, 124.91, 115.68, 53.78, 37.19, 34.71, 31.23,

30.93, 28.48. ESI-MS (m/z): calcd. for C25H27ClN2O 406.1812, found 407.1963 [M + H]+ 813.3723

[2M + H]+ and 835.3417 [2M –H + Na]

+.

2-(4-tert-Butylphenyl)-3-(4-chlorophenyl)-6,6-dimethyl-[1,3]dioxino[4,5-c]pyrazol-4(2H)-one

(63add)

M.p.: 249 – 251 °C. 1H NMR (500 MHz, DMSO-d6) δ 7.46 (dd, J =

9.6, 2.65 Hz, 2H), 7.35 (d, J = 8.55 Hz, 2H), ( 7.08 (d, J = 9.6, 2.67

Hz, 2H), 7.08 (d, J = 8.55 Hz, 2H), 2.01 (s, 6H), 1.28 (s, 9H). 13

C

NMR (125 MHz, DMSO-d6) δ 210.11, 154.96, 148.33, 137.62,

135.48, 133.16, 130.11, 129.42, 129.31, 123.30, 117.17, 115.16

104.89, 32.14, 31.15, 29.34. ESI-MS (m/z): calcd. for C23H23ClN2O3 410.1397, found 411.1423

[M + H]+.

Chapter-I

30

2-(4ꞌ-tert-Butylphenyl)-6,7-dihydro-6,6-dimethyl-3-p-tolyl-2H-indazol-4(5H)-one (63ade)


8.12 Hz, 2H), 7.26 (d, J = 7.56 Hz, 2H), 7.15 (d, J = 8.12 Hz, 2H),

7.13 (d, J = 7.56 Hz, 2H), 2.81 (s, 2H), 2.41 (s, 2H), 2.35, (s, 3H),

1.30 (s, 9H), 1.19 (s, 6H). 13

C NMR (125 MHz, DMSO-d6) δ 193.46,

156.37, 151.03, 143.27, 139.28, 136.74, 130.24, 128.75, 125.82,

125.27, 124.85, 115.47, 53.83, 37.25, 34.84, 34.64, 34.24, 28.49, 21.47. ESI-MS (m/z): calcd. for

C26H30N2O 386.2358, found 387.2453 [M + H]+ and 773.4806 [2M+H]

+.

1.5.4 Procedure for c-Src kinase activity assay

The effect of synthesized compounds on the activity of c-Src kinase was assessed by Transcreener®

ADP2 FI Assay, from Bell Brook Labs, Madison, WI, (catalogue no. 3013-1K) according to

manufacturer’s protocol. 384-well Low volume Black non binding surface round bottom microplate

was purchased from Corning (3676). In summary, the kinase reaction was started in 384-well low

volume black microplate with the incubation of the 2.5 L of the reaction cocktail (0.7 nM of His6-

Src kinase domain in kinase buffer) with 2.5 L of prediluted compounds (dissolved in 10%

DMSO, 4X target concentration) for 10 min at room temperature using microplate shaker. The

reaction cocktail was made using the kinase buffer HEPES (200 mM, pH 7.5), MgCl2 (16 mM),

EGTA (8 mM), DMSO (4%), Brij-35 (0.04%), and 2-mercaptoethanol (43 mM). Kinase reaction

was started by adding 5 L of ATP/substrate (40 M/600M) cocktail and incubated for 30 min at

room temperature on microplate shaker. Src optimal peptide (AEEEIYGEFEAKKKK) was used as

the substrate for the kinase reaction. Kinase reaction was stopped by adding 10 L of the 1X ADP

Detection Mixture to the enzyme reaction mixture and mixed using a plate shaker. The mixture was

incubated at room temperature for 1 h, and the fluorescence intensity was measured. The 1X ADP

Detection Mixture was prepared by adding ADP2 Antibody-IRDyeR QC-1 (10 g/mL) and ADP

Alexa594 Tracer (8 nM) to Stop & Detect Buffer B(1X). Fluorescence Intensity measurements

were performed using fluorescence intensity optical module using the excitation of 580 nm and

emission of 630 nm with band widths of 10 nm by Optima, BMG Labtech microplate reader. IC50

of the compounds were calculated using ORIGIN 6.0 (origin lab) software. IC50 is the concentration

of the compound that inhibited enzyme activity by 50%. All the experiments were carried out in

triplicate.

Chapter-I

31

1.5.5 Procedure for cell culture

Human colon adenocarcinoma HT-29 (ATCC no. HTB-38) was obtained from American Type

Culture Collection. Cells were grown on 75 cm2 cell culture flasks with EMEM (Eagle’s minimum

essential medium), supplemented with 10% fetal bovine serum, and 1% penicillin/streptomycin

solution (10,000 units of penicillin and 10 mg of streptomycin in 0.9% NaCl) in a humidified

atmosphere of 5% CO2, 95% air at 37 ºC.

Cell proliferation assay was carried out using CellTiter 96 aqueous one solution cell proliferation

assay kit (Promega, USA). Briefly, upon reaching about 75-80% confluency, 5000 cells/well were

plated in 96-well microplate in 100 µL media. After seeding for 24 h, the cells were treated with 50

µM compound in triplicate. Doxorubicin (10 µM) was used as the positive control. At the end of the

sample exposure period (72 h), 20 µL CellTiter 96 aqueous solution was added. The plate was

returned to the incubator for 1 h in a humidified atmosphere at 37C. The absorbance of the

formazan product was measured at 490 nm using microplate reader. The blank control was recorded

by measuring the absorbance at 490 nm with wells containing medium mixed with CellTiter 96

aqueous solution but no cells. Results were expressed as the percentage of the control (without

compound set at 100%).

1.5.6 Procedure for molecular modeling

Simulations were performed with the Accelrys Discovery Studio 2.5 modeling package, with the

CHARMm-based force field. Model of PP1 bound to Src was constructed based on the X-ray

crystal structures of PP1 bound to Hck (1QCF) and AMP-PNP bound to c-Src (2SRC) templates

from RCSB Protein Data Bank. The coordinates and positions of the backbone atoms of PP1 was

superimposed on the corresponding atoms in AMP-PNP after which Hck was deleted. For

refinement, the PP1-Src complex underwent CHARMm minimization. All default parameters were

used in the minimization process. For the molecular modeling of 63aaj and 63ada, after initial

energy minimization, the coordinates and positions of the backbone atoms of phenyl groups were

superimposed on the corresponding atoms in PP1 in complex with c-Src after which PP1 was

deleted. The energy minimization was carried out as described above.

Chapter-I

32

Part-B: Synthesis of Flavanone and Dihydroquinolinones using

Yb(OTf)3 in Ionic Liquid

Flavanone, quinolinone and its derivatives are important constituents of natural products found in

fruits, vegetables, grains, tea, and wine etc.78

For instance, Hesperetin, Naringenin are important

natural products, possessing immense importance in the field of pharmaceuticals.79-81

Most of the

flavonoids present in plants are attached to sugars (glycosides), although occasionally they are

found as aglycones. The health benefits of flavonoids has increased due to their potent antioxidant

and free-radical scavenging activities observed in vitro.78

Figure 1.8 depicts different structural

flavonoids 64-69. Flavanones are secondary metabolites of plants and they possess a variety of

biological activities such as antitumor,82-84

antiviral,85

antioxidant,86

antibacterial, anti-

inflammatory,87,88

aromatase inhibitors.89

Apart from these, flavanones also serve as important

intermediates in the synthesis of many biologically active compounds.90

The substituted aza analogs of flavanoid derivatives also possess numerous therapeutic

functions.91,92

Lee et al. have synthesized tetrahydroquinolones and evaluated them for interaction

with tubulin and cytotoxic activity against different cancer cell lines. 3ꞌ-Fluoro-6,7-

(methylenedioxy)-1,2,3,4-tetrahydro-2-phenyl-4-quinolone 70, 3ꞌ-methoxy-6-pyrrolinyl-1,2,3,4-

tetrahydro-2-phenyl-4-quinolone 71 and 3ꞌ-chloro-6-pyrrolinyl-1,2,3,4-tetrahydro-2-phenyl-4-

quinolone 72 were shown to have potent cytotoxic and antitubulin effects with ED50 values (0.012-

0.95 μg/ml) in the nanomolar or sub nanomolar range against different cell lines (HCT-8, MCF-7,

CAKI-1, SKMEL-2, and KB).92

Figure 1.8 The main structural categories of flavonoids and structures of some bioactive quinolinones

Chapter-I

33

1.6 Literature method for synthesis of flavanones and quinolinones

Most common method for the synthesis of flavanones and quinolinones is the isomerization of

2'-hydroxychalcones and 2'-aminochalcones, respectively. Several protocols have been reported for

this transformation by employing different catalysts such as orthophosphoric acid,93

sulphuric

acid,94

zeolites,95

silica gel,96

silica supported reagents,97,98

base catalysts,99

PEG-400,100

microwave

irradiation,101

and chiral Brønsted acids and bases.102

A brief overview of some recent protocols

developed for this transformation is described below.

Yang et al.103

synthesized 2-arylchroman-4-one derivatives 74 by phosphoric acid catalyzed

isomerization of corresponding 2ꞌ-hydroxychalcones 73 in ethanol (Scheme 1.18). The reaction

required 48 h and resulted in 70% yield of 2-arylchroman-4-one.

Scheme 1.18 H3PO4 catalyzed isomerization of 2'-hydroxychalcones

Cagir et al.104

developed a protocol for the synthesis of stilbene-fused flavanones 76 by the

isomerization of substituted 2ꞌ-hydroxychalcones 75 using NaOAc as a catalyst in ethanol (Scheme

1.19). The reaction required longer reaction time (24 h) and gave moderate yield of the cyclized

product.

Scheme 1.19 Synthesis of stilbene-fused flavanones

Yao et al.105

developed iodine catalyzed one-pot synthesis of flavanone 79 via Mannich type

reaction. When they used 2'-hydroxyacetophenone 78 as enolizable ketone in Mannich reaction

with aldehyde 77 and aniline, flavanone derivative 79 was obtained instead of β-aminocarbonyl

compound. They further prepared a series of flavanone derivatives from different arylaldehydes and

2ꞌ-hydroxyacetophenone in the presence of iodine as catalyst and aniline as co-catalyst (Scheme

1.20).

Chapter-I

34

Scheme 1.20 Iodine catalyzed one-pot synthesis of flavanone derivatives

Kumar et al.100

found polyethylene glycol (PEG-400) as a recyclable reaction medium for the

isomerization of 2ꞌ-hydroxychalcones 73 and 2ꞌ-aminochalcones 80 to give corresponding flavanone

74 and quinolinone derivatives 81 in good yields (Scheme 1.21).

Scheme 1.21 PEG-400 catalyzed isomerization of 2ꞌ-hydroxychalcones and 2ꞌ-aminochalcones

Lier et al.98

developed a silica gel-supported tantalum(V) bromide as catalyst for the isomerization

of 2ꞌ-aminochalcones 80 to the corresponding 2-aryl-2,3-dihydroquinolin-4(1H)-ones 81 under

solvent-free conditions (Scheme 1.22) in good yield. They also found that isomerization of

2'-hydroxychalcones 73 resulted in poor yields of flavanones 74 using TaBr5.

Scheme 1.22 Silica gel-supported TaBr5 catalyzed and 2ꞌ-aminochalcones

Most of these protocols are associated with several drawbacks such as long reaction time or

requirement of high energy source, use of halogenated solvents, toxic agents and accompanied with

unwanted side reactions. Thus mild, simple, non-polluting and more efficient protocols are still

desirable for the isomerization of 2'-hyrdoxychalcones and 2'-aminochalcones to yield

corresponding flavanone and quinolinone derivatives in good yields. With our interest in

developing novel reaction methodologies using metal triflates as mild and safe Lewis acid catalysts

we have developed a new methodology for the synthesis of flavonones and dihydroquinolinones in

using Yb(OTf)3 in ionic liquid (Scheme 1.23).

Chapter-I

35

Scheme 1.23 Synthesis of flavanone and dihydroquinolinones using Yb(OTf)3 in ionic liquid


In the first set of experiments, synthesis of flavanone 74a by isomerization of 2ꞌ-hydroxychalcone

73a was studied using different Lewis acids as catalyst in ionic liquid [bmim][BF4] (Table 1.4).

The ionic liquid [bmim][BF4] was chosen as solvent for this reaction as it has been found that

[bmim][BF4] itself acts as a catalyst for isomerization of 2ꞌ-hydroxychalcone and 2ꞌ-aminochalcones

under microwave irradiation.101

Among the catalysts screened, Ce(OTf)3, Yb(OTf)3, In(OTf)3,

Zn(OTf)2 and pTSA were found to give good to excellent yield of 74a (Table 1.4, entries 4, 8-10 &

14) and Yb(OTf)3 gave the highest yield of 74a under these conditions and thus was selected as

choice of catalyst.

Table 1.4 Yields of 74a by different catalysts in [bmim][BF4].

Entry Catalyst Catalyst (mol%) Time (h) Yield (%)a

1 - - 12 38b

2 Yb(OTf)3 10 4 61

3 Yb(OTf)3 20 4 73

4 Yb(OTf)3 30 4 86

5 Yb(OTf)3 40 4 79

6 Yb(OTf)3 50 4 63

7 Sc(OTf)3 30 4 53

8 Zn(OTf)2 30 4 58

9 Ce(OTf)3 30 4 76

10 Y(OTf)3 30 4 55

11 Ba(OTf)3 30 4 52

12 In(OTf)3 30 4 66

13 Er(OTf)3 30 4 54

14 PTSA 30 4 64

15 MgO 30 4 57

aIsolated yields.

b1-Phenyl-3-(4ꞌ-chlorophenyl)propenone 73a gave 74a in 49% yield in

[bmim][BF4] under MW irradiation after 1.5 min.101

Chapter-I

36

Next, we optimized the catalysts quantity using different amount of catalyst and found that

increasing the catalyst loading beyond 30 mol% did not lead to an improved results (Table 1.4,

entry 1-6). It is worthy to mention that use of Yb(OTf)3 as Lewis acid in [bmim][BF4] has

dramatically increased the yield of 74a as compared to that in only [bmim][BF4] (Table 1.4, entry 1

and 4). To demonstrate the advantage of the reaction in ionic liquid [bmim][BF4], isomerization of

73a catalyzed by Yb(OTf)3 was investigated in different organic solvents, ionic liquids, and water.

Interestingly, the best yield was observed in ionic liquid [bmim][BF4] at 130 °C. When shifting the

solvent to acetonitrile, water, THF, dichloromethane and toluene, only small amount or a trace of

desired product was detected (Table 1.5, entries 1-5) and reactions remained incomplete even after

heating at higher temperature for long time. Moderate to good yield were observed in DMSO and

ionic liquid [bmim][Br] & [bmim][PF6] (Table 1.5, entries 6-8). Significant solvent effect was

observed in our investigation with solvent screen and thus, ionic liquid [bmim][BF4] was selected

as the solvent of choice for continuing this isomerization study.

Table 1.5 Effect of solvent on yield of 74a

Entry Solvent Temp. (°C) Yield (%)a,b

1 Acetonitrile 82 10

2 Water 100 -c

3 THF 66 -c

4 Dichloromethane 40 -c

5 Toluene 110 -c

6 DMSO 130 79

7 [bmim][BF4] 130 86

8 [bmim][PF6] 130 61

9 [bmim][Br] 130 45

aIsolated yield.

b Reaction condition: 2ꞌ-hydroxychalcone (0.712 mmol), Yb(OTf)3 (81 mg, 30 mol%).

cTrace

of product formation was observed.

To examine the scope and generality of the protocol for synthesis of flavanone 74, different

2ꞌ-hydroxychalcones substituted with electron-donating or electron-withdrawing groups were

employed as the reaction substrates (Table 1.6). The substrates with electron-donating substituent

in the aldehydic aromatic group afforded the corresponding cyclic products (flavanones) in

Chapter-I

37

excellent yields whereas substrates with electron withdrawing substituent in the aldehydic aromatic

group resulted in poor yield of cyclized product. For instance, 73d required only 4 h to give 74d in

81% yield, whereas 73h did not give desired product 74h even after heating at 160 °C for 12 h. This

perhaps is due to reversal of polarity of β-carbon in case of 73h by electron withdrawing substituent

in the aromatic ring of aldehydic aryl group.

Table 1.6 Synthesis of flavanones 74

Entry Substrate Ar Product Time (h) Yield (%)a

1 73a 4-ClC6H4 74a 4 86

2 73b C6H5 74b 4 79

3 73c 3-Cl C6H4 74c 4 80

4 73d 4-CH3O C6H4 74d 4 81

5 73e 4-CH3 C6H4 74e 4 78

6 73f 3-NO2 C6H4 74f 6 20b

7 73g 2-Furyl 74g 4 74

8 73h 4-NO2 C6H4 74h 12 -c

aIsolated yield.

bYield at 160 °C, almost quantitatively reactant was recovered at 80 °C

cNo product was observed even at 160 °C.

The structure of all the synthesized flavanones was confirmed by different spectroscopic data. For

example 1H NMR of 73a showed a characteristic peak at for C-2 proton double doublet at δ 5.43

along with other protons and peak for carbon of C=O group appeared at δ 191.60 in 13

C NMR

(Figure 1.9). The mass peak were observed at m/z 258.9804 [M + H]+ and 280.9562 [M + Na]

+ in

HRMS spectrum of 74a. Having ascertained the efficacy of Yb(OTf)3 catalyzed isomerization of

2ꞌ-hydroxychalcones in [bmim][BF4], this methodology was extended to isomerization of

2ꞌ-aminochalcone 80c to give corresponding dihydroquinolinone 81c in 93% yield. The structure of

81c was confirmed by mass, 1H,

13C NMR and IR spectroscopic data. Peaks at m/z 237.1153 and

238.0259 were observed in HRMS spectrum of 81c. In the 1H NMR spectra of 81c a doublet, triplet

and singlet were observed at 4.70, 2.80, 2.62 and 2.30 ppm for CH, CH2 (1H), CH2 (1H) and CH3

along with other protons. In 13

C NMR characteristic peak for C=O was observed at δ 193.04 along

with other carbons (Figure 1.10).

Chapter-I

38

Figure 1.9a 1H NMR of compound 74a

Figure 1.9b 13

C NMR of compound 74a

Chapter-I

39

Figure 1.10a 1H NMR of compound 81c

Figure 1.10b 13

C NMR of compound 81c

Chapter-I

40

In IR spectra, NH peak appearing at 3350 cm-1

and C=O peak appearing at 1649 cm-1

, confirmed

structure of 81c. Encouraged with the excellent result for synthesis of 81c by the isomerization of

80c, we performed reaction of different 2ꞌ-aminochalcones 81b-g under similar conditions and

results are summarized in Table 1.7. The influence of field effect of substituent in the aromatic ring

of aldehydic aryl group was similar to that in case of 2ꞌ-hydroxychalcones (Table 1.7, entries 3-6).

Table 1.7 Synthesis of dihydroquinolinones 81

Entry

Substrate Ar Product Time (Min) Yield (%)a

1 80a 4-ClC6H4 81a 5 92

2 80b C6H5 81b 5 85

3 80c 4-CH3C6H4 81c 5 93

4 80d 2,4-(CH3O)2C6H3 81d 5 94

5 80e 3-NO2C6H4 81e 30 70

6 80f 4-NO2C6H4 81f 360 60b

7 80g 2-Furyl 81g 10 89

aIsolated yield.

bYield at 160 °C.

It was also observed that the isomerization for 2ꞌ-aminochalcone was faster as compared to

2ꞌ-hydroxychalcones and the higher reactivity of 2ꞌ-aminochalcones relative to 2ꞌ-hydroxychalcones

could be rationalized based on differential nucleophilicity of amino group versus hydroxyl group

and differences in the activation energy (Eact) for the cyclization which is 57 Kcal/mole for 2ꞌ-

aminochalcones as compared to 117.886 Kcal/mole for 2ꞌ-hydroxychalcones.

101 The mechanism of

the isomerization reaction seems to be similar to the Lewis acid catalyzed nucleophilic addition to,

-unsaturated ketones. A plausible mechanism is shown in (Scheme 1.24). The higher rate of

reaction is probably due to higher acidity of Yb(OTf)3 compared to other lanthanide triflates and

ability of ionic liquid to stabilize the formation of charged species by coordination of Yb(OTf)3

with carbonyl oxygen. It is expected that this coordination of Yb(OTf)3 activates the nucleophilic

attack at β-carbon by inducing electrophilic character at this carbon and it also allows rotation

through the O=C-C bond to give trans-s-trans conformations required for cyclization from its

original trans-s-cis106

conformations by disrupting intermolecular hydrogen bonding.

Chapter-I

41

Scheme 1.24 A plausible mechanism for isomerization of 2ꞌ-hydroxychalcones and

2ꞌ-aminochalcones

Finally, recycling of the catalysts was studied using 73b as model substrate and it was found that

recycled Yb(OTf)3 in [bmim][BF4] showed good catalytic activity yielding 74b in 86, 82, 79, 74, 76

and 73% in six successive runs, respectively

1.8 Conclusions

In summary, we have developed a simple, economical and more efficient method for the synthesis

of flavanone and dihydroquinolinones by isomerization of 2ꞌ-hydroxychalcones and

2ꞌ-aminochalcones using Yb(OTf)3 (30 mol%) as a catalyst in ionic liquid. Apart from the efficient

and environmentally benign reaction conditions, excellent yield and short reaction time this process

offers to recycle Yb(OTf)3/[bmim][BF4].

1.9 Experimental

1.9.1 Representative procedure for the isomerization:

To a mixture of 2ꞌ-hydroxychalcone/ 2ꞌ-aminochalcone (0.712 mmol) and ionic liquid [bmim][BF4]

(2 mL) was added Yb(OTf)3 (81 mg, 30 mol%). The whole reaction mass was stirred at 130 ºC. The

reaction progress was followed by TLC (hexanes/AcOEt 8: 2, v/v). After stirring the reaction

mixture for appropriate time as mentioned in table 1.6 and 1.7, diethyl ether (10 mL) was added and

the organic layer was separated. The solvent was dried with anhydrous sodium sulphate and

evaporated under reduced pressure, and the residue was percolated through a bed of silica gel (60-

120) using hexane/AcOEt (9:1 v/v) as an eluent to afford corresponding compounds in 20-94%

yield.

Chapter-I

42


2-(4ꞌ-Chlorophenyl)-2,3-dihydro-4H-chromen-4-one (74a)

M.p.: 95 – 97 °C (lit. 94 – 95).101

1H NMR (400 MHz, CDCl3) δ 7.93

(dd, J = 7.8, 1.5 Hz, 1H), 7.51 (dt, J = 7.60, 1.60 Hz, 1H), 7.46 – 7.37

(m, 4H), 7.10 – 7.01 (m, 2H), 5.46 (dd, J = 13.1, 2.9 Hz, 1H), 3.04

(dd, J = 16.80, 13.20 Hz, 1H), 2.88 (dd, J = 16.8, 3.0 Hz, 1H). 13

C

NMR (101 MHz, CDCl3) δ 191.60, 161.34, 137.29, 136.37, 134.62,

129.09, 127.56, 127.13, 121.87, 120.92, 118.14, 78.86, 44.63.

IR (KBr) νmax: 1697, 1300, 1221cm-1

. ESI-MS (m/z): calcd. for C15H11ClO2 258.0448 [M+], found:

258.9804 [M + H]+, 280.9562 [M + Na]

+.

2-Phenyl-2,3-dihydro-4H-chromen-4-one (74b)

M.p.: 75 – 77 °C (lit. 77 – 78).101

1H NMR (300 MHz, CDCl3) δ

7.91 (dd, J = 8.00, 2.80 Hz, 1H), 7.47 – 7.36 (m, 6H), 7.05 – 7.04 (m,

2H), 5.48 (d, J = 13.60 Hz, 1H), 3.11 – 3.03 (m, 1H), 2.88 (dd, J =

16.80, 4.40 Hz, 1H). IR (KBr) νmax: 1692, 1310, 1218 cm-1

. ESI-MS

(m/z): calcd. for C15H12O2 224.0837, found 225.0308 [M + H]+,

247.0061 [M + Na]+

2-(3ꞌ-Chlorophenyl)-2,3-dihydro-4H-chromen-4-one (74c)

M.p.: 97 – 99 °C. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 6.80 Hz,

1H), 7.51 (m, 2H), 7.35 (m, 3H), 7.06 (d, J = 7.60 Hz, 2H), 5.45 (dd,

J = 13.20, 2.80 Hz, 1H), 3.03 (dd, J = 16.80, 13.60 Hz, 1H), 2.88 (dd,

J = 16.80, 2.80 Hz, 1H). IR (KBr) νmax: 1694, 1302, 1220 cm-1

. ESI-

MS (m/z): calcd. for for C15H11ClO2 258.0448,

found 258.9804, 280.9552 [M + Na]+.

2-(4ꞌ-Methoxyphenyl)-2,3-dihydro-4H-chromen-4-one (74d)

M.p.: 88 – 89 °C (lit. 87 – 88).101


(d, J = 6.4 Hz, 1H), 7.48 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 6.40 Hz,

2H), 7.04 – 7.02 (m, 2H), 6.96 (d, J = 6.40 Hz, 2H), 5.41 (d, J =

11.20 Hz, 1H), 3.82 (s, 3H), 3.13 – 3.10 (m, 1H), 2.87 – 2.83 (m,

1H). IR (KBr) νmax: 1692, 1311, 1222 cm-1

. ESI-MS (m/z): calcd. for

Chapter-I

43

C16H14O3 254.0942, found 255.0326 [M + H]+, 277.0081 [M + Na]

+.

2-(p-Tolyl)-2,3-dihydro-4H-chromen-4-one (74e)

M.p.: 82 – 84 °C (lit. 83 – 84).101


(d, J = 6.40 Hz, 1H), 7.49 – 7.46 (m, 1H), 7.37 (d, J = 5.60 Hz, 2H),

7.24 (d, J = 5.60 Hz, 2H), 7.04 – 7.01 (m, 2H), 5.44 (d, J = 9.2 Hz,

1H), 3.12 – 3.08 (m, 1H), 2.88 – 2.84 (m, 1H), 2.37 (s, 3H). IR

(KBr) νmax: 1683, 1325, 1220 cm-1


C16H14O2 238.0993, found 239.0426 [M + H]+, 261.0186 [M + Na]

+.

2,3-Dihydro-2-(3ꞌ-nitrophenyl)chromen-4-one (74f)


– 8.14 (m, 1H), 7.97 – 7.70 (m, 2H), 7.06 – 7.00 (m, 2H), 6.45 (s,

1H), 6.39 (s, 1H), 5.53 (dd, J = 11.45, 3.63 Hz 1H), 3.25 – 3.22 (m,

1H), 2.97 – 2.95 (m, 1H). IR (KBr) νmax: 1681, 1547, 1327, 1223

cm-1

. ESI-MS (m/z): calcd. for C15H11NO4 269.0688, found 270.0017

[M + H]+.

2-(Furan-2ꞌ-yl)-2,3-dihydro-4H-chromen-4-one (74g)

M.p.: 78 – 79 °C (lit. 80).101

1H NMR (300 MHz, CDCl3) δ 7.91 (dd,

J = 7.60, 2.40 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.06 – 7.00 (m, 2H),

6.45 (s, 1H), 6.39 (s, 1H), 5.53 (dd, J = 11.60, 3.60 Hz, 1H), 3.26 –

3.33 (m, 1H), 2.98 – 2.96 (m, 1H). IR (KBr) νmax: 1680, 1315, 1223

cm-1

. ESI-MS (m/z): calcd. for C13H10O3 214.0629, found 215.0155

[M + H]+.

2-(4'-Chlorophenyl)-2,3-dihydro-4(1H)-quinolinone (81a)

M.p.: 168 – 170 °C (lit. 167 – 168).101


7.85 (d, J = 7.60 Hz, 1H), 7.41 – 7.32 (m, 5H), 6.79 (dd, J = 7.24,

7.20 Hz, 1H), 6.72 (d, J = 8.40 Hz, 1H), 4.73 (dd, J = 13.20, 4.16

Hz, 1H), 4.52 (brs, 1H), 2.83 (dd, J = 16.20, 13.20 Hz, 1H), 2.74 (dd,

J = 16.20, 4.16 Hz, 1H). IR (KBr) νmax: 3302, 1651 cm-1

. ESI-MS

(m/z): calcd. for C15H12ClNO 257.0607, found 257.9585 [M + H]+.

Chapter-I

44

2-Phenyl-2,3-dihydro-4(1H)-quinolinone (81b)

M.p.: 150 – 151 °C (lit. 149 – 150).101


7.87 (d, J = 7.66 Hz, 1H), 7.47 – 7.32 (m, 6H), 6.80 (dd, J = 7.64,

7.23 Hz, 1H), 6.71 (d, J = 8.41 Hz, 1H), 4.76 (dd, J = 13.62, 4.00 Hz,

1H), 4.52 (brs, 1H), 2.88 (dd, J = 16.41, 13.62 Hz, 1H), 2.77 (dd, J =

16.42, 3.98 Hz, 1H). IR (KBr) νmax: 3325, 1648 cm-1

. ESI-MS (m/z):

calcd. for C15H13NO 223.0997, found 224.0154 [M + H]+

2-(p-Tolyl)-2,3-dihydro-4(1H)-quinolinone (81c)

M.p.: 149 – 150 °C (lit. 149).101

1H NMR (400 MHz, DMSO-d6) δ

7.59 (d, J = 7.0 Hz, 1H), 7.34 (dd, J = 18.6, 6.8 Hz, 3H), 7.24 – 7.06

(m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 6.63 (brs, 1H), 4.70 (d, J = 11.0

Hz, 1H), 2.80 (t, J = 13.9 Hz, 1H), 2.62 (d, J = 15.5 Hz, 1H), 2.30 (s,

3H). 13

C NMR (101 MHz, DMSO-d6) δ 193.04, 152.98, 139.13,

137.38, 135.55, 129.51, 127.24, 126.81, 118.13, 116.89, 116.75,

56.45, 45.84, 21.19. IR (KBr) νmax: 3350 , 1649 cm

-1. ESI-MS (m/z): calcd. for C16H15NO 237.1153,

found 238.0259 [M + H]+.

2-(2ꞌ,4

ꞌ-Dimethoxyphenyl)-2,3-dihydro-4(1H)-quinolinone (81d)


Hz, 1H), 7.11 (d, J = 7.64, 1H), 6.79 – 6.75 (m, 1H), 6.73 (d, J =

7.64, 1H), 6.70 (d, J = 7.76 Hz, 1H), 6.63 (s, 1H), 4.69 (dd, J =

13.60, 3.46 Hz, 1H), 4.54 (brs, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.88

(dd, J = 16.44, 13.80 Hz, 1H), 2.72 (dd, J = 3.46, 16.44 Hz, 1H). IR

(KBr) νmax: 3326, 1649 cm-1

. ESI-MS (m/z): calcd. for C17H17NO3 283.1208, found 284.0089 [M +

H]+, 305.9772 [M + Na]

+.

2-(3ꞌ-Nitrophenyl)-2,3-dihydro-4(1H)-quinolinone (81e)

M.p.: 159 – 160 °C. 1H NMR (300 MHz, CDCl3 δ 8.37 (s, 1H), 8.20

(td, J = 8.20, 1.32, 1H), 7.97 (d, J = 7.64 Hz, 1H), 7.70 (t, J = 8.0 Hz,

1H), 7.60 (d, J = 8.0 Hz,1 H), 7.36 (td, J = 8.32, 1.56 Hz, 1H), 7.27

(s, 1H), 6.91 (d, J = 8.32 Hz,1H), 6.68 (t, J = 7.80 Hz,1H), 4.97 (dd,

Chapter-I

45

J = 11.52, 4.24 Hz, 1H), 2.90 (dd, J = 16.08, 11.80 Hz, 1H), 2.77

(dd, J = 16.08, 4.32 Hz, 1H).IR (KBr) νmax: 3351, 1653 cm-1


C15H12N2O3 268.0847, found 269.0281 [M + H]+, 290.0031 [M + Na]

+.

2-(4ꞌ-Nitrophenyl)-2,3-dihydro-4(1H)-quinolinone (81f)

M.p.: 199 – 200 °C. 1H NMR (300 MHz, CDCl3 )δ 8.26 (d, J = 8.64

Hz, 1H), 7.77 (d, J = 8.64 Hz, 1H), 7.60 (d, J = 7.88 Hz,1H), 7.35

(td, J = 7.62, 1.24 Hz, 1H), 7.28 (s, 1H), 6.90 (d, J = 8.32 Hz,1H),

6.67 (t, J = 7.64 Hz,1H), 4.96 (dd, J = 10.88, 4.72 Hz, 1H), 2.87 –

2.74 (m, 2H). IR (KBr) νmax: 3338, 1649 cm-1

. ESI-MS (m/z): calcd.

for C15H12N2O3 268.0847, found 269.0282 [M + H]+, 290.0029 [M + Na]

+.

2-(Furan-2ꞌ-yl)-2,3-dihydro-4(1H)-quinolinone (81g)

Pale yellow liquid. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.00

Hz, 1H), 7.38 – 7.26 (m, 2H), 6.79 – 6.69 (m, 2H), 6.32 (d, J = 1.39

Hz, 1H), 6.25 (d, J = 1.53 Hz, 1H), 4.84 – 4.78 (m, 2H), 3.07 – 2.92

(m, 2H). IR (KBr) νmax: 3331, 1658 cm-1


C13H11NO2 213.0789, found 214.0136 [M + H]+, 235.0146 [M +

Na]+.

1.9.3 General procedure for recovery and reuse of catalyst

After extracting the product using diethyl ether, the ionic liquid layer containing Yb(OTf)3 was

dried under vacuum. The flask containing recovered Yb(OTf)3 in ionic liquid was again charged

with 73b (185 mg, 0.712 mmol) and same procedure was repeated as given in general procedure for

isomerization.

Chapter-I

46

1.10 References

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Chapter-I

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CHAPTER - II

Microwave -Assisted Synthesis of

2,3-Diarylnaphthofurans and

Quinolines

Chapter-II

52

2.1 Introduction:

The use of microwave activation as a non-conventional energy frequency with relatively large

wavelengths (1 mm –1 m) in organic synthesis has become increasingly in the pharmaceutical

industry.1 One of the most important goals is to decrease the energy input of reactions and

processes, the energy requirements should be accepted for their environmental and economic

impacts.2 Presently, thermally driven organic transformations take place by two ways: The first

way is conventional heating, where conventional reactants are slowly activated by external heat

source and the heat passes through the wall to solvent and reactants. In the second way

microwave heating, the microwaves couple directly with molecules of the entire reaction

mixture, leading to a rapid rise in temperature. The result is an instantaneous localized

superheating of any substance that will respond to dipole rotation or ionic conduction.3,4

The

advantage of controlled microwave dielectric heating for chemical synthesis is the dramatic

reduction in reaction time from days and hours to minutes. Moreover, microwave heating is able

to reduce side reactions, increase yields, improve reproducibility, allow control of temperature

and pressure, and even realize impossible reactions by conventional heating.5

The applications of microwave technology to rapid synthesis of biologically significant

heterocyclic molecules are very promising. This technology has been recognized as a useful tool

for a drug-discovery program especially in combinatorial chemistry.6 It is well known that the

heterocyclic system is an important structural element in medicinal chemistry showing a broad

spectrum of pharmacological activities, such as antiviral including anti-HIV, anti-parasitic,

antihistaminic, anti-cancer, anti-malarial etc.6-8

The development of innovative catalysts for selective bond formation is an important task in

organic chemistry. Metal triflates have found wide spread application in organic synthesis as

they are highly effective, hydrolytically stable and non-toxic catalyst.9 Some selected metal

triflate catalyzed microwave assisted reactions are discussed below.

Ollevier et al.10

synthesized homoallylic alcohols 3 using aldehyde 1 and allylstannane alcohol 2

under microwave irradiation using catalytic amount of Bi(OTf)3 (Scheme 2.1). The reaction

afforded moderate to good yields (63–93%) in a very short reaction time. The advantage of the

reaction is that it proceeds under mild conditions and only stoichiometric amount of nucleophile

is required.

Chapter-II

53

Scheme 2.1 Bi(OTf)3 catalyzed synthesis of homoallylic alcohols

Ollevier et al. have reported 2-amino alcohols 6 have been obtained from the neat mixtures of

epoxides 4 and amines 5 using catalytic amount of Bi(OTf)3.4H2O as catalyst under microwave

irradiation.11

A wide variety of aliphatic amines were reacted with cycloalkene oxide, styrene

oxide, and stilbene oxide (Scheme 2.2). The reaction proceeded rapidly and afforded the 2-amino

alcohols in high yields (48-99%).

Scheme 2.2 Bi(OTf)3 catalyzed synthesis 2-amino alcohols

Tran et al.12

have reported Bi(OTf)3 immobilized in [bmim][PF6] ionic liquid as an efficient

catalytic system for the Friedel–Crafts acylation (Scheme 2.3) of arene under microwave

irradiation allowing rapid synthesis of aryl ketones 9 in excellent yields. The catalyst was reused

up to five times.

Scheme 2.3 Bi(OTf)3 catalyzed Friedel–Crafts acylation of arenes

Sello et al.13

developed one-pot reaction to convert triacylglycerols 10 and free fatty acids

(FFAs) 11 into corresponding methyl esters 12 and 13 in methanol using Sc(OTf)3 as a catalyst

(Scheme 2.4) under microwave condition. Further, the catalyst can be recovered and reused in

subsequent esterifications without loss of activity.

Chapter-II

54

Scheme 2.4 One pot reaction to convert both triglycerides and FFAs to methyl esters

Singh et al.14

developed an efficient, rapid, and green synthesis of functionalized pyrazoles 17 by

the reaction of arylhydrazine 15, arylaldehydes 14 and ethyl acetoacetate 16 using Sc(OTf)3 as a

catalyst under microwave condition (Scheme 2.5). Excellent yields were obtained in shorter

reaction time.

Scheme 2.5 Sc(OTf)3 catalyzed synthesis of pyrazoles

Liu et al.15

synthesized amino-thieno[3,2-b]pyridines 20 from mixtures of 2-amino-3-

thiophenecarbonitriles 18 and arylketones 19 using Yb(OTf)3 as a catalyst under microwave

condition (Scheme 2.6). The one-pot modified reaction gave excellent yield and the reaction

time was shortened from 18 h to 5 min. The catalyst can be easily recovered and reused.

Scheme 2.6 Yb(OTf)3 catalyzed synthesis of amino-thieno[3,2-b]pyridines

Lee et al.16

performed a Kabachnik‒Fields reaction using Yb(OTf)3 as catalyst under microwave

condition (Scheme 2.7). The α-aminophosphonates 23 could be rapidly synthesized form

arylaldehyde 14, arylanilne 21 and diethyl phosphate 22 and the catalyst was recovered and

reused several times without loss of catalytic activity.

Chapter-II

55

Scheme 2.7 Yb(OTf)3 catalyzed synthesis of α-aminophosphonates

Liu et al.17

developed a microwave-assisted, Cu(OTf)2 catalyzed three-component synthesis of

dihydropyrimidinones 26 from arylaldehyde 14, ethyl acetoacetate 25 and urea 24 (Scheme 2.8).

To check the substrate scope of the reaction, ethyl acetoacetate was replaced with ethyl

butyrylacetate, ethyl propionylacetate, and acetylacetone. The respective DHPMs were obtained

in quantitative yield (90-95%).

Scheme 2.8 Cu(OTf)2 catalyzed synthesis of dihydropyrimidinones

Lekhok et al.18

developed an efficient procedure for the preparation of 2,4-disubstituted

quinoline 29 from 2-aminoaryl ketones 27 and phenylacetylenes 28 in the presence of In(OTf)3

as a catalyst under microwave irradiation (Scheme 2.9). The reaction proceeds by sequential

alkenylation/cyclization reaction. The yields of the quinolines were good to excellent and the

catalyst could be recycled up to four times.

Scheme 2.9 In(OTf)3 catalyzed synthesis of 2,4-disubstituted quinoline

The highly efficient and environmentally benign reaction processes are required for developing a

flexible and operationally simple route to achieve this goal. In continuation of our interest to

develop environmental benign methods for the synthesis of biologically active compounds we

explored the application of microwave irradiation in combination with metal triflate for the

synthesis of 2,3-diarylnaphthofurans and quinolines.

Chapter-II

56

Part-A: Synthesis of 2,3-Diarylnaphthofurans

The benzofurans and naphthofurans are important classes of heterocyclic compounds that are

present as key structural motifs in many natural products, as well as synthetic pharmaceutical

compounds.19-21

Considerable attention has been directed towards the synthesis of compounds

with benzofuran and naphthofuran framework because of their remarkable biological

activities.22-35

Biological significance of these motifs has been clearly exemplified by natural

products and synthetic compounds, such as Furomollugin 30,36

Viniferifuran 33,37

7-methoxy-2-

nitronaphtho[2,1-b]furan (R7000) 31,38

Moracin 32 and Anigopreissin A 3439,40

(Figure 2.1).

The naphthofuran is a powerful paradigm in the development and design of potentially active

compounds for anticancer,19

regulators of the nuclear receptor HNF4α,41

and imaging agents for

β-amyloid plaques in the brain.42

Naphthofurans derivatives can be used also as fluorescent

markers.43,44

Figure 2.1 Structures of some bioactive benzofurans and naphthofurans

2.2 Literature methods for synthesis of naphthofuran and benzofuran

In recent years, considerable attention has been attributed towards palladium-catalyzed oxidative

addition reactions in particular direct arylation through C-H bond activation.45-50

Acardi et al.

described the first palladium-catalyzed intramolecular cyclization of arylsubstituted alkynes

possessing a hydroxyl group at ortho-position to the triple bond for the synthesis of 2,3-

diarylbenzofuran.51

Since then transition metal catalyzed coupling/cyclization of suitably

functionalized alkynes as starting materials has been the focus of research for the synthesis of

2,3-diarylbenzofurans and 2,3-diarylnaphthofurans.52-55

Some recent protocols for the synthesis

of naphthofuran and benzofuran are described below.

Jiang et al.56

developed synthesis of 2,3-disubstituted benzofurans 37 via copper catalyzed

nucleophilic addition and oxidative cyclization of phenols 35 and arylalkynes 36 using oxygen as

Chapter-II

57

the oxidant (Scheme 2.10 ) in good yield. The yield of 2,3-disubstituted benzofurans were good

however the reaction time was very long (24 h).

Scheme 2.10 Copper catalyzed synthesis of 2,3-disubstituted benzofurans

Wang et al.26,57

developed reaction of chalcone epoxides 38 with 2-naphthyl ethers 39 initiated

by tris(4-bromophenyl)aminium hexachloroantimonate (TBPA+.

SbCl6‒) as a catalyst and

subsequent aerobic oxidative aromatization to give polysubstituted naphtho[2,1-b]furans 40 in

good yield (Scheme 2.11 ).

Scheme 2.11 Synthesis of polysubstituted naphtho[2,1-b]furans

Musgrave et al.58

synthesized of 2,3-diarylnaphthofurans 43 in the presence of SnCl4.5H2O as

catalyst using benzil 41 and 2-naphthol 42 (Scheme 2.12). The reaction gave very poor yield

(6%) of 2,3-diarylnaphthofurans and required long reaction time and high temperature.

Scheme 2.12 SnCl4.5H2O catalyzed synthesis of 2,3-diarylnaphthofurans

Flynn et al.22

developed synthesis of substituted benzo[b]furans 48 in three step process (Scheme

2.13). Initially it involves deprotonation of terminal alkyne 44 and o-iodophenol 45 with

MeMgCl to give the corresponding magnesium phenolate and magnesium acetylide respectively.

Addition of Pd(PPh3)2Cl2 and heating leads to a coupling to give o-alkynylphenoxy magnesium

Chapter-II

58

chloride 46. Dilution with an equal volume of DMSO and addition of aryl halide 47 gives the

coupled product 48.

Scheme 2.13 Synthesis of 2,3-diarylbenzo[b]furans

A number of methods have been developed for synthesis of 2,3-diarylbenzofurans, but synthetic

routes for naphthofurans are limited,27,34

and thus synthesis of diversified naphthofurans still

presents a major challenge in organic synthesis.

Encouraged by the illustrated biological and synthetic interest in 1,2-diarylnaphtho[2,1-b]furans

and prompted by the recent results for metal catalyzed C-H activation reactions, we envisaged a

novel synthetic pathway to 2,3-diarylnaphthofurans starting from 2-naphthols 42, aryl alkynes

44, and haloarenes 47. It was expected that hydroarylation of 42 with 44 in the presence of Lewis

acids will generate α-hydroxy styrenes 49,59-64

which on Heck-oxyarylation with aryl iodide 47

will afford the desired 2,3-diarylnaphthofurans (Figure 2.2).

Figure 2.2 Retrosynthetic analysis of 1,2-diarylnaphthofurans.


In our initial investigation, 2-naphthol 42, phenylacetylene 44 and iodobenzene 47 were used as

substrates to form 2,3-diphenylnaphtofuran 50 using Yb(OTf)3 as a catalyst for hydroarylation

and Pd(OAc)2 for in-situ Heck-oxyarylation. This strategy was unsuccessful since hydroarylation

did not happen under these conditions. Thus, first the reaction conditions for hydroarylation of

Chapter-II

59

42a with 44a to give 1-(1-phenylvinyl)naphthalen-2-ol 49 were optimized using different Lewis

acid catalysts (Table 2.1). Among different screened metal triflates, Cu(OTf)2, Sc(OTf)3, and

Bi(OTf)3 afforded 49a in good to moderate yields (30-81%, Table 2.1, entries 7-9). In case of

Cu(OTf)2 homocoupled product of 44a was also obtained in 30% yield along with 49a. An

excellent yield of 49a (91%) was obtained by the use of In(OTf)3 (10 mol%) under microwave

irradiation in toluene (Table 2.1, entry 10). It is noteworthy to mention that when hydroxyl group

was converted to methoxy and acetoxy, hydroarylation did not occur to give corresponding 1-

substituted-α-hydroxy styrene. It is expected that the reaction proceeds through the mechanism

as proposed in literature.65,66

Table 2.1 Optimization of hydroarylation conditions for 49a.

Entry Catalyst Moles (%) Time (min.) Solvent Yielda (%)

1 Yb(OTf)3 10 40 Toluene -b, c

2 Y(OTf)3 10 40 Toluene Trace

3 Ce(OTf)3 10 40 Toluene -b

4 Ln(OTf)3 10 40 Toluene Trace

5 Gd(OTf)3 10 40 Toluene 10

6 Zn(OTf)2 10 40 Toluene Trace

7 Cu(OTf)2 10 40 Toluene 30

8 Sc(OTf)3 10 40 Toluene 81

9 Bi(OTf)3 10 40 Toluene 59

10 In(OTf)3 10 40 Toluene 91 (76)c

11 In(OTf)3 10 20 Toluene 66

12 In(OTf)3 5 40 Toluene 61

13 In(OTf)3 10 20 ACN 79

14 In(OTf)3 10 20 THF 71

a Isolated yield after MW irradiation for 40 min at 120 C;

b No product was formed;

c Thermal heating at

reflux condition for 10 h.

Following the optimized reaction conditions for the hydroarylation, 42a and 7-methoxynaphthol

(42b) were hydroarylated with different 4-substituted phenylacetylenes (44a-c) in the presence

of In(OTf)3 to give the corresponding 1-vinylnaphthols or 1-substituted-α-hydroxy styrenes

(49a-f) in high yields (85-95%, Table 2.2).

Chapter-II

60

Table 2.2 Synthesis of 1-vinylnaphthols 49a-f

The structures of 49a-f were determined by NMR and high-resolution mass spectroscopy

(HRMS). Vinylic CH2 protons for 49a resonated at 6.33 and 5.51 with splitting constant of 1.5

Hz and phenolic proton resonated at 5.61 as a singlet in 1H NMR spectra (Figure 2.3). In

13C

NMR, a total of 16 carbons appeared which is as expected for the structure of 49a, and a peak at

247.1126 for [M + H]+ ion in HRMS spectra further confirmed the structure of 49a.

Figure 2.3a

1H NMR spectrum of compound 49a

Entry R1 R

2 Product Time (min.) Yield (%)b

1 H H 49a 40 91

2 H 4-CH3 49b 40 92

3 H 4-OCH3 49c 30 95

4 7-OCH3 H 49d 35 86

5 7-OCH3 4-CH3 49e 35 85

6 7-OCH3 4-OCH3 49f 30 86

a Reaction conditions: 42 (1.39 mmol), 44 (1.66 mmol), In(OTf)3 (78 mg, 10 mol%), toluene (2 mL) MW at

120C, 30 psi; bIsolated yield.

OH

Chapter-II

61

Figure 2.3b

13C NMR spectrum of compound 49a

Next, the reaction conditions were standardized for one-pot sequential palladium-catalyzed

cross-coupling reaction and oxyarylation (Heck-oxyarylation) of these 1-substituted-α-hydroxy

styrenes (49) with haloarenes (47) to afford desired 2,3-disubstituted-naphtofurans (Scheme

2.14). The model reaction performed with 1-(1-phenylvinyl)-2-naphthol (49a) using iodobenzene

(47a) in the presence of Pd(OAc)2 (5 mol%) and potassium carbonate (2 equiv) in N,N-

dimethylacetamide (DMA) resulted in 18% isolated yield of 1,2-diphenylnaphtho[2,1-b]furan

(50a) after 14 h at 140 C. When triphenylphosphine (PPh3) was used as a ligand in the above

reaction, in contrast to our earlier result, 50a was obtained in 50% yield.

Scheme 2.14 Synthesis of 2,3-diarylnaphthofurans

OH

Chapter-II

62

The optimization of reaction condition using different palladium catalysts, ligands, bases, and

solvents (Table 2.3) led to improvement in yield of 50a. The highest yield of 50a (72%, entry 2)

was obtained by using Pd(OAc)2 (5 mol%) in the presence of PPh3 and Cs2CO3 in DMA. The

yield of 50a was moderate to good (27-64%) with other palladium catalysts such as PdCl2,

Pd(PPh3)2Cl2, Pd(dba)2, and Pd(dppf)Cl2 (Table 2.3, entries 2-4, 18).

Table 2.3 Optimization of Heck-oxyarylation condition for 50a

Entry Catalyst Ligand Base Solvent Yield (%)b

1 Pd(OAc)2 - Cs2CO3 DMA 18

2 Pd(OAc)2 PPh3 Cs2CO3 DMA 72

3 PdCl2 PPh3 Cs2CO3 DMA 27

4 Pd(PPh3)2Cl2 PPh3 Cs2CO3 DMA 59

5 Pd(dba)2 PPh3 Cs2CO3 DMA 64

6 Pd(OAc)2 PPh3 KOH DMA 15

7 Pd(OAc)2 PPh3 TEA DMA Trace

8 Pd(OAc)2 PPh3 K2CO3 DMA 50

9 Pd(OAc)2 PPh3 tBuOK DMA 64

10 Pd(OAc)2 PPh3 Cs2CO3 DMF 48

11 Pd(OAc)2 PPh3 Cs2CO3 Toluene 35

12 Pd(OAc)2 Phenc Cs2CO3 DMA 50

13 Pd(OAc)2 biPyd Cs2CO3 DMA 30

14 Pd(OAc)2 (Tol)3P Cs2CO3 DMA 55

15 Pd(OAc)2 TFPe Cs2CO3 DMA 62

16 Pd(OAc)2 TCPf Cs2CO3 DMA 55

17 Pd(OAc)2 DMEDAg Cs2CO3 DMA 52

18 Pd(dppf)Cl2h PPh3

Cs2CO3 DMA 20 aReaction conditions: Catalyst (5 mol%), Ligand (10 mol%), Base (2 equiv), Solvent (5 mL), 140˚C, 14 h.

b

Isolated yield. c Phen = 1,10-phenanthroline.

d biPy = 2,20-bipyridine.

eTFP = Tri(2-furyl)-phosphine.

fTCP =

Tricyclohexylphosphine. gDMEDA = N,N-Dimethylethylenediamine (5 mol%).

hPd(dppf)Cl2 = [1,10-Bis-

(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM.

Chapter-II

63

The synthetic merit of the methodology was demonstrated by varying the substrates in the

reactions (Table 2.4). Various haloarenes and α-hydroxy styrenes containing electron donating

or withdrawing groups could be used for this reaction satisfactory. For example 1-(1-(4-

methoxyphenyl)vinyl)naphthalen-2-ol (49c) reacted with 47a to give 50b in 68% yield (Table

2.4, entry 2) and 7-methoxy-1-(1-(4-methoxyphenyl)vinyl)naphthalen-2-ol (49f) reacted with

47a to afford 50k in 65% (Table 2.4, entry 11). Reaction of 49a with 4-nitroiodo-benzene

afforded corresponding naphthofuran 50i in 51% yield (Table 2.4, entry 9).

Table 2.4 Synthesis of 2,3-diarylnaphthofurans 50a-n

Entry R1 R

2 R

3 Product Time (h) Yield

b (%)

1 H H H 50a 14 72

2 H 4-OCH3 H 50b 12 68

3 H 4-CH3 H 50c 14 57

4 H H 4-OCH3 50d 12 72

5 H H 4-CH3 50e 14 53

6 H 4-CH3 4-CH3 50f 14 50

7 H 4-OCH3 4-CH3 50g 11 52

8 H H 2-CH3 50h 14 51

9 H H 4-NO2 50i 14 41

10 H H 2,3-C4H4 50j 14 36

11 7-OCH3 4-OCH3 H 50k 10 65

12 7-OCH3 4-OCH3 4-CH3 50l 10 62

13 7-OCH3 H 4-CH3 50m 11 56

14 7-OCH3 4-CH3 4-CH3 50n 11 39

a Reaction condition: 49 (0.81 mmol), 47 (0.975 mmol), Pd(OAc)2 (0.04 mmol), Ph3P (0.081 mmol), Cs2CO3

(1.63 mmol), DMA (5 mL), 140 °C, 14h. bIsolated yield.

Chapter-II

64

The structures of all the synthesized 2,3-diarylnaphthofurans (50a-n) were established by IR,

NMR (1H &

13C) and mass spectrometry data. In

1H NMR of 50a peak for vinylic methylene

protons and phenolic proton of 49a disappeared and only signal for aromatic protons and 20

carbons peaks in 13

C NMR (Figure 2.4) were observed. Similarly peak for phenolic OH group

disappeared in the region 3517–3316 cm–1

in IR spectrum of 49a indicating cyclization of vinyl

phenol to napthofuran.

Figure 2.4a 1H NMR spectrum of compound 50a

O

Chapter-II

65

Figure 2.4b 13

C NMR spectrum of compound 50a

The sequential hydroarylation/Heck-oxyarylation was not limited to naphthol derivatives and

was also applied for the synthesis of 2,3-diarylbenzofurans from electron rich phenols. Indeed,

this catalytic system also proved viable with 4-methoxyphenol (51). The reaction of (51) with

44a using In(OTf)3 under microwave irradiation for 10 min gave corresponding α-hydroxy

styrene (4-methoxy-2-(1-phenylvinyl)phenol, 52) in 68% yield. The structure of 52 was

elucidated by IR, 1

H NMR, 13

C NMR, and mass spectrometry. In IR, a peak for phenolic OH

group appeared in the region of 3417-3525 cm-1

. In 1H NMR, a peak for vinylic and phenolic

protons appeared at δ 5.41 and 5.85 as doublets and at δ 4.79 as a singlet, respectively (Figure

2.5). The reaction of 52 with 47a in the presence of Pd(OAc)2 (5 mol%), Ph3P and Cs2CO3 gave

5-methoxy-2,3-diphenylbenzofuran (53) in 75% yield (Scheme 2.15).

Scheme 2.15 Synthesis of 5-methoxy-2,3-diphenylbenzofuran.

O

Chapter-II

66

Figure 2.5a 1H NMR spectrum of compound 52

Figure 2.5b 13

CNMR spectrum of compound 52

Chapter-II

67

The structure of 53 was unambiguously elucidated by spectroscopic analysis. 1H NMR spectrum

showed only one singlet in aliphatic region at δ 3.80 for OCH3 group and integration for

aromatic region matched with the required 13 aromatic protons of 52. Presence of a peak at δ

55.98 of OCH3 group along with other 16 carbons peaks in 13

C NMR (Figure 2.6) and molecular

ion peak at 323.1065 for [M + Na]+ ion in HRMS confirmed the structure of 52. Structure of 52

was further independently confirmed by X-ray crystal structure (CCDC 923801) (Figure 2.7).

The two aryl rings generate steric strain, and they are oriented in different planes.

Figure 2.6a 1H NMR spectrum of compound 53

Figure 2.6b 13

C NMR spectrum of compound 53

Chapter-II

68

Figure 2.7 ORTEP diagram of 53

Based on the structure of the product obtained and literature reports67,68

the mechanism of the

reaction is proposed as shown in Scheme 2.16. It is expected that initially 49 reacts with Ar-Pd-I

to form an oxygen-coordinated Pd(II)-aryl complex (A) which on insertion of alkene gives a five

membered oxygen- coordinated palladium(II) complex (B). This intermediate on β-hydride

elimination gives an intermediate with OPd(II)

H (C). Intramolecular addition of this alkene of C

to OPd(II)

H gives six membered oxygen-coordinated Pd(II) complex (D). Reductive elimination

of D gives tetrahydrofuran derivative (E). Subsequent, oxidation of E results in formation of

naphthofuran (50)/benzofuran (53).

Scheme 2.16 Proposed mechanism for the Heck-oxyarylation (For clarity ligand for Pd are

omitted).

Chapter-II

69

2.4 Conclusions

In conclusion, 2,3-diarylnaphthofurans were synthesized in an efficient and general synthetic

strategy in good to high yield from easily available naphthols, alkynes, and iodoarenes. An

interesting feature of the methodology is that it accommodates functionalities amenable to

further functional-group manipulation and with a rapid increase in molecular complexity.

2.5 Experimental

2.5.1 General information

All chemicals were obtained from commercial suppliers and used without further purification.

Melting points were determined in open capillary tubes on a MPA120-Automated melting point

apparatus and are uncorrected. Reactions were monitored by using thin layer chromatography

(TLC) on 0.2 mm silica gel F254 plates (Merck). The chemical structures of final products were

characterized by nuclear magnetic resonance spectra (1H NMR,

13C NMR) determined on a

Bruker NMR spectrometer (300 MHz) or a Varian NMR spectrometer (500 MHz). 13

C NMR

spectra are fully decoupled. Chemical shifts were reported in parts per millions (ppm) using

deuterated solvent peak or tetramethylsilane (internal) as the standard. The chemical structures of

final products were confirmed by an Applied Biosystems QSTAR® Elite (QqTOF) high

resolution mass spectrometer.

2.5.2 Representative procedure for the synthesis of 49a

In a 10 mL microwave vial was added 2-naphthol (200 mg, 1.39 mmol), phenylacetylene (168

mg, 1.66 mmol), In(OTf)3 (78 mg, 10 mol%), and toluene (2 mL). The reaction mixture in the

vial was irradiated with microwaves at 120 ºC, 30 psi for 40 min. The reaction was quenched

with the addition of H2O (2 mL) and the reaction mixture was extracted with ethyl acetate

(EtOAC, 2 × 5 mL). The combined organic layer was dried over anhydrous Na2SO4 and then

concentrated on rotator evaporator under vacuum. The crude product was purified by column

chromatography over silica gel (100-200 mesh) using hexane-EtOAc as eluent to give off white

solid (311 mg).


A two neck round bottom flask was charged with 49a (200 mg, 0.81 mmol), Cs2CO3 (587 mg,

1.63 mmol), PPh3 (21.2 mg, 0.08 mmol), and dry DMA (5 mL). The reaction mixture was

degassed, and nitrogen was purged. After purging nitrogen, Pd(OAc)2 (9 mg, 0.04 mmol) and

iodobenzene (198 mg, 0.98 mmol) were added to the reaction mixture and heated at 140 °C for

Chapter-II

70

14 h under N2 atmosphere. On completion of the reaction, the reaction mixture was diluted with

EtOAc and filtered through celite. The filtrate was washed with brine solution and extracted with

EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and then concentrated

under vacuum. The crude product was purified by column chromatography over silica gel (100-

200 mesh) using hexane-EtOAc to give off white solid (187 mg).


1-(1-Phenylvinyl)naphthalen-2-ol (49a)

M.p.: 112 – 113 C. 1H NMR (300 MHz, CDCl3) δ 7.79 (dd, J = 9.2,

4.3 Hz, 2H), 7.57 – 7.47 (m, 1H), 7.36 (dd, J = 6.5, 3.1 Hz, 2H), 7.32

– 7.23 (m, 6H), 6.35 – 6.30 (br, 1H), 5.61 (s, 1H), 5.53 – 5.50 (br,

1H). 13

C NMR (75 MHz, CDCl3) δ 150.43, 142.56, 138.76, 132.79,

129.67, 128.95, 128.76, 128.59, 128.06, 126.56, 126.33, 120.05,

118.97, 117.34. IR (neat) νmax : 3479, 3055, 1597, 1466, 1396, 1319,

1196, 1134, 925, 817, 516 cm‒1

. HRMS (ESI-MS) m/z: calcd for C18H15O+

247.1117, found

247.1126 [M + H]+.

1-(1-p-Tolylvinyl)naphthalen-2-ol (49b)

Pale yellow liquid. 1H NMR (300 MHz, CDCl3) 7.83 – 7.75 (m, 2H),

7.55 – 7.48 (m, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H),

7.25 (dd, J = 5.0, 3.1 Hz, 3H), 7.08 (d, J = 8.1 Hz, 2H), 6.29 (d, J =

1.5 Hz, 1H), 5.61 (s, 1H), 5.45 (d, J = 1.5 Hz, 1H), 2.31 (s, 3H).

13C NMR (75 MHz, CDCl3) δ 150.38, 142.31, 138.59, 135.88, 132.82,

129.55, 129.46, 128.92, 128.02, 126.52, 126.24, 124.95, 123.29, 120.23, 117.96, 117.32, 21.18.

IR (neat) νmax : 3487, 3055, 1597, 1512, 1466, 1389, 1327, 1196, 1134, 818, 748, 516 cm‒1

.

HRMS (ESI-MS) m/z: calcd for C19H17O+ 261.1274, found 261.1266 [M + H]

+.

1-(1-(4-Methoxyphenyl)vinyl)naphthalen-2-ol (49c)

M.p.: 83 – 84 C. 1

H NMR (300 MHz, CDCl3) δ 7.83 – 7.72 (m,

2H), 7.57 – 7.48 (m, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.30 – 7.26 (m,

3H), 7.25 (d, J = 1.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.21 (d, J =

1.5 Hz, 1H), 5.64 (s, 1H), 5.39 (d, J = 1.5Hz, 1H), 3.76 (s, 3H). 13

C

NMR (75 MHz, CDCl3) δ 159.97, 150.37, 141.79, 132.81, 131.22,

Chapter-II

71

129.53, 128.92, 128.02, 127.66, 126.50, 124.97, 123.29, 120.27, 117.31, 116.74, 114.08, 55.28.

IR (neat) νmax : 3441, 3024, 1605, 1512, 1466, 1396, 1296, 1250, 1180, 1126, 1026, 918, 817,

748, 516 cm‒1

. HRMS (ESI-MS) m/z: calcd for C19H17O2+ 277.1223, found 277.1227 [M + H]

+.

7-Methoxy-1-(1-phenylvinyl)naphthalen-2-ol (49d)

Pale yellow liquid. 1

H NMR (300 MHz, CDCl3) δ 7.69 (dd, J =

12.2, 8.9 Hz, 2H), 7.40 – 7.35 (m, 2H), 7.30 – 7.27 (m, 3H), 7.12

(d, J = 8.8 Hz, 1H), 6.94 (dd, J = 8.9, 2.5 Hz, 1H), 6.78 (d, J = 2.5

Hz, 1H), 6.30 (d, J = 1.4 Hz, 1H), 5.63 (s, 1H), 5.54 (d, J = 1.4

Hz, 1H), 3.63 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 158.16,

151.06, 143.01, 138.93, 134.01, 129.55, 129.38, 128.75, 128.54, 126.39, 124.29, 119.31, 118.92,

115.54, 114.73, 103.98, 55.00. IR (neat) νmax : 3502, 3057 1620, 1512, 1466, 1381, 1327, 1219,

1180, 1026, 833, 518 cm‒1

. HRMS (ESI-MS) m/z: calcd for C19H17O2+ 277.1223, found

277.1218 [M + H]+.

7-Methoxy-1-(1-p-tolylvinyl)naphthalen-2-ol (49e)


H NMR (300 MHz, CDCl3) δ 7.68 (dd, J =

11.0, 8.4 Hz, 1H), 7.25 (d, J = 1.8 Hz, 2H), 7.10 (t, J = 8.3 Hz,

3H), 6.94 (dd, J = 8.9, 2.4 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.25

(br, 1H), 5.62 (s, 1H), 5.47 (br, 1H), 3.65 (s, 3H), 2.32 (s, 3H). 13

C

NMR (75 MHz) δ 158.13, 151.00, 142.75, 138.51, 136.03,

134.07, 129.52, 129.45, 129.26, 126.30, 124.28, 119.53, 117.96, 115.50, 114.72, 104.00, 55.03,

21.17. IR (neat) νmax : 3495, 2955, 1620, 1512, 1458, 1380, 1327, 1219, 1180, 825 cm‒1

. HRMS

(ESI-MS) m/z: calcd for C20H19O2+ 291.1380, found 291.1375 [M + H]

+.

7-Methoxy-1-(1-(4-methoxyphenyl)vinyl)naphthalen-2-ol (49f)

M.p.: 119 – 120 C. 1H NMR (300 MHz, CDCl3) δ 7.68 (t, J = 9.4

Hz, 2H), 7.35 – 7.24 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.94 (dd, J

= 8.9, 2.3 Hz, 1H), 7.85 – 7.76 (m, 3H), 6.19 (br, 1H), 5.65 (s,

1H), 5.41 (br, 1H), 3.77 (s, 3H), 3.65 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 159.93, 158.13, 151.00, 142.19, 134.05, 131.31, 129.53,

129.25, 127.70, 124.28, 119.54, 116.75, 115.49, 114.72, 114.07, 104.02, 55.29, 55.05. IR (neat)

νmax : 3441, 1612, 1512, 1466, 1243, 1180, 1134, 1026, 833, 570, 517 cm‒1

. HRMS (ESI-MS)

m/z: calcd for C20H19O3+ 307.1329, found 307.1318 [M + H]

+.

Chapter-II

72

4-Methoxy-2-(1-phenylvinyl)phenol (52)


H NMR (300 MHz, CDCl3) δ 7.40 – 7.36 (m,

2H), 7.35 – 7.31 (m, 3H), 6.87 (d, J = 8.8 Hz, 1H), 6.82 (dd, J =

8.8, 2.9 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 5.86 (d, J = 1.1 Hz,

1H), 5.41 (d, J = 1.1 Hz, 1H), 4.79 (s, 1H), 3.74 (s, 3H). 13

C NMR

(75 MHz, CDCl3) δ 153.35, 147.11, 145.34, 139.17, 128.74,

127.03, 116.79, 116.58, 115.32, 115.11, 55.78. IR (neat) νmax : 3525, 3418, 1605, 1489, 1211,

1203, 1034, 779, 517 cm‒1

. HRMS (ESI-MS) m/z: calcd for C15H15O2 226.0994, found 226.0994

[M]+.

1,2-Diphenylnaphtho[2,1-b]furan (50a)

M.p.: 105 – 106 ºC. 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 8.1

Hz, 1H), 7.73 (d, J = 2.1 Hz, 2H), 7.59 – 7.49 (m, 8H), 7.38 (t, J =

7.5 Hz, 1H), 7.24 (t, J = 6.1 Hz, 4H). 13


δ 151.43, 150.09, 134.73, 130.94, 130.89, 130.59, 129.42, 128.96,

128.43, 128.36, 128.23, 127.80, 126.22, 126.01, 125.99, 124.28,

123.66, 123.09, 119.57, 112.22. IR (neat) νmax : 3055, 2924, 1443, 1389, 1265, 1219, 1064, 1003,

802, 748, 694, 609 cm‒1

. HRMS (ESI-MS) m/z: calcd for C24H17O 320.1201, found 320.1230

[M]+.

1-(4-Methoxyphenyl)-2-phenylnaphtho[2,1-b]furan (50b)

M.p.: 133 – 134 ºC. 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J =

8.0 Hz, 1H), 7.72 (d, J = 2.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 3H),

7.45 (d, J = 8.5 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.32 – 7.20 (m,

4H), 7.09 (d, J = 8.5 Hz, 2H), 3.94 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 159.53, 151.37, 150.21, 131.65, 131.01, 130.92, 128.94,

128.43, 127.73, 126.59, 126.16, 125.98, 125.89, 124.25, 123.87, 123.11, 119.23, 114.87, 112.22,

55.3. IR (neat) νmax : 2997, 2881, 1597, 1512, 1142, 1173, 1026, 802, 516 cm‒1

. HRMS (ESI-

MS) m/z: calcd for C25H19O2 350.1701, found 350.1732 [M]+.

Chapter-II

73

2-Phenyl-1-p-tolylnaphtho[2,1-b]furan (50c)


8.1 Hz, 1H), 7.72 (d, J = 1.6 Hz, 2H), 7.62 – 7.53 (m, 3H), 7.43

(d, J = 7.9 Hz, 2H), 7.35 (d, J = 7.8 Hz, 3H), 7.31 – 7.20 (m, 4H),

2.51 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 151.40, 150.08,

137.88, 131.51, 131.02, 130.93, 130.36, 130.16, 128.93, 128.45,

128.41, 127.72, 126.19, 125.96, 125.90, 124.24, 123.78, 123.16, 119.58, 112.22, 21.55. IR (neat)

νmax : 3041, 2923, 2854, 1450, 1389, 1285, 1064, 1003, 802, 764, 694, 516 cm‒1

. HRMS (ESI-

MS) m/z: calcd for C25H19O 334.1358, found 334.1371 [M]+.

2-(4-Methoxyphenyl)-1-phenylnaphtho[2,1-b]furan (50d)


8.1 Hz, 1H), 7.71 (s, 2H), 7.60 – 7.51 (m, 6H),, 7.48 (d, J = 8.7

Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 6.80 (d,

J = 8.7 Hz, 2H), 3.77 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ

159.30, 151.14, 150.32, 134.92, 130.93, 130.73, 129.37, 128.92,

128.26, 128.11, 127.69, 125.84, 125.41, 124.16, 123.76, 123.66, 123.11, 118.00, 113.93, 112.14,

55.26. IR (neat) νmax : 2962, 1512, 1385, 972, 833, 764, 694, 610, 574, 516 cm‒1

. HRMS (ESI-

MS) m/z: calcd for C25H19O2 350.1701, found 350.1714 [M]+.

1-Phenyl-2-p-tolylnaphtho[2,1-b]furan (50e)


8.1 Hz, 1H), 7.72 (s, 2H), 7.58 – 7.51 (m, 6H), 7.44 (d, J = 8.2

Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.26 – 7.21 (m, 1H), 7.07 (d, J =

8.1 Hz, 2H), 2.31 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 151.28,

150.42, 137.78, 134.87, 130.93, 130.65, 129.36, 129.16, 128.93,

128.32, 128.13, 128.10, 126.19, 125.92, 125.69, 124.21, 123.70, 123.11, 118.88, 112.20, 21.29.

IR (neat) νmax : 3083, 1389, 1249, 998, 802, 748, 694, 516 cm‒1

. HRMS (ESI-MS) m/z: calcd for

C25H18O 354.1358, found 354.1359 [M ]+.

Chapter-II

74

1,2-di-p-Tolylnaphtho[2,1-b]furan (50f)


8.1 Hz, 1H), 7.71 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.49 – 7.39

(m, 4H), 7.36 – 7.31 (m, 3H), 7.29 – 7.21 (m, 1H), 7.08 (d, J = 8.0

Hz, 2H), 2.51 (s, 3H), 2.31 (s, 3H). 13


151.24, 150.40, 137.77, 137.67, 131.64, 130.90, 130.41, 130.10,

129.13, 128.89, 128.40, 128.22, 126.15, 125.85, 125.59, 124.16, 123.82, 123.16, 118.86, 112.19,

21.54, 21.29. IR (neat) νmax : 3040, 2916, 1515, 1389, 802, 749, 517 cm‒1

. HRMS (ESI-MS) m/z:

calcd for C26H21O 348.1514, found 348.1501 [M]+.

1-(4-Methoxyphenyl)-2-p-tolylnaphtho[2,1-b]furan (50g)


8.1 Hz, 1H), 7.71 (s, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.46 (dd, J =

8.0, 6.5 Hz, 4H), 7.38 (t, J = 7.5 Hz, 1H), 7.31 – 7.22 (m, 1H),

7.09 (d, J = 8.4 Hz, 4H), 3.94 (s, 3H), 2.31 (s, 3H). 13

C NMR (75

MHz, CDCl3) δ 159.47, 151.22, 150.53, 137.68, 131.70, 130.91,

129.15, 128.91, 128.41, 128.22, 126.74, 126.12, 125.89, 125.58, 124.17, 123.91, 123.12, 118.51,

114.82, 112.20, 55.34, 21.30. IR (neat) νmax : 3031, 2962, 1520, 1497, 1389, 1242, 1173, 1033,

803, 725, 596, 517 cm‒1

. HRMS (ESI-MS) m/z: calcd for C26H20O2+

365.1536, found 365.1366

[M + H]+.

1-Phenyl-2-o-tolylnaphtho[2,1-b]furan (50h)

M.p.: 138 – 139 ºC. 1

H NMR (300 MHz, CDCl3) δ 7.94 (d, J =

8.0 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.74 (q, J = 8.9 Hz, 2H),

7.51 – 7.36 (m, 6H), 7.36 – 7.28 (m, 1H), 7.27 – 7.17 (m, 3H),

7.13 – 7.04 (m, 1H), 2.27 (s, 3H). 13


152.30, 151.97, 138.13, 134.01, 131.11, 130.91, 130.73, 130.47,

130.10, 128.97, 128.85, 128.61, 128.34, 127.58, 125.90, 125.65, 125.36, 124.26, 123.29, 122.23,

120.91, 112.40, 20.54. IR (neat) νmax : 3047, 2962, 1629, 1518, 1389, 1257, 1026, 802, 758, 694,

517 cm‒1

. HRMS (ESI-MS) m/z: calcd for C25H18NaO+ 334.1358, found 334.1365 [M]

+.

Chapter-II

75

2-(4-Nitrophenyl)-1-phenylnaphtho[2,1-b]furan (50i)


8.6 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H),

7.72 (d, J = 9.0 Hz, 1H), 7.69 – 7.58 (m, 5H), 7.57 – 7.47 (m,

3H), 7.46 – 7.38 (m, 1H), 7.28 (dd, J = 13.8, 5.6 Hz, 1H). 13

C

NMR (75 MHz, CDCl3) δ 152.30, 151.97, 138.13, 134.01,

131.11, 130.91, 130.73, 130.47, 130.10, 128.97, 128.85, 128.61, 128.34, 127.58, 125.90, 125.65,

125.36, 124.26, 123.29, 122.23, 120.91, 112.40, 20.54. IR (neat) νmax : 3062, 3031, 2924, 2360,

1589, 1504, 1329, 1095, 1084, 802, 748, 694, 517 cm‒1


C24H15NO3+ 366.1215, found 366.1245 [M + H]

+.

2-(Naphthalen-1-yl)-1-phenylnaphtho[2,1-b]furan (50j)


8.3 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.92 – 7.74 (m, 5H), 7.53 –

7.28 (m, 11H). 13

C NMR (75 MHz, CDCl3) δ 152.24, 151.67,

133.87, 133.74, 132.42, 130.99, 130.69, 129.66, 129.43, 129.02,

128.59, 128.38, 128.31, 127.95, 127.63, 126.59, 126.15, 126.04,

126.01, 125.93, 124.99, 124.36, 123.36, 122.45, 122.06, 112.49. IR (neat) νmax : 3062, 2924,

1599, 1504, 1327, 1095, 1084, 848, 802, 833, 748, 694, 517 cm‒1

. HRMS (ESI-MS) m/z: calcd

for C28H19O+

371.1430, found 371.1421 [M + H]+.

8-Methoxy-1-(4-methoxyphenyl)-2-phenylnaphtho[2,1-b]furan (50k)

Yellow liquid. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.9 Hz,

1H), 7.69 – 7.62 (m, 2H), 7.62 – 7.54 (m, 2H), 7.49 (d, J = 8.5

Hz, 2H), 7.32 – 7.21 (m, 3H), 7.11 (d, J = 8.5 Hz, 2H), 7.02 (dd,

J = 8.9, 2.5 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 3.91 (s, 3H), 3.49

(s, 3H). 13

C NMR (75 MHz, CDCl3) δ 159.55, 157.68, 151.86,

149.69, 131.89, 131.05, 130.24, 129.53, 128.42, 127.65, 126.74, 126.03, 125.79, 125.63, 123.19,

118.98, 116.25, 114.71, 109.72, 102.46, 55.44, 54.72. IR (neat) νmax : 3062, 2954, 2931, 1627,

1512, 1466, 1234, 1178, 1026, 854, 517 cm‒1


382.1558, found 383.0629 [M + 2H]+.

Chapter-II

76

8-Methoxy-1-(4-methoxyphenyl)-2-p-tolylnaphtho[2,1-b]furan (50l)


8.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H),

7.49 (t, J = 7.4 Hz, 4H), 7.09 (d, J = 8.3 Hz, 4H), 7.01 (dd, J =

8.9, 2.1 Hz, 1H), 6.95 – 6.90 (m, 1H),3.90 (s, 3H), 3.48 (s, 3H),

2.32 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 159.50, 157.62,

151.71, 150.02, 137.61, 131.95, 130.22, 129.49, 129.16, 128.27, 126.90, 126.01, 125.79, 125.34,

123.24, 118.26, 116.20, 114.66, 109.71, 102.46, 55.43, 54.72, 21.29. IR (neat) νmax : 2955, 1620,

1519, 1466, 1234, 1172, 1028, 825, 764, 588, 516 cm‒1


C27H23O3+ 395.1642, found 395.1617 [M + H]

+.

8-Methoxy-1-phenyl-2-p-tolylnaphtho[2,1-b]furan (50m)


8.9 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.61 – 7.52 (m, 5H), 7.48

(d, J = 8.2 Hz, 3H), 7.08 (d, J = 8.0 Hz, 2H), 7.00 (dd, J = 8.9,

2.3 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 3.41 (s, 3H), 2.31 (s, 3H).

13C NMR (75 MHz, CDCl3) δ 157.67, 151.76, 149.84, 137.70,

135.06, 130.88, 130.23, 129.41, 129.22, 129.17, 128.16, 128.06, 126.04, 125.79, 125.43, 123.07,

118.63, 116.36, 109.69, 102.32, 54.62, 21.29. IR (neat) νmax : 3055, 2924, 1620, 1466, 1211,

1026, 818, 848, 516 cm‒1

. HRMS (ESI-MS) m/z: calcd for C26H20NaO2+ 387.1356, found

387.1346 [M + H]+.

8-Methoxy-1,2-di-p-tolylnaphtho[2,1-b]furan (50n)

Yellow liquid. 1

H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.9

Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 – 7.43 (m, 5H), 7.36 (d,

J = 7.9 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 7.00 (dd, J = 8.9, 2.4

Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 3.44 (s, 3H), 2.48 (s, 3H),

2.31 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 157.59, 151.72,

149.81, 137.70, 137.59, 131.84, 130.69, 130.17, 129.88, 129.46, 129.14, 128.28, 126.00, 125.78,

125.33, 123.22, 118.61, 116.22, 109.70, 102.49, 21.40, 21.29. IR (neat) νmax : 3062, 2986, 1605,

1466, 1443, 1219, 1149, 1034, 833, 764, 694, 516 cm‒1


C27H22NaO2+ 401.1512, found 401.1453 [M + Na]

+.

Chapter-II

77

5-Methoxy-2,3-diphenylbenzofuran (53)

M.p.: 93 – 94 ºC. 1H NMR (300 MHz, CDCl3) δ 7.65 – 7.59

(m, 2H), 7.51 – 7.39 (m, 6H), 7.33 – 7.29 (m, 1H), 7.29 – 7.23

(m, 2H), 6.93 (dd, J = 7.8, 2.3 Hz, 2H), 3.80 (s, 3H). 13

C NMR

(75 MHz, CDCl3) δ 156.27, 151.40, 149.00, 132.98, 130.77,

130.75, 129.77, 129.06, 128.41, 128.30, 127.64, 126.94,

117.71, 113.59, 111.63, 102.25, 55.98. IR (neat) νmax : 3062, 2986, 1605, 1466, 1443, 1219,

1149, 1034, 833, 764, 694, 516 cm‒1


300.1223,

found 301.1205 [M + H]+.

Chapter-II

78

Part-B: Synthesis of Quinolines

Quinoline is a common heterocyclic scaffold in many natural and synthetic compounds having

medicinal and biological significance,69

especially in alkaloids. The quinoline skeleton is often

used for the design of many synthetic compounds with diverse pharmacological properties. For

example, kynurenic acid is a useful agent for the potential control of neurodegenerative

disorders.70

Quinoline-2-carboxylates used as potent 5-hydroxytryptamine antagonist, and potent

lead for inhibiting the binding of Insulin-like Growth Factor (IGF) to IGF-binding proteins71

Antimalarial drugs containing quinoline are mainstays of chemotherapy against malaria.72,73

Quinoline based compounds show a broad range of biological activities like anti-HIV,74

antituberculosis,75

antimicrobial and antifungal, and anticancer.76-78

Figure 2.8 depicts structure

of some bioactive quinoline compounds. Due to their great application as synthetic intermediates

and their unique biological activities, there has been growing interest in development of synthetic

methods for these molecules.

Figure 2.8 Structure of bioactive quinoline compounds.

2.6 Literature methods for synthesis of substituted quinolines

The pioneering work to access quinoline nucleus was reported in 1880 by Zdenko Hans Skraup,

and the reaction is referred as Skraup synthesis.79

Briefly, Skraup reaction produces

unsubstituted quinolines by treating aniline and glycerol in presence of strong acid and oxidizing

agent. Since its first report, several methods have been developed to produce these privileged

structural motifs and each method gained its own importance. For example, 2-substituted

quinolines can be obtained by Doebner-Miller reaction80

which involves the reaction of anilines

and α,β-unsaturated carbonyl compounds, whereas 2-substituted quinoline-4-carboxylic acids

can be achieved via Doebner method by treating anilines with pyruvic acid.81

Similarly, Knorr

method produces 2-hydroxyquinolines and Gould-Jacobs procedure affords 4-

hydroxyquinolines.82

The Conrad–Limpach reaction is a suitable method for the synthesis of 2,3-

disubstituted-4-hydroxyquinolines.83

Particularly, Combes reaction,84

Friedlander

Chapter-II

79

condensation85-88

and Povarov methods are known to produce 2,4-substituted quinolines. Figure

2.9 shows different methods for the synthesis of quinolines. Among these methods, Friedlander

reaction and Povarov reaction are frequently employed methods in the literature because of their

synthetic simplicity and structural diversity. 2-Aminobenzaldehyde derivatives and ketones are

the key substrates for Friedlander method whereas Povarov reaction utilizes aniline, aldehydes

and alkynes as raw materials.89-91

Povarov reaction is generally preferred when compared to the

other, because the substrates 2-aminobenzaldehydes or 2-aminoacetophenones in Friedlander

condensation are commercially unavailable for the diversity. The Povarov reaction referred as an

inverse electron demand hetero DielsAlder reaction proceeds via [4+2] cycloaddition of

aldimines and alkynes. This method is also considered as multicomponent reaction as the

substrates aniline, aldehyde and alkyne can be mixed in one-pot in presence of Lewis acid. Initial

imine formation followed by cycloaddition results in the formation of 1,2-dihydroquinoline

nucleus which on either aerobic oxidation or presence of additional oxidant affords quinolines.

Although, several protocols appear in the literature for the synthesis of 2,4-disubstituted

quinolines by Povarov approach, the development of more convenient and efficient protocol to

access these scaffolds with greener approach is still desirable.

Figure 2.9 Synthesis of quinoline derivatives by different synthetic route

Chapter-II

80

In recent years multicomponent reactions (MCR) have emerged as a powerful tool for the

diversity oriented organic synthesis.92-95

These reactions can provide drug-like molecules with

several degrees of structural diversity in a one-pot operation and offer significant advantages

over conventional linear-type syntheses such as high atom economy and E-factors, low cost,

reduction in overall reaction time and operational simplicity. A three-component reactions of

aldehydes, anilines and alkynes have been developed for the synthesis of quinolines with

transition metal complexes,90,96,97

oxidizing agents,98,99

strong acids.100,101

However, the yields of

quinolines were moderate to good and reaction required extended time. From environmental and

efficiency point of view lanthanide triflates have become highly attractive Lewis acid catalysts

for various chemical reactions. Some recent methods developed for the synthesis of 2,4-

disubstituted quinoline derivatives using this multi-component reactions are described below.

Fan et al.96

developed a three-component coupling of arylamines 21, arylaldehydes 14, and

arylalkynes 28 for the synthesis of 2,4-diphenylquinoline derivatives 54 using FeCl3 (Scheme

2.17). The protocol requires longer reaction time to complete the reaction and gave moderate to

good yields of quinolines.

Scheme 2.17 FeCl3 catalyzed synthesis of 2,4-disubstituted quinoline derivatives

Wang et al.102

developed a sequential catalytic process for the synthesis of quinoline derivatives

by AuCl3/CuBr. The three-component coupling of arylaldehydes 14, arylalkynes 28, and

arylamines 21 in presence of AuCl3 resulting in a mixture of quinoline derivatives 54 and

propargyl amine 55 (Scheme 2.18). Further to improve the yields of quinoline derivatives CuBr

was used as a co-catalyst.

Chapter-II

81

Scheme 2.18 AuCl3/CuBr catalyzed synthesis of 2,4-disubstituted quinolines

Nagarajan et al. 97

developed CuI/La(OTf)3 catalyzed tandem reaction for the efficient synthesis

of isomeric ellipticine derivatives 57 in ionic liquid [bmim][BF4] (Scheme 2.19). The reaction

was achieved from aminocarbazole 56, arylaldehydes 14 and arylalkynes 28. It was found that

the absence of Lewis acid reduces the yield of the product.

Scheme 2.19 CuI/La(OTf)3 catalyzed synthesis of isomeric ellipticine derivatives

The ionic liquids have excellent microwave coupling capability due to their ionic character. Ionic

liquids, especially based on imidazolium salt have been used as excellent reaction medium for

microwave assisted organic synthesis.103-105

Ionic liquids have been utilized for the Friedlander

synthesis of quinolines under milder reaction conditions.88

These solvents not only act as solvent

but have also been reported to enhance rate of chemicals reactions. Microwave-assisted reactions

are of great interest because of simplicity in operation, enhanced reaction rates and greater

selectivity.106-108

The novel reaction methodologies using Yb(OTf)3 and ionic liquid

straightforward and practical microwave assisted one-pot three-component method for efficient

synthesis of substituted quinolines was developed.


First, we selected multicomponent reaction of benzaldehyde 14a, phenylacetylene 28a and

aniline 21a in ionic liquid to give corresponding quinoline 54a as a model reaction to find the

optimum condition (Scheme 2.20). When the model reaction was carried out using Yb(OTf)3 (10

Chapter-II

82

mol%) as a catalyst under thermal heating at 120 °C (oil bath) in an open vessel it took 10 h to

give 54a in only 60% yield (Table 2.5, entry 16). However, when the reaction was carried out in

a CEM Discover Benchmate microwave reactor using closed vessel the yield of 54a was

dramatically enhanced to 90% (Table 2.5, entry 4).

Scheme 2.20 Synthesis of quinolines using Yb(OTf)3 under MW irradiation in [bmim][BF4]

Next, we screened different metal triflates and solvents for the model reaction and it was found

that under the same reaction conditions, other metal triflates, resulted in lower yield of 54a

(Table 2.5, entries 11-15).

Table 2.5 Optimization of the reaction condition for synthesis of 54a

Entry Solvent Catalyst Cat. Mol (% ) Time (Min.) Yield (%)B

1 [bmim][BF4] - - 3 33

2 - Yb(OTf)3 10 3 45

3 [bmim][BF4] Yb(OTf)3 5 3 74

4 [bmim][BF4] Yb(OTf)3 10 3 90

5 [bmim][BF4] Yb(OTf)3 20 3 88

6 [bmim][BF6] Yb(OTf)3 10 3 65

7 [PyBu][Br] Yb(OTf)3 10 3 25

8 PEG Yb(OTf)3 10 3 45

9 Ethanol Yb(OTf)3 10 3 40

10 CH3CN Yb(OTf)3 10 3 45

11 [bmim][BF4] Ag(OTf) 10 3 62

12 [bmim][BF4] Cu(OTf)2 10 3 58

13 [bmim][BF4] Sc(OTf)3 10 3 60

14 [bmim][BF4] Ce(OTf)3 10 3 55

15 [bmim][BF4] Sc(OTf)3 10 3 50

16 [bmim][BF4] Yb(OTf)3 10 600 60c

aReaction condition: Benzaldehyde (1.0 mmol), phenylacetylene (1.0 mmol), aniline (1.0 mmol), MW

irradiation at 80 W, 80 °C, and 80 Psi, bIsolated yield,

cThermal heating at 120 °C, [PyBu]Br: n-

Butylpyridinium bromide.

Chapter-II

83

The yield of 54a was also best in [bmim][BF4] among all the solvents screened with Yb(OTf)3 as

catalyst (Table 2.5, entries 6-10). The role of Yb(OTf)3 and [bmim][BF4] was confirmed by the

fact that only 33% and 45% yield was observed for 54a in the absence of Yb(OTf)3 and

[bmim][BF4], respectively under similar reaction condition (Table 2.5, entry 1-2). The optimum

catalyst loading was found to be 10 mol% and increasing the amount of Yb(OTf)3 did not

improve the yields, whereas decreasing the amount of Yb(OTf)3 reduced the yield of 54a (Table

2.5, entries 3-5). The optimal reaction condition for model reaction was found to be 10 mol%

Yb(OTf)3, 80W irradiation power for 3 min.

After determining the optimized reaction conditions, we next studied the substrate scope by

varying arylaldehydes 14, arylalkynes 28 and arylamines 21 for synthesis of various substituted

quinolines 54. A wide range of structurally diverse arylaldehydes gave the corresponding

quinolines in good to excellent yields (Table 2.6). Arylaldehydes with both electron-donating

and electron withdrawing groups reacted to afford the corresponding products in almost equally

high yields.

The present method is equally effective for aromatic amines with both electron donating and

electron withdrawing substituent affording the desired quinolines in almost equally high yields

(Table 2.6 entries 9-20). We also studied scope of alkynes and it was found that substituted

phenylacetylens were good substrate for the synthesis of corresponding substituted quinolines.

The structure of all the synthesized compounds was confirmed by IR, 1H NMR and

13CNMR

spectroscopic data. A representative 1H and

13C NMR spectra for compound 54p are shown in

Figure 2.10. In 1H NMR a peak was observed at δ 2.49 for CH3 along with other aromatic

protons. A peak appeared at δ 21.36 ppm for CH3 and at δ 118.95 for CN along with all other

carbons in 13

C NMR. In IR a characteristic peak for CN streaching was observed at 2223 cm‒1

.

Various electron-withdrawing groups were tolerated to give satisfactory yields.

Chapter-II

84

Table 2.6 Synthesis of substituted quinolines using Yb(OTf)3 in ionic liquid under MWa

Product R R1 R

2 Yieldb (%)

54a Ph C6H5 C6H5 90

54b 3,4,5-(CH3O)3C6H3 C6H5 C6H5 88

54c 3,4-(CH3O)2C6H4 C6H5 C6H5 77

54d 2-FPh C6H5 C6H5 76

54e 4-(PhCH2O)C6H4 C6H5 C6H5 82

54f 4-(C3H5O)C6H4 C6H5 C6H5 83

54g C4H3S C6H5 C6H5 69

54h 4-NO2C6H4 C6H5 C6H5 89

54i 4-CH3C6H4 C6H5 C6H5 92

54j C6H5 4-BrC6H4 C6H5 96

54k 4-(C3H5O)C6H4 4-BrC6H4 C6H5 91

54l 4-CH3C6H4 4-BrC6H4 C6H5 90

54m C6H5 4-ClC6H4 C6H5 87

54n 3-ClC6H4 4-NO2C6H4 C6H5 89

54o 4-CNC6H4 4-IC6H4 C6H5 86

54p 4-CNC6H4 C6H5 4-CH3C6H4 88

54q 3,4,5-(CH3O)3C6H3 4-BrC6H4 4-CH3C6H4 91

54r 3,4,5-(CH3O)3C6H3 4-NO2C6H4 4-CH3C6H4 93

54s 4-CNC6H4 4-BrC6H4 4-CH3C6H4 90

aReaction condition: Aldehyde (1.0 mmol), alkyne (1.0 mmol), aniline (1.0 mmol), MW irradiation at 80 W, 80 °C,

and 80 Psi, 3 min.

bIsolated yield.

Chapter-II

85

Figure 2.10a 1H NMR spectrum of compound 54p

Figure 2.10b 13

C NMR spectrum of compound 54p

Chapter-II

86

The reaction is supposed to proceed through four-step domino sequence as shown in Scheme

2.21. The first step is believed to be formation of imine (58). The in situ generated imine

undergoes nucleophilic attack by phenylacetylene to give propargyl amine derivative (59).

Propargyl amine derivative (59) further undergoes intramolecular cyclization to give the

dihydroquinoline (60). This further aromatizes to quinolines by aerial oxidation. It is believed

that Yb(OTf)3 assists in imine form by activating arylaldehyde for nucleophilic attack and

activates triple bond in propargyl amine derivative (59) to promote intermolecular cyclization.

The role of ionic liquid is not clear, however it is expected that the acidic nature of C2‒ proton

(pKa = 22.7 in DMSO) of imidazolium facilitates the formation of imine by the activation of the

aldehyde carbonyl through hydrogen bonding.109

Scheme 2.21 Proposed mechanism for the synthesis of quinolines by three component reaction

We subsequently investigated the possibility of recycling of the catalyst. After first cycle for

model reaction the product was extracted by ethyl acetate/ hexane and the ionic liquid containing

Yb(OTf)3 was dried on rotatory evaporator under vacuum for subsequent reactions. The ionic

liquid thus recovered was charged with fresh benzaldehyde, phenylacetylene and aniline and

irradiated in microwave for 3 mins under same conditions. After completion of reaction the

product was extracted. The above sequence was repeated four times to give 54a in good yields

(90, 88, 85 & 86%) without much loss in catalytic activity of Yb(OTf)3.

Chapter-II

87

2.8 Conclusions

In summary, we have developed a straightforward and efficient method for the synthesis of

quinolines by the Yb(OTf)3 catalyzed three-component reaction of aldehydes, alkynes, and

amines under microwave in ionic liquid. A series of 2,4-disubstituted quinolines have been

synthesized in excellent yields (69-93%). The catalyst can be recycled upto four cycles without

much decrease in catalytic activity. Short reaction times, use of environment friendly catalyst

and excellent yields are the advantages of this method which will make it a practical route for

synthesis of substituted quinolines over existing methods.

2.9 Experimental

2.9.1 General information


Melting points were determined in open capillary tubes on a MPA120-Automated melting point

apparatus and are uncorrected. Reactions were monitored by using thin layer chromatography

(TLC) on 0.2 mm silica gel F254 plates (Merck). The chemical structures of final products were

determined by nuclear magnetic resonance spectra (1H NMR,

13C NMR) recorded on a Bruker

NMR spectrometer (300 MHz) or a Varian NMR spectrometer (500 MHz). 13

C NMR spectra are

fully decoupled. Chemical shifts were reported in parts per million (ppm) using deuterated

solvent peak or tetramethylsilane (internal) as the standard. The IR spectra were recorded using

KBr pellets on Shimadzu Prestige-21 FTIR spectrophotometer, and νmax was expressed in cm‒1

.


A mixture of benzaldehyde (106 mg, 1.0 mmol), aniline (93 mg, 1.0 mmol), phenylacetylene

(102 mg, 1.0 mmol) and Yb(OTf)3 (62 mg, 10 mol%) was taken in a tube containing 2 mL of

[bmim][BF4] and placed under microwave irradiation in CEM Discover BenchMate. The

reaction parameters were set to 80W, 80 °C for 3 min. under stirring. After completion of the

reaction, the mixture was extracted with ethyl acetate: hexane (1: 1, v/v) (3 × 10 mL).

Evaporation of solvent gave the crude product which was purified by in silica column to give

pure 54a (253 mg, 90%) as off white solid.

Chapter-II

88


2,4-Diphenylquinoline (54a)

M.p.: 108 – 110 °C (lit. 109 – 111 °C).110 1

H NMR (500 MHz, CDCl3)

δ 8.24 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 6.9 Hz, 2H), 7.89 (d, J = 7.9

Hz, 1H), 7.81 (s, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.60 ‒ 7.47 (m, 7H),

7.46 ‒ 7.40 (s, 2H). 13

C NMR (75 MHz, CDCl3) δ 154.65, 153.60,

144.52, 139.49, 138.06, 130.45, 130.38, 129.14, 129.03, 128.46,

128.10, 127.82, 126.44, 125.23, 124.15, 119.83, 115.97.

IR (neat) νmax : 3069, 3053, 3030, 1589, 1545, 1489, 1444, 1406, 1357, 889, 771, 703 cm‒1

.

4-Phenyl-2-(3,4,5-trimethoxyphenyl)quinoline (54b)


1H), 8.19 (d, J = 6.9 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H),

7.72 (t, J = 7.3 Hz, 1H), 7.60 ‒ 7.47 (m, 7H), 7.46 ‒ 7.40 (s, 2H). 13

C

NMR (125 MHz, CDCl3) δ 154.72, 154.38, 153.55, 144.56, 141.73,

139.49, 131.37, 130.37, 129.14, 129.03, 128.46, 127.81,

126.72, 126.44, 124.15, 116.57, 114.03, 60.65, 56.78. IR (neat) νmax : 3055, 2945, 2823, 1587,

1546, 1540, 1421, 1360, 1126, 1007, 860, 767, 708 cm‒1

.

2-(3,4-Dimethoxyphenyl)-4-phenylquinoline (54c)

M.p.: 142 – 144 °C. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 8.4,

1H), 7.73 (dd, J = 7.4, 1.5 Hz, 1H), 7.65 (s, 1H), 7.64 – 7.56 (m,

4H), 7.48 (td, J = 7.5, 1.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.39 –

7.32 (m, 2H), 7.00 (d, J = 7.5 Hz, 1H), 3.81 (s, 6H). 13

C NMR (75

MHz, CDCl3) δ 154.26, 154.08, 152.54, 149.89, 144.50, 139.49,

130.93, 130.38, 129.14, 129.14, 129.03, 128.46, 128.46, 127.82, 126.44, 126.26, 124.15, 122.87,

116.45, 115.52, 113.21, 56.79, 56.79. IR (neat) νmax : 3061, 2974, 2943, 1589, 1543, 1514, 1489,

1259, 1168, 1024, 859, 769, 717 cm‒1

.

2-(2-Fluorophenyl)-4-phenylquinoline (54d)


1H), 8.12 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.7

Hz, 1H), 7.77 ‒ 7.25 (m, 1H), 7.59 – 7.48 (m, 6H), ), 7.46 – 7.40 (m,

1H), 7.35 – 7.31 (m, 1H), ), 7.23 – 7.16 (m, 1H). 13

C NMR (126 MHz,

Chapter-II

89

CDCl3) δ 161.71, 159.73, 153.62, 148.76, 148.64, 138.15, 131.54, 130.86, 130.05, 129.66,

129.53, 128.59, 128.43, 126.70, 125.72, 124.72, 122.75, 122.69, 116.35, 116.17. IR (neat) νmax :

3051,3030, 2983, 1589, 1487, 1448, 1408, 1359, 1259, 1205, 1014, 869, 761, 711 cm‒1

.

2-(4-(Benzyloxy)phenyl)-4-phenylquinoline (54e)

M.p.: 117 – 119 °C. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J =

8.4 Hz, 1H), 8.16 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.3 Hz, 1H),

7.84 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.73 – 7.68 (m, 1H), 7.57

– 7.53 (m, 3H), 7.47 – 7.44 (m, 2H), 7.41 – 7.37 (m, 3H), 7.19

(d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.5

Hz, 1H), 5.14 (s, 2H). 13

C NMR (126 MHz, CDCl3) δ 159.98,

156.40, 149.00, 138.49, 136.76, 132.45, 129.90, 129.57, 129.47, 129.12, 128.93, 128.64, 128.58,

128.37, 128.05, 127.53, 126.00, 125.63, 120.88, 118.94, 115.16, 70.05. IR (neat) νmax :

3059,3049, 2875, 1604, 1514, 1438, 1359, 1249, 1232, 1174, 1021, 837, 764, 704 cm‒1

.

2-(4-Cyclopropoxyphenyl)-4-phenylquinoline (54f)

M.p.: 114 – 116 °C. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J =

7.5, 1H), 7.94 (d, J = 7.5 Hz, 2H), 7.74 (dd, J = 7.5, 1.4 Hz,

1H), 7.67 (s, 1H), 7.61 (dd, J = 7.5, 1.2 Hz, 2H), 7.51 ‒ 7.45

(m, 3H), 7.43 (t, J = 7.4 Hz, 2H), 7.39 – 7.32 (m, 2H), 2.18 ‒

2.06 (m, 1H), 1.10 – 1.00 (m, 2H), 0.88 – 0.77 (m, 2H).

13C NMR (126 MHz, CDCl3) δ 154.65, 153.60, 147.20, 144.51, 139.49, 137.31, 135.55, 130.37,

129.14, 129.03, 128.46, 127.81, 126.44, 125.23, 124.15, 120.26, 115.97, 21.08, 10.06. IR (neat)

νmax : 3062, 2962, 2870, 1602, 1579, 1534, 1489, 1359, 1249, 1232, 1174, 1021, 837, 764, 704

cm‒1

.

4-Phenyl-2-(thiophen-2-yl)quinoline (54g)

Viscous liquid. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.4,

1H), 7.89 (s, 1H), 7.78 (dd, J = 7.5, 1.4 Hz, 1H), 7.72 (dd, J =

7.5, 1.6 Hz, 1H), 7.66 ‒ 7.61 (m, 2H), 7.50 (td, J = 7.5, 1.4

Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.42 – 7.34 (m, 3H), 7.30 (t,

J = 7.5 Hz, 1H). 13

C NMR (126 MHz, CDCl3) δ 157.25,

Chapter-II

90

150.21, 148.65, 139.49, 136.57, 132.02, 130.37, 129.14, 129.03, 128.79, 128.46, 127.81, 127.05,

126.44, 124.15, 121.64, 113.06. IR (neat) νmax : 3053, 3030, 1714, 1589, 1546, 1504, 1427, 1238,

1225, 1042, 827, 771, 702 cm‒1

.

2-(4-Nitrophenyl)-4-phenylquinoline (54h)

M.p.: 162 – 164 °C. 1H NMR (500 MHz, CDCl3) δ 8.39 –

8.35 (m, 4H), 8.28 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.4 Hz,

1H), 7.86 (d, J = 1.0 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.62 – 7.53

(m, 6H). 13

C NMR (126 MHz, CDCl3) δ 154.03, 150.20,

148.50, 148.37, 145.17, 137.80, 130.25, 130.03, 129.51,

128.80, 128.76, 128.42, 127.43, 126.19, 125.84, 124.04, 119.21. IR (neat) νmax : 3078, 3059,

3028, 1589, 1548, 1514, 1487, 1421, 1346, 1319, 1109, 860, 843, 759, 698 cm‒1

.

4-Phenyl-2-p-tolylquinoline (54i)

M.p.: 108 – 110 °C (lit. 102 °C)111

. 1H NMR (500 MHz,

CDCl3) δ 8.23 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H),

7.89 (dd, J = 8.4, 0.9 Hz, 1H), 7.80 (s, 1H), 7.75 – 7.70 (m,

1H), 7.56 – 7.54 (m, 3H), 7.53 – 7.70 (m, 1H), 7.47 – 7.43 (m,

1H), 7.34 – 7.33 (m, 1H), 7.32 – 7.31 (m, 1H), 7.16 – 7.13 (m,

1H), 2.43 (s, 3H). 13

C NMR (126 MHz, CDCl3) δ 156.85,

149.07, 148.76, 139.46, 138.46, 130.00, 129.59, 129.58, 129.48, 129.30, 129.24, 128.59, 128.38,

127.46, 126.16, 125.63, 119.23, 117.46, 112.80, 21.38. IR (neat) νmax : 3049, 3026, 1591, 1539,

1494, 1487, 1420, 1332, 1182, 821, 773, 704 cm‒1

.

6-Bromo-2,4-diphenylquinoline (54j)

M.p.: 153 – 155 °C. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J

= 7.3 Hz, 2H), 8.12 (d, J = 9.0 Hz, 1H), 8.04 (s, 1H), 7.83 (s,

1H), 7.80 (d, J = 6.8 Hz, 1H), 7.59 – 7.50 (m, 7H), 7.50 – 7.46

(m, 1H). 13

C NMR (126 MHz, CDCl3) δ 157.15, 148.62,

147.14, 138.92, 137.59, 133.16, 131.59, 129.74, 129.44,

128.94, 128.86, 128.79, 127.82, 127.60, 126.98, 120.55, 120.14. IR (neat) νmax : 3084, 3057,

3026, 1587, 1539, 1481, 1357, 1151, 1060, 1028, 885, 821, 779, 698 cm‒1

.

Chapter-II

91

6-Bromo-2-(4-cyclopropoxyphenyl)-4-phenylquinoline (54k)


= 8.8 Hz, 2H), 8.05 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 2.1 Hz,

1H), 7.79 – 7.74 (m, 2H), 7.60 – 7.49 (m, 5H), 7.00 (d, J = 8.8

Hz, 2H), 4.88 – 4.83 (m, 1H), 1.85 – 1.79 (m, 2H), 1.68 – 1.61

(m, 2H). 13

C NMR (126 MHz, CDCl3) δ 159.63, 156.85,

148.11, 147.41, 137.82, 132.85, 131.58, 131.14, 129.43, 128.81, 128.79, 128.64, 127.73, 126.68,

119.85, 119.57, 115.83, 79.37, 32.88, 24.10. IR (neat) νmax : 3055, 2970, 2870, 1606, 1537, 1514,

1481, 1350, 1238, 1172, 958, 829, 704 cm‒1

.

6-Bromo-4-phenyl-2-p-tolylquinoline (54l)

M.p.: 120 – 122 °C. 1H NMR (500 MHz, CDCl3) δ 8.10 –

8.06 (m, 2H), 8.02 (s, 1H), 7.83 – 7.75 (m, 2H), 7.61 – 7.50

(m, 5H), 7.33 (d, J = 7.2 Hz, 2H), 2.43 (s, 3H). 13

C NMR (126

MHz, CDCl3) δ 157.13, 148.29, 147.33, 139.83, 137.74,

136.27, 132.96, 131.68, 129.65, 129.45, 128.82, 128.69,

127.76, 127.42, 126.90, 120.22, 119.90, 21.40. IR (neat) νmax : 3045, 3028, 2916, 1587, 1539,

1483, 1355, 1340, 1149, 877, 812, 767, 705 cm‒1

.

6-Chloro-2,4-diphenylquinoline (54m)

M.p.: 127 – 129 °C (122 °C).112

1H NMR (500 MHz, CDCl3)

δ 8.28 (d, J = 7.5 Hz, 1H), 7.96 (dd, J = 7.5, 1.2 Hz, 2H), 7.67

(d, J = 1.4 Hz, 1H), 7.64 (s, 1H), 7.62 ‒ 7.55 (m, 2H), 7.50

(dd, J = 7.5, 1.4 Hz, 1H), 7.46 ‒ 7.39 (m, 4H), 7.38 – 7.30 (m,

2H). 13

C NMR (125 MHz, CDCl3) δ 151.75, 146.59, 141.24,

139.49, 138.06, 130.98, 130.75, 130.45, 129.31, 129.14, 129.02, 128.46, 128.10, 127.81, 126.28,

123.80, 117.59. IR (neat) νmax : 3059, 3041, 1589, 1539, 1485, 1357, 1342, 1153, 1076, 883, 823,

747, 700 cm‒1

.

2-(3-Chlorophenyl)-6-nitro-4-phenylquinoline (54n)

M.p.: 218 – 220 °C. 1H NMR (500 MHz, CDCl3) δ 8.61 (dd, J =

10.0, 4.5 Hz, 2H), 8.03 (s, 1H), 7.92 – 7.83 (m, 2H), 7.81 (s, 1H),

7.67 (dd, J = 7.5, 1.4 Hz, 1H), 7.63 – 7.59 (m, 2H), 7.43 (t, J = 7.5

Hz, 2H), 7.39 – 7.31 (m, 3H). 13

C NMR (125 MHz, CDCl3) δ 151.01,

Chapter-II

92

148.32, 143.27, 142.77, 139.49, 138.44, 134.19, 129.97, 129.54, 129.14, 128.46, 127.81, 127.69,

127.47, 125.72, 123.98, 122.89, 118.24. IR (neat) νmax : 3082, 3064, 1593, 1552, 1485, 1342,

1226, 1083, 893, 843, 788, 690 cm‒1

.

4-(6-Iodo-4-phenylquinolin-2-yl)benzonitrile (54o)


= 7.5 Hz, 2H), 8.05 (d, J = 1.4 Hz, 1H), 7.90 – 7.81 (m, 2H),

7.75 (d, J = 7.5 Hz, 2H), 7.62 (s, 1H), 7.43 (t, J = 7.5 Hz, 2H),

7.38 – 7.32 (m, 3H). 13

C NMR (125 MHz, CDCl3) δ 152.19,

148.04, 143.14, 141.91, 139.49, 137.34, 133.51, 132.65,

131.90, 130.36, 129.14, 128.46, 127.81, 126.11, 122.76, 119.12, 117.07, 96.54. IR (neat) νmax :

3064, 3032, 2222, 1587, 1537, 1479, 1320, 1093, 873, 833, 823, 781, 765, 698 cm‒1

.

4-(4-p-Tolylquinolin-2-yl)benzonitrile (54p)


= 7.6 Hz, 2H), 8.23 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.4 Hz,

1H), 7.83 – 7.79 (m, 3H), 7.78 – 7.74 (m, 1H), 7.55 – 7.50 (m,

1H), 7.46 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 2.49

(s, 3H). 13

C NMR (125 MHz, CDCl3) δ 154.46, 149.90,

148.76, 143.74, 138.69, 135.01, 132.60, 130.20, 129.96,

129.43, 129.42, 128.08, 127.09, 126.23, 125.84, 118.95, 118.87, 112.68, 21.36. IR (neat) νmax :

3064, 3028, 2989, 2912, 2860, 2223, 1591, 1541, 1494, 1417, 1355, 1083, 873, 844, 815, 759,

704 cm‒1

.

6-Bromo-4-p-tolyl-2-(3,4,5-trimethoxyphenyl)quinoline (54q)


= 8.9 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.81 – 7.77 (m, 1H),

7.75 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.42 – 7.38 (m, 4H),

3.99 (s, 6H), 3.92 (s, 3H), 2.50 (s, 3H). 13

C NMR (125 MHz,

CDCl3) δ 156.77, 153.59, 148.44, 147.28, 139.57, 138.81,

134.83, 134.74, 133.01, 131.68, 129.56, 129.34, 127.86,

127.06, 120.31, 119.78, 104.71, 60.99, 56.31, 21.36. IR (neat) νmax : 3044, 3018, 2941, 2894,

1591, 1537, 1487, 1415, 1357, 1118, 1004, 835, 822, 815, 692 cm‒1

.

Chapter-II

93

6-Nitro-4-p-tolyl-2-(3,4,5-trimethoxyphenyl)quinoline (54r)


= 1.4 Hz, 1H), 8.62 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.69 –

7.65(m, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.32 (d, J = 2.0 Hz,

3H), 7.30 (s, 1H), 3.84 (s, 6H), 3.82 (s, 3H), 2.36 (s, 3H). 13

C

NMR (125 MHz, CDCl3) δ 153.55, 151.38, 148.59, 143.27,

142.63, 141.73, 137.89, 134.80, 131.37, 129.97, 129.35,

129.29, 127.63, 123.98, 122.89, 118.40, 110.03, 60.65, 56.78, 21.12.

IR (neat) νmax : 3008, 2941, 2835, 1593, 1556, 1506, 1407, 1338, 1128, 1006, 863, 823, 701

cm‒1

.

4-(6-Bromo-2-p-tolylquinolin-4-yl)benzonitrile (54s)


= 7.5 Hz, 1H), 7.91 (s, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.79 –

7.73 (m, 5H), 7.63 (s, 1H), 7.58 – 7.54 (m, 1H), 7.29 (d, J =

7.5 Hz, 2H), 2.35 (s, 3H). 13


155.09, 152.77, 143.64, 143.08, 141.71, 136.25, 134.16,

133.90, 131.93, 130.43, 129.53, 128.44, 126.82, 123.35,

119.12, 117.40, 116.53, 115.24, 21.12. IR (neat) νmax : 3043, 3028, 2916, 2220, 1587, 1537,

1483, 1407, 1149, 1058, 879, 833, 813 cm‒1

.

Chapter-II

94

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CHAPTER - III

Cu(OTf)2 Catalyzed Synthesis of

1,3,5-Triarylpyrazoles and Bis(5-

methyl-2-furyl)methanes

Chapter-III

99

3.1 Introduction:

The use of catalyst have an important role in the area of modern synthetic chemistry.1 Copper(II)

trifluoromethanesulfonate commonly known as copper triflate (Cu(OTf)2) is a mild and efficient

catalyst. The growing interest in use of copper triflate is due to their ease of handling, non-

corrosiveness, reusability, unique reactivity and selectivity. Many useful reactions are catalyzed

presence of copper triflate using catalytic amount in various organic transformations, such as

carbon-carbon, carbon-heteroatom bond formation reactions,2 oxidative coupling reactions,

3

reactions of diazocompounds,4 cycloaddition reactions,

5 and protection-deprotection reactions.

6,7

A brief overview of some recent Cu(OTf)2 catalyzed reactions are discussed below.

Chan et al.8 exploited the exciting reactivities of 2-alkyl substituted 1,3-dicarbonyl compounds 1

using Cu(OTf)2 as a catalyst and PhI=NTs 2 to prepare α-acyl-β-amino acid 4 and 2,2-

diacylaziridine 3 (Scheme 3.1). The advantage of the protocol is readily available 2-alkyl

substituted 1,3-dicarbonyl compound and complete control of product selectivity in the reaction

to give good yield.

Scheme 3.1 Cu(OTf)2 catalyzed synthesis of α-acyl-β-amino acid and 2,2-diacylaziridine

Wu et al.9 reported Cu(OTf)2 catalyzed regio-selective addition of β-diketones to styrenes,

norbornene, cyclic enolether, and diene (Scheme 3.2). The solvent plays an important role on

these reactions and desired addition products were obtained in good yields.

Scheme 3.2 Cu(OTf)2 catalyzed synthesis of substituted β-diketones

Chapter-III

100

Hii et al.10

achieved N-(1-phenylethyl)benzenesulfonamide 10 by regioselective addition of

arylsulfonamides 9 to vinylarenes 8, using inexpensive, air stable Cu(OTf)2 as catalyst under

mild conditions (Scheme 3.3). The scope of the reaction was examined by introducing electron-

deficient group on vinylarenes result in good yield.

Scheme 3.3 Cu(OTf)2 catalyzed synthesis of N-(1-phenylethyl)benzenesulfonamide

Powell et al.11

synthesized N-(2,3-dihydro-1H-inden-1-yl)benzenesulfonamide 12 derivatives

from 2,3-dihydro-1H-indene 11 and benzenesulfonamide 9 in presence of Cu(OTf)2 as a catalyst

(Scheme 3.4). The reaction is applicable to the coupling of a diverse set of hydrocarbon species

with aryl, heteroaryl, and alkyl sulfonamides and is tolerant of a variety of functional groups.

Scheme 3.4 Cu(OTf)2 catalyzed amidation of indane with sulfonamides

Larsen et al.12

developed a three component reaction of propargylamines 16 from amine 13,

aldehydes 14 and alkynes 15 bearing alkyl, halogenated, silyl, aryl, and heteroaryl groups in

presenace of Cu(OTf)2 as a catalyst (Scheme 3.5). The copper-catalyzed alkynylation involving

p-toluenesulfonamide provides high yields of N-tosyl-protected propargylamines. The protocol

avoids the usage of base and lignad.

Scheme 3.5 Cu(OTf)2 catalyzed synthesis of propargylamines

Chapter-III

101

Sekar et al.13

described an economically attractive protocol for synthesis of 2-arylbenzo[b]furans

19 from coupling of o-iodophenols 17 with aryl acetylenes 18 catalyzed by Cu(OTf)2 in presence

of BINAM ligand (Scheme 3.6).The formation of final product through domino Sonogashira

coupling followed by 5-endo-dig cyclization favored in non-polar solvent result in good yield.

Scheme 3.6 Synthesis of 2-arylbenzo[b]furans using Cu(OTf)2-BINAM complex

Ito et al.14

explored intramolecular cyclization of phenol derivatives with C=C double bond on a

side chain was examined using Cu(OTf)2 as a catalyst (Scheme 3.7). The 2-allylphenol 20 was

converted in to 2,3-dihydro-2-methylbenzofuran 21 in good yield. Furthermore, the protocol

was extended to construct six member ring using 2-(3-Butenyl)phenol 22 converted into 3,4

dihydro-2-methyl-2H-1-benzopyran 23 in good yield.

Scheme 3.7 Cu(OTf)2 catalyzed synthesis of dihydrobenzofuran and dihydrobenzopyran

Ghorai et al.15

developed a Cu(OTf)2 mediated [3+2] cycloaddition reaction for the synthesis of

substituted imidazolines 26 from various α-alkyl or aryl substituted N-tosylaziridines 24 with

nitriles 25 (Scheme 3.8). The advantage of the protocol is formation of cycloadducts with simple

alkylaziridines in good yields.

Scheme 3.8 Cu(OTf)2 catalyzed synthesis of imidazolines

Chapter-III

102

Chai et al.16

explored diacetoxylation of olefins using PhI(OAc)2 in the presence of Cu(OTf)2 as

a catalyst. The reaction is effective for aryl and aliphatic olefins to give the corresponding vicinal

diacetoxy compounds 27 in good yields (Scheme 3.9).

Scheme 3.9 Cu(OTf)2 catalyzed diacetoxylation of styrene

Perumal et al.17

developed intramolecular 6-endo-dig cyclization in good yields for the synthesis

of 1,2-dihydrobenzo[g]quinoline-5,10-diones 29 from N-propargylamino-naphthoquinones 28

using Cu(OTf)2 as catalyst (Scheme 3.10).

Scheme 3.10 Cu(OTf)2 catalyzed synthesis of 1,2-dihydrobenzo[g]quinoline-5,10-diones

Ramamurthy et al.18

developed a novel and efficient Cu(OTf)2/CuCl catalyzed synthesis of

highly conjugated regioisomers of 3-spiroheterocyclic 2-oxindoles 32 & 33 via multi-component

reaction of isatin 30, aryl alkyne 18, and 1-aminoanthraquinone 31 (Scheme 3.11). The unusual

reactivity of 1-aminoanthraquinone provided structurally unique oxindoles as fluorophores. Both

the regioisomers exhibited considerable optical properties and found as fluorescence materials.

Scheme 3.11 Cu(OTf)2 catalyzed synthesis of regioisomeric 3-spiroheterocyclic 2-oxindoles

Chapter-III

103

Part A: Synthesis and Anti‒cancer Activities of 1,3,5-Triarylpyrazoles

Pyrazoles and their derivatives are well recognized as an important class of heterocyclic

compounds that have found extensive use in the pharmaceutical, material, and agrochemical

industries.19

Compounds containing pyrazole moiety have exhibited diverse biological activities.

For example, 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylate derivatives can act as

cannabinoid-1 (CB1) receptor antagonists,20-25

Iκβ kinase β (IKKβ or IKK-2) inhibitors,26

and

anti-inflammatory agents.27

Pyrazole derivatives have been shown to have good binding affinity

towards estrogen receptor.28-30

Some of the pyrazole derivatives have been reported to possess

anti-depressant, anti-convulsant,31

anti-inflammatory, and anti-arthritics32

activities. Pyrazole

scaffold constitutes the basic framework of several drug molecules such as celecoxib 34 (a non-

steroidal anti-inflammatory drug)32

and rimonabant 35 (an anorectic antiobesity drug) (Figure

3.1).

Figure 3.1 Chemical structures of drug molecules Celecoxib and Rimonabant

3.2 Literature methods for the synthesis of 1,3,5-triarylpyrazoles

Pyrazoles have received considerable attention of chemists because of their diverse bioactivities.

Thus, a number of synthetic strategies have been developed for their synthesis.33,34

The most

common approach for the synthesis of substituted pyrazoles is the condensation of α,β-

unsaturated carbonyl compounds with hydrazines. However, this strategy results in the formation

of 4,5-dihydro-1H-pyrazoles (pyrazolines) that need to be further oxidized to the corresponding

pyrazoles. For this oxidative aromatization of pyrazolines to pyrazoles, various reagents have

been employed such as I2,35

Bi(NO3)3.5H2O,36

MnO2,37

DDQ,38

Pd/C,39

NaOEt,40

PhI(OAc)2,41

TBBDA,42

and ionic liquid.43,44

Many of these oxidative methods suffer from relatively high

Chapter-III

104

oxidant loading, use of strong oxidants and chlorinated organic solvents, harsh conditions, poor

yields, and longer reaction time. Some recent protocols for the synthesis of 1,3,5-triarylpyrazoles

are described below.

Liu et al.45

developed a protocol for the synthesis of 1,3,5-triarylpyrazoles 38 using chalcones

36 with phenylhydrazine 37 in acetic acid as a solvent. The reaction required very long reaction

time for oxidation and aerial oxygen is used as oxidant (Scheme 3.12).

Scheme 3.12 Synthesis of 1,3,5-triarylpyrazoles

Hayashi et al.39

synthesized 1,3,5-triarylpyrazoles 40 from 1,3,5-trisubstituted pyrazolines 39 by

using catalytic amount of Pd/C in acetic acid in good yields (Scheme 3.13).

Scheme 3.13 Pd/C catalyzed synthesis of 1,3,5-triarylpyrazoles

Katzenellenbogen et al.37

reported synthesis of 1,3,5-triarylpyrazoles 42 from 1,3,5-

triarylpyrazoles 41 by the oxidation using MnO2 or DDQ as oxidant (Scheme 3.14).

Chapter-III

105

Scheme 3.14 MnO2 catalyzed synthesis of 1,3,5-triarylpyrazoles

Zolfigol et al.46

reported trichloroisocyanuric acid an effective oxidizing agent for the oxidation

of 1,3,5-triarylpyrazolines 39 to corresponding pyrazoles 38 in good yields (Scheme 3.15).

Scheme 3.15 Trichloroisocyanuric catalyzed synthesis of 1,3,5-triarylpyrazoles

The protocols developed for the synthesis of pyrazoles require longer reaction time, use organic

solvents and require additional oxidant for aromatization. Thus, development of environmentally

benign process with the use of alternative solvents such as ionic liquids in place of organic

solvent and a catalytic amount of eco-friendly catalyst that avoid harsh oxidizing reagents is

highly desirable. As a part of ongoing work on the development of novel reaction methodologies

using metal triflates,47-49

and evaluation of small molecules as anticancer agents.49-52

We have

developed a copper triflate-mediated protocol for the synthesis of 1,3,5-triarylpyrazoles

employing reaction of hydrazines with α,β-unsaturated ketones in 1-butyl-3-methylimidazolium

hexafluorophosphate ([bmim][PF6]) ionic liquid (Scheme 3.16).

Chapter-III

106

Scheme 3.16 Synthesis of substituted 1,3,5-triarylpyrazoles in [bimm][PF6].


3.3.1 Chemistry

In the standardization experiment, 1,2-diphenylprop-2-en-1-one (36) and 4-tert-

butylphenylhydrazine hydrochloride (37) were reacted in ethanol under reflux in the presence of

Cu(OTf)2 (20 mol%), 1-(4-tert-butylphenyl)-3,5-diphenyl-4,5-dihydro-1H-pyrazoline (39a) was

obtained in 62% yield (Table 3.1, entry 8). Further optimization of reaction conditions was

carried out by changing solvents, catalysts, and catalyst loading. As shown in Table 3.1, the use

of 20 mol% Cu(OTf)2 in [bmim][PF6] gave 1-(4-tert-butylphenyl)-3,5-diphenyl-4,5-dihydro-1H-

pyrazole 38a in excellent yield (82%) (Table 3.1, entry 2). When Cu(OTf)2 was replaced with

other catalysts such as pTSA, Sc(OTf)3, Ce(OTf)3, Zn(OTf)2, AgOTf, or Yb(OTf)3, a mixture of

39a and 38a was observed. Use of Ce(OTf)3 in [bmim][PF6] resulted in 75% yield of 39a along

with 10% of 38a whereas use of pTSA in [bmim][PF6] gave 69% of 39a (Table 3.1, entry 11-

12). There was not much increase in yield of 38a on changing the amount of Cu(OTf)2 from 20

mol% to 30 mol%. However, reducing the amount of Cu(OTf)2 to 10 mol% decreased the yield

of 38a to 64% along with the formation of 39a in 15% (Table 3.1, entries 1-3). These data

indicate that Cu(OTf)2 was involved in aerobic oxidation of 39a to 38a. It is necessary to

mention that 38a was not formed in the absence of Cu(OTf)2 in [bmim[PF6] ionic liquid, and

only 39a was isolated in 20% yield along with starting material and yield of 39a did not increase

with increasing time up to 2 h.

Chapter-III

107

Table 3.1 Optimization of reaction conditions for the synthesis of 38aa.

Entry Catalyst Mol % Solvent Yield (39a) (%)b Yield (38a) (%)

b

1 Cu(OTf)2 10 [bmim][PF6] 15 64c

2 Cu(OTf)2 20 [bmim][PF6] - 82d,e

3 Cu(OTf)2 30 [bmim][PF6] - 84

4 Cu(OTf)2 20 [bmim][BF4] 35 50

5 Cu(OTf)2 20 [bmim][Br] 50 21

6 Cu(OTf)2 20 DMSO - 15

7 Cu(OTf)2 20 DMF - 33

8 Cu(OTf)2 20 Ethanol 62f -

9 Cu(OTf)2 20 PEG 60 -

10 Sc(OTf)3 20 [bmim][PF6] 61 19

11 Ce(OTf)3 20 [bmim][PF6] 75 10

12 pTSA 20 [bmim][PF6] 69 -

13 Zn(OTf)2 20 [bmim][PF6] 55 30

14 AgOTf 20 [bmim][PF6] 15 65

15 Yb(OTf)3 20 [bmim][PF6] 58 22

aReaction condition: Chalcone (1.0 mmol), arylhydrazine (1.2 mmol), catalyst (20 mol%), solvent (2 mL), 130

°C, 2 h. bIsolated yield.

cOnly 20% of 39a was formed after 30 min in the absence of Cu(OTf)2 under similar

conditions. dAt 100 C, complete conversion of 39a to 38a was not observed and it requires longer reaction

time. eWhen isolated 39a was used 95% yield of 38a was obtained.

fReflux condition.

The structure of 38a was confirmed by 1H NMR,

13C NMR (Figure 3.2), and mass spectroscopy

data. In the 1H NMR spectra, a singlet was observed at δ 6.81 for the proton at C4-position of

pyrazole ring and 1.31 ppm for the –C(CH3)3 along with other protons on aryl substituents. In the

13C NMR, a peak appeared at δ 104.97 for the C4-carbon of pyrazole ring along with other

carbons. Presence of a peak at m/z 355.2173 for [M + H]+ ion with molecular formula C25H27N2

+

confirmed the structure of 38a.

Chapter-III

108

Figure 3.2a


Figure 3.2b


Based on the intermediate formed as pyrazoline 39a and structure of the product 38a, the

reaction is proposed to proceed through the sequential steps as shown in Scheme 3.17. The first

step is believed to be 1,2-addition of hydrazine to chalcone mediated by Cu(OTf)2. The 3-

hydroxypyrazoline (C) undergoes elimination in the presence of Cu(OTf)2 to give 1,3,5-

triarylpyrazoline derivative (39). Oxidative aromatization of 39 in the presence of Cu(OTf)2

yields corresponding 1,3,5-triarylpyrazole (38). We did not observe formation of 38a, when

NN

NN

Chapter-III

109

isolated 39a was treated with Cu(OTf)2 under nitrogen atmosphere. This further confirms that

39a is converted to 38a via oxidation with atmospheric oxygen in presence of Cu(OTf)2. It

appeared that ionic liquid helps in stabilization of charged intermediate generated by

coordination of Cu(OTf)2 to carbonyl of chalcone and thereby increases electrophilicity of

chalcone.

Scheme 3.17 Proposed mechanism for the synthesis of 1,3,5-triarylpyrazoles

To explore the synthetic scope and versatility of the protocol, a series of arylhydrazines (37)

were reacted with different α,β-carbonyl compounds (36) under the optimal reaction conditions.

The results are summarized in Table 3.2. Various functional groups such as F, Cl, NO2, OCH3,

CH3 and -C(CH3)3 on arylhydrazines and chalcones were well tolerated under these conditions to

afford corresponding 1,3,5-substituted pyrazoles (38a-o) in good to high yields (71–84%). By

monitoring the model reaction between 1,2-diphenylprop-2-en-1-one (36) and tert-

butylphenylhydrazine hydrochloride (37) in the presence of 20 mol% Cu(OTf)2 in [bmim][PF6]

at different time interval it was found that in first 30 minutes pyrazoline (39a) was the major

product, which was oxidized to pyrazole in the reaction as time progressed. We thus decided to

synthesize the pyrazolines using this protocol in order to evaluate them in our biological assay.

The reaction of 36 and 37 afforded 1,3,5-triarylpyrazolines (39a–o) via a one-pot addition–

cyclocondensation process in good to high yields (60-84%). Several α,β-unsaturated carbonyl

compounds with both electron-rich and electron-deficient arenes were successfully applied to

this reaction. The results of pyrazoline synthesis are summarized in Table 3.3.

Chapter-III

110

Table 3.2 Synthesized 1,3,5-triarylpyrazoles (38a-o)

Compd. R1 R

2 R

3 Time (h) Yield (%)

a

38a H H 4-C(CH3)3 2 82b

38b H H 2-CH3 2 81

38c H H 3,4-Cl 3 80

38d H H 3-Cl, 4-CH3 2.5 72

38e 4-OMe H 3,4-Cl 2 71

38f 4-OMe H 3-Cl, 4-CH3 2 77

38g 3-OMe 4-CH3 3,4-Cl 2 79

38h 4-CH3 4-CH3 3,4-Cl 2 74

38i 4-CH3 4-CH3 3-Cl, 4-CH3 2 77

38j 4-CH3 4-CH3 4-C(CH3)3 1.5 77

38k 2-F 4-Cl 4-C(CH3)3 2 84

38l 2-F 4-Cl 2-CH3 2 82

38m 4-NO2 4-OMe 4-C(CH3)3 1 75

38n 4-NO2 4-OMe 3-Cl, 4-CH3 1 81

38o H H 4-OMe 1.5 78

aIsolated yield.

bIn four consecutive recycle experiment 38a was observed in 82, 80, 78, and 79% yield,

respectively

Chapter-III

111

Table 3.3 Synthesized 1,3,5-triarylpyrazolines (39a-n)

Compd. R

1 R

2 R

3 Time (Min.) Yield (%)

a

39a H H 4-C(CH3)3 30 84

39b H H 2-CH3 30 66

39c H H 3,4-Cl 30 77

39d H H 3-Cl, 4-CH3 30 68

39e 4-OMe H 3,4-Cl 30 72

39f 4-OMe H 3-Cl, 4-CH3 30 78

39g 3-OMe 4-CH3 3,4-Cl 30 60

39h 4-CH3 4-CH3 3,4-Cl 30 72

39i 4-CH3 4-CH3 3-Cl, 4-CH3 30 74

39j 4-CH3 4-CH3 4-C(CH3)3 30 79

39k 2-F 4-Cl 4-C(CH3)3 30 63

39l 2-F 4-Cl 2-CH3 30 65

39m 4-NO2 4-OMe 4-C(CH3)3 20 72

39n 4-NO2 4-OMe 3-Cl, 4-CH3 20 80

aIsolated yield.

The chemical structures of all synthesized compounds were elucidated by 1H NMR,

13C NMR

(Figure 3.3) and mass spectrometry data. For example in the 1H NMR spectra of 39a, doublet of

doublet was observed at δ 5.19, 3.80 and 3.11 for the proton at C4-position, C5-position of

pyrazoline ring along with other protons on aryl substituents. In the 13

C NMR, a peak appeared at

δ 113.14 for the C4-carbon of pyrazoline ring along with other carbons. In mass spectrum of peak

at m/z 335.1532 for [M + Na]+ ion with molecular formula C25H27N2Na

+ confirmed the structure

of 39a.

Chapter-III

112

Figure 3.3a


Figure 3.3b


We also investigated the possibility of recycling of the catalyst. After performing the first cycle,

the product was extracted with ethyl acetate/hexane mixture, and Cu(OTf)2 in ionic liquid was

properly dried under vacuum. Fresh chalcone and 4-tert-butyl phenylhydrazine hydrochloride

NN

NN

Chapter-III

113

were added to recover ionic liquid containing Cu(OTf)2 and the reaction was carried out under

same conditions. The above procedure was repeated four times to give 38a in high yields (82, 80,

78, and 79%) without much loss of catalytic activity (Table 3.2).

3.3.2 Biological evaluation


To evaluate the anti-cancer activity of synthesized compounds, all pyrazole derivatives 38a-o

and pyrazoline derivatives 39a-n were evaluated for their inhibitory activity on the proliferation

of human ovarian adenocarcinoma (SK-OV-3), human colon adenocarcinoma (HT-29), and

human cervical adenocarcinoma (HeLa) cells. Doxorubicin (Dox) and DMSO were used as

positive and negative controls, respectively.

The anti-proliferative activity results of compounds 38a-o and 39a-n at 50 µM after 72 h

incubation are shown in Figure 3.4. Among all derivatives 39c, 38e, 38f, 38g, 38h, 38i, and 38k

inhibited the proliferation of HeLa cells by 50%, 55%, 45%, 39%, 54%, 42%, and 50%,

respectively. However, they did not exhibit significant inhibitory potency in HT-29 and SK-OV-

3 cells. 1,3,5-Triarylpyrazolines derivatives (39a-n) showed high to weak anti-proliferative

activity against HeLa cells after 72 h incubation. Compounds 39c, 39d, 39e, 39k, 39l, and 39m

inhibited the proliferation of HeLa cells by 62%, 50%, 35%, 58%, 23%, and 40%, respectively.

The pyrazoline derivatives showed modest to weak potency in SK-OV-3 and HT-29 cells. 2-

Methylsubstituted compound 39b showed the highest potency by 80% inhibition of HeLa cells

which was comparable to the doxorubicin (10 M) in HeLa cells at 50 M.

Figure 3.4 Anti-proliferative activities of 38a-o and 39a-n

Chapter-III

114

3.4 Conclusions

In summary, we have developed a simple, efficient and environmental friendly protocol for the

synthesis of 1,3,5-triarylpyrazoles and 1,3,5-triarylpyrazolines in [bimm][PF6] ionic liquid using

Cu(OTf)2 as catalyst. The reaction protocol exhibited tolerance with different functional groups,

generating pyrazoles in good to high yields (71-82%) without any requirement for additional

reagent for the oxidation of in situ generated pyrazolines. The catalyst can be reused up to four

cycles without much loss in catalytic activity. The pyrazoles (38a-o) and pyrazolines (39a-n)

were evaluated for antiproliferative activity. Compound 39b inhibited cell proliferation of HeLa

cells by 80% at a concentration of 50 μM. All other synthesized derivatives exhibited a modest

inhibition against the proliferation of SK-OV-3, HT-29 and HeLa cells. Further structure-activity

relationship studies are required for optimizing anti-proliferative activities of these classes of

compounds.

3.5 Experimental

3.5.1 General


Melting points were determined in open capillary tubes on a MPA120-Automated Melting Point

apparatus and are uncorrected. NMR spectra were recorded on a Bruckner (300 MHz) NMR

spectrometer using CDCl3 as solvent and the chemical shifts were expressed in ppm. Metal

triflates were purchased from Sigma-Aldrich and used as received. All other reagents and

solvents were purchased from Merck (India), Spectrochem Chemicals, S. D. Fine Chemicals,

India and used without further purification unless otherwise specified. Reactions were monitored

by using thin layer chromatography (TLC) on 0.2 mm silica gel F254 plates (Merck). The α,β-

unsaturated ketones (chalcones) 36 were prepared by the treatment of an appropriate

acetophenone with benzaldehydes in the presence of sodium hydroxide as reported in literature53

3.5.2 Representative procedure for the synthesis of 38 and 39:

Chalcone (1.0 mmol), arylhydrazine hydrochloride (1.2 mmol) and Cu(OTf)2 (0.2 mmol, 20

mol%) were added to a 10 mL round bottom flask containing [bmim][PF6] ionic liquid (2 mL).

The reaction mixture was heated at 130 ºC with stirring for 30 min (for 39) or 1-2.5 h (for 38).

After completion of reaction as indicated by TLC, the reaction mixture was extracted with ethyl

acetate-hexane mixture and the solvent was removed under vacuum. The crude compound was

Chapter-III

115

purified by passing through a bed of silica gel (100-200 mesh) to give pure 39 or 38.


1-(4-tert-Butylphenyl)-3,5-diphenyl-1H-pyrazole (38a)


Hz, 2H), 7.42 (t, J = 7.5 Hz, H), 7.37 – 7.25 (m, 10H), 6.81 (s, 1H),

1.31 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 151.74, 150.54, 144.30,

137.68, 133.17, 130.73, 128.76, 128.63, 128.46, 128.21, 127.92,

125.87, 125.80, 124.79, 104.97, 34.65, 31.35. HRMS (ESI-MS) m/z:

calcd for C25H27N2+ 355.2169, found 355.2173 [M + H]

+.

3,5-Diphenyl-1-o-tolyl-1H-pyrazole (38b)

M.p.: 112 – 113 C. 1H NMR (300 MHz, CDCl3) δ 7.79 (dd, J = 9.2,

4.3 Hz, 2H), 7.57 – 7.47 (m, 1H), 7.36 (dd, J = 6.5, 3.1 Hz, 2H), 7.32

– 7.23 (m, 6H), 6.35 – 6.30 (br, 1H), 5.61 (s, 1H), 5.53 – 5.50 (br,

1H). 13

C NMR (75 MHz, CDCl3) δ 150.43, 142.56, 138.76, 132.79,

129.67, 128.95, 128.76, 128.59, 128.06, 126.56, 126.33, 120.05,

118.97, 117.34. IR (neat) νmax : 3479, 3055, 1597, 1466, 1396, 1319,

1196, 1134, 925, 817, 516 cm‒1

. HRMS (ESI-MS) m/z: calcd for C22H18N2+ 311.1543, found

311.1546 [M + H]+.

1-(3,4-Dichlorophenyl)-3,5-diphenyl-1H-pyrazole (38c)


Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.39 –

7.35 (m, 4H), 7.33 (s, 1H), 7.29 (dd, J = 6.6, 2.9 Hz, 2H), 7.08 (dd, J

= 8.6, 2.4 Hz, 1H), 6.81 (s, 1H). 13


152.62, 144.57, 139.34, 132.93, 132.60, 131.19, 130.30, 130.05,

128.84, 128.79, 128.75, 128.35, 126.71, 125.87, 123.95, 106.05.

HRMS (ESI-MS) m/z: calcd for C21H15Cl2N2+ 365.0607, found

365.0589 [M + H]+.

Chapter-III

116

1-(3-Chloro-4-methylphenyl)-3,5-diphenyl-1H-pyrazole (38d)

M.p.: 113 – 114 °C. 1

H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.3

Hz, 2H), 7.50 (s, 1H), 7.43 (t, J = 7.3 Hz, 2H), 7.36 – 7.27 (m, 6H),

7.13 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 2.37

(s, 3H). 13

C NMR (75 MHz, CDCl3) δ 152.15, 144.43, 138.87,

135.29, 134.51, 132.90, 130.78, 130.35, 128.76, 128.69, 128.60,

128.52, 128.12, 125.84, 125.69, 123.26, 105.41, 19.74. HRMS (ESI-

MS) m/z: calcd for C22H18ClN2+ 345.1153, found 345. 1138 [M +

H]+.

1-(3,4-Dichlorophenyl)-5-(4-methoxyphenyl)-3-phenyl-1H-pyrazole (38e)


Hz, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.38 –

7.21 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.09 (dd, J = 8.6, 2.3 Hz,

1H), 6.89 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 3.83 (s, 3H).13

C NMR

(75 MHz, CDCl3) δ 159.98, 152.53, 144.43, 139.47, 132.90, 132.70,

131.07, 130.28, 130.09, 128.72, 128.28, 126.72, 125.84, 123.96,

122.34, 114.23, 105.57, 55.34. HRMS (ESI-MS) m/z: calcd for C22H17Cl2N2O+ 395.0712, found

395.0696 [M + H]+.

1-(4-Chloro-3-methylphenyl)-5-(4-methoxyphenyl)-3-phenyl-1H-pyrazole (38f)


Hz, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (t, J

= 7.2 Hz, 1H), 7.26 – 7.12 (m, 3H), 7.04 (dd, J = 8.1, 1.7 Hz, 1H),

6.87 (d, J = 8.6 Hz, 2H), 6.74 (s, 1H), 3.82 (s, 3H), 2.37 (s, 3H). 13

C

NMR (75 MHz, CDCl3) δ 159.74, 152.05, 144.28, 138.99, 135.17,

134.49, 132.99, 130.77, 130.04, 128.65, 128.04, 125.82, 125.71,

123.28, 122.71, 114.04, 104.91, 55.30, 19.73. HRMS (ESI-MS) m/z: calcd for C23H20ClN2O+

375.1259, found 375.1273 [M + H]+.

Chapter-III

117

1-(3,4-Dichlorophenyl)-5-(3-methoxyphenyl)-3-p-tolyl-1H-pyrazole (38g)


Hz, 2H), 7.64 (d, J = 1.7 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.29 –

7.21 (m, 3H),7.10 (dd, J = 8.5, 1.8 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H),

6.87 – 6.74 (m, 3H), 3.76 (s, 3H), 2.39 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 159.69, 152.65, 144.29, 139.37, 138.20, 132.87, 131.36,

131.07, 130.24, 129.85, 129.75, 129.44, 126.62, 125.75, 123.88,

121.23, 114.38, 114.32, 105.96, 55.33, 21.35. HRMS (ESI-MS) m/z:

calcd for C23H20ClN2O+ 375.1259, found 375.1273 [M + H]

+.

1-(3,4-Dichlorophenyl)-3,5-di-p-tolyl-1H-pyrazole (38h)


Hz, 2H), δ 7.63 (d, J = 2.7Hz, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.24 (d,

J = 7.4 Hz, 2H), 7.20 – 7.13 (m, 4H), 7.08 (dd, J = 9.0, 2.7 Hz, 1H),

6.74 (s, 1H), 2.39 (s, 3H), 2.38 (s, 3H). 13


δ 152.62, 144.56, 139.50, 138.81, 138.12, 132.87, 130.99, 130.23,

129.85, 129.46, 129.42, 128.63, 127.18, 126.71, 125.75, 123.96,

105.68, 21.34, 21.33. HRMS (ESI-MS) m/z: calcd for C23H19Cl2N2+

393.0920, found 393.0897 [M + H]+.

1-(3-Chloro-4-methylphenyl)-3,5-di-p-tolyl-1H-pyrazole (38i)


2H), 7.52 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.15 (q, J = 8.5 Hz, 5H),

7.03 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 2.38 (s, 3H), 2.36 (s, 6H). 13

C

NMR (75 MHz, CDCl3) δ 152.15, 144.41, 139.03, 138.41, 137.84,

135.10, 134.46, 130.72, 130.15, 129.35, 129.27, 128.60, 127.48,

125.72, 123.29, 105.03, 21.33, 21.30, 19.73. HRMS (ESI-MS) m/z:

calcd for C24H22ClN2+ 373.1466, found 373.1483 [M + H]

+.

Chapter-III

118

1-(4-tert-Butylphenyl)-3,5-di-p-tolyl-1H-pyrazole (38j)


Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.21 –

7.16 (m, 4H), 7.11 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 2.37 (s, 3H),

2.35 (s, 3H), 1.31 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 151.73,

150.35, 144.26, 138.04, 137.81, 137.59, 130.41, 129.30, 129.15,

128.59, 127.87, 125.82, 125.69, 124.79, 104.56, 31.35, 21.33, 21.30.

HRMS (ESI-MS) m/z: calcd for C27H29N2+ 381.2325, found

381.2327 [M + H]+.

1-(4-tert-Butylphenyl)-3-(4-chlorophenyl)-5-(2-fluorophenyl)-1H-pyrazole (38k)


Hz, 2H), 7.36 (dd, J = 14.7, 8.4 Hz, 5H), 7.29 – 7.18 (m, 3H), 7.16 –

7.03 (m, 2H), 6.83 (s, 1H), 1.30 (s, 9H). 13


δ 159.94 (d, JC,F = 250 Hz), 150.65(d, JC,F = 2.0 Hz), 138.05, 137.58,

133.65, 133.61, 131.36 (d, JC,F = 23.0 Hz), 130.61 (d, JC,F = 8.1 Hz),

128.80, 127.04, 125.87, 124.11 (d, JC,F = 3.7 Hz), 123.93, 118.88,

118.68, 116.14 (d, JC,F = 22.0 Hz), 106.44 (d, J = 2.0 Hz), 34.62,

31.29. HRMS (ESI-MS) m/z: calcd for C25H22ClFN2Na+ 427.1348,

found 427.1351 [M + Na]+.

3-(4-Chlorophenyl)-5-(2-fluorophenyl)-1-o-tolyl-1H-pyrazole (38l)


Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.25 – 7.12 (m, 5H), 7.08 – 6.92

(m, 3H), 6.86 (d, J = 1.2 Hz, 1H), 2.08 (s, 3H). 13

C NMR (75 MHz,

CDCl3) δ 159.49 (d, JC,F = 250 Hz), 150.72, 139.42, 139.14, 135.55,

133.67, 131.79, 131.16 , 130.78 (d, JC,F = 22.0 Hz), 130.54 (d, JC,F =

8.2 Hz), 129.02, 128.86, 127.81, 127.12, 126.47, 124.04 (d, JC,F =

3.7 Hz), 118.40, 118.21, 116.09 (d, JC,F = 22.0 Hz), 105.35 (d, JC,F =

3.2 Hz), 17.69. HRMS (ESI-MS) m/z: calcd for C22H16ClFN2Na+ 385.0878, found 385.0885 [M +

Na]+.

Chapter-III

119

1-(4-tert-Butylphenyl)-3-(4-methoxyphenyl)-5-(4-nitrophenyl)-1H-pyrazole (38m)


Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.42 (dd, J = 12.6, 8.6 Hz, 4H),

7.28 – 7.21 (m, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.85 (s, 1H), 3.85 (s,

3H), 1.33 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 159.79, 152.04,

151.37, 147.21, 141.81, 137.11, 136.94, 129.18, 127.07, 126.26,

125.29, 124.92, 123.79, 114.12, 105.54, 55.32, 34.74, 31.30. HRMS

(ESI-MS) m/z: calcd for C26H25N3NaO3+ 450.1788, found 450.1793

[M + Na]+.

1-(3-Chloro-4-methylphenyl)-3-(4-methoxyphenyl)-5-(4-nitrophenyl)-1H-pyrazole (38n)


Hz, 2H), 7.83 (d, J = 7.9 Hz, 2H), 7.57 – 7.38 (m, 3H), 7.19 (d, J =

7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 3H), 6.84 (s, 1H), 3.85 (s, 3H), 2.40

(s, 3H). 13

C NMR (75 MHz, CDCl3) δ 159.94, 152.44, 147.38,

141.92, 138.32, 136.55, 136.16, 134.94, 131.14, 129.25, 127.13,

125.86, 125.01, 123.91, 123.38, 114.18, 106.02, 55.34, 19.78.

HRMS (ESI-MS) m/z: calcd for C23H19ClN3O3+ 420.1109, found 420.1121 [M + H]

+.

1-(4-Methoxyphenyl)-3,5-diphenyl-1H-pyrazole (38o)


Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.36 – 7.25 (m, 8H), 6.86 (d, J =

8.9 Hz, 2H), 6.81 (s, 1H), 3.81 (s, 3H). 13


158.85, 151.63, 144.34, 133.45, 133.17, 130.62, 128.84, 128.63,

128.45, 128.17, 127.89, 126.75, 125.78, 114.11, 104.64, 55.50.

HRMS (ESI-MS) m/z: calcd for C22H18N2NaO+ 349.1311, found

349.1298 [M + Na]+.

Chapter-III

120

1-(4-tert-Butylphenyl)-4,5-dihydro-3,5-diphenyl-1H-pyrazole (39a)


Hz, 2H), 7.39 – 7.29 (m, 8H), 7.20 (d, J = 8.7 Hz, 2H), 7.01 (d, J =

8.6 Hz, 2H), 5.19 (dd, J = 12.2, 8.0 Hz, 1H), 3.80 (dd, J = 17.0, 12.4

Hz, 1H), 3.11 (dd, J = 17.0, 8.0 Hz, 1H), 1.25 (s, 9H). 13

C NMR (75

MHz, CDCl3) δ 146.30, 142.97, 142.90, 141.92, 132.88, 129.14,

128.53, 128.46, 127.54, 126.00, 125.71, 124.81, 113.14, 65.06,

43.70, 33.96, 31.48. HRMS (ESI-MS) m/z: calcd for C22H18N2NaO+

349.1311, found 349.1298 [M + Na]+.

4,5-Dihydro-3,5-diphenyl-1-o-tolyl-1H-pyrazole (39b)


Hz, 2H), 7.41 – 7.30 (m, 5H), 7.29 – 7.19 (m, 3H), 7.12 (d, J = 7.4

Hz, 1H), 7.05 – 6.85 (m, 3H), 5.26 (t, J = 10.8 Hz, 1H), 3.69 (dd, J =

16.5, 11.1 Hz, 1H), 3.19 (dd, J = 16.4, 10.5 Hz, 1H), 2.43 (s, 3H).

13C NMR (75 MHz, CDCl3) 148.13, 144.28, 141.00, 132.99, 131.47,

131.25, 128.69, 128.55, 127.66, 126.93, 126.01, 125.65, 123.28,

119.27, 67.66, 42.67, 20.46. HRMS (ESI-MS) m/z: calcd for C22H20N2Na+ 335.1519, found

335.1532 [M + Na]+.

1-(3,4-Dichlorophenyl)-4,5-dihydro-3,5-diphenyl-1H-pyrazole (39c)


Hz, 2H), 7.42 – 7.31 (m, 5H), 7.30 – 7.23 (m, 4H), 7.14 (d, J = 8.9

Hz, 1H), 6.73 (dd, J = 8.9, 2.5 Hz, 1H), 5.22 (dd, J = 12.2, 6.7 Hz,

1H), 3.85 (dd, J = 17.3, 12.3 Hz, 1H), 3.16 (dd, J = 17.3, 6.7 Hz,

1H). 13

C NMR (75 MHz, CDCl3) δ 148.22, 144.02, 141.52, 132.65,

132.15, 130.30, 129.35, 129.15, 128.65, 127.98, 125.95, 125.75,

121.59, 114.94, 112.47, 64.18, 43.78. HRMS (ESI-MS) m/z: calcd for C21H17Cl2N2+ 367.0763,

found 367.0782 [M + H]+.

Chapter-III

121

1-(3-Chloro-4-methylphenyl)-4,5-dihydro-3,5-diphenyl-1H-pyrazole (39d)


Hz, 2H), 7.41 – 7.27 (m, 8H), 7.21 (d, J = 2.1 Hz, 1H), 6.95 (d, J =

8.4 Hz, 1H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 5.20 (dd, J = 12.3, 7.2

Hz, 1H), 3.82 (dd, J = 17.1, 12.3 Hz, 1H), 3.12 (dd, J = 17.1, 7.2 Hz,

1H), 2.23 (s, 3H). 13

C NMR (75 MHz, CDCl3) δ 147.15, 143.90,

142.17, 134.68, 132.52, 130.92, 129.22, 128.77, 128.58, 127.73,

125.93, 125.85, 125.81, 114.08, 111.56, 64.51, 43.65, 19.03.

HRMS (ESI-MS) m/z: calcd for C22H20ClN2+ 347.1310; found 347.1321 [M + H]

+.

1-(3,4-Dichlorophenyl)-4,5-dihydro-5-(4-methoxyphenyl)-3-phenyl-1H-pyrazole (39e)


Hz, 2H), 7.38 (d, J = 7.5 Hz, 3H), 7.29 – 7.24 (m, 1H), 7.16 (t, J =

8.6 Hz, 3H), 6.85 (d, J = 8.6 Hz, 2H), 6.75 (dd, J = 8.7, 2.7 Hz, 1H),

5.18 (dd, J = 12.1, 6.7 Hz, 1H), 3.83 (dd, J = 9.9, 7.3 Hz, 1H), 3.77

(s, 3H), 3.13 (dd, J = 17.3, 6.7 Hz, 1H). 13


δ 159.23, 148.23, 144.06, 133.53, 132.60, 132.23, 130.26, 129.10,

128.64, 126.96, 125.92, 121.51, 114.95, 114.67, 112.54, 63.72, 55.29, 43.81. HRMS (ESI-MS)

m/z: calcd for C22H19Cl2N2O+ 397.0869, found 397.0874 [M + H]

+.

1-(3-Chloro-4-methylphenyl)-4,5-dihydro-5-(4-methoxyphenyl)-3-phenyl-1H-pyrazole (39f)


Hz, 2H), 7.37 (dd, J = 12.8, 5.3 Hz, 3H), 7.23 – 7.17 (m, 3H), 6.96

(d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 6.2 Hz,

1H), 5.16 (dd, J = 12.1, 7.1 Hz, 1H), 3.85 – 3.80 (m, 1H), 3.76 (s,

3H), 3.10 (dd, J = 17.1, 7.1 Hz, 1H), 2.23 (s, 3H). 13

C NMR (75

MHz, CDCl3) δ 159.07, 147.17, 143.94, 134.63, 134.21, 132.60,

130.90, 130.05, 128.73, 128.57, 127.05, 125.86, 125.79, 114.55, 114.09, 111.63, 64.04, 55.27,

43.68, 19.03. HRMS (ESI-MS) m/z: calcd for C23H22ClN2O+ 377.1415, found 377.1427 [M + H]+.

Chapter-III

122

1-(3,4-Dichlorophenyl)-4,5-dihydro-5-(3-methoxyphenyl)-3-p-tolyl-1H-pyrazole (39g)


Hz, 2H), 7.30 – 7.10 (m, 5H), 6.89 – 6.75 (m, 3H), 6.73 (dd, J = 8.9,

2.6 Hz, 1H), 5.13 (dd, J = 12.2, 6.9 Hz, 1H), 3.89 – 3.78 (m, 1H),

3.75 (s, 3H), 3.13 (dd, J = 17.2, 6.9 Hz, 1H), 2.37 (s, 3H). 13

C NMR

(75 MHz, CDCl3) δ 160.36, 148.48, 144.25, 143.36, 139.34, 132.59,

130.44, 130.26, 129.35, 125.93, 121.42, 117.96, 114.88, 113.09,

112.42, 111.36, 64.14, 55.26, 43.85, 21.44. HRMS (ESI-MS)

m/z: calcd for C23H21Cl2N2O+ 411.1025, found 411.1043 [M + H]

+.

1-(3,4-Dichlorophenyl)-4,5-dihydro-3,5-di-p-tolyl-1H-pyrazole (39h)


Hz, 2H), 7.25 (d, J = 2.6 Hz, 1H), 7.21 – 7.16 (m, 2H), 7.13 – 7.11

(m, 4H), 6.73 (dd, J = 8.9, 2.5 Hz, 1H), 5.16 (dd, J = 12.2, 6.7 Hz,

1H), 3.80 (dd, J = 17.2, 12.2 Hz, 1H), 3.11 (dd, J = 17.2, 6.7 Hz,

1H), 2.37 (s, 3H), 2.31 (s, 3H). 13


148.41, 144.20, 139.27, 138.67, 137.64, 132.57, 130.23, 129.96,

129.44, 129.34, 125.90, 125.69, 121.27, 114.84, 112.41, 63.90,

43.91, 21.43, 21.11. HRMS (ESI-MS) m/z: calcd for C23H21Cl2N2+ 395.1076, found 395.1102 [

M + H]+.

1-(3-Chloro-4-methylphenyl)-4,5-dihydro-3,5-di-p-tolyl-1H-pyrazole (39i)


Hz, 2H), 7.20 – 7.18 (m, 2H), 7.17 – 7.14 (m, 3H), 7.13 – 7.09 (m,

2H), 6.94 (d, J = 8.4 Hz, 1H), 6.74 – 6.68 (m, 1H), 5.14 (dd, J =

12.1, 7.2 Hz, 1H), 3.77 (dd, J = 17.1, 12.2 Hz, 1H), 3.08 (dd, J =

17.1, 7.2 Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H). 13

C NMR

(75 MHz, CDCl3) δ 147.37, 144.12, 139.33, 138.83, 137.33, 134.62,

130.88, 129.84, 129.81, 129.39, 129.28, 128.61, 125.79, 125.78,

125.64, 114.00, 111.51, 64.25, 43.81, 21.41, 21.11, 19.02. HRMS (ESI-MS) m/z: calcd for

C24H24ClN2+ 375.1623; found 375.1635 [M + H]

+.

Chapter-III

123

1-(4-tert-Butylphenyl)-4,5-dihydro-3,5-di-p-tolyl-1H-pyrazole (39j)


Hz, 2H), 7.33 (d, J = 11.0 Hz, 1H), 7.26 – 7.20 (m, 3H),, 7.19 – 7.13

(m, 4H),, 7.01 (d, J = 8.7 Hz, 2H), 5.13 (dd, J = 12.2, 8.1 Hz, 1H),

3.76 (dd, J = 17.0, 12.3 Hz, 1H), 3.06 (dd, J = 17.0, 8.1 Hz, 1H),

2.36 (s, 3H), 2.32 (s, 3H), 1.25 (s, 9H). 13


δ 146.54, 143.15, 141.66, 140.13, 138.46, 137.11, 129.76, 129.22,

128.60, 125.93, 125.66, 124.97, 113.07, 64.82, 43.87, 33.94, 31.48,

21.39, 21.12. HRMS (ESI-MS) m/z: calcd for C27H31N2+ 383.2482, found 383.2503 [M + H]

+.

1-(4-tert-Butylphenyl)-3-(4-chlorophenyl)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole (39k)


2H), 7.33 (d, J = 11.0 Hz, 1H), 7.26 – 7.20 (m, 3H),, 7.19 – 7.13 (m,

4H), 7.01 (d, J = 8.7 Hz, 2H), 5.13 (dd, J = 12.2, 8.1 Hz, 1H), 3.76

(dd, J = 17.0, 12.3 Hz, 1H), 3.06 (dd, J = 17.0, 8.1 Hz, 1H), 2.36 (s,

3H), 2.32 (s, 3H), 1.25 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 159.71

(d, JC,F = 245.6 HZ), 145.64, 142.36, 134.25, 131.26, 129.22, 129.09

(d, JC,F = 3.6 HZ), 128.83, 128.75, 127.64 (d, JC,F = 3.9 HZ), 127.10,

126.88, 125.87 (d, JC,F = 3.8 HZ), 124.84 (d, JC,F = 3.5 HZ), 123.99,

115.66 (d, JC,F = 21.0 HZ), 113.00, 64.82, 43.87, 33.94, 31.48, 21.39,

21.12. HRMS (ESI-MS) m/z: calcd for C25H25ClFN2+ 407.1685, found 407.1712 [M + H]

+.

3-(4-Chlorophenyl)-5-(2-fluorophenyl)-1-o-tolyl-4,5-dihydro-1H-pyrazole (39l)


Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 9.1 Hz, 4H), 7.09 (dd,

J = 20.6, 9.0 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.52 (dd, J = 12.4,

7.5 Hz, 1H), 3.83 (dd, J = 17.1, 12.4 Hz, 1H), 3.05 (dd, J = 17.1, 7.5

Hz, 1H), 1.26 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 160.36 (d, JC, F

= 246.0 Hz), 147.06, 142.36, 143.62, 134.29, 131.65, 131.40,

131.06, 129.20 (d, JC, F = 8.2 Hz), 128.75, 128.23 (d, JC, F = 4.0 Hz),

126.82 , 126.08, 124.54 (d, JC, F = 3.5 Hz), 123.40, 118.36, 115.46

(d, JC, F = 21.6 Hz), 60.09 (d, JC, F = 2.5 Hz), 40.06, 20.42. HRMS (ESI-MS) m/z: calcd for

C22H19ClFN2+ 365.1215, found 365.1208 [M + H]

+.

Chapter-III

124

1-(4-tert-Butylphenyl)-3-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydro-1H-pyrazole (39m)


Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.21 (d, J

= 8.7 Hz, 2H), 6.92 (dd, J = 8.7, 3.7 Hz, 4H), 5.25 (dd, J = 12.2, 8.0

Hz, 1H), 3.90–3.79 (m, 1H), 3.83 (s, 3H), 3.06 (dd, J = 17.0, 7.9 Hz,

1H), 1.25 (s, 9H). 13

C NMR (75 MHz, CDCl3) δ 160.33, 150.33,

147.43, 146.46, 142.70, 142.39, 127.27, 127.04, 125.87, 125.04,

124.51, 114.09, 113.08, 64.35, 55.36, 43.59, 33.98, 31.44. HRMS

(ESI-MS) m/z: calcd for C26H28N3O3+ 430.2125, found 430.2136 [M + H]

+.

1-(3-Chloro-4-methylphenyl)-3-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydro-1H-

pyrazole (39n)


Hz, 2H), 7.64 (d, J = 6.9 Hz, 2H), 7.46 (d, J = 6.9 Hz, 2H), 7.12 (s,

1H), 6.94 (dd, J = 22.2, 7.2 Hz, 3H), 6.62 (d, J = 6.0 Hz, 1H), 5.26

(dd, J = 9.3, 6.0 Hz, 1H), 4.07–3.87 (s, 1H), 3.83 (s, 3H), 3.07 (dd, J

= 15.8, 5.5 Hz, 1H), 2.23 (s, 3H). 13


160.56, 149.55, 147.52, 147.27, 143.74, 134.87, 131.09, 127.43,

126.93, 126.41, 124.66, 124.59, 114.15, 114.02, 111.43, 63.80,

55.38, 43.58, 19.02. HRMS (ESI-MS) m/z: calcd for C23H20ClN3NaO3+

444.1085, found

444.1108 [M + Na]+.

3.5.4 Anti-cancer assay protocol

3.5.4.1 Procedure for cell culture: Human ovarian adenocarcinoma cells (SK-OV-3), colon

adenocarcinoma (HT-29) and cervical adenocarcinoma (HeLa) were obtained from American

Type Culture Collection. Cells were grown on 75 cm2

cell culture flasks with EMEM (Eagle’s

minimum essential medium), supplemented with 10% fetal bovine serum, and 1%

penicillin/streptomycin solution (10,000 units of penicillin and 10 mg of streptomycin in 0.9%

NaCl) in a humidified atmosphere of 5% CO2, 95% air at 37 ºC.

3.5.4.2 Procedure for cell proliferation assay: Cell proliferation assay was carried out using

CellTiter 96 aqueous one solution cell proliferation assay kit (Promega, USA). Briefly, upon

reaching about 75-80% confluency, 5000 cells/well were plated in 96-well microplate in 100 EL

media. After seeding for 72 h, the cells were treated with 50 EM compound in triplicate.

Chapter-III

125

Doxorubicin (10 EM) was used as the positive control. At the end of the sample exposure period

(72 h), 20 EL CellTiter 96 aqueous solutions were added. The plate was returned to the incubator

for 1 h in a humidified atmosphere at 37 °C. The absorbance of the formazan product was

measured at 490 nm using microplate reader. The blank control was recorded by measuring the

absorbance at 490 nm with wells containing medium mixed with CellTiter 96 aqueous solution

but no cells. Results were expressed as the percentage of the control (without compound set at

100%).

Chapter-III

126

Part-B: Synthesis of Bis(5-methyl-2-furyl)methanes

Bis(furyl)methanes are industrially important compounds.54,55

They have been used as an

intermediate for the synthesis of tetraoxaquaterenes56

and other macromolecules which are used

as metal ions carriers.57

Some compounds of this class are of interest in dye chemistry,58

copy

engineering and agricultural chemistry.59-61

The derived bisfurylalkane materials have a useful

range of applications, mostly for foundry cores and molds, corrosion-resistant materials, and

precursors to graphitic composites and adhesives.62

In particular, some bis(2-furyl)methanes can

be used as monomers and cross-linking reagents in polymer manufacturing.63

Ring-hydroxylated

triarylmethanes have also been reported to exhibit antitumor and antioxidant activities.64

Moreover diheteroarylmethanes are of interest to the food industry as natural components of

certain food and beverage items as well as flavor agents in coffee.65

3.6 Literature methods for synthesis of bis(5-methyl-2-furyl)methanes

Synthesis of bis(furyl)methanes is an important and challenging goal. A variety of catalytic

systems have been introduced for the synthesis of bis(2-furyl)methanes by condensation of 2-

methylfuran with carbonyl compounds61,66,67

such as glacial acetic acid/phosphoric anhydride,

sulfonic acid-functionalized mesoporous silicas,68

MCM-41 supported Mo/Zr mixed oxides,69

Hg(ClO4)2, Tl(ClO4)3, HClO4, InCl3, p-TSA, AuCl3,70

and zeolites.71

They have also been

synthesized by acid catalyzed self-condensation of furfuryl alcohols,72

but acid-promoted self-

condensation of furfuryl alcohol gives low yield along with a mixture of products. Recently,

Genovese et al.73

have reported Yb(OTf)3 catalyzed solvent free synthesis of triaryl- and

triheteroarylmethanes from substituted aldehydes and 2-methylfuran or methoxybenzene.

However, the reaction of 2-methylfuran with hexadeuteroacetone in presence of 0.7 mol%

Yb(OTf)3 is reported to give only 5% conversion to bis(2-furyl)hexadeuteropropane after 2

days.69

Due to high reactivity of furan ring towards electrophilic aromatic substitution large amounts of

tarry oligomers and unidentified decomposition materials are generally produced during the

reactions of furan heterocycles under conventional Lewis acids. In addition to this, these

methodologies are associated with one or more problem from environmental point of view such

as relatively long reaction time, costly catalysts, harsh reaction conditions and toxic aqueous

waste resulting from the catalyst. Here, some of the protocol for the synthesis of bis(5-methyl-2-

furyl)methanes are described below.

Chapter-III

127

Hashmi et al.70

developed AuCl3 catalyzed synthesis of bis(5-methyl-2-furyl)methanes 42 in

quantitative yield (Scheme 3.18). The condensation product obtained from 2-methylfuran 40 and

aldehydes or acetone 41. The disadvantage of this procedure is longer reaction time (48 h).

Scheme 3.18 AuCl3 catalyzed synthesis of bis(5-methyl-2-furyl)methanes

Jang et al.69

developed a MoO3/ZrO2/MCM-41 heterogeneous catalyst for the synthesis of bis(5-

methyl-2-furyl)methanes 42 in good yields (Scheme 3.19). The product is produced by the

condensation of 2-methylfuran 41 and acetone 42.

Scheme 3.19 MoO3/ZrO2/MCM-41 catalyzed synthesis of bis(5-methyl-2-furyl)methanes

Rhijn et al.74

synthesized a novel mesoporous material sulfonic acid functionalised MCM for the

synthesis of bis(5-methyl-2-furyl)methanes 42 from 2-methylfuran 40 and acetone/aldehyde 41

in good yield (Scheme 3.20).

Scheme 3.20 MCM–SO3H catalyzed synthesis of bis(5-methyl-2-furyl)methanes

The quest for cheap, environmentally friendly catalysts and mild reaction conditions is still a

major challenge for the synthesis of bis(furyl)methanes. Recently, there has been a growing

interest in solvent free reactions in organic synthesis.75-79

The advantages associated with solvent

free reactions are safety, economy, short reaction time, easy work up procedure. In this part of

chapter we have developed a solvent free method for the bis(furyl)methanes using Cu(OTf)2 as

catalyst (Scheme 3.21)

Chapter-III

128

Scheme 3.21 Synthesis of bis(furyl)methanes


Initially we selected 2-methylfuran 40 and benzaldehyde 41a/cyclopentanone 41k as model

substrates for the synthesis of bis(furyl)methanes to evaluate catalytic activity of different metal

triflates under solvent free conditions. Among the metal triflates used Cu(OTf)2, Yb(OTf)3,

Zn(OTf)2 and Sc(OTf)3 were found to give the product 42a or 42k in good yield and Cu(OTf)2

was found to be most efficient among all catalysts studied to give 42a in 61% yield (Table 3.4).

After finding Cu(OTf)2 as best catalyst for this condensation reaction, the effect of catalyst

loading, solvent and reaction temperature was investigated. We explored the reaction in the

presence of 1, 5, 10, 20 and 30 mol% of Cu(OTf)2 (Table 3.4, entries 5-9). It was found that 10

mol% of Cu(OTf)2 was enough to accomplish the reaction at room temperature and increasing

the amount of catalyst did not improve the yield. When the model reaction was carried out in

various solvents such as water, MeOH, PEG-400, DCM, CHCl3, DMF, acetonitrile, and ionic

liquid [bmim][BF4] using Cu(OTf)2 as catalyst the yield of 42a was lower than under solvent free

condition. Only CHCl3 and CH2Cl2 were found to be effective reaction media to give 42a in 18

and 22% yield respectively, at room temperature after 6 h. Reaction of 40 with 41a at higher

temperature resulted in sluggish reaction mixture. It should also be pointed out here that the

reaction did not proceed in the absence of Cu(OTf)2, confirming the effectiveness of the catalyst.

Chapter-III

129

Table 3.4 Optimization of reaction conditions for the synthesis of bis(furyl)methanesa

entry Substrate Catalyst Catalyst (mol %) Time (h) Yield (%)b

1 CHO

Zn(OTf)2 10 6 45

2 CHO

Cu(OTf)2 10 6 61

3 CHO

Yb(OTf)3 10 6 40

4 CHO

In(OTf)3 10 8 34

5 O

Cu(OTf)2 1 6 21

6 O

Cu(OTf)2 5 6 36

7 O

Cu(OTf)2 10 6 51

8 O

Cu(OTf)2 20 6 48

9 O

Cu(OTf)2 30 6 45

10 O

Zn(OTf)2 10 6 36

11 O

Sc(OTf)3 10 6 33

12 O

Yb(OTf)3 10 8 30

13 O

In(OTf)3 10 8 16

14 O La(OTf)3 10 36 -

c

15 O

Eu(OTf)3 10 36 12

aReaction conditions: 2-Methylfuran (2.0 mmol), carbonyl compound (1.0 mmol), and catalyst.

bIsolated

yield. c

No product formation was observed, starting materials was recovered.

Chapter-III

130

The product 42a was characterized by 1H NMR,

13C NMR, and mass spectral data. It showed a

peak at m/z 291.0156 for [M + K]+ in MS, a characteristic singlet peak at 5.33 in

1H NMR for

ethane proton and a peak at 45.27 in 13

C NMR for methane carbon along with other aromatic

and aliphatic protons and carbons (Figure 3.5).

Figure 3.5a


Figure 3.5b 13

C NMR spectrum of compound 42a

Chapter-III

131

After success of the model reaction, the condensation reaction of 40 was carried out with other

aldehydes and aliphatic ketones (41b-n) to give corresponding bis(furyl)methanes (42b-n) in

moderate to good yield (Table 3.5). The structures of 42a-n were confirmed by spectral analysis

and all the products showed satisfactory spectral data. Aromatic aldehydes with electron

withdrawing substituent gave lower yield than aromatic aldehydes with electron donating groups

(Table 3.5, entry 7). This may be due to stabilization of intermediate 44a by the electron

releasing substituents in aryl ring. It is also noteworthy to mention that acetophenone and

benzophenone did not result in the formation of expected products. This is in accordance to the

literature reports that furan reacts with some methyl ketones in the presence of hydrochloric acid,

to give anhydrotetramers, but neither acetophenone nor pinacolone reacts.80

Table 3.5 Cu(OTf)2-promoted synthesis of bis(furyl)methanes 42a-n

Entry Carbonyl Compound Product Time (h) Yield (%)a

42a CHO

O

O

6 61

42b CHOH3CO

O

O

H3CO

6 63

42c CHO

H3CO

O

OH3CO

6 65

42d CHO

OCH3

O

O

H3CO

6 57

42e CHO

H3CO

H3CO

O

O

H3CO

H3CO

6 66

42f CHO

O

O

6 59

Chapter-III

132

42g CHO

Cl

O

O

Cl

8 57

42h CH3CH2CHO

O

O

8 60

42i CHO

O

O

8 58

42j O

O

O

6 75

42k O

O

O

6 51

42l O

O

O

6 61

42m O

O

O

6 55

42n CHO

O2N

O

O

O2N

8 34

aIsolated yield

It is expected that the reaction mechanism is similar to the previously reported acid catalyzed

mechanism.60

A plausible mechanistic pathway for the reactions that form the bis(5-methyl-2-

furyl)methanes is shown in scheme 3.22. The reaction proceeds through furfuryl alcohol

derivative followed by condensation with another molecule of carbonyl compound to give the

desired product. However, we did not succeed in isolating (5-methylfuran-2-yl)(phenyl)methanol

(43a), instead we observed a peak at m/z 171.0717 in mass analysis of reaction mixture for

Chapter-III

133

reaction of 40 with 41a which corresponds to C12H11O+ ion (44a) (calculated 171.0810)

generated from 43a and thus confirmed formation of 43a as intermediate (Scheme 3.22).

Scheme 3.22 Proposed mechanism for the synthesis of bis(furyl)methanes

Similar observation were also made in the reaction of 40 with 41c, 41d, 41e, 41f, 41g, 41h, 41i,

41k and 41l with a peak at m/z 201.0871 (calculated 201.0916), 201.0872 (calculated 201.0916),

231.1030 (calculated 231.1021), 205.0409 (calculated 205.0420), 185.0918 (calculated

185.0966), 123.0883 (calculated 123.0804), 137.0752 (calculated 137.0961), 149.0752

(calculated 149.0961), and 123.0883 (calculated 123.0810), respectively suggesting formation of

corresponding furfuryl alcohol as intermediate. Further, evidence for the intermediate 43a in this

pathway was gained by independent synthesis of 43a from 2-methylfuran and benzaldehyde in

presence of butyl lithium (Scheme 3.23) followed by reaction of 43a with 2-methylfuran

catalyzed by Cu(OTf)2 to give 42a.

Scheme 3.23 Synthesis of (5-methylfuran-2-yl)(phenyl)methanol

Finally, the reusability of the recovered catalyst was investigated by using 2-methylfuran (40a)

and benzaldehyde (41a) as model substrates. After extracting the product (42a) in organic layer,

the aqueous layer was concentrated and dried to recover the catalyst. This recovered catalyst was

again used for the reaction of 40 and 41a and this was repeated three times to give 42a in 56, 53

and 52%, respectively. Thus, the catalyst showed good catalytic activity without noticeable

decrease in yield of the product up to four successive cycles.

Chapter-III

134

3.8 Conclusions

In summary, we have developed a facile and efficient method for the synthesis of bis(5-methyl-

2-furyl)methanes from the reaction of 2-methylfuran and carbonyl compounds catalyzed by

Cu(OTf)2 under solvent-free conditions. The main advantages of this method are mild, clean and

solvent-free reaction conditions, moderate to good yields and an environmentally benign

catalyst. This reaction system not only provides a novel method for the synthesis of

bis(furyl)methanes but also is an environmentally friendly chemical process.

3.9 Experimental

3.9.1 General

The 1H and

13C NMR spectra were recorded on Bruker-400 instrument with TMS as an internal

standard and CDCl3 as the solvent. Mass spectra (ESI-MS) were recorded using QSTAR®

Elite

LX/MS/MS mass spectrometer from Applied Biosystems. Column chromatography was carried

out over silica gel (100–200 mesh, S. D. Fine, India) and TLC was performed using silica gel

GF254 (Merck) plates. The chemicals, reagents and solvents were purchased either from

Spectrochem, India or Sigma-Aldrich, India and were used as received.


A mixture of 2-methylfuran (2.0 mmol), carbonyl compound (1.0 mmol) and Cu(OTf)2 (10

mol%) was vigorously stirred at room temperatures for 6-36 h under solvent free conditions.

After completion of the reaction, water (5.0 mL) was added to the reaction mixture and resulting

solution was extracted with ethyl acetate (3 5 mL). The combined organic phase was dried

with anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was

purified by passing through a bed of silica gel using ethyl acetate and hexane as eluent.

3.9.3 Synthesis of (5-methylfuran-2-yl)(phenyl)methanol 43a

n-Butyllithium (1.6 M in hexane) (1.1 equiv.) was added slowly to a round bottom flask

containing 2-methylfuran (1.5 mmol) in THF at -30 °C and stirred for 20 min at same

temperature. The reaction mixture was then allowed to come at 0 °C and benzaldehyde (1.5

mmol) was added to it and stirred for additional 3 h at room temperature. Excess of n-

butyllithium was quenched by saturated ammonium chloride and product was extracted by ethyl

acetate (3 × 10 mL), dried over sodium sulphate and concentrated on a rotatory evaporator under

Chapter-III

135

vacuum. The crude product was purified by column chromatography using hexane/ethyl acetate

as eluent (70: 30 v/v) to give 43a in 62% yield.

3.9.4 Synthesis of bis(5-methyl-2-furyl)methane from (5-methylfuran-2-yl)(phenyl)-

methanol

To a reaction mixture containing (5-methylfuran-2-yl)(phenyl)methanol 43a (1.0 mmol) and

2-methyfuran (1.0 mmol) was added Cu(OTf)2 (10 mol%) and stirred it for 3 h at room

temperature. The progress of reaction was monitored by TLC. On completion of the reaction the

product was extracted by ethyl acetate (10 mL) and concentrated on a rotatory evaporator under

vacuum. The crude product was purified by column chromatography using hexane as eluent.


2-Methyl-5-((5-methylfuran-2-yl)(phenyl)methyl)-furan (42a)

M.p.: 98 – 100 °C (lit. 95 – 100)73

. 1H NMR (400 MHz, CDCl3) δ

7.31 – 7.29 (m, 2H), 7.26 – 7.24 (m, 3H), 5.88 – 5.86 (m, 4H), 5.33

(s, 1H), 2.25 (s, 6H). 13

C NMR (101 MHz, CDCl3) δ 153.00, 151.61,

140.17, 128.59, 128.55, 127.12, 108.34, 106.22, 45.27, 13.8. HRMS

(ESI-MS) m/z: calcd. for C17H16O2 252.1150, found 291.0156 [M + K]+.

2-((4-Methoxyphenyl)(5-methylfuran-2-yl)methyl)-5-methylfuran (42b)

Brown liquid. 1H NMR (400 MHz, CDCl3,) δ 7.13 (d, J = 7.5 Hz,

2H), 6.81 (d, J = 7.5 Hz, 2H), 5.91 – 5.86 (m, 4H), 5.32 (s, 1H), 2.26

(s, 6H). 13

C NMR (101 MHz, CDCl3) δ 157.43, 153.06, 151.72,

138.24, 128.41, 128.11, 126.56, 109.84, 108.01, 56.26, 45.27, 13.83.

HRMS (ESI-MS) m/z: calcd. for C18H18O3 282.1256, found

289.1176 [M + Li]+, 305.1162 [M + Na]

+.

2-((3-Methoxyphenyl)(5-methylfuran-2-yl)methyl)-5-methylfuran (42c)

Brown liquid. 1H NMR (400 MHz, CDCl3,) δ 7.25 – 7.21 (m, 1H), 6.86

–6.79 (m, 3H), 5.81 – 5.76 (m, 4H), 5.31 (s, 1H), 3.77 (s, 3H), 2.55 (s,

6H). 13C NMR (101 MHz, CDCl3) δ 159.80, 152.84, 151.61, 141.73,

129.54, 121.01, 114.47, 112.40, 108.36, 106.25, 55.34, 45.26, 13.86.

HRMS (ESI-MS) m/z: calcd. for C18H18O3 282.1256, found 201.0871

[M – C5H5O], 305.1178 [M + Na]+, 321.0967 [M + K]+.

Chapter-III

136

2-((2-Methoxyphenyl)(5-methylfuran-2-yl)methyl)-5-methylfuran (42d)

Brown liquid. 1H NMR (400 MHz, CDCl3,) δ 7.27 – 7.24 (m, 1H),

7.16 – 7.14 (m, 1H), 6.92 – 6.90 (m, 2H), 5.88 – 5.84 (m, 5H), 3.84

(s, 3H), 2.26 (s, 6H). 13

C NMR (101 MHz, CDCl3) 156.67, 153.00,

151.22, 129.31, 128.25, 128.11, 120.51, 110.70, 108.03, 106.00,

55.70, 37.48, 13.74. HRMS (ESI-MS) m/z: calcd. for C18H18O3

282.1256, found 201.0872 [M – C5H5O]+, 305.1177 [M + Na]

+,

321.0968 [M + K]+

2-((3,4-Dimethoxyphenyl)(5-methylfuran-2-yl)methyl)-5-methylfuran (42e)

M.p.: 62 – 64 °C. 1

H NMR (400 MHz, CDCl3,) δ 6.81 (m, 3H), 5.89

– 5.87 (m, 4H), 5.29 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.26 (s, 6H).

13C NMR (101 MHz, CDCl3) δ 153.06, 151.44, 147.95, 132.51,

120.42, 111.72, 111.02, 108.36, 106.07, 55.85, 44.72, 13.68. HRMS

(ESI-MS) m/z: calcd. for C19H20O4 312.1362, found 231.1030 [M –

C5H5O]+, 335.1145 [M + Na]

+, 647.2627 [2M + Na]

+.

2-Methyl-5-((5-methylfuran-2-yl)(p-tolyl)methyl)furan (42f)

M.p.: 44 – 46 °C. 1

H NMR (400 MHz, CDCl3,) δ 7.17 – 7.12 (m,

4H), 5.88 – 5.87 (m, 4H), 5.31 (s, 1H), 2.34 (s, 3H), 2.25 (s, 6H). 13

C

NMR (101 MHz, CDCl3) δ 153.25, 151.54, 137.22, 136.70, 129.32,

128.43, 108.21, 106.21, 44.93, 21.28, 13.82. HRMS (ESI-MS) m/z:

calcd. for C18H18O2 266.1307, found 185.0918 [M – C5H5O]+,

289.1176 [M + Na]+, 305.0962 [M + K]

+.

2-((3-Chlorophenyl)(5-methylfuran-2-yl)methyl)-5-methylfuran (42g)

Brown liquid. 1

H NMR (400 MHz, CDCl3,) δ 7.39 – 7.19 (m, 3H),

7.16 – 7.06 (m, 1H), 5.88 – 5.85 (m, 4H), 5.30 (s, 1H), 2.24 (s, 6H).

13C NMR (101 MHz, CDCl3) δ 151.99, 151.77, 142.06, 129.72,

128.58, 127.26, 126.68, 108.51, 106.20, 99.64, 44.77, 13.68. HRMS

(ESI-MS) m/z: calcd. for C17H15ClO2 286.0761, found 105.0409 [M

– C5H5O]+, 309.0598 [M + Na]

+.

Chapter-III

137

2-Methyl-5-(1-(5-methylfuran-2-yl)propyl)furan (42h)


H NMR (400 MHz, CDCl3,) δ 5.94 – 5.84 (m,

4H), 3.85 (t, J = 6.7 Hz, 1H), 2.27 (s, 6H), 2.06 – 1.88 (m, 2H), 0.93

(t, J = 6.6 Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 156.39, 153.04,

108.57, 108.28, 43.09, 28.56, 16.00, 14.49. HRMS (ESI-MS) m/z:


205.0081 [M + Na]+.

2-Methyl-5-(1-(5-methylfuran-2-yl)butyl)furan (42i)

Pale yellow liquid. 1H NMR (400 MHz, CDCl3,) 6.12 – 5.92 (m, 2H),

5.90 – 5.77 (m, 2H), 3.96 (t, J = 6.71 Hz, 1H), 2.27 (s, 6H), 1.94 (t, J =

6.7 Hz, 2H), 1.34 – 1.33 (m, 2H), 0.93 (t, J = 6.6 Hz, 3H). 13C NMR

(101 MHz, CDCl3) δ154.19, 150.63, 106.02, 105.90, 38.73, 35.15,

20.63, 13.90, 13.64. HRMS (ESI-MS) m/z: calcd. for C14H18O2

218.1307, found 137.0752 [M – C5H5O]+, 241.1987 [M + Na]+.

2-Methyl-5-(1-(5-methylfuran-2-yl)cyclohexyl)furan (42j)

M.p.: 45 – 47 °C. 1

H NMR (400 MHz, CDCl3,) δ 6.11 – 5.72 (m,

4H), 2.25 (s, 6H), 2.12 (t, J = 6.40 Hz, 4H), 1.53 – 1.47 (m, 6H). 13

C

NMR (101 MHz, CDCl3) δ 157.83, 150.42, 105.94, 105.75, 41.77,

34.14, 26.07, 22.70, 13.82. HRMS (ESI-MS) m/z: calcd. for

C16H20O2 244.1463, found 185.1218 [M + Na – C5H6O]+, 283.1164

[M + K]+, 306. 0962 [M + Na + K]

+.

2-Methyl-5-(1-(5-methylfuran-2-yl)cyclopentyl)furan (42k)


H NMR (400 MHz, CDCl3,) δ 5.87 – 5.84 (m,

4H), 2.24 (s, 6H), 1.72 (t, J = 6.7 Hz, 4H), 1.26 (t, J = 6.7 Hz, 4H).

13C NMR (101 MHz, CDCl3) δ 157.36, 150.78, 105.90, 105.65,

47.77, 37.08, 24.16, 13.84. HRMS (ESI-MS) m/z: calcd. for

C15H18O2 230.1307, found 149.0752 [M – C5H5O]+, 269.0997 [M + K]+.

Chapter-III

138

2-Methyl-5-(2-(5-methylfuran-2-yl)propan-2-yl)furan (42l)


H NMR (400 MHz, CDCl3,) δ 5.86 – 5.84 (m,

4H), 2.23 (s, 6H), 1.58 (s, 6H). 13


159.22, 150.57, 105.87, 104.67, 26.64, 13.79. HRMS (ESI-MS) m/z:


243.0781 [M + K]+.

2-Methyl-5-(2-(5-methylfuran-2-yl)butan-2-yl)furan (42m)


H NMR (400 MHz, CDCl3,) δ 5.90 – 5.85 (m,

4H), 2.25 (s, 6H), 1.98 (q, J = 6.8 Hz, 2H), 1.53 (s, 3H), 0.79 (t, J =

6.8 Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 157.96, 150.64, 105.79,

105.62, 41.38, 31.86, 22.58, 13.82, 9.04. HRMS (ESI-MS) m/z:

calcd. for C14H18O2 218.1307, found 241.1925 [M + Na] +

, 257.0939

[M + K]+.

2-Methyl-5-((5-methylfuran-2-yl)(3-nitrophenyl)methyl)-furan (42n)

M.p.: 94 – 96 °C (lit. 95 – 96).73 1

H NMR (400 MHz, CDCl3,) δ 8.29

– 8.13 (m, 2H), 7.62 – 7.60 (m, 2H), 7.52 – 7.48 (m, 2H), 5.95 – 5.93

(m, 4H), 5.45 (s, 1H), 2.27 (s, 6H). 13


152.12, 151.16, 142.25, 134.64, 129.37, 123.48, 122.21, 108.86,

106.32, 44.70, 13.64. HRMS (ESI-MS) m/z: calcd. for C17H15NO4

297.1001, found 320.1925 [M + Na] +

.

Chapter-III

139

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CHAPTER - IV

Silica‒Supported Yb(OTf)3

Catalyzed Synthesis of

3-Substituted Indoles

Chapter-IV

143

4.1 Introduction

Lewis acid catalyzed reactions are of great interest because of their unique reactivity, selectivity

and mild conditions used in organic transformations.1 However, most of these conventional

Lewis acids such as AlCl3, BF3, TiCl4 etc, suffer from the inherent problems of corrosiveness,

sensitivity to water, difficulty in recovery, environmental hazards and waste control after the

reaction. The lanthanide triflates appeared in 1991, showed a remarkable Lewis acid catalyst in

several organic transformations. They have been used widely in C‒C and C‒X bond forming

reactions.2-4

Unlike traditional Lewis acids that are often used in stoichiometric amounts,

lanthanide triflates promote these reactions in catalytic amount and are resistant towards water

and can be recovered, reused without loss of activity.5,6

Lanthanide trifluoromethanesulfonates (triflates), especially ytterbium triflate (Yb(OTf)3) is a

novel class of mild Lewis acid and has gained importance in recent years.7-11

It’s found to be

stable in water. The high Lewis acidity of Yb(III) may be attributed to its small ionic radii.

Kobayashi and his group reported the use of Yb(OTf)3 for hydroxymethylation reaction of silyl

enol ethers with commercial aqueous formaldehyde solution. Many useful reactions are

catalyzed by Yb(OTf)3 in aqueous media.5 Yb(OTf)3 is active in the coexistence of many Lewis

bases containing nitrogen, oxygen, phosphorous and sulfur atoms. In almost all cases, catalytic

use, recovery, and reuse are possible. Several synthetic reactions have been described using

Yb(OTf)3 as catalyst such as Aldol reaction, Michael reaction, allylation reaction, Diels-Alder

reaction, Friedel-Crafts acylation reaction, glycosylation reaction etc.12

4.1.2 Silica‒supported catalysis

Conventional homogeneously catalyzed processes utilized by the fine chemicals industries

produce enormous amounts of waste on removal of the catalyst from the reaction. Stringent

environmental legislations have led to a drive to develop new heterogeneous systems.13

Heterogeneous organic reactions have proven to be useful to chemists in the laboratory as well as

in the industrial context.14,15

These reactions are affected by the reagents immobilized on the

porous solid supports and have advantages over the conventional solution phase reactions

because of the good dispersion of active reagent sites, associated selectivity and easier work-up.

The recyclability of some of these solid supports leads to eco-friendly green protocols.

Previously, polymer‒supported catalysts were widely used in research and in process chemistry,

Chapter-IV

144

but their use is limited due to easy damage to the organic polymer16

and the use of silica, alumina

and zeolites has predominated on the preparation of supported catalysts. Silica‒supported

synthesis has played an important role in the organic synthesis as well in petrol refining

industries.17

Several organic reactions have been reported using silica‒supported catalysts such

as Strecker reaction,18

Biginelli reaction,19,20

acetylation and formylation of alcohols,21-23

Beckmann rearrangement,24

pyrrole synthesis,25

Friedel–Crafts acylations,26

deprotection,27

Diels-Alder reaction,28

condensation reaction,29

Suzuki reaction,30

Michel addition31

etc. A brief

overview of some recent applications of silica-supported Lewis acids in organic transformation is

given below.

Clark et al.32

used a novel heterogeneous catalyst Zn(OTf)2–SiO2 for the rearrangement of α-

pinene oxide 1 (Scheme 4.1). Campholenic aldehyde 2 is an important intermediate used by the

fragrance industry in the synthesis of santalol. It was prepared from α-pinene oxide in high

turnover using Zn(OTf)2–SiO2. The advantage of the catalyst is reusability without decrease in

selectivity towards preparation of campholenic aldehyde. The leaching studies reveal that loss of

zinc was <0.5% in non-polar solvents.

Scheme 4.1 Synthesis of campholenic aldehyde

Vankar et al.33

synthesized 2,3‒unsaturated O-glycosides 5 using Bi(OTf)3–SiO2 as catalyst by

the reaction of tri-O-acetylglycals 3 with different alkyl and aryl alcohols 4 (Scheme 4.2). The

protocol gave good anomeric selectivity and excellent yields in short reaction time.

Scheme 4.2 Synthesis of 2,3‒unsaturated O-glycosides

Jeong et al.34

synthesized Betti bases from the three-component coupling of aryl aldehyde 6, 2-

naphthol 8, and alicyclic amine 7 under neat conditions using Cu(OTf)2‒SiO2 as catalyst

(Scheme 4.3). The product was obtained in good yield and catalyst could be recycled.

Chapter-IV

145

Scheme 4.3 Synthesis of substituted Betti bases

Pore et al.35

developed a mild, expedient, solvent-free synthesis of bis(indolyl)alkanes 12 and 14

from indoles 10 and 13 by treating with different aryl aldehyde/ketones 11 using silica sulfuric

acid (SSA, H2SO4-SiO2) a reusable catalyst (Scheme 4.4).

Scheme 4.4 Synthesis of bis(indolyl)alkanes

Yamamoto et al.36

synthesized limonene 16 and camphene 17 from α-pinene 15 by employing

silica-supported ytterbium oxide as a catalyst (Scheme 4.5). The catalyst exhibits a strong acidity

due to local interaction between silica and ytterbium oxide. Finally the catalyst helped the α-

pinene isomerization into limonene and camphene.

Scheme 4.5 Synthesis of limonene and camphene from α-pinene

Yadav et al.37

developed an environmentally benign organic transformation for propargylation of

aromatic compounds 19 by arylpropargyl alcohols 18 to give diarylpropy-1-ynols 20 in the

Chapter-IV

146

presence of PMA–silica gel as heterogeneous catalyst (Scheme 4.6). The advantages of the

protocol are simple reaction conditions and reusability of the catalyst.

Scheme 4.6 Propargylation of aromatic compounds catalyzed by PMA–silica gel

Baskaran et al.38

developed a simple protocol for the preparation of β-amino ethers 23 by

regioselective opening of activated N-tosyl aziridines 21 with alcohols 22 in the presence of

PMA–SiO2 as the catalyst in good yields (Scheme 4.7).

Scheme 4.7 PMA–silica gel catalyzed synthesis of β-amino ethers

Shinde et al.39

developed a silica gel-supported NaHSO4 and used as catalyst in the Pechmann

condensation. The coumarin derivatives 26 were obtained by the reaction of phenols 24 with

ethyl acetoacetate 25 (Scheme 4.8). The advantages of the procedure are simple and mild

reaction conditions, short reaction times and high yields.

Scheme 4.8 Synthesis of coumarin derivatives

Eshghi et al.40

developed an efficient protocol for synthesis of enaminones and enamino esters

29 by the condensation of different dicarbonyl compounds 27 and amines 28 using silica gel-

supported Fe(HSO4)3 as a heterogeneous, recyclable and stable catalyst (Scheme 4.9) .

Scheme 4.9 Synthesis of enaminone and enamino esters derivatives

Chapter-IV

147

4.1.3 3-Substituted indoles

3-Substituted indole is a structural unit in many natural and biologically interesting compounds

that possess various pharmacological activities.41-43

The derivatives of indole serve as an active

scaffolds in a number of antibacterial,44

antiviral,45

and protein kinase inhibitors.46,47

Indole

based compounds are widely used as anti-cancer agents. Indole-3-carbinols have been known to

act on different cellular signaling pathways and thus show anticancer properties against different

type of human cancers.48

Gramine, a natural indole alkaloid 30 exhibits wide pharmaceutical

activities similar to ephedrine such as relaxation of bronchial smooth muscle, vasorelaxation,

blood pressure elevation, relief of bronchitis nephritis and bronchial asthma.49

3-Aroylindole 31

have shown potent cytotoxicity against different human cancer cell lines.50

Several indole

derivatives have shown tyrosine kinase inhibition in low micromolar range.47,48

3-Substituted

2,2-dithiobis(1H-indoles) have been reported to show inhibition against protein tyrosine kinases

(PTKs) such as EGFR and non receptor v-src tyrosine kinases.51

SU5416 32 (Figure 4.1) is an

indole based FIK-1/KDR inhibitor and is currently in clinical trials against ovarian cancer.50,52,53

Figure 4.1 Chemical structures of Gramine, Aplysinopsin derivative and SU541

4.2 Literature methods for the synthesis of 3-aminoalkylated indoles

3-Aminoalkylated indoles have shown promising activities for different biological targets. The

most common method for the synthesis of 3-aminoalkylated indoles is one-pot reaction of indole,

amine and aldehyde.54-57

Some recent protocols for the synthesis of 3-aminoalkylated indoles are

described below.

Yang et al.58

developed general approach to synthesize Gramine analogues 36 from the three-

component reaction of appropriate substituted aromatic aldehyde 34, heteroaryl amine 35 and

indole or N-methylindole 33 under catalyst free and solvent free conditions (Scheme 4.10).

Chapter-IV

148

Scheme 4.10 Synthesis of Gramine analogues

Das et al.59

synthesized 3-[(N-alkylanilino)(aryl)methyl]indoles 38 using three component

reaction of indoles 33, arylaldehydes 34, and N-alkylanilines 37 in the presence of 2,4,6-

trichloro-1,3,5-triazine (TCT) at room temperature in good yields (Scheme 4.11).

Scheme 4.11 TCT catalyzed synthesis of 3-[(N-alkylanilino)(aryl)methyl]indoles

Kumar et al.60

described synthesis of dialkylaminoarylated indoles 41 using multi-component

reaction of indoles 33, formaldehyde 39, and tertiary aromatic amines 40 in the presence of

silica-supported perchloric acid (HClO4–SiO2) as catalyst in good yields (Scheme 4.12).

Scheme 4.12 HClO4–SiO2 catalyzed synthesis of dialkylaminoarylated indoles

Yadav et al.57

developed bromodimethylsulfonium bromide (BDMS)-catalyzed three-component

coupling reaction between indoles 33, aldehydes 34, and N-alkylamines 42 to give substituted 3-

aminoalkylated indoles 43 at room temperature in good yields (Scheme 4.13).

Chapter-IV

149

Scheme 4.13 BDMS catalyzed synthesis of dialkylaminoarylated indoles

The reaction requires longer time, high temperature and is generally accompanied by formation

of bis-indolyl compound. Thus, there is need for the development of an efficient and better

method for the synthesis of 3-substituted indole derivatives. With our interest in developing

simple and efficient organic transformations, in this chapter we have summarized our results on

role of silica-supported ytterbium triflate for the synthesis of 3-substituted indoles by the three

component condensation of indole, arylaldehydes and amides. The synthesized 3-substituted

indoles were also evaluated for c-Src kinase inhibition and antibacterial activities.


4.3.1 Chemistry

3-Substituted indoles 45a-r were synthesized by one–pot condensation reaction of indole or N-

methylindole 33, substituted aldehydes, 34 and N-methylaniline 44 (Scheme 4.14).

Scheme 4.14 Synthesis of 3-substituted indoles

The reaction conditions were optimized by monitoring the model reaction to prepare 45a. The

model reaction was carried out in various solvents such as DCM, DMSO, DMF, THF,

acetonitrile (CH3CN), and ionic liquid [bmim][BF4], using Yb(OTf)3‒SiO2 as catalyst. Among

these solvents CH3CN was found to be most efficient reaction medium to give 45a in good yield

(88%). while the yield of 45a in other solvents was very poor (10–20%).

Chapter-IV

150

Further, the reaction conditions were optimized by using different catalysts, varying catalyst

loading, and time period of reaction (Table 4.1). The yield of 45a was poor and required longer

time when reaction was performed with either Yb(OTf)3 or silica gel alone. Among the screened

catalysts Yb(OTf)3‒SiO2 (5-10 mol%), Ce(OTf)3‒SiO2 (5 mol%), and Cu(OTf)2‒SiO2 (5 mol%)

were found to give good yield of 45a (Table 4.1, entries 11, 12, 14 and 15). In case of other

acidic catalysts supported on silica gel such as pTSA‒SiO2 (71%), FeCl3‒SiO2 (59%) the yield

of 45a was moderate but accompanied with bis(indolyl)methane (5-30%) as by-product. The

Yb(OTf)3‒SiO2 (5 mol%) gave the highest yield (88%) of 45a and therefore further studies were

carried out using this as a catalyst of choice.

Table 4.1 Optimization of reaction condition to prepare 45a

Entry Catalyst Catalyst (Mol%) Time (h) Yielda (%)

1 SiO2 - 6 15

2 Yb(OTf)3 5 4 72

3 Zn(OTf)2 5 4 52

4 Ce(OTf)3 5 4 71

5 Cu(OTf)2 5 4 68

6 Ba(OTf)2 5 4 50

7 Yb(OTf)3-SiO2 1 2 47

8 Yb(OTf)3-SiO2 2 2 58

9 Yb(OTf)3-SiO2 3 2 67

10 Yb(OTf)3-SiO2 4 2 74

11 Yb(OTf)3-SiO2 5 2 88

12 Yb(OTf)3-SiO2 10 2 84

13 Zn(OTf)2-SiO2 5 2 62

14 Ce(OTf)3-SiO2 5 2 81

15 Cu(OTf)2-SiO2 5 2 81

16 Ba(OTf)2-SiO2 5 2 67

17 FeCl3-SiO2 5 2 59

18 p-TSA-SiO2 5 3 71

aIsolated yield.

Chapter-IV

151

To explore the scope of this reaction, various substituted aromatic aldehydes 34 were reacted

with substituted indoles 33, and N-methylaniline 44 under optimized reaction conditions and an

array of 18 compounds was prepared (Table 4.2). Structures of all the synthesized compounds

were confirmed by 1H NMR and

13C NMR spectroscopic data. Representative NMR (1H and

13C) spectra of compound 45b are shown in figure 4.2. In

1H NMR spectra of 45b, two singlets

were observed at δ 2.83, 2.34 for N-methyl group and CH3 groups, respectively and a singlet at δ

5.56 for aryl-CH along with other aromatic protons. Similarly, characteristic peaks appeared at δ

47.56 for aryl-CH and at δ 30.96 and 21.09 for N-methyl and CH3 groups, respectively in 13

C

NMR along with all other carbons.

Figure 4.2a 1H NMR spectrum of compound 45b

Figure 4.2b

13C NMR spectrum of compound 45b

Chapter-IV

152

Aromatic aldehydes having electron-donating groups gave higher yield when compared with

aldehydes with electron-withdrawing group substituents (Table 4.2, entries 1-12). The reaction

was equally effective with N-methylindole and 5-substituted indoles to afford the desired 3-

aminoalkylated indoles in good to excellent yields (Table 4.2). When aliphatic amines were used

it did not result in 3-substituted indole under these conditions.

Table 4.2 Synthesis of different 3-substituted indoles 45a-r

Entry Compound R R1 R

2 Yield (%)

a

1 45a H H 4-Cl 88

2 45b H H 4-CH3 83

3 45c H H 4-CH3O 86

4 45d H H H 78

5 45e H H 4-OH 75

6 45f H H 3-Br, 4-OH 84

7 45g H H 3-CH3O 82

8 45h H H 2,4-CH3O 81

9 45i H CH3 H 79

10 45j H CH3 4-Cl 81

11 45k H CH3 4-CH3 82

12 45l H H 3-NO2 51

13 45m H H H 72

14 45n 5-OCH3 H 4-OCH3 88

15 45o 5-OCH3 H 4-CH3 85

16 45p 5-Br H 4-CH3 78

17 45q 5-Br H 4-OCH3 80

18 45r 5-OCH3 H 4-Cl 83

aIsolated yield

Chapter-IV

153

The reaction is assumed to proceed through formation of imine followed by attack of indole to

give 3-substituted indoles as shown in Scheme 4.15. It is expected that the Yb(OTf)3 activates

carbonyl group for nucleophilic addition by coordination with oxygen atom and elimation of

hydroxylgroup generates iminium ion. Nucleophilic attack of indole on this iminium ion X leads

to Y which on deprotonation gives 3-substituted indole 45.

Scheme 4.15 Plausible mechanism for the synthesis of 45a

4.3.2 Biological activity

4.3.2.1 c-Src kinase inhibitory activity.

All the synthesized compounds were evaluated fot the c-Src kinase inhibition. The results are

shown in (Table 4.3). Among all screened compounds, 45d, 45j, 45k, 45l, and 45r showed

moderate inhibition of Src kinase with IC50 values of 50.6-98.3 M.

The data suggest that the presence of either electron–donating or electron–withdrawing groups

on the phenyl ring (R2 position) was less tolerated. The unsubstituted indole derivative 45d

showed an IC50 value of 50.6 M while introduction of electron–withdrawing group (NO2) at 3-

position of phenyl ring 45l also exhibited comparable inhibitory activity (IC50 = 58.3 µM).

Chapter-IV

154

Table 4.3 c-Src kinase inhibitory activity of 3-substituted indoles 45ar

Compound IC50 (µM)a Compound IC50 (µM)

a

45a 150 45j 98.3

45b 150 45k 60.5

45c 150 45l 58.3

45d 50.6 45m 71.6

45e 150 45n 100.0

45f 150 45o 150

45g 150 45p 150

45h 150 45q 106

45i 150 45r 87

aThe concentration at which 50% of enzyme activity is inhibited.

4.3.2.2 Molecular modeling

DS visualizer docking studies61

were used to study the interactions of 45d with the ATP binding

site of the Src kinase and compared with anilinoquanzoline AZD05030, a dual specific c-Src/Abl

kinase inhibitor.62

Compound 45d was overlapped on a reference quinazoline ligand in complex

with the Src kinase (PDB 2H8H). As can be seen from Figure 4.3, 45d interacts with the ATP

binding pocket in slightly different orientation when compared with reference quinazoline

ligand. The chloro group in reference ligand oriented towards and interacts with Ala403, whereas

in 45d, phenyl rings lie in hydrophobic binding pocket. N1-H of indole ring in compound 45d

shows specific hydrogen bonding interaction with Ile336. The hydrogen bonding interaction was

not observed when N1 was methylated in 45i. This interaction may have contributed to higher

inhibitory activity of non methylated compounds 45d versus N1-methylated analog 45j. On the

other hand, N1-methylated compounds 45a and 45b exhibited improved inhibition activity versus

45j and 45k respectively, suggesting that hydrophobic interactions of methyl with Ile336 may

also contribute to moderate inhibitory activity. The binding energy for 45d was observed as

‒7.42 kcal/mol and estimated inhibition constant at 3.67 µM while the reference ligand binding

energy and estimated inhibition constant were ‒7.36 kcal/mol and 4.01 µM, respectively. The

RMSD of the test compound with that of reference ligand is 1.230.

Chapter-IV

155

Figure 4.3 Comparison of interactions of 45d (grey) and AZD05030 (oxygen (red), nitrogen

(purple), carbon (light green), chlorine (green) in ATP binding site of the Src kinase based on

molecular modeling. The compounds and side chains of amino acids (yellow) are rendered in

stick styles. Compounds are in the lowest energy conformers predicted. The Figure is drawn

using the Accelrys DS visualizer 2.5 system.


The effect of the compounds on the cell proliferation of human ovarian adenocarcinoma (SK-

OV-3), and colon adenocarcinoma (HT-29) cancer cells were evaluated at the concentration of

50 M (Figure 4.4). In general the most compounds were more active against SK-OV-3 cells.

Indole-based SU5416 is also currently in clinical trials against ovarian cancer. Consistently

compounds 45or inhibited the cell proliferation of both cancer cells significantly while 45a

only inhibited SK-OV-3. The 4-methylphenyl 45o, 45p and 4-methoxyphenyl 45q indole

derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 70-77%, whereas 4-

chloro derivatives 45a and 45r inhibited the growth of ovarian cancer cells (SK-OV-3) by

approximately 72% and 77%, respectively (Figure 4.4). SAR studies suggest that the presence of

bromo or methoxy substituent at position 5 of indole ring (R) in addition to methyl, methoxy, or

chloro substitutent at R2 is critical for maximum anticancer activity as seen in compounds 45or.

Chapter-IV

156

Figure 4.4 Inhibition of HT-29 and SK-Ov-3 cell proliferation by compounds 45ar (50 µM)

after 72 h incubation. The results are shown as the percentage of the control DMSO that has no

compound (set at 100%). All the experiments were performed in triplicate.

In general, poor correlation was observed between Src kinase inhibitory potency of the

compounds and the inhibition of cell proliferation in cancer cells, suggesting that differential

cellular uptake and contribution of other mechanisms in anticancer activities of these

compounds. Compounds 45d and 45r that showed moderate Src kinase inhibition also inhibited

the growth of SK-OV-3 by 77% and 55%, respectively.

4.3.2.4 Anti‒bacterial activity

All the substituted indoles (45ar) were evaluated for their antibacterial activity against both

Gram positive and Gram negative bacteria. The results of antibacterial activity of compounds

(45ar) are shown in Table 4.4. The compounds showing notable antibacterial activity are

indicated in bold (Table 4.4). Compounds 45q, 45r, 45i and 45b showed significant antibacterial

activity against Gram positive bacteria and 45r, 45b, 45o and 45l against Gram negative

bacteria. These results suggest that analogs 45b and 45r can be used as potential broad spectrum

antibacterial agent as they are potent against both Gram positive and Gram negative bacteria.

Compound 45d (without functional groups) was not showing any antibacterial activity, however,

substitution with electron withdrawing groups at phenyl ring 45l, 45f exhibited increase in

0

20

40

60

80

100

120

140

DM

SO

DO

X

45

a

45

b

45

c

45

d

45

e

45

f

45

g

45

h

45

i

45

j

45

k

45

l

45

m

45

m

45

o

45

p

45

q

45

r

HT-29 SK-OV-3

Ce

ll P

roli

fera

tio

n (

%)

Chapter-IV

157

antibacterial activity against Gram negative organisms in Table 1.4. Interestingly, introduction

of electron releasing group at phenyl ring 45b showed good activity against both the Gram

positive and Gram negative bacterial strains. Among the compounds 45i-k, the compound 45i

showed antibacterial activity only against B. subtilis, but substituting the R2 position with an

electron withdrawing group 45j, chloro results in relatively less activity. In contrast, introducing

an electron releasing group at R2 position 45k, methoxy made it further ineffective towards B.

subtilis but found to be active against other two bacterial strains.

Table 4.4 Zone of inhibition and MIC values of 45a-r against Gram‒positive and Gram negative

bacteria

Compound E. coli B. subtilis S. aureus

Zone of

Inhibition

(mm)

MIC

(g /ml)

Zone of

Inhibition

(mm)

MIC

(g /ml)

Zone of

Inhibition

(mm)

MIC

(g /ml)

45a 13 >128 14 128 15 128

45b 16 64 16 64 10 >128

45c 14 128 14 128 15 128

45d 13 >128 14 128 13 128

45e 14 128 13 >128 11 >128

45f 15 128 12 >128 10 >128

45g 15 128 12 >128 13 128

45h 13 >128 14 128 11 >128

45i 14 128 17 64 12 >128

45j 13 128 15 128 12 >128

45k 14 128 13 >128 13 128

45l 15 64 12 >128 14 128

45m 14 128 14 128 12 >128

45n 14 128 14 128 13 128

45o 15 64 13 >128 10 >128

45p 13 128 14 128 12 >128

45q 13 128 18 64 14 128

45r 16 64 17 64 14 128

Chloramphenicol 21 16 24 16 22 16

Chapter-IV

158

4.4 Conclusions

We have developed an eco‒friendly and economical method for the synthesis of 3‒substituted

indoles by one pot three‒component coupling reaction of aldehydes, N‒methylaniline, and indole

or N-methylindole using Yb(OTf)3‒SiO2 as catalyst. The compounds 45d, 45j, 45k, 45l and 45r

showed moderate inhibition of Src kinase while compounds 45or inhibited the cell proliferation

of ovarian and colon cancer cells significantly. SAR studies revealed the importance of the

presence of a 5‒substituted indole ring for anticancer activity. Compound 45b and 45r showed

good anti‒bacterial activity against both Gram positive and Gram negative strains. However,

inversing the property of substituent 45r to 45q resulted in the significant fall in the magnitude

of anti‒bacterial activity against E. coli. Thus, this study of 3‒substituted indoles provides

insights for optimizing the Src kinase inhibition and anticancer activities which may leads to

discovery of potent anti-cancer agents.

4.5 Experimental

4.5.1 General

Melting points were determined in open capillary tubes on a MPA120‒Automated Melting Point

apparatus and are uncorrected. The 1H and

13C NMR spectra were recorded on a Bruker Heaven

11400 (400 MHz) spectrometer using TMS as internal standard and CDCl3 or DMSO-d6 as

solvent and the chemical shifts are expressed in ppm. The chemical structures of final products

were confirmed by a high-resolution Biosystems QSTAR® Elite (QqTOF) mass spectrometer.

All the metal triflates, indole, N‒methylindole, N-methylaniline, aldehydes, 5,5-

dimethylcyclohexane-1,3-dione, cyclohexane-1,3-dione were purchased from Sigma-Aldrich and

SD Fine Chemicals (India). The products were purified by column chromatography using silica

gel (60-120 mesh, S. D. Fine, India).

4.5.2 Representative procedure for synthesis of 45a

To a solution of N‒methylaniline (1.2 mmol) and arylbenzaldehyde (1.0 mmol) in acetonitrile

(10 mL) was added Yb(OTf)3‒SiO2 (30 mg on 300 mg SiO2). The reaction mixture was stirred at

room temperature. After 30 minutes, indole or N-methylindole (0.71 mmol) was added to the

reaction and the mixture was allowed to stir for additional 90 min. The progress of reaction was

monitored by TLC. After completion of the reaction Yb(OTf)3–SiO2 was removed by filtration

Chapter-IV

159

and washed with ethyl acetate (3 × 5 mL). The filtrate was dried over anhydrous sodium sulfate

and concentrated to obtain the crude product, which was purified by column chromatography on

silica gel (100–200 mesh) using ethyl acetate/hexane as eluents to yield a pure product.


N-((4-Chlorophenyl)(1H-indol-3-yl)methyl)-N-methylbenzenamine (45a)


(d, J = 4.0 Hz, 2H), 7.27 – 7.16 (m 5H), 7.03 (d, J = 8.0 Hz, 3H),

6.57 (d, J = 8.0 Hz, 3H), 5.55 (s, 1H), 2.83 (s, 3H). 13

C NMR (100

MHz, DMSO-d6) δ 147.47, 141.59, 137.03, 135.45, 132.87, 129.76,

129.08, 129.03, 127.33, 124.21, 121.87, 120.76, 120.19, 119.29,

113.11, 111.21, 47.59, 31.02. ESI-MS (m/z): calcd. for C22H19ClN2+

346.1237, found 347.7975 [M + H]+.

N-((1H-Indol-3-yl)(p-tolyl)methyl)-N-methylbenzenamine (45b)


(d, J = 7.5 Hz, 1H), 7.28 (d, J = 6.2 Hz, 1H), 7.22 – 6.92 (m, 9H),

6.65 – 6.48 (m, 3H), 5.56 (s, 1H), 2.83 (s, 3H), 2.34 (s, 3H). 13

C

NMR (100 MHz, CDCl3) δ 147.59, 141.76, 136.73, 135.39, 133.21,

129.69, 128.91, 128.83, 127.17, 123.93, 121.95, 120.85, 120.14,

119.27, 112.42, 110.97, 47.56, 30.96, 21.09. ESI-MS (m/z): calcd.

for C23H22N2+

326.1783, found 327.6365 [M + H]+.

N-((1H-Indol-3-yl)(4-methoxyphenyl)methyl)-N-methylbenzenamine (45c)

M.p.: 177 – 179 °C. 1H NMR (400 MHz, CDCl3 ) δ 7.93 (s, 1H),

7.42 – 7. 26 (m, 3H), 7.16 (d, J = 7.6 Hz, 3H), 7.06 – 6.98 (m, 3H),

6.83 (d, J =7.6, 2H), 6.56 (d, J = 8.0 Hz, 3H), 5.54 (s, 1H), 3.80 (s,

3H), 2.83 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 168.98, 157.90,

147.56, 136.99, 133.29, 129.85, 129.65, 127.13, 123.90, 121.97,

120.76, 120.16, 119.27, 113.56, 112.40, 110.97, 55.21, 47.13, 30.95.

ESI-MS (m/z): calcd. for C23H22N2O+ 342.1732, found 343.4446 [M + H]

+.

Chapter-IV

160

N-((1H-Indol-3-yl)(phenyl)methyl)-N-methylbenzenamine (45d)


7.57 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26 – 7.20 (m, 4H), 7.17 –

7.14 (m, 2H), 7.09 – 6.86 (m, 3H), 6.60 (d, J = 2.0 Hz, 3H), 5.53 (s,

1H), 2.79 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 147.67, 144.88,

132.96, 130.14, 129.75, 128.98, 128.21, 127.19, 124.00, 121.99,

120.69, 120.12, 119.30, 113.63, 112.41, 111.00, 47.99, 30.93.

ESI-MS (m/z): calcd. for C22H20N2+

312.1626, found 313.5450 [M + H]+.

N-((1H-Indol-3-yl)(4-hydroxy phenyl)methyl)-N-methylbenzenamine (45e)


– 7.01 (m, 7H), 6.75 – 6.57 (m, 4H), 5.84 (s, 1H), 5.31 (s, 1H), 2.83

(s, 3H). 13

C NMR (100 MHz, CDCl3) δ 153.82, 136.78, 133.51,

130.51, 130.06, 129.85, 127.08, 126.42, 123.90, 123.55, 121.94,

120.02, 119.28, 115.07, 112.30, 111.05, 47.11, 39.46, 30.99. ESI-MS

(m/z): calcd. for C22H20N2O+ 328.1576, found 329.4327 [M + H]

+.

N-((4-Hydroxy-3-bromophenyl)(1H-indol-3-yl)methyl)-N-methylbenzenamine (45f)


– 7.19 (m, 4H), 7.08 – 6.93 (m, 5H), 6.59 (s, 3H), 5.50 (s, 1H), 2.84

(s, 3H). 13

C NMR (100 MHz, CDCl3) δ 150.32, 147.61, 138.54,

136.88, 132.02, 129.69, 129.62, 127.04, 123.94, 123.60, 122.60,

122.13, 119.95, 119.43, 115.70, 112.64, 111.05, 110.08, 46.91,

31.02. ESI-MS (m/z): calcd. for C22H19BrN2O+ 406.0681, found

407.3101 [M + H]+ and 408.5105 [M + 2 + H]

+.

N-((1H-Indol-3-yl)(3-methoxyphenyl)methyl)-N-methylbenzenamine (45g)


– 7.22 (m, 3H), 7.20 – 7.17 (m, 3H), 7.08 – 6.86 (m, 2H), 6.84 – 6.81

(m, 2H), 6.57 (d, J = 7.6 Hz, 2H), 5.56 (s, 1H), 3.75 (s, 3H), 2.83 (s,

3H). 13

C NMR (100 MHz, CDCl3 δ 159.54, 148.50, 147.56, 146.46,

145.79, 136.71, 132.89, 129.70, 127.12, 123.94, 121.98, 121.55,

120.07, 119.93, 114.96, 112.52, 111.15, 110.09, 55.48, 48.03,

31.00. ESI-MS (m/z): calcd. for C23H22N2O+ 342.1732, found 343.3968 [M + H]

+.

Chapter-IV

161

N-((1H-Indol-3-yl)(2,4-dimethoxyphenyl)methyl)-N-methylbenzenamine (45h)


– 7.27 (m, 2H), 7.16 – 6.92 (m, 4H), 6.57 – 6.37 (m, 4H), 5.59 (s,

1H), 3.79 (s, 6H), 2.83 (s, 3H). 13


159.90, 157.93, 147.28, 136.79, 130.23, 130.05, 129.65, 125.72,

124.99, 123.85, 121.80, 120.22, 119.09, 112.40, 112.32, 110.88,

103.82, 95.58, 55.72, 55.29, 39.07, 31.05. ESI-MS (m/z): calcd. for

C24H24N2O2+ 372.1838, found 373.4427 [M + H]

+.

N-Methyl-N-((1-methyl-1H-indol-3-yl)(phenyl)methyl)benzenamine (45i)

M.p.: 189 – 191 °C. 1H NMR (400 MHz, CDCl3) ) δ 7.28 – 7.22 (m,

8H), 7.04 (dd, J = 8.0 Hz, 4H), 6.58 – 6.45 (m, 3H), 5.59 (s, 1H),

3.71 (s, 3H), 2.84 (s,3H). 13

C NMR (100 MHz, CDCl3) δ 129.73,

128.97, 128.71, 128.35, 128.18, 125.94, 124.55, 122.32, 121.67,

121.52, 120.18, 119.04, 118.72, 112.37, 109.06, 94.27, 47.90, 32.68,

30.93. ESI-MS (m/z): calcd. for C23H22N2+ 326.1783, found 327.355

[M + H]+.

N-((4-Chlorophenyl)(1-methyl-1H-indol-3-yl)methyl)-N-methylbenzenamine (45j)

M.p.: 208 – 210 °C. 1H NMR (400 MHz, CDCl3) ) δ 7.29 – 7.18 (m,

7H), 7.03 (d, J = 8.0 Hz, 3H), 6.57 (d, J = 4.0 Hz, 4H), 6.42 (s, 1H),

5.54 (s, 1H), 3.71 (s, 3H), 2.84 (s, 3H). 13


δ 147.77, 143.46, 137.50, 132.52, 131.64, 130.87, 130.16, 129.65,

129.56, 128.70, 128.31, 121.66, 120.48, 118.55, 112.62, 109.15,

47.34, 32.71, 30.89. ESI-MS (m/z): calcd. for C23H21ClN2+ 360.1393,

found 361.5002 [M + H]+.

N-Methyl-N-((1-methyl-1H-indol-3-yl)(p-tolyl)methyl)benzenamine (45k)


3H), 7.19 –7.01 (m, 8H), 6.57 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H), 5.56

(s, 1H), 3.71 (s, 3H), 2.84 (s, 3H), 2.35 (s, 3H). 13

C NMR (100 MHz,

CDCl3) δ 147.58, 141.95, 137.49, 135.34, 133.38, 129.69, 128.90,

128.83, 128.66, 127.54, 121.48, 120.22, 119.21, 118.70, 112.38,


Chapter-IV

162

C24H24N2+

340.1939, found 341.03266 [M + H]+.

N-((1H-Indol-3-yl)(3-nitrophenyl)methyl)-N-methylbenzenamine (45l)


3H), 7.59 (d, J = 8.0 Hz, 1H), 7.46 – 7.38 (m, 2H), 7.22 – 7.20 (d, J

= 8.0 Hz, 2H), 7.06 – 7.02 (m, 3H), 6.66 – 6.57 (m, 3H), 5.68 (s,

1H), 2.84 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 148.14, 147.79,

146.78, 136.52, 134.86, 130.87, 129.37, 128.84, 126.38, 123.80,

123.51, 122.10, 121.09, 119.41, 119.35, 112.30, 112.21, 110.96,

47.46, 30.58. ESI-MS (m/z): calcd. for C22H19N3O2+ 358.1477, found 358.4007 [M + H]

+.

N-((5-Bromo-1H-indol-3-yl)(phenyl)methyl)-N-methylbenzenamine (45m)


(s, 1H), 7.27 – 7.23 (m, 7H), 7.02 (d, J = 8.0 Hz, 2H), 6.58 (d, J =

8.0 Hz, 3H), 5.52 (s, 1H), 2.83 (s, 3H). 13


δ 147.50, 144.27, 135.34, 132.69, 129.67, 128.86, 128.30, 126.18,

125.17, 124.93, 122.47, 120.39, 112.66, 112.48, 47.69, 31.07. ESI-

MS (m/z): calcd. for C22H19BrN2+ 390.0732, found 391.8823 [M + H]+ and 392.9105 [M + 2 + H]+.

N-((5-Methoxy-1H-indol-3-yl)(4-methoxyphenyl)methyl)-N-methylbenzenamine (45n)


7.24 – 7.20 (m, 3H), 7.09 (d, J = 4.0 Hz, 1H), 6.91 (d, J = 8.0 Hz,

1H), 6.81 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 6.70 – 6.66 (m, 3H), 6.60

– 6.53 (m, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.68 (s, 3H),

3.44 (s, 3H), 2.48 (s, 3H). 13

C NMR (100 MHz, DMSO-d6) δ 157.79,

153.08, 137.72, 132.29, 129.86, 129.69, 129.42, 127.40, 124.67,

122.07, 118.52, 113.82, 112.45, 111.87, 110.94, 102.00, 55.73, 55.41, 46.97, 30.40. ESI-MS

(m/z): calcd. for C24H24N2O2+ 372.1838, found 373.3681 [M + H]

+.

Chapter-IV

163

N-((5-Methoxy-1H-indol-3-yl)(p-tolyl)methyl)-N-methylbenzenamine (45o)


7.21 – 7.20 (d, J = 4.0 Hz, 3H), 7.07 – 7.05 (d, J = 8.0 Hz, 3H), 6.91

– 6.90 (d, J = 4.0 Hz, 1H), 6.77 (s, 1H), 6.69 – 6.66 (m, 3H), 6.59 –

6.52 (m, 1H), 6.43 – 6.41 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.57 (s,

3H), 2.48 (s, 3H), 2.23 (s, 3H). 13


153.08, 148.94, 142.46, 134.98, 132.26, 129.45, 129.07, 128.85,

128.68, 127.47, 124.70, 118.30, 112.44, 111.94, 110.94, 101.97, 55.72, 47.40, 30.38, 21.11. ESI-

MS (m/z): calcd. for C24H24N2O+ 356.1889, found 357.5747 [M + H]

+.

N-((5-Bromo-1H-indol-3-yl)(p-tolyl)methyl)-N-methylbenzenamine (45p)


7.29 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.0

Hz, 1H), 7.08 – 7.00 (m, 4H), 6.89 (d, J = 4.0 Hz, 2H), 6.75 (d, J =

8.0 Hz, 1H), 6.68 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 2H), 5.39

(s, 1H), 2.48 (s, 3H), 2.22 (s, 3H). 13


148.74, 142.42, 135.67, 135.26, 131.74, 129.39, 129.22, 128.70,

126.01, 123.94, 121.71, 119.36, 116.54, 114.03, 112.00, 111.33, 47.04, 30.35, 21.07. ESI-MS

(m/z): calcd. for C23H21BrN2+ 404.0888, found 405.4683 [M + H]

+ and 406.3072 [M + 2 + H]

+.

N-((5-bromo-1H-indol-3-yl)(4-methoxyphenyl)methyl)-N-methylbenzenamine (45q)

M.p.: 190 – 191 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s,1H),

7.29 (d, J = 4.0 Hz,1H), 7.19 (s, 1H), 7.11 (d, J = 4.0 Hz, 1H), 7.05

(d, J = 4.0 Hz, 2H), 6.88 (d, J = 4.0 Hz, 2H), 6.83 (d, J = 8.0 Hz,

3H), 6.67 (s, 1H), 6.43 (d, J = 4.0 Hz, 2H), 5.39 (s, 1H), 3.69 (s, 3H),

2.47 (s, 3H). 13

C NMR (100 MHz, DMSO-d6) δ 157.84, 148.63,

137.40, 135.84, 131.70, 129.80, 129.36, 128.89, 126.00, 123.86,

121.75, 119.27, 116.87, 113.99, 111.98, 111.12, 55.43, 46.58, 30.36. ESI-MS (m/z): calcd. for

C23H21BrN2+ 404.0837, found 405.4261 [M + H]

+ and 406.2073 [M + 2 + H]

+.

Chapter-IV

164

N-((4-Chlorophenyl)(5-methoxy-1H-indol-3-yl)methyl)-N-methylbenzenamine (45r)

M.p.: 201– 203 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H),

7.31 – 7.28 (m, 5H), 7.22 – 7.17 (m, 2H), 6.91 (s, 1H), 6.79 (s, 1H),

6.69 (s, 1H), 6.52 (s, 1H), 6.41 (d, J = 4.0 Hz, 2H), 5.73 (s, 1H), 3.30

(s, 3H), 2.47(s, 3H). 13

C NMR (100 MHz, DMSO-d6) δ 153.20,

148.93, 144.57, 132.27, 131.17, 130.77, 130.60, 129.47, 128.44,

127.34, 125.34, 125.24, 124.83, 117.67, 112.56, 111.11, 55.74,

47.34, 30.33. ESI-MS (m/z): calcd. for C23H21ClN2O+ 376.1342, found 377.5223 [M + H]

+

4.5.4 Procedure for c‒Src kinase assay

The effect of synthesized compounds on the activity of c-Src kinase was assessed by

Transcreener® ADP2 FI Assay, from Bell Brook Labs, Madison, WI, (catalogue no. 3013-1K)

according to manufacturer’s protocol. 384-well Low volume black non binding surface round

bottom microplate was purchased from Corning (#3676). The kinase reaction was started in 384-

well low volume black microplate with the incubation of the 2.5 L of the reaction cocktail (0.7

nM of His6-Src kinase domain in kinase buffer) with 2.5 L of prediluted compounds (dissolved

in 10% DMSO, 4X target concentration) for 10 min at room temperature using microplate

shaker. The reaction cocktail was made using the kinase buffer HEPES (200 mM, pH 7.5),

MgCl2 (16 mM), EGTA (8 mM), DMSO (4%), Brij-35 (0.04%), and 2-mercaptoethanol (43

mM). Kinase reaction was started by adding 5 L of ATP/substrate (40 M/600M) cocktail and

incubated for 30 min at room temperature on microplate shaker. Src optimal peptide

(AEEEIYGEFEAKKKK) was used as the substrate for the kinase reaction. Kinase reaction was

stopped by adding 10 L of the 1X ADP Detection Mixture to the enzyme reaction mixture and

mixed using a plate shaker. The mixture was incubated at room temperature for 1 h, and the

fluorescence intensity was measured. The 1X ADP Detection Mixture was prepared by adding

ADP2 Antibody-IRDyeR QC-1 (10 g/mL) and ADP Alexa594 Tracer (8 nM) to Stop & Detect

Buffer B(1X). Fluorescence Intensity measurements were performed using fluorescence intensity

optical module using the excitation of 580 nm and emission of 630 nm with band widths of 10

nm by Optima, BMG Labtech microplate reader. IC50 of the compounds were calculated using

ORIGIN 6.0 (origin lab) software. IC50 is the concentration of the compound that inhibited

enzyme activity by 50%. All the experiments were carried out in triplicate.

Chapter-IV

165

4.5.5 Procedure for molecular modeling

Docking studies were performed with the autodock 4.1 package. Src kinase X-ray crystal

structure with AZD05030 (PDB 2H8H) was obtained from RCSB Protein Data Bank. The

structure of ligands were drawn using Chemdraw Ultra 8.0 and energy minimized by MOPAC

AM1 module. The energy minimized ligand structure were then converted to pdb file format.

The ligand and protein were processed with MGL tool. Docking studies were performed with

AutoDock 4.2 force field. Lamarckian genetic algorithm (LGA) was used as a search paparmeter

with default setting. AutoDock was 4 several times to give several docked conformations, and

analysis of the predicted energy and the consistency of results was combined to identify the best

solution. The image files were generated using Accelrys DS visualizer 2.5 system.

4.5.6 Procedure for anti‒cancer activities

4.5.6.1 Procedure for cell culture

Cell Culture Human ovarian adenocarcinoma cell line SK-OV-3 (ATCC no. HTB-77) and

human colon adenocarcinoma HT-29 (ATCC no. HTB-38) were obtained from American Type

Culture Collection. Cells were grown on 75 cm2 cell culture flasks with EMEM (Eagle’s

minimum essential medium), supplemented with 10% fetal bovine serum, and 1%

penicillin/streptomycin solution (10,000 units of penicillin and 10 mg of streptomycin in 0.9%

NaCl) in a humidified atmosphere of 5% CO2, 95% air at 37 ºC.

4.5.6.2 Procedure for cell proliferation assay

Cell proliferation assay was carried out using CellTiter 96 aqueous one solution cell proliferation

assay kit (Promega, USA). Briefly, upon reaching about 75-80% confluency, 5000 cells/well

were plated in 96-well microplate in 100 µL media. After seeding for 72 h, the cells were treated

with 50 µM compound in triplicate. Doxorubicin (Dox, 10 µM) was used as the positive control.

At the end of the sample exposure period (72 h), 20 µL CellTiter 96 aqueous solutions were

added. The plate was returned to the incubator for 1 h in a humidified atmosphere at 37 C. The

absorbance of the formazan product was measured at 490 nm using microplate reader. The blank

control was recorded by measuring the absorbance at 490 nm with wells containing medium

mixed with CellTiter 96 aqueous solution but no cells. Results were expressed as the percentage

of the control (without compound set at 100%).

Chapter-IV

166

4.5.7 Procedure for anti‒bacterial assay

Zone of inhibition assay was performed at 128 μg mL-1

concentration for all the compounds

using disk diffusion method for this purpose, Mueller-Hilton (HiMedia, India) agar medium was

prepared and sterilized by autoclaving at 121°C at 15 psi for 15 min. The medium was poured

into sterile Petri dishes under aseptic conditions using laminar air flow chamber. After the

solidification of medium, the suspension of the test organism (106 cfu mL-1

) was swabbed onto

the individual media plates using a sterile glass spreader. A sterile disk (9-mm diameter)

impregnated with compound was placed over media surface and the plates were incubated at

37°C for 18-24 h under dark conditions. The determination as to whether the organism is

susceptible, intermediate, or resistant was made by measuring the size of zone of inhibition in

comparison with standard antibiotic. MIC assay was performed to determine the lowest

concentration of compound necessary to inhibit a test organism. MIC values were evaluated for

all the compounds using broth micro dilution method as per the standard guidelines. Assay was

carried out for the compounds at 0.5, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, 64.0, 128.0 μg mL-1

concentrations. A set of tubes containing Muller Hilton broth medium with different

concentrations of compounds were prepared. The tubes were inoculated with bacterial cultures

(106 cfu mL-1

) and incubated on a rotary shaker (180 rpm) at 37°C for 18-24 h under dark

conditions. MIC values were defined as lowest concentration of compound that prevented the

visible growth of bacteria after the incubation period. All the experiments were performed in

three replicates.

Chapter-IV

167

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Appendices

Appendices

List of publications [A-1]

1 VK Rao, G Shelke, R Tiwari, K Parang, Anil Kumar, A simple and efficient synthesis of 2,3-

diarylnaphthofurans using sequential hydroarylation/ Heck-oxyarylation, Org. Lett. 2013, 15,

2190-2193.

2 VK Rao, BS Chhikara, R Tiwari, AN Shirazi, K Parang, Anil Kumar, Copper(II) triflate

mediated synthesis of 1,3,5‒triarylpyrazoles in [bmim][PF6] ionic liquid and evaluation of

their anticancer activities, RSC Adv. 2013, 3, 15396-15403.

3 K Pericherla, AN Shirazi, VK Rao, RK Tiwari, N DaSilva, KT Mccaffrey, Y Ahmadibeni,

A González-Sarrías, NP Seeram, K Parang, Anil Kumar, Synthesis and antiproliferative

activities of quebecol and its analogs, Bioorg. Med. Chem. Lett. 2013, 23, 5329-5331.

4 GM Shelke, VK Rao, R Tiwari, K Parang, Anil Kumar, Bismuth triflate catalyzed reaction of

indole with acetone RSC Adv. 2013, 3, 22346-22352.

5 VK Rao, BS Chhikara, R Tiwari, AN Shirazi, K Parang, Anil Kumar, One‒pot regioselective

synthesis of tetrahydroindazolones and evaluation of their anticancer and Src kinase inhibition

activities, Bioorg. Med. Chem. Lett. 2012, 22, 410–414.

6 Anil Kumar, VK Rao, Microwave‒assisted and Yb(OTf)3 promoted one‒pot multicomponent

synthesis of substituted quinolines in ionic liquid, Synlett. 2011, 2157-2162.

7 VK Rao, BS Chhikara, AN Shirazi, R Tiwari, K Parang, Anil Kumar, 3-Substitued indoles:

one‒pot synthesis and evaluation of anticancer and Src kinase inhibitory activities, Bioorg.

Med. Chem. Lett. 2011, 21, 3511-3514.

8 VK Rao, MS Rao, N Jain, J Panwar, Anil Kumar, Silver triflate catalyzed synthesis of

3‒aminoalkylated indoles and evaluation of their antibacterial activities, Org. Med. Chem.

Lett. 2011, 1, 10.

9 VK Rao, MS Rao, Anil Kumar, Isomerization of 2'–hydroxychalcone and 2'‒aminochalcones

catalyzed by ytterbium(III) triflate in ionic liquid, J. Heterocyclic Chem. 2011, 48, 1356-

1360.

10 VK Rao, MM Kumar, Anil Kumar, An efficient and simple synthesis of tetraketones

catalysed by Yb(OTf)3–SiO2 under solvent free conditions, Indian. J. Chem. 2011, 50B, 1128-

1135.

11 MK Muthyala, VK Rao, Anil Kumar, Cu(OTf)2 catalyzed synthesis of bis(5-methyl-2-furyl)-

methanes by condensation of 2–methylfuran with carbonyl compounds under solvent free

conditions, Chin. J. Chem. 2011, 29, 1483-1488.

12 Anil Kumar, MS Rao, VK Rao, Sodium dodecyl sulfate-assisted synthesis of 1-(benzo-

thiazolylamino)methyl-2-naphthols in water, Aust. J. Chem. 2010, 63, 1538–1540.

13. Anil Kumar, MS Rao, VK Rao, Cerium Triflate: An efficient and recyclable catalyst for

chemoselective thioacetalization of carbonyl compounds under solvent-free conditions, Aust.

J. Chem. 2010, 63, 135-140.

List papers presented in conferences [A-2]

1. VK Rao. “Synthesis of selected heterocyclic compounds using metal triflates and ionic liquids” at

National Conference on Recent Trends in Chemical Sciences, Organized by Department of

Chemistry at Birla Institute of Technology and Science, Pilani. (March 25, 2012. Oral)

2. VK Rao.; GM Shelke.; R Tiwari.; K Parang.; A Kumar. Sequential hydroarylation/Heck

oxyarylation: A simple and efficient strategy for synthesis of 2,3‒diarynaphthofurans” at 19th

International Conference on Chemical Biology for Discovery: Perspectives and Challenges

Organized by the Indian Society of Chemists & Biologists (ISCBC-2013), at Department of

Chemistry, Mohanlal Sukhadia University, Udaipur. (March 2-5, 2013).

3. GM Shelke.; VK Rao.; R Tiwari.; K Parang.; A Kumar. “Bismuth triflate catalysed reaction of

indole with acetone” at 19th International Conference on Chemical Biology for Discovery:

Perspectives and Challenges Organized by the Indian Society of Chemists & Biologists (ISCBC-

2013) at Department of Chemistry, Mohanlal Sukhadia University, Udaipur. (March 2-5, 2013).

4. AB Naidu.; VK Rao.; A Kumar.; KL Catherine.; C Barden.; A Jha. “Development of selective

estrogen receptor modulators” at 3rd

International Conference on Annual Cancer Conference

Organized by BHCRI Cancer Research Halifax, Canada. (November 5-6, 2012).

5. N McDonald.; Y Yadav.; AB Naidu.; VK Rao.; A Kumar.; KL Catherine.; C Barden.; A Jha.

“Development of selective estrogen receptor modulators,” at 3rd

International Conference on

Annual Cancer Conference Organized by BHCRI Cancer Research Halifax, Canada. (November

7-8, 2011).

6. VK Rao.; VK Chaitanya.; BS Chhikara.; R Tiwari.; K Parang.; A Kumar. “A greener one–pot

synthesis of tetrhydroindazolones and their src kinase inhibitory activity and anti cancer activity”

at National Conference on Advances in Chemistry, Organized by Department of Chemistry at

Birla Institute of Technology and Science, Pilani. (March 26, 2011).

7. VK Rao.; BS Chhikara.; R Tiwari.; K Parang.; N Jain.; J Panwa.; A Kumar. “Synthesis of 3-

substitued indoles and evaluation of their Src kinase inhibition and antibacterial activity” at 15th

International Conference on Chemical Biology for Discovery: Perspectives and Challenges

organized by the Indian Society of Chemists & Biologists (ISCBC-2011) at Department of

Chemistry, Saurastra University, Rajkot. (February 4-7, 2011).

8. VK Rao.; K Parang.; A Kumar. “Synthesis of 3-substitued indoles catalyzed by Yb(OTf)3–SiO2”

at 14th International Conference on Chemical Biology for Discovery: Perspectives and

Challenges (ISCBC-2010) Organized by the Indian Society of Chemists & Biologists at

Central Drug Research Institute, Lucknow. (January 15-18, 2010).

9. VK Rao.; MS Rao.; A Kumar. “Ytterbium(III) triflate catalyzed isomerization of 2ꞌ-

hydroxychalcone and 2ꞌ-aminochalcones in ionic liquid” at National Conference on Green and

Sustainable Chemistry, Organized by Department of Chemistry at Birla Institute of Technology

and Science, Pilani. (February 19-21, 2010).

10. VK Rao.; K Parang.; A Kumar. “Efficient synthesis of pyrazoles catalyzed by Cu(OTf)2 in

ionic liquid” at National Conference on Green and Sustainable Chemistry, Organized by

Department of Chemistry at Birla Institute of Technology and Science, Pilani. (February 19-21,

2010).

BRIEF BIOGRAPHY OF THE CANDIDATE [A-3]

V. Kameswara Rao obtained his Master degree in Organic Chemistry from University of

Mysore, Mysore, India. He worked as a chemist for two and half years at Syngene

International Ltd (A Biocon Company), Bangalore. In 2008, he joined the Department of

Chemistry, BITS Pilani for his doctoral research under the supervision of Prof. Anil

Kumar. During his doctoral study he received assistantship from a DST sponsored project

and Fellowship from BITS Pilani. In 2012 he was awarded Senior Research Fellowship

by CSIR New Delhi. He also received a six month Graduate Assistantship from

Department of Chemistry, University of Acadia to work in the laboratory of Dr. Amitabh

Jha. He has published twelve research articles in peer reviewed international journals and

presented papers in ten conferences/symposiums. His research interst lies in developing

new methodologies using environmental friendly technologies such as use of microwave,

alternative solvents and benign reagents.

BRIEF BIOGRAPHY OF THE SUPERVISOR [A-4]

Prof. Anil Kumar is an Associate Professor in Department of Chemistry, Birla Institute

of Technology and Science, Pilani. He received his PhD degree from Department of

Chemistry, University of Delhi in 2004 under the supervision of Prof. SMS Chauhan.

During his doctoral studies Prof. Anil Kumar worked on development of heterogeneous

catalyst for organic synthesis with emphasis on green chemistry. He was postdoctoral

fellow at Department of Biomedical and Pharmaceutical Sciences, University of Rhode

Island in Prof. Keykavous Parang laboratory. In his postdoctoral studies he has worked on

synthesis of novel Src kinase inhibitory agents and solid phase synthesis.

Prof. Anil Kumar joined BITS Pilani in May 2006 as Assistant Professor and promoted as

Associate Professor in 2013. He has 12 year of research experience and 7 year of teaching

experience. He has visited several times University of Rhode Island, Kingston during

summer as visiting scientist in Prof. Parang’s laboratory. He is recipient of Harrison

McCain Foundation award from Acadia University, Canada for 2012. He is supervising

nine PhD students and co-supervising three students. As a result of his research

accomplishment he has published 82 research papers in peer reviewed journals, presented

papers and delivered lectures in several national and international conferences.

Additionally, to his credit he also has one US patent, book chapter. He has completed two

research project as PI and one as Co-PI sponsored by DST. Currently, he has two major

projects from CSIR and UGC and one industry project from Ranbaxy in collaboration

with Prof. Dalip Kumar.

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