prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/668/2/1039s.pdfii declaration i hereby...
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SYNTHESIS, CHARACTERIZATION AND
BIOLOGICAL STUDIES OF HETEROCYCLIC
CHALCONES AND THEIR DERIVATIVES
A THESIS SUBMITTED TO
THE UNIVERSITY OF THE PUNJAB
FOR THE AWARD OF DEGREE OF
DOCTOR OF PHILOSOPHY IN
CHEMISTRY
Session 2010
SUBMITTED BY:
SYED UMAR FAROOQ RIZVI
RESEARCH SUPERVISOR
PROF. DR. HAMID LATIF SIDDIQUI
INSTITUTE OF CHEMISTRY
UNIVERSITY OF THE PUNJAB, LAHORE
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DEDICATION
This work is dedicated to
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Declaration
I hereby declare that the work described in this thesis was carried out by me under
the supervision of Prof. Dr. Hamid Latif Siddiqui at the Institute of Chemistry, University
of the Punjab, Lahore.
I also hereby declare that the substance of this thesis has never been submitted
elsewhere for any other degree.
I further declare that the thesis embodies the results of my own research work or
advanced studies and that it has been composed by myself. Where appropriate, I have
made acknowledgement of the work of others.
Syed Umar Farooq Rizvi
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APPROVAL CERTIFICATE
This is to certify that this dissertation titled as “Synthesis, Characterization and
Biological Studies of Heterocyclic Chalcones and Their Derivatives” submitted by Mr.
Syed Umar Farooq Rizvi is accepted in its present form by the Institute of Chemistry,
University of the Punjab, Lahore, Pakistan, as satisfying the partial requirement for the
degree of Doctor of Philosophy in Organic Chemistry.
Supervisor: Dr. Hamid Latif Siddiqui
Professor of Organic Chemistry,
Institute of Chemistry,
University of Punjab,
Lahore, Pakistan.
Co-Supervisor: Dr. Saeed Ahmed
Associate Professor,
Department of Chemistry,
Gomal University,
Dera Ismail Khan, Pakistan.
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ACKNOWLEDGEMENTS
ll praises to the ALMIGHTY ALLAH who induced the man with
intelligence, knowledge, sight to observe, mind to think and judge. Peace
and blessings of Allah be upon the Hazrat Muhammad (S. A. W. W.) and
his pure and pious progeny who exhorted his followers to seek knowledge
from cradle to grave.
I am greatly obliged to my worthy supervisor Prof. Dr. Hamid Latif Siddiqui,
Institute of Chemistry, University of the Punjab, Lahore, whose knowledge, skillful
guidance, encouragement and kindness have helped me in each and every stage of my
research work. Indeed it is an honor and pleasure for me to work with him. I have been
fortunate to learn a great deal of chemistry from him.
I am whole-heartedly thankful to my cosupervisor Dr. Saeed Ahmed, Associate
Professor, Department of Chemistry, Gomal University, Dera Ismail Khan, who guided
me in my research work. I am especially thankful to him for his constant care and
encouragement.
I am also grateful to Dr. Saeed Ahmad Nagra, Director, Institute of Chemistry,
University of the Punjab Lahore, for providing me research facilities during my research
work. I am indeed grateful to all teachers of Chemistry section, especially Dr. Jamil
Anwar Chaudhary for providing me good working environment and research facilities.
I would like to thank Higher Education Commission (HEC) of Pakistan for
providing me the necessary funds for carrying out my research project. I also
acknowledge HEJ Research Institute of Chemistry Karachi for facilitating me regarding
the spectral and biological analysis of my compounds.
I am thankful to Dr. Masoom Yasinzai, Institute of Biochemistry, University of
Balochistan, Quetta, Pakistan for leishmanicidal studies.
I am also grateful to Dr. Raymond F. Schinazi, Center for AIDS Research,
Veterans Affairs Medical Center and Department of Pediatrics, Emory University School
of Medicine, Decatur, Georgia 30033, USA, for evaluating the synthesized compounds
for anti-HIV-1 and cytotoxic activities.
I am highly grateful to my colleagues Mehmood Akbar Siddiqui, Shehzad Nasim,
Atif Yaqoob, Tafazzul Hussain Bhutta and Raja Rizwan Nazeer, Muhammad Tariq,
Hafeez-ur-Rehman, Muhammad Liaqat and Muhammad Sadiq Hussain for their
cooperation during my thesis write-up.
A
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I would like to express my thanks to my friends and research fellows particularly
Mujahid Hussain Bukhari, Naveed Ahmed, Irfan Ashiq, Rana Amjad Ayyub Bhatti,
Amjid Iqbal, Khizar Iqbal Malik, Shehbaz Nazeer, Muhammad Azad, Rana Altaf
Hussain, Sheikh Muhammad Israr, Muhammad Shahid, Bushra Maliha and Mrs. Sana
Matloob and Ms. Zunera for their cooperation, good wishes and moral support during the
course of my research work.
I am highly thankful to my dearest, best friends and my research fellows Mr,
Waqar Nasir and Mr. Matloob Ahmad for enlightening me with their knowledge,
opinions and most importantly their precious time.
I am highly obliged and thankful to my parents, sisters and other family members
who guided and prayed for me in every step of my life and always believed in me to
complete the task. I specially wish to thank my daughter for her love and encouragement.
I hardly find words to thank my wife “Fehmina Jabeen” for her consistent
support, cooperation and sacrifice towards the successful completion of my works. I can
never forget her untiring efforts in every step of this project and my life.
Syed Umar Farooq Rizvi
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CONTENTS
Chapter-1 INTRODUCTION & LITERATURE SURVEY 1
1.1 Chalcones and their Chemistry 1
1.2 Natural sources of chalcones 2
1.2.1 Dietary Chalcones 6
1.3 Pharmacological Profile of chalcones 7
1.3.1 Antimalarial Chalcones 8
1.3.2 Antibacterial Chalcones 12
1.3.3 Antifungal Chalcones 16
1.3.4 Anti-inflammatory Chalcones 19
1.3.5 Antileishmanial Chalcones 22
1.3.6 Antiviral Chalcones 24
1.3.7 Antituberculous Chalcones 26
1.3.8 Antitrichomonal Chalcones 27
1.4 Applications in Synthetic Organic Chemistry 28
1.4.1 Oxidation of Chalcones 28
1.4.2 Reduction of Chalcones 29
1.4.3 Conversion of Chalcones to 1,5-Diketones 30
1.4.4 Conversion of Chalcones to Ferrocenyl Chalcones 30
1.4.5 Conversion of Chalcones to Imidazoles and Pyrimidines 31
1.4.6 Conversion of Chalcones to 2-Pyrazolines 32
1.4.7 Conversion of Chalcones to Isoxazoles 32
1.4.8 Conversion of Chalcones to Flavanones 33
1.4.9 Conversion of Chalcones to (±)-1-(5-aryl-3-pyridin-2-yl-4,5-
dihydro-pyrazol-1-yl)-2-imidazol-1-yl-ethanone 33
1.4.10 Conversion of Chalcones to 5-amino-1,3,4-thiadiazole-2-thiol
imines and imino-thiobenzyl1 34
1.4.11 Conversion of Chalcones to 2,4,6-trisubstituted pyrimidines 35
1.4.12 Reaction of Chalcones with Diethyl Malonate 36
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1.4.13 Reactions of Chalcones with Thiosemicarbazide 37
1.4.14 Conversion of Chalcones to Di- and Triphenylquinoline 37
1.4.15 Conversion of Chalcones to Chromones & Chromanones 38
1.4.16 Conversion of Chalcones to 5-aryl-1-isonicotinoyl-3-(pyridin-2-
yl)-4, 5-dihydro-1H-pyrazole Derivatives 39
1.4.17 Conversion of Chalcones to Pyrazolines by Ultrasound
Irradiation 39
1.4.18 Reaction of Chalcones with Pyridine-2-carboxamidrazone 40
1.4.19 Reaction of Chalcones with 4,5,6-Triaminopyrimidine 41
1.4.20 Synthesis of Coumarinyl Derivatives of Chalcones 41
1.5 Methods of Chalcone Synthesis 42
1.5.1 Conventional Method─Claisen-Schmidt Reaction 42
1.5.2 Microwave Assisted Synthesis of Chalcones 42
1.5.3 Ultrasound Irradiation Synthesis of Chalcones 43
1.5.4 Synthesis of Chalcones Using a Solid Base Catalyst 43
1.5.5 Synthesis of Chalcones Using PTC 44
1.6 Aim of the Project 45
1.7 Plan of Work and Experimental Schemes 49
1.7.1 Scheme─I 50
1.7.2 Scheme─II 51
1.7.3 Scheme─III 51
1.7.4 Scheme─IV 52
Chapter-2 EXPERIMENTAL 53
2.1 General 53
2.1.1 Substrates and Reagents 53
2.1.2 Solvents 53
2.1.3 Instruments 53
2.2 Methods of Preparation of Precursors for Chalcones 54
2.2.1 N-acetylation of Substituted Anilines 54
2.2.2 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-A; 54
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Conventional Thermal Method)
2.2.3 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-B;
Microwave Irradiation Method) 54
2.2.4 Method for N-arylation of Piperidine (9) (Scheme─III) 56
2.3 General Method for the Synthesis of Quinolinyl Chalcones (1a-
k, 2a-k, 3a-s and 4a-s) (Scheme─I) 56
2.3.1 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-thien-3-ylprop-2-en-
1-one (1a) 56
2.3.2 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (1b) 57
2.3.3 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (1c) 58
2.3.4 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (1d) 58
2.3.5 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dimethylthien-
3-yl)prop-2-en-1-one (1e) 59
2.3.6 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (1f) 60
2.3.7 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-chlorothien-2-
yl)pr2.3.8 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-
dichlorothien-3-yl)prop-2-en-1-one (1h) op-2-en-1-one (1g)
61
2.3.8 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dichlorothien-
3-yl)prop-2-en-1-one (1h) 61
2.3.9 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-3-
yl)prop-2-en-1-one (1i) 62
2.3.10 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-3-
yl)prop-2-en-1-one (1j) 63
2.3.11 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (1k) 63
2.3.12 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-thien-3-ylprop-2-en-
1-one (2a) 64
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2.3.13 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (2b) 65
2.3.14 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (2c) 65
2.3.15 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (2d) 66
2.3.16 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dimethylthien-
3-yl)prop-2-en-1-one (2e) 67
2.3.17 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (2f) 67
2.3.18 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (2g) 68
2.3.19 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dichlorothien-3-
yl)prop-2-en-1-one (2h) 69
2.3.20 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-7-methylquinolin-3-
yl)prop-2-en-1-one (2i) 69
2.3.21 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-7-methylquinolin-3-
yl)prop-2-en-1-one (2j) 70
2.3.22 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (2k) 71
2.3.23 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-thien-3-ylprop-2-en-
1-one (3a) 71
2.3.24 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (3b) 72
2.3.25 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (3c) 73
2.3.26 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (3d) 73
2.3.27 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dimethylthien-
3-yl)prop-2-en-1-one (3e) 74
2.3.28 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(3-chlorothien-2- 75
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yl)prop-2-en-1-one (3f)
2.3.29 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (3g) 75
2.3.30 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dichlorothien-
3-yl)prop-2-en-1-one (3h) 76
2.3.31 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-6-methylquinolin-3-
yl)prop-2-en-1-one (3i) 77
2.3.32 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-6-methylquinolin-3-
yl)prop-2-en-1-one (3j) 77
2.3.33 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (3k) 78
2.3.34 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1H-pyrrol-2-
yl)prop-2-en-1-one (3l) 81
2.3.35 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-methyl-2-
furyl)prop-2-en-1-one (3m) 81
2.3.36 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dimethyl-3-
furyl)prop-2-en-1-one (3n) 84
2.3.37 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methylquinolin-3-
yl)prop-2-en-1-one (3o) 84
2.3.38 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-
benzodioxin-6-yl)prop-2-en-1-one (3p) 85
2.3.39 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1-naphthyl)prop-2-
en-1-one (3q) 88
2.3.40 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2-naphthyl)prop-2-
en-1-one (3r) 91
2.3.41 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methylquinolin-3-yl)prop-2-
en-1-one (3s) 91
2.3.42 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-thien-3-ylprop-2-
en-1-one (4a) 92
2.3.43 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (4b) 93
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2.3.44 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (4c) 93
2.3.45 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (4d) 94
2.3.46 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-
dimethylthien-3-yl)prop-2-en-1-one (4e) 95
2.3.47 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (4f) 95
2.3.48 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (4g) 96
2.3.49 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-
dichlorothien-3-yl)prop-2-en-1-one (4h) 97
2.3.50 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-6-methoxyquinolin-3-
yl)prop-2-en-1-one (4i) 97
2.3.51 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-6-methoxyquinolin-3-
yl)prop-2-en-1-one (4j) 98
2.3.52 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (4k) 99
2.3.53 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1H-pyrrol-2-
yl)prop-2-en-1-one (4l) 99
2.3.54 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-methyl-2-
furyl)prop-2-en-1-one (4m) 100
2.3.55 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-dimethyl-3-
furyl)prop-2-en-1-one (4n) 101
2.3.56 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methoxyquinolin-3-
yl)prop-2-en-1-one (4o) 101
2.3.57 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,3-dihydro-1,4-
benzodioxin-6-yl)prop-2-en-1-one (4p) 102
2.3.58 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1-naphthyl)prop-
2-en-1-one (4q) 103
2.3.59 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2-naphthyl)prop- 103
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2-en-1-one (4r)
2.3.60 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methoxyquinolin-3-yl)prop-2-
en-1-one (4s) 104
2.4 General Method for the Synthesis of 2-Pyrazolines (5a-k, 6a-k,
7a-s and 8a-s) (Scheme─II) 105
2.4.1 2-Chloro-8-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-
5-yl)quinoline (5a) 105
2.4.2 2-Chloro-8-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (5b) 106
2.4.3 2-Chloro-8-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (5c) 107
2.4.4 2-Chloro-8-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (5d) 107
2.4.5 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-8-methylquinoline (5e) 108
2.4.6 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-8-methylquinoline (5f) 109
2.4.7 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-8-methylquinoline (5g) 110
2.4.8 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-8-methylquinoline (5h) 110
2.4.9 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-8-methylquinoline (5i) 111
2.4.10 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-8-methylquinoline (5j) 112
2.4.11 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-8-methylquinoline (5k) 113
2.4.12 2-Chloro-7-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-
5-yl)quinoline (6a) 113
2.4.13 2-Chloro-7-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (6b) 114
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2.4.14 2-Chloro-7-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (6c) 115
2.4.15 2-Chloro-7-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (6d) 116
2.4.16 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (6e) 116
2.4.17 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-7-methylquinoline (6f) 117
2.4.18 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-7-methylquinoline (6g) 118
2.4.19 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (6h) 119
2.4.20 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-7-methylquinoline (6i) 119
2.4.21 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-7-methylquinoline (6j) 120
2.4.22 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-7-methylquinoline (6k) 121
2.4.23 2-Chloro-6-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-
5-yl)quinoline (7a) 122
2.4.24 2-Chloro-6-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (7b) 122
2.4.25 2-Chloro-6-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (7c) 123
2.4.26 2-Chloro-6-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (7d) 124
2.4.27 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methylquinoline (7e) 124
2.4.28 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-6-methylquinoline (7f) 125
2.4.29 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol- 126
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5-yl]-6-methylquinoline (7g)
2.4.30 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methylquinoline (7h) 126
2.4.31 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methylquinoline (7i) 127
2.4.32 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methylquinoline (7j) 128
2.4.33 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-6-methylquinoline (7k) 128
2.4.34 2-Chloro-6-methoxy-3-(3-thiophen-3-yl-4,5-dihydro-1H-
pyrazol-5-yl)quinoline (8a) 129
2.4.35 2-Chloro-6-methoxy-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (8b) 130
2.4.36 2-Chloro-6-methoxy-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (8c) 131
2.4.37 2-Chloro-6-methoxy-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (8d) 131
2.4.38 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methoxyquinoline (8e) 132
2.4.39 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-6-methoxyquinoline (8f) 133
2.4.40 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-6-methoxyquinoline (8g) 133
2.4.41 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methoxyquinoline (8h) 134
2.4.42 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methoxyquinoline (8i) 135
2.4.43 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methoxyquinoline (8j) 135
2.4.44 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-6-methoxyquinoline (8k) 136
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2.5 General Method for the Synthesis of Piperidinyl Chalcones
(9a─l) (Scheme─III) 137
2.5.1 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-2-ylprop-2-en-1-one
(9a) 137
2.5.2 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-3-ylprop-2-en-1-one
(9b) 138
2.5.3 (2E)-1-(3-Methylthiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9c) 139
2.5.4 (2E)-1-(4-Methylthiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9d) 139
2.5.5 (2E)-1-(5-Methylthiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9e) 140
2.5.6 (2E)-1-(2,5-Dimethylthiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9f) 141
2.5.7 (2E)-1-(3-Chlorothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9g) 141
2.5.8 (2E)-1-(5-Chlorothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9h) 142
2.5.9 (2E)-1-(2,5-Dichlorothiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9i) 143
2.5.10 (2E)-1-(3-Bromothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9j) 143
2.5.11 (2E)-1-(5-Bromothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9k) 144
2.5.12 (2E)-1-(5-Iodothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-2-
en-1-one (9l) 145
2.6 General Method for the Synthesis of 2-Pyrazolines of 4-
piperidin-1-ylbenzaldehyde (10a─l) (Scheme─IV) 145
2.6.1 1-[4-(3-Thiophen-2-yl-4,5-dihydro-1H-pyrazol-5-
yl)phenyl]piperidine (10a) 146
2.6.2 1-[4-(3-Thiophen-3-yl-4,5-dihydro-1H-pyrazol-5- 146
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xvi
yl)phenyl]piperidine (10b)
2.6.3 1-{4-[3-(3-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10c) 147
2.6.4 1-{4-[3-(4-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10d) 148
2.6.5 1-{4-[3-(5-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10e) 148
2.6.6 1-{4-[3-(2,5-Dimethylthiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10f) 149
2.6.7 1-{4-[3-(3-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10g) 150
2.6.8 1-{4-[3-(5-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10h) 150
2.6.9 1-{4-[3-(2,5-Dichlorothiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10i) 151
2.6.10 1-{4-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10j) 152
2.6.11 1-{4-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10k) 152
2.6.12 1-{4-[3-(5-Iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10l) 153
2.7 Protocols for Biological Studies 154
2.7.1 Antimicrobial Assay 154
2.7.2 Antileishmanial Assay 154
2.7.3 Determination of IC50 values of the titled compounds (1a-k, 2a-
k, 3a-s, 4a-s, 5a-k, 6a-k and 9a-l) 155
2.7.4 Anti-HIV-1 Assay 155
2.7.5 Cytotoxic Assay 155
2.7.6 Determination of EC50 and EC90 156
2.8 X-Ray Crystallography 156
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xvii
Chapter-3 RESULTS & DISCUSSION 158
3.1 Chemistry of Quinolyl Chalcones and their 2-Pyrazoline
Derivatives 158
3.1.1 Chemistry of Quinolyl Chalcones (1a-k, 2a-k, 3a-s and 4a-s) 158
3.1.2 Chemistry of Pyrazolines of Quinolyl Chalcones (5a-k, 6a-k, 7a-
k and 8a-k) 160
3.2 Chemistry of Piperidyl Chalcones and their 2-Pyrazoline
Derivatives 162
3.2.1 Chemistry of Piperidyl Chalcones (9a-l) 162
3.2.2 Chemistry of Pyrazolines of Piperidyl Chalcones (10a-l) 163
3.3 Biological Activities of Chalcones 164
3.3.1 Antimicrobial Studies of Quinolyl Chalcones (3a-s and 4a-s) 165
3.3.2 Antileishmanial Studies of Quinolyl Chalcones (3a-s and 4a-s) 167
3.3.3 Antileishmanial Studies of Quinolyl Chalcones (1a-k and 2a-k)
and their 2-pyrazoline derivatives (5a-k and 6a-k) 169
3.3.4 Anti-HIV-1 and Cytotoxic Studies of 2-Pyrazoline Derivatives
of Quinolyl Chalcones (5a-k and 7a-k) 171
3.3.5 Antileishmanial Studies of Piperidyl Chalcones (9a-l) 172
3.3.6 Cytotoxic Studies of Piperidyl Chalcones and their 2-Pyrazoline
Derivatives (10a-l) 172
3.4 Achievements and Problems 175
3.5 Conclusion 175
3.6 Future Perspectives 177
BIBLIOGRAPHY 178
LIST OF PUBLICATIONS 193
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LIST OF TABLES
Page No
Table 1 Natural sources of chalcones and their derivatives 3
Table 2 Contents of dihydrochalcones in apple juices and other apple
products 7
Table 3 Experimental results of MW irradiation synthesis of chalcones 43
Table 4 Experimental results of synthesis of chalcones using HT-OtBu
catalyst 44
Table 5 A comparison of the methods producing chloroquinoline-
carbaldehyde, in terms of yields & reaction kinetics 55
Table 6 Results of antimicrobial activity of compounds 3a-s and 4a-s 165
Table 7 Results of antileishmanial activity of the series 3a-s and 4a-s 167
Table 8 Results of antileishmanial activity of the series 1a-k, 2a-k, 5a-k and
6a-k 169
Table 9 Results of anti-HIV-1 activity in human PBM cells and cytotoxicity
of the series 5a-k and 7a-k 171
Table 10 Results of antileishmanial activity of the series 9a-l 172
Table 11 Results of anti-HIV-1 activity and cytotoxicity of the Series 9a-l
and 10a-l 173
Table 12 Significantly active antimicrobial agents 176
Table 13 Categories of antileishmanial chalcones (1a-k, 2a-k, 3a-s, 4a-s and
9a-l) 176
Table 14 Categories of antileishmanial pyrazoline derivatives 5a-k and 6a-k 177
Table 15 Categories of antiviral/cytotoxic compounds 5a-k, 7a-k, 9a-l and
10a-l 177
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xix
LIST OF FIGURES
Page No.
Figure 1 1,3-Diphenyl-2-propene-1-one or chalcone 1
Figure 2 Mesityl oxide 1
Figure 3 Conversion of flavone to chalcone 2
Figure 4 Structures of chalcone based drugs 45
Figure 5 Structures of quinoline based drugs 46
Figure 6 Structures of two piperidine-based drugs 47
Figure 7 Structures of some thiophene based drugs 47
Figure 8 Structures of some thiophene based drugs 48
Figure 9 Synthesis of quinolinyl chalcones 50
Figure 10 Synthesis of 2-pyrazoline derivatives of chalcones 51
Figure 11 Synthesis of piperidyl chalcones 51
Figure 12 Conversion of piperidyl chalcones to 2-pyrazoline derivatives 52
Figure 13 ORTEP diagram of compound 3k 79
Figure 14 ORTEP diagram of compound 3m 82
Figure 15 ORTEP diagram of compound 3p 86
Figure 16 ORTEP diagram of compound 3q 89
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xx
LIST OF ABBREVITIONS
HIV-1 Human immunodeficiency virus type 1
DMSO Dimethylsulphoxide
DMF Dimethylformamide
MeOH Methanol
EtOH Ethanol
FDA Food and Drug Administration
EU European Union
DHC’s Dihydrochalcones
RBC’s Red Blood Cells
MIC Minimum Inhibitory Concentration
GST’s Glutathione-S-transferase
HIV Human immunodeficiency virus
TB Tuberculosis
TN Thallic Nitrate
THF Tetrahydrofuran
DCM Dichloromethane
PTC Phase Transfer Catalyst
AcOEt Ethyl acetate
CDCl3 Deuterated Chloroform
CTAB Cetyltrimethylammonium bromide
NSAID Non-steroidal Anti-inflammatory Drug
TLC Thin Layer Chromatography
MW
HEPES
Microwave
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
AIDS Acquired immunodeficiency syndrome
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xxi
SUMMARY
Four series, consisting of sixty (60) new heterocyclic chalcones were
synthesized by the condensation of methyl/methoxy substituted formylquinolines
with various substituted heteroaromatic ketones. The precursors
(formylquinolines) were prepared by Vilsmeier Haack formylation of substituted
acetanilides, which in turn were synthesized by N-acetylation of various
substituted anilines with the help of acetic acid in the presence of ortho
phosphoric acid. Another series of piperidyl-thienyl chalcones was synthesized.
For this purpose, the precursor 4-piperidin-1-ylbenzaldehyde was prepared by N-
arylation of piperidine with 4-fluorobenzaldehyde in the presence of K2CO3 and a
phase transfer catalyst CTAB in DMF solvent. The 4-piperidin-1-ylbenzaldehyde
was then condensed with various thienyl ketones in alkaline medium with
constant stirring at room temperature to give the fifth series consisting of twelve
(12) new chalcones. The ketoethylinic group of chalcones was then cyclized into
2-pyrazolines by refluxing them with hydrazine hydrate in ethanolic solution. In
this way fifty six (56) new pyrazoline derivatives of chalcones were obtained.
Finally all of the synthesized compounds (128 in number) were screened for their
antibacterial, antifungal, antileishmanial, anti-HIV-1 and cytotoxic activities.
Many of the prepared chalcones as well as their 2-pyrazoline derivatives were
proved to be potent biologically active compounds.
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Chapter – 1
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Chapter -1 Introduction & Literature Survey
1
Chapter 1
INTRODUCTION & LITERATURE SURVEY
1.1 Chalcones and their Chemistry
Chalcone is the trivial name given to the α,β-unsaturated ketones obtained by
condensing an aromatic aldehyde with an aryl methyl ketone in the presence of a
base. They are designated structurally as Ar CH=CHC(O) Ar´ and their IUPAC name
is 1,3-Diphenyl-2-propene-1-one.1 The substituents attached to the benzene rings of
chalcone are numbered as shown in the figure below (Figure 1).
O
R1 B A R2
23
4
6 6'
5'
4'
3'
2'
5
Figure 1. 1,3-Diphenyl-2-propene-1-one or chalcone
In this structure, the group ─CH=CHC(=O)─ is known as the chalcone
functionality or chalcone moiety or ketoethylenic group.2 Due to this functionality,
chalcones are also called α,β-unsaturated carbonyl systems or α,β-unsaturated
ketones. The parent member of the chalcone series is benzylideneacetophenone. Other
names given to chalcone are phenyl styryl ketone, β-phenylacrylophenone, γ-oxo-α, γ-
diphenyl-α-propylene, and α-phenyl-β-benzoylethylene.3 The term “chalcone” was
first used by Kostanecki.4 All the α,β-unsaturated ketones are not necessarily be
chalcones but all the chalcones are α,β-unsaturated ketones e.g. Mesityl oxide (Figure
2) is an α,β-unsaturated ketone (but not a chalcone) with the formula
CH3C(O)CH=C(CH3)2. This compound is a colorless, volatile liquid with a strong
peppermint odor.5
O
Figure 2. Mesityl oxide
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Chapter -1 Introduction & Literature Survey
2
The difference is the “aromaticity” on position 1 and 3 of the α,β-unsaturated
carbonyl system. If the groups attached to ─CH=CHC(=O)─ moiety do not possess
aromaticity, then the resulting compound is just α,β-unsaturated ketone and not the
chalcone.
Chalcones have a diverse array of groups on the two aromatic rings of 1,3-
Diaryl-2-propene-1-one, as shown in the Figure1 above, where the substituents R1 and
R2 may be same or different and they may be present anywhere on the two rings.
Moreover, R1 or R2 may not necessarily be a single substituent i.e. more than one
substituent may be present on any of the two rings. Also, the two aromatic rings may
be homocyclic or heterocyclic.6,7
Chalcones belong to flavonoid family. Structurally, chalcones are open-chain
flavonoids, which were derived by the cleavage of the C ring in the flavonoids,7 as
shown below (Figure 3).
O
O
AR
B R'
C
OH
O
AR
B R'
Figure 3. Conversion of flavone to chalcone
1.2 Natural sources of chalcones
Chalcones are abundantly present in nature, from ferns to higher plants.
During 1960‟s and 70‟s many chalcones have been reported to be isolated from the
various parts of plants: buds, leaves, blossoms, heart wood, roots, seeds, flowers, and
inflorescence. These compounds exist both in free and combined states either in the
form of chalcones or glycosides respectively. These compounds have been found to
carry many different substituents like methyl, isopentyl, methoxy and hydroxyl,
which may be present either on ring A and/or ring B of the chalcone molecule. Many
higher plants have been found to contain dihydrochalcones, as given in the table 1.8
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Chapter -1 Introduction & Literature Survey
3
Table 1. Natural sources of chalcones and their derivatives
No Plant Source Chalcones/ Derivatives of Chalcones Ref
1 Alpinia
speciosa
(seeds)
OH OH
OMeO
2‟,4‟-Dihydroxy-6‟-methoxychalcone (Cardamonin)
9
2 Angelica keiskei
(roots)
O
OH
OH
MeO
Hydroxyderricin
10
3 Coreopsis
tinctoria
(ray flowers)
OH
OH
O
OH
OH
Glu-O
4‟-glucocidoxy-2‟,3‟,3,4-tetrahydroxychalcone (marein)
11
4 Gossypium
hirsutum
“Cotton”
(flowers)
O
OHOHMeO
O
OHOH
OH
O
H
OHH
H
H
6‟-glucocidoxy-2‟,4-dihydroxychalcone
12
5 Cryptocarya
bourdilloni
(roots)
O
OH
OH
H
O
5-hydroxy-4-[(2E)-3-phenylprop-2-enoyl]- 3a,7a-dihydro-1-benzofuran-2(3H)-one
13
14
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Chapter -1 Introduction & Literature Survey
4
6 Flemingia
stricta
(leaves)
O
OHOH
(2E)-1-[2,4-dihydroxy-3-(3-methylbut-2-en-1-yl) phenyl]-3-phenylprop-2-en-1-one
15
7 Flemingia
congesta
(Inflorescences)
O
OHOH
OH
O
(Chromenochalcone)
16
8 Flemingia
wallichii
(leaves)
OH
OH
O
R1
R2
OH
OH
Homoflemingin: R1
= H, R2 = OMe
Flemiwallichin: R1
= OMe, R2 = H
17
9 Gnaphalium
affine
(flowers) O
OHOH
OH
O
H
OHH
H
H
O
OH
OH
OH
OMe
4‟-glucocidoxy-3‟,6,4-trihydroxychalcone
18
10 Lindera
umbellate
(leaves)
O OH
OH OMe
2‟,6‟-Dihydroxy-4‟-methoxychalcone
19
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Chapter -1 Introduction & Literature Survey
5
11 Lonchocarpus
sericeus
(seeds and
roots)
O
OH
OH
O
(2E)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)- 3-(4-hydroxyphenyl)prop-2-en-1-one
20
12 Myrica gale
(fruits)
O OH
OH OMe
CH3
CH3
2‟,6‟-Dihydroxy-4‟-methoxy-3‟,5‟-dimethyldihydro-
Chalcone
21
13 Prunus cerasus
L.
(heart wood)
O OMe
OH OMeOMeMeO
2‟-Hydroxy-2,4,4‟,6‟-tetramethoxychalcone (cerasidin);
O OMe
OH OHOMeMeO
2‟,4‟-Dihydroxy-2,4,6‟-trimethoxychalcone (cerasin)
22
14 Psorelea
corylifolia
(seeds)
O
OMe
4‟-O-methylchalcone O OH
OH OMeOH
CHO
5‟-Formyl-2‟,4-dihydooxy-4‟-methoxychalcone
23,
24
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Chapter -1 Introduction & Literature Survey
6
15 Glycyrrhiza
glabra
(root bark)
O
OH
OH
OMe
OH
(2E)-3-(3,4-dihydroxy-2-methoxyphenyl)-1-
(4-hydroxyphenyl)prop-2-en-1-one
25
1.2.1 Dietary Chalcones
Chalcones is one of the major classes of natural products which are widely
distributed in spices, tea, beer, fruits and vegetables and have been recently a subject
of great interest for their pharmacological activities.26
According to Francisco A. et al. the major dietary source of dihydrochalcones
is apples.27
The US FDA (Food and Drug Administration) and EU (European Union)
have approved the neohesperidin dihydrochalcone to be used as sweetener in various
foods like non-alcoholic soft drinks, desserts and confectionery etc. at concentrations
in the range 10-400 mg kg-1
(or mg l-1
),28
or as a flavor modifier at concentrations of
up to 5 mg kg-1
.29
Native chalcone glycosides tend to convert to flavanone glycosides during
extraction. Due to this characteristic, chalcones by themselves have limited
occurrence in foods. Naringenin chalcone is found in tomato skin but it is present in
traces in its juice, paste and ketchup.30-33
Mixtures of retrochalcones (e.g. echinatin,
licochalcones A and B) are present in licorice (liquorice) root (Glycyrrhiza spp) and
some medicines based on licorice. Also, the confectionery containing licorice root
extracts, might contain these chalcones.34-38
Similarly prenyl-chalcones (e.g.
xanthohumol, desmethylxanthohumol) occur in hops and beer.39
Mixture of
Flavanone-chalcone (e.g. cerasinone, cerasin) have also been shown to exist in Prunus
spp.40
Dihydrochalcones (DHCs) are characteristic of apples and derived products
(apple juice, cider, pomace, etc).
Phloretin 2'-glucoside (phloridzin) content of apples varies widely depending
upon the cultivar.41-43
Some English cider apples contain phloridzin as much as 190
mgkg-1
, while cultivar Verde Doncella contains less than 0.1 mgkg-1
.44
They are
present in the skin, pulp and especially the seeds, but the skin is 5-10 times richer than
that of flesh.45
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Chapter -1 Introduction & Literature Survey
7
While eating an apple, we usually discard its core and seeds, thus some of the
apple dihydrochalcones are not ingested. If fruits are eaten without peel, then the
DHC‟s intake is smaller.
Table 2. Contents of dihydrochalcones in apple juices and other apple products.
Values are mg L-1
(juices) or mg kg-1
(jams, etc)__________________________
Content (mg L-1
or mg kg-1
as appropriate)
Commodity and method of preparation Phloridzin Total DHC _ Juice (domestic extractor) 4.4 8.4
Juice (experimental) 13-18 40-51
Juice (experimental) 5.4 9.2
Juice (commercial) 2.7-3.3 4.8-5.6
Jam (commercial) 2.3 4.0
Compote (commercial) 9.1 14.3
Jelly (commercial) 1.0 1.4
Juice (domestic extractor) 4 9
Juice commercial clear 38 72
Juice commercial cloudy 12 39
Mash commercial 33 86
Nectar commercial 12 29
Juice (domestic) 83-196 97-223
_________________________________________________________________
The DHCs contents in clear or cloudy commercial apple juices may be 5-10
times more than those in the juices obtained in a domestic juice extractor.46
This is
due to the fact that in industrial process, the whole apples (seeds, core and peels) are
extracted and the use of thermal treatments make the degrading enzymes
(polyphenoloxidases) inactive, which is clear from the table 2.47
1.3 Pharmacological Profile of chalcones
Chalcones, either natural or synthetic, are known to exhibit a broad spectrum
of various biological activities. The presence of α,β-unsaturated carbonyl moiety as
well as of substituted aromatic rings render the chalcones biologically active. Some
substituted chalcones and their derivatives, including some of their heterocyclic
analogues have been reported to possess strong biological properties which have been
proved detrimental to the growth of microbes,48,49
tubercle bacilli,50,51
malarial
parasites52
and intestinal worms.53`
Many chalcones have been claimed to be toxic to
various animals54,55
and insects56,57
and have also shown inhibitory effects on several
enzymes58,59
and herbaceous plants.60
A few major biological activities which have
been reported to be associated with chalcones include: anti-inflammatory,61,62
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Chapter -1 Introduction & Literature Survey
8
antifungal,63-66
antioxidant,67-70
antimalarial,71-74
antituberculosis,75
analgesic,76
anti-
HIV77
and antitumor activities77-79
. Some of them act as anticancer,80
antiviral,81
and
anti-AIDS agents.82
Quinoline-based chalcones have been reported to possess
antimalarial activity.83
1.3.1 Antimalarial Chalcones
Malaria is becoming a major public health problem in more than one hundred
tropical and subtropical countries of the world. An estimated 400 to 900 million
people are affected by it each year, and it causes one to three million deaths
annually.84,85
The causal organisms of human malaria are following protozoan
parasites: Plasmodium falciparum, P. malariae, P. vivax and P. ovale. However, P.
falciparum is the most pervasive of these, and it causes about 80% of infections and
90% of deaths.86
Many drugs have been developed for the treatment of malaria, of
which chloroquine is most commonly used, but P. falciparum has become resistant to
conventional antimalarial drugs, and the search for new antimalarial drugs is still
underway.87,88
(16) R1R
2= H R
3= CF 3
R1
R2
O
H3CO
OCH 3
(18) R1R
2= OCH3
(20) R1= H R
2= CF 3
(21) R1R
2= F
(19) R1= H R
2= C2H5
R1
R3
R2
O
H3CO
OCH 3
H3CO
(17) R1R
3= Cl R
2= H
According to Liu et al.89
and Go et al.,90
the properties of ring „A‟ of
chalcones, determine the in vitro antimalarial activity against human malarial parasite,
P. falciparum. The important parameters are the size as well as the hydrophobicity of
the substituents. For instance, the alkoxylated chalcones 16-21 (IC50 < 6.5 μM) were
proven to be more active than their corresponding hydroxylated derivatives.
The compound 22, among the hydroxylated chalcones, was found to be the
most active (IC50= 12.3 μM). The IC50 values of other hydroxylated chalcones 23-26
were below 20 μM.
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Chapter -1 Introduction & Literature Survey
9
R2
O
OHR
1
OOH
OH
R4
R3
R2
R1
(22) R1R
2R
4= H R
3= Cl
(23) R1R
3= F R
2R
4= H
(24) R1= pyridinyl R
2R
3R
4= H
(26) R1= H R
2= N(CH 3)2
(25) R1R
2= Cl
Inhibitors of sorbitol-induced hemolysis of RBCs have been proven to be good
antiplasmodial agents as well. The mode of action of alkoxylated and those of
hydroxylated chalcones is also the same. They seem to inhibit sorbitol-induced
hemolysis of infected erythrocytes at a concentration of 10 μM.90
Yenesew et al.91
have reported the antiplasmodial activity of 27-29 with IC50
10.3-16.1 μM.
O
OH
OH
OH
OH
(27) 5-prenylbutein
OCH3
OH
O
OH
(28) Licoagrochalcone A
OH
OOH
OH
OCH 3
(29) Homobutein
Domínguez et al.92
reported phenylurenyl chalcone derivatives, with
substitution in ring B (IC50 = 1.76-10 μM) as potent growth inhibitors against in vitro
cultured P. falciparum. The data suggests that the activity depends on the substituents
on ring B. The para-position in the urenyl ring of 4‟-phenylurenyl chalcones 30-32
plays a crucial role in their antimalarial activity e.g. chloro-substituted compounds at
this position showed good activity.
O
N N
R1
O
R3
R2
R4
HH
Cl
(30) R1R
3= Cl R
2R
4= H
(31) R1R
3= F R
2R
4= H
(32) R1= H R
2R
3R
4= OCH3
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Chapter -1 Introduction & Literature Survey
10
3‟-phenylurenylchalcone derivatives 33-36 displayed better activity than
corresponding 4‟-phenylurenyl chalcones.92
(33) R2R
3R
4= OCH3 R
1= H
(34) R1R
3= Cl R
2R
4= H
(35) R1R
2R
4= H R
3= CH3
R1
O
R3
R2
R4
O
N N
HH
(36) R1R
4= H R
2R
3= OCH3
An outstanding antimalarial agent 37 was reported by Chen et al.93
which
exhibited antimalarial activity not only against human (in vitro) but also against
rodent (in vivo) parasites without any toxicity.
H9C4O
OCH 3
O
OCH 3
(37)
Naturally occurring chalcone crotaorixin (38) isolated from Crotalaria
orixensis has 100% inhibitory effect on the maturation of P. falciparum parasites at
concentrations 50 μg/ml and 10 μg/ml from ring stage to schizont stage. Medicagenin
(39) is a diprenylated chalcone, extracted from Crotalaria medicagenia roots showed
100% inhibition at 2.0 μg/ml.94
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Chapter -1 Introduction & Literature Survey
11
OH
O
OH
OCH 3
OH
(38) crotaorixin
OH
O
OH
OH
(39) medicagenin
Chromenodihydrochalcones (100, 40 and 41) extracted from Crotalaria
ramosissima were proved to be weaker antimalarial agents.94
OH
OOH
O
CH3
CH3
(100)
(40) R1= H R
2= OCH3
OH O
R2
R1OCH3
CH3
(41) R1R
2= OH
(42) xanthohumol
OCH 3 O
OH
OH
OH
Prenylated chalcone (xanthohumol, 42), isolated from hops (Humulus
lupulus), was screened for antiplasmodial activity by Frölich et al.95
against poW
(chloroquine-sensitive strain) and Dd2 (Multiresistant clone), exhibited significant
activity (IC50 = 8.2 ± 0.3 and 24.0 ± 0.8 μM for poW and Dd2 respectively)
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Chapter -1 Introduction & Literature Survey
12
N Cl
MeO
MeO
O
ClCl
(43)
Domínguez et al.96
reported the synthesis of twelve novel quinolyl chalcones
and found their biological activity against a chloroquine resistant strain of P.
falciparum. Only the compound (2E)-3-(2-chloro-6,7-dimethoxyquinolin-3-yl)-1-
(2,4-dichlorophenyl)prop-2-en-1-one (43) was found to be the most promising
compound with IC50 = 19.0 μM.
MeO
MeO
O
OMeOH
(44)
Lim et al.97
prepared twenty derivatives of flavonoids and chalcones. In the
chalcone series the compound (44) was found to be the most active, EC50 = 1.0 μg/mL
with 100% inhibition against P. falciparum and at the final concentration of 5.4
μg/ml.
1.3.2 Antibacterial Chalcones
Antibacterial activity of chalcones is being studied extensively. Researchers
have not only identified the structures of the bactericidal chalcones, isolated from
various plants, but have also synthesized or modified them. The antibacterial effects
depend upon the binding of the chalcone moiety to a nucleophilic group, like thiol
group of an essential protein98
(An essential protein is a protein that cannot be
synthesized de novo by the organism, usually referring to humans, and therefore must
be supplied in the diet.) The increase in the number of multi-drug resistant
microorganisms, has reached to an alarming level all over the world. Many resistant
strains of Staphylococcus aureus and other antibiotic-resistant pathogenic bacteria
have already been reported. A series of quinolinyl chalcones have been tested for
their in vitro antibacterial activity against different strains of gram negative and gram
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Chapter -1 Introduction & Literature Survey
13
positive bacteria, which have shown significant activity aginst Staphylococcus aureus,
Bacillus subtilis, Escherichia coli and Salmonella typhosa.99
Retrochalcones (chalcones which do not have an oxygen function at the 2-
positin) isolated from Glycyrrhiza inflata e.g. licochalcone A (45) and licochalcone C
(46) have been found to possess potent antibacterial activity especially to
Staphylococcus aureus, Bacillus subtillis and Micrococcus luteus.98
Kromann et al.100
observed that the free hydroxyl group at 4‟-posision in ring A is responsible for the
antibacterial effect of licochalcone A.
O
OH
OCH 3
OH
CH3
CH3
Licochalcone A
O
OH
OCH 3
OH
CH3
CH3
Licochalcone C
(45) (46)
Conversely, the activity of (45), with hydroxyl group at position 4 of ring B
has not affected if the hydroxyl group is replaced by chloro group (47, MIC= 10 μΜ
against S. aureus), or blocked by a methyl group or even removed permanently.
Complete elimination of activity has been observed when both the hydroxyl groups
are either removed or blocked by methylation. Also the removal of the lipophilic
prenyl group results in the total loss of activity.100
OCH 3
R2
R1
O
OH
(47) R1= C(CH 3)2CH=CH 2 R
2=Cl
(48) R1= C6H13 R
2=OH
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Chapter -1 Introduction & Literature Survey
14
A more potent chalcone (48) than licochalcone A (45) results by the
incorporation of a longer hexyl group which means that a direct relationship is present
between the lipophilicity and bactericidal activity.100
Compound 49-52 form a novel class of chalcones due to the presence of
aliphatic amino substituents.101
Aliphatic amines positioned in the ring A, has a minor
effect on the activity. The activity is not affected by the distance between aliphatic
amino group and the aromatic ring A, whereas in case ring B, this distance plays an
important role towards the activity. The most potent compound in this study is 49
(MIC= 2 μM against methicillin-resistant S. aureus, and MIC= 5 μΜ against E.
faecium and E. coli). Again the lipophilicity is an important parameter that controls
the antibacterial activity in chalcones. Another property observed, is the bulkiness of
the substituent in position 5 of ring B. There observed a direct relationship between
the antibacterial activity and the bulkiness of the substituent in position 5 of ring B.
(50) R1= 4-methylpiperazine R
3= NHCH2CH2N(CH)3 R
2R
4= H
(51) R1= OCH2CH2N(CH3)2 R
2= F R
3= H R
4= OCH3
(52) R1= OCH2CH2N(CH3)2 R
2= CH2N(CH3)2 R
3= H R
4= OCH3
(49) R1= piperazine R
3= NHCH2CH2N(CH)3 R
2R
4= H
R1
O
CH3 CH3
R2
R3
R4
Machado et al.102
have reported the antibacterial activity of isoliquiritigenine
(53) against S. aureus, S. epidermidis and S. heamolyticus, with MIC= 250 μg ml-1
.
Pinocembrin chalcone (54) was found active against S. aureus.103
Belofsky et al.104
isolated chalcones (55) from Dalea versicolor, which was
found to be active individually as well as in combination with other common
antibiotics (berberin, tetracycline and erythromycin) against human pathogen S.
aureus and B. cereus.
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Chapter -1 Introduction & Literature Survey
15
R5
R4
CH3OH
R3
OH
R2
R1
(53) R1R
3R
4R
5= H R
2= OH
(54) R2R
3R
4R
5= H R
1= OH
(55) R1R
2= H R
3R
4= CH 3 R
5= OCH 3
Chalcones (56 and 57) have been shown to possess bateriostatic profile i.e.
they exhibited inhibitory effect rather than killing of bacteria even at higher
concentrations (16 times MIC). The difference between the mechanisms of carboxy
and hydroxychalcones is that the later are bactericidal ( cause killing of bacteria) and
the former are bateriostatic (inhibit the growth).105
Lin et al.106
reported that chalcones (58 and 59) with the 2-hydroxy group in
ring A and 3-chloro- or 3-iodo- group in ring B, exhibited the strongest activity, with
a growth inhibition of 90-92%.
CH3R3
R4
R1
R2
(56) R1 R
2 = CF 3 R
3 = H R
4 = COOH
(57) R1R
2 = Br R
3 = H R
4 = COOH
(58) R1 = Cl R
2 R
4 = H R
3 = OH
(59) R1 = I R
2 R
4 = H R
3 = OH
The bioassay of dihydrochalcones (60-63) showedthat these compounds have
relatively good activity against Gram-positive bacteria S. aureus an B. subtilis, and
the Gram-negative bacterium Pseudomonas aeruginosa.107-109
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Chapter -1 Introduction & Literature Survey
16
OHR2
R1
OH O
R3
(60) R1R
3= H R
2= OCH 3
(61) R1= CH 3 R
2= OH R
3= H
(62) R1= CHO R
2= OH R
3= H
(63) R1= H R
2= OCH 3 R
3= OH
1.3.3 Antifungal Chalcones
Candida albicans is a well known human pathogen, responsible for the oral
and vaginal infections. It is a major cause of invasive fungal disease. The intensive
use of antifungal drugs results in the generation of new resistant strains of Candida
species, due to which there is an increasing interest to develop new suitable
therapeutics.110
Chalcones seem to be a solution to all these problems, because the mechanism
of antifungal action of chalcones is the inhibition of cell wall.111
As far as the
therapeutic viewpoint is concerned, chalcones inhibit glutathione-S-transferases
(GSTs) enzymes that are apparently involved in drug resistance.112
It has also been
reported that thiol alkylation is one of the steps involved in chalcones detoxification
action in yeasts.113
Chalcone functionality is fundamental for growth inhibition against Candida
species, but some conflicting results have also been obtained about the fungicidal
effects of hydroxyl-chalcones. The antifungal activity of chalcones largely depends on
their potential to interact with sulfhydryl groups.114
Tsuchiya H. et al. have reported
that the cyclization of chalcones to flavones or reduction to dihydrochalcones results
in the loss of their antifungal properties.115
Chalcones devoid of phenolic groups, have also been reported to possess
either low or no activity.116
Some natural hydroxyl-chalcones have exhibited low
activity against C. Albicans.117,118
On the other hand some plant-derived chalcones
after hydroxylation in ring A are strong candidates as antifungal agents,111
and the
position of the hydroxyl group in the ring B is largely associated with its antifungal
activity.
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Chapter -1 Introduction & Literature Survey
17
Lopez et al.119
examined the antifungal activity of chalcones (64-67) against a
group of dermatophytic fungi. The presence of electron-donating groups on ring B,
make them weak antifungal agent. Conversely, electron-withdrawing groups in the
para position increase the activity. The presence of α,β-unsaturated carbonyl group
enhances the antifungal activity, but it is not sufficient alone.
The compound 67 is the most active one, although it neither possesses any electron-
withdrawing group, in the para position of ring „B‟, nor does it have any substituent
in ortho position. This compound showed antifungal activities against Microsporum
canis (MIC = 25 μgml-1
), Microsporum gypseum (1.5 μgml-1
), Trichophyton
mentagrophytes (3 μgml-1
), Trichophyton rubrum (3 μgml-1
) and Epidermophyton
floccosum (0.5 μgml-1
).119
ElSohly et al.120
isolated the prenylated chalcones (isobavachalcone 68) and
69 from the leaves of Maclura tinctoria were found active against the two fungal
pathogens Candida albicans (IC50 of 3 and 15 mg ml-1
, respectively) and
Cryptococcus neoformans (IC50 = 7 mg ml-1
).
R3
O
R2
R1
(64) R1R
3= H R
2= NO 2
(65) R1= OCH 3 R
2R
3= H
(66) R1R
3= H R
2= CH 3
(67) R1= OCH 3 R
2= H R
3= Br
OH
O
R1
R2
OH
(68) R1= OH R
2= CH 2CH=C(CH 3)2
(69) R1= OH R
2= CH 2CH(OH)C(CH 3)=CH 2
(70) R1= H R
2= OCH 3
(71) R1R
2= H
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Chapter -1 Introduction & Literature Survey
18
Svetaz et al.121
reported that the compounds 70 and 71 exhibited very good
antifungal activities, which they extracted from Zuccagnia punctata. Their MIC
values were found to be 6.25 μgml-1
and 3.12 μgml-1
respectively, against Phomopsis
longicolla Hobbs CE117, whereas against Collectotrichum truncatum CE175 the MIC
= 6.25 μgml-1
.
The chalcone 72 (crotmadine) has been reported to be extracted from the
leaves and stems of Crotalaria madurensis. This compound displayed antifungal
property against T. mentagrophytes at a concentration 62.5 μgml-1
.122
(72) crotmadine
O O
OH
OH
Okunade et al. reported that the dihydrochalcone 60 was found to be a good
antifungal agent against two AIDS-related fungal pathogens C. albicans and C.
neoformans.107
Compound 61 displayed promising antifungal activity against T.
mentagrophytes at 60 μg/disk.108
Miles D. H. et al.123
showed that dihydrochalcone 62
exhibited potent antifungal activity against Rhizoctonia solani and Helminthosporium
teres, and antibacterial activity against Xanthomonas campestris.
OHR2
R1
OH OH
R3
(60) R1R
3= H R
2= OCH 3
(61) R1= CH 3 R
2= OH R
3= H
(62) R1= CHO R
2= OH R
3= H
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Chapter -1 Introduction & Literature Survey
19
1.3.4 Anti-inflammatory Chalcones
The procedures adopted in the treatment of various inflammatory diseases
include inhibition of prostaglandin E2 (PGE2) and nitric oxide (NO) production.
Excessive amounts of NO cause tissue damage. Rheumatoid arthritis, an
inflammatory disorder, is caused due to excessive NO production by activated
macrophages. Therefore, it is necessary to produce potent and selective NO inhibitors
for potential therapeutic use.98
A series of chalcones was screened for anti-inflammatory effect by Herencia
et al.124-127
Chalcone 73 was found to be significantly as a superoxide anion
scavenger, with IC50 value of 0.1 μM. It also inhibits the inducible NO synthase
expression via a superoxide-dependent mechanism in stimulated mouse peritoneal
macrophages, and secluded the cells against oxidant stress.
Rojas et al.128
reported the concentration-dependent inhibition of the NO
production of the chalcones 74 and 75 with IC50 = 0.6 and 0.7 μM, respectively.
R5
R4
R3
R2
R1
O
N
CH3
CH3
(73) R1R
4R
5= H R
2R
3= OCH 3
(74) R1R
5= OCH 3 R
2R
3R
4= H
(75) R1R
4= OCH 3 R
2R
3R
5= H
A series of Trimethoxychalcones with diverse patterns of fluorination, was
prepared by Rojas et al.129
The chalcone 76 showed inhibitory effect (76.3%
inhibition at 10 μM) on the generation of NO as well as of prostaglandin E2 in
lipopolysaccharide-stimulated RAW 264.7 macrophage cells. The inhibition depends
on amount of dose with no cytotoxicity.
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Chapter -1 Introduction & Literature Survey
20
OCF3
OCH 3
OCH 3H3CO
(76)
The chalcone derivatives 77-79 extracted from the fruits of Mallotus
philippinensis130
and 42, 80-82 from hops (H. lupulus),131
displayed inhibition in the
generation of NO, induced by lipopolysaccharide (LPS) and INF-γ in murine
macrophage-type cell line, RAW 264.7.
R2
OH OH
OH
R1
OO
CH3R3
(77) R1= H R
2= CH 2CH=C(CH 3)CH2CH2CH=C(CH 3)2 R
3= CH 3 (Mallotophilippens C)
(78) R1= OH R
2= CH 2CH=C(CH 3)CH2CH2CH=C(CH 3)2 R
3= CH 3 (Mallotophilippens D)
(79) R1= OH R
2= CH 2CH=C(CH 3)2 R
3= CH 2CH2CH=C(CH 3)2 (Mallotophilippens E)
(42) xanthohumol
OCH 3 O
OH
OH
OH
O OCH 3
OOH
OH
OH
(80) xanthohumol B
OCH 3
OH
OHOH
O
OH
OCH 3
OH
OH O
OH
(81) xanthohumol D (82) dihydroxanthohumol
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Chapter -1 Introduction & Literature Survey
21
Madan et al.132
reported that the 2‟-Hydroxychalcone 83 has the ability to
control cell trafficking by the blockage in the expression of cell adhesion molecules.
Its inhibitory effect on both TNF-α and LPS-induced expression of leukocyte
adhesion molecules was almost the same.
OOH
(83)
The potential of all the hydroxyl and alkoxychalcones (84-92) to inhibit the
release of β-glucuronidase and lysozyme has been reported133-136
from rat neutrophils
stimulated with formyl-Met-Leu-Phe/cytochalasin B (fMLP/CB). Among the
hydroxychalcones, compound 86 is found to be the most active one in the inhibition
of release of β-glucuronidase (IC50= 1.6 μM) and lysozyme (IC50= 1.4 μM) from
fMLP/CB stimulated rat neutophils.
The mode of action of dialkokxychalcones (90-92) as anti-inflammatory
agents is not the inhibition of mast cells and neutophils degranulation. They actually
suppress NO formation from N9 cells. Compound 90 showed the greatest ability to
inhibit NO formation from LPS-stimulated murine microglial cell lines (IC50 = 0.7
μM). Compound 92 exhibited strong activity in dose-dependent inhibition of β-
glucuronidase from peritoneal mast cells of rats stimulated with compounds: 30/74
(10 μg/ml).135
R1
R3
R2
OOH
(84) R1R
2= H R
3= OH
(85) R1= H R
2R
3= Cl
(86) R1= OH R
2R
3= H
OR1
ClR
2
(89) R1R
2= OC 3H7
(90) R1R
2= OC 4H9
(91) R1R
2= OC 2H5
(92) R1R
2= OH
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Chapter -1 Introduction & Literature Survey
22
OH
OOH
OH
CH3
O
O
R1
OH
(87) R1= H
(88) R1= OCH 3
1.3.5 Antileishmanial Chalcones
Leishmaniasis is a group of diseases caused by various species of protozoan
parasites which belong to the genus Leishmania. Over 12 million people of 88
countries are affected by it, with an annual increase of 2-3 million cases. According to
a careful investigation, a population of 350 million is under threat of infection.137
Amphotericin B and pentamidine have been used for medication of the disease.138
During the past decade, chalcones emerged as a new class of antileishmanial
agents.139-141
Licochalcone A, extracted from a Chinese plant Glycyrrhiza spp is one
of the most studied leishmanicidal chalcones, which inhibits the parasite enzyme
fumarate reductase.142,143
Chen et al.144
studied that licochalcone A not only inhibited
the in vitro growth of the parasites L. major and L. donovani promastigotes but also
killed the intracellular amastigotes of both. The in vivo study was carried out in mice
and hamsters infected with L. major and L. donovani parasites respectively. The
results exhibited the inhibition in growth of these parasites, both in mice and
hamsters. The study supports the importance of licochalcone A and its analogues in
the development of new antileishmanial drugs.
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Chapter -1 Introduction & Literature Survey
23
O
OH
OCH 3
OH
CH3
CH3
Licochalcone A
O
OH
OCH 3
OH
CH3
CH3
Licochalcone C(45) (46)
As far as licochalcone C is concerned, its extent of growth inhibition of the L.
major parasite is the same as that of the licochalcone A.145
Chalcones 93 and 94 displayed potent antileishmanial activity against both
extracellular and intracellular forms (IC50 = 153 and 118 μM, respectively). Some new
oxygenated chalcones 95-98 and 1 were found to inhibit the in vitro growth of L.
major promastigotes (IC50 = 4.0-10.5 μM) and L. donovani amastigotes (IC50 = 0.65-
6.1 μM) in human monocyte-derived macrophages (MDM).146
OCH 3
OCH 3
O
R2
R1
(93) R1= H R
2=OCH2CH=CH2
(95) R1= OH R
2= H
(96) R1R
2= H
(97) R1= H R
2= OH
(98) R1= H R
2= OCH2CH=CH2
(94) R1= H R
2= OC4H9
Torres-Santos et al. screened in vitro the dihydoxychalcone 99 against
promastigotes and intracellular amastigotes of L. amazonensis and found ED50 = 0.5
and 24 µg/mL respectively. The ultrastructural studies indicate that this chalcone
enlarges and disorganizes the mitochondria of promastigotes. The inhibitory effect on
intracellular amastigotes is a direct effect on parasites, without any disarrangement of
macrophage organelles, even at 80 µg/mL of 99.147
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Chapter -1 Introduction & Literature Survey
24
O
H3CO
OH
OH
(99)
OH
OOH
O
CH3
CH3
(100)
The extracellular promastigotes of L. donovani and intracellular amastigotes
residing within murine macrophages were tested with chromeno chalcone 100
(crotaramosmin). It was observed that 100 was found potent, with 84% and 74%
inhibition against promastigotes and amastigotes respectively at 50 µg/mL dose.148,149
Hermoso et al.150
synthesized dihydrochalcones 101-103 and screened them
against L. braziliensis, L. tropica and L. infantum. The activity as well as toxicity
increases by substituting the methoxy group at C-4‟ (ring A) with an acetate group.
R1
O
H3CO
R2
R3
(101) R1
= H R2
R3
= OCOCH3
(102) R1R
3= OCOCH3 R
2= OH
(103) R1R
2R
3= OCOCH3
Neilson et al.151
reported the fact that the pharmacophore consists of two
aromatic rings, while the propanone chain‟s function is just to provide space. The
tendency of a chalcone to act as an antileishmanial agent depends upon the
substituents on both the rings as well as the ratio of their lipophilicity to
hydrophilicity. Also the substitutions on ring A did not play a major role towards
antileishmanial activity, but replacing acetate groups with hydroxyl groups not only
enhances the activity but also reduces the cytotoxicity to murine macrophages.
1.3.6 Antiviral Chalcones
In the studies of inhibitory effects of chalcones against plant viruses and
human rhinoviruses, the antiviral property of chalcones was discovered. The antiviral
activity specifically depends on the substitution patterns.98
Onyilagha et al.152,153
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Chapter -1 Introduction & Literature Survey
25
tested a few hydroxy and methoxy chalcones for activity against tomato ringspot
nepovirus (ToRSV) infectivity. The chalcones‟ ability of inducing resistance against
ToRSV was analyzed in time course experiments. It was observed that the application
of chalcones before or after ToRSV infection, results in a loss of activities.
Compounds 71 and 104-107 were found to be most effective antiviral agents.
OH
O
R1
R2
OH
(71) R1R
2= H
R2
OCH 3
OCH 3
R1
O
R3
(104) R1R
3= H R
2= OCH 3
(105) R1R
2= OH R
3= OCH 3
OH
R2
OH O
R1
(106) R1R
2= OH
(107) R1= H R 2= OCH 3
Xanthohumol 42 has been reported by Wang et al.154
as a selective inhibitor of
HIV-1 and it may represent a new therapeutic agent against HIV-1 infection. The
EC50 values of 42 on HIV-1 p24 antigen inhibition and RT production were 1.28 and
0.50 μg/ml, respectively.
(42) xanthohumol
OCH 3 O
OH
OH
OH
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Chapter -1 Introduction & Literature Survey
26
Wu and coworkers155
determined that chalcone 108, extracted from the genus
Desmos, exhibited potent anti-HIV activity.with EC50 = 0.022 μg/ml.
CHO
H3CO OH
OOH
CH3
OH
(108)
OH
R2 R
3
R4
R1
O
OH
(109) R1R
4= OH R
2R
3= H
(110) R1R
2= H R
3= OCH 3 R
4= OH
(111) R1= H R
2R
4= OH R
3= OCH 3
The chalcone 109 (butein) was tested for inhibitory effect on HIV-1 by Xu et
al.156
using fluorescence and HPLC assays. The results suggested that butein 109
applied at 50 μg/ml caused more than 50% inhibition of HIV-1 protease.
Licochalcones A 45 and B 110 as well as 111 screened by Uchiumi et al.,157
were found to reduce the TPA-induced HIV promoter, while they didn‟t cause a
decrease in the Luc activity in pCMVLuc transfected cells. These chalcones displayed
a negative effect on HIV transcription, possibly due to their binding with some
specific protein factors. Moreover, cardamonin 112 showed significant anti-HIV-1 PR
activity (75.1% inhibition) with an IC50 = 31 μg/ml.158-160
OH OCH 3
OOH
(112)
1.3.7 Antituberculous Chalcones
A very frequently encountered disease caused by mycobacterium, is
Tuberculosis (TB). Although it is almost wiped out significantly from industrially
more developed countries, it is still a major health problem in most developing
countries. The infection rate of TB in developing countries is 0.1−0.3 % annually,
with high mortality rate. Mycobacterium tuberculosis has developed resistance against
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Chapter -1 Introduction & Literature Survey
27
conventional anti-TB drugs, and for the past 40 years no new drug with different
mode of action has been developed. Therefore, new anti-TB drugs are needed to be
developed, which have potential to reduce the therapy duration, treatment of multiple
drug resistant tuberculosis (MDR-TB) by single dosage regiment and of course
reduction in total expenditure.161
Two approaches can be adopted to develop new pharmacophore, which have
anti-TB activity: (i) synthesis of new compounds better than those of existing ones,
(ii) Searching for those novel compounds which have never been exposed to M.
tuberculosis strains to address multi-drug resistant tuberculosis.162
Shahar Yar et al. synthesized a novel series of eleven chalcones, which were
tested for antimycobacterial activity against M. tuberculosis H37RV using a BACTEC-
460 radiometric system. Among the eleven chalcones, only six were found to be
active. The compounds 114 and 118 exhibited largest efficacy and displayed >90%
inhibition at MIC ≈ 6.25 μg/ml in the primary screen, whereas the chalcones 113, 115,
116 and 117 displayed ≈ 90% inhibition with MIC values greater than 6.25 μg/ml.
OH
O
CH3
R1
R2
R3R
4
(113) R1R
2R
4= H R
3= Cl
(114) R1R
2R
4= H R
3= NMe 2
(115) R1R
4= H R
2R
3= OMe
(116) R1R
2R
4= H R
3= F
(117) R2R
3R
4= H R
1= Cl
(118) R2R
3= H R
1R
4= Cl
The data suggest that dimethylaminophenyl substituted chalcones are good
antitubercular agents.161
1.3.8 Antitrichomonal Chalcones
Trichomonas gallinae, a flagellated protozoan, parasitizes upper digestive tract
and different organs of various birds and urogenital duct in humans. The domestic
pigeon and some dove species like white-wing doves are primary hosts of this
parasite.
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Chapter -1 Introduction & Literature Survey
28
Metronidazole was proven to be effective against T. gallinae [Bussieras et al.
1961]163
and therefore, used in the treatment of human urogenital trichomonosis since
its discovery [Krieger et al. 1985].164
Despite of their extensive use worldwide, cases
of clinical resistance to nitroimidazoles are very rare in man. Oyedapo et al.165
synthesized a series of ten chalcones and examined them for antitrichomonal
activities. Five of the prepared chalcones 119-123 were found active at concentrations
≤100 μg/ml. Chalcones 119-121 showed activity (MLC = 100±0, 0.78±0 and 50±0
μg/ml) due to the presence of 2‟-hydroxyl group which would form flavones or
isoflavones via intramolecular cyclization. Compound 122 displayed same MLC
value as that of 121 i.e. 50±0 μg/ml. The dihydroxychalcone 123 was found to be the
2nd
most active compound (MLC = 3.13±0 μg/ml) after compound 120 which was
proven to be the most active one, with MLC value of 0.78±0 μg/ml equal to the
standard drug metronidazole.
(119) R1R
3R
5= H R
2= OH R
4= OMe
(120) R4R
5= H R
2= OH R
1R
3= OMe
(121) R1R
3R
5= H R
2= OH R
4= Cl
(122) R2R
3= H R
1R
4R
5= OMe
(123) R1R
2R
3= H R
4R
5= OH
R1
R2
R3
R5
R4
O
1.4 Applications in Synthetic Organic Chemistry
Chalcones are very reactive organic compounds and most of their reactions are
due to α,β-unsaturated carbonyl moiety. They undergo oxidation,166-170
reduction,171-
174 Michael addition, Suzuki cross coupling reactions etc. They serve as precursors for
the synthesis of various heterocyclic compounds like pyrimidines177
, imidazoles177
, 2-
pyrazolines178
, isoxazoles179
, flavonoids.180
A few examples of various reactions of
chalcones are given under the following schemes.
1.4.1 Oxidation of Chalcones166-170
Chalcones can easily and smoothly be oxidized to their corresponding
flavones by employing selenium dioxide.166-168
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Chapter -1 Introduction & Literature Survey
29
Cl
OH
O
OMe
OMe
SeO2
Cl
O
O
OMe
OMe
Scheme 1(i). Oxidation of chalcones to flavones using SeO2
Another very convenient and efficient method of oxidation of chalcones to prepare
symmetrical169
and unsymmetrical170
benzils, is with thallic nitrate (TN).
O
O
O
R1
R2
R1
R2
TN
in aq acid/glyme
Scheme 1(ii). Oxidation of chalcones to benzyls using thallic nitrate (TN)
The yield of this reaction is 45-70%. However, the reaction fails due to the presence
of electron-withdrawing groups.
1.4.2 Reduction of Chalcones171-174
Selective reduction of double bond in chalcone takes place upon reacting with
sodium borohydride in pyridine.171
Reduction of chalcones by lithium amalgam172
produces a small quantity of its
corresponding alcohol. Sodium metal reduces chalcone to corresponding
benzylacetophenone.173
Another reducing agent is zinc metal in ethanol-acetic acid
system, which reduces butein to corresponding flavan.174
OH
O
OH
OH
OH
OOH
OH
OH
OHH
(Butein) 4,7,3',4'-Tetrahydroxyflavan
Zn
CH3COOH
Scheme 2. Reduction of butein to 4,7,3’,4’-Tetrahydroxyflavan using Zn in CH3COOH
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Chapter -1 Introduction & Literature Survey
30
1.4.3 Conversion of Chalcones to 1,5-Diketones175
Ceylan and Gezegen reported the synthesis of a series of eight 1,5-diketones
through Michael-type addition reaction. Different chalcones (1mol) were treated with
cyclohexanone (2mol) in the presence of KOH (6% mol) under solvent-free
conditions by employing phase transfer catalyst (benzyltriethylammonium chloride;
6% mol). The mixture was stirred at r. t. and gave good yields i.e. 40-83%.
O O O O
+X X 6%KOH, 6%PTC
r.t., 3-4 h
(1a-h) (2) (3a-h)
3a) X = H; b) X = o-Cl; c) X = m-Cl; d) X = p-Cl
e) X = o-Br; f) X = o-OMe; g) X = m-OMe; h) X = p-OMe
Scheme 3. Synthesis of 1,5-Diketones by addition of cyclohexanone to chalcones
It was observed that the yield was affected by the position of substituents. Low
yields were obtained in o-substituted products, due to steric hindrance.
1.4.4 Conversion of Chalcones to Ferrocenyl Chalcones176
Song et al. synthesized two new organometallic derivatives of chalcones by
Suzuki cross-coupling reaction. Acetyl ferrocene was treated first with 3-
Bromobenzaldehyde to give chalcone (1) which upon refluxing in inert atmosphere
with aryl boronic acid in the presence of Pd(0) in aqueous Na2CO3 soln. gave the
corresponding 3-biaryl-1-ferrocenyl-2-propene-1-ones (2a-b).
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Chapter -1 Introduction & Literature Survey
31
(1)
(2a-b)
Fc
O
CH3
+
O
BrFc
Br
O
Fc = ferrocenyl
Ar =
O
,
ArB(OH) 2Pd(0)
Ar
O
Fe
Scheme 4. Synthesis of 3-biaryl-1-ferrocenyl-2-propene-1-ones
1.4.5 Conversion of Chalcones to Imidazoles and Pyrimidines177
Varga et al. reported the conversion of chalcones into two major classes of
organic compounds, i.e. imidazoles and pyrimidines. The reagent used for cyclization
was guanidine in the presence of 50% KOH and 30% hydrogen peroxide. The type of
product depends on the order of addition of H2O2. If H2O2 is added at initial stage then
imidazole would be the final product.
Ar1 Ar
2
O
+ NH2 NH2
NH
NH
N
O
NH2
Ar1
Ar2
Imidazoles
EtOH, 50% aq. KOH,
30% aq. H2O2, 80 °C
Scheme 5 (i). Conversion of chalcones to imidazoles using H2O2 in Ist step
But if H2O2 is added to the reaction mixture after 1h refluxing, in small
portions and over a period of 1h, then the final product is pyrimidine.
Ar1 Ar
2
O
+ NH2 NH2
NH
NN
NH2
Ar2Ar1
Pyrimidines
1) EtOH, 50% KOH,
rflx., 1-3h
2) 30% aq. H2O2
Scheme 5 (ii). Conversion of chalcones to pyrimidines using H2O2 in IInd
step
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1.4.6 Conversion of Chalcones to 2-Pyrazolines178
Lévai reported the synthesis of chlorinated 3,5-diaryl-2-pyrazolines
derivatives from chlorochalcones. He treated different chalcones with hydrazine
hydrate or phenyl hydrazine in acetic acid, and the reaction mixture was refluxed for
3h. The crude product was obtained by filtration and recrystallized from methanol.
N N
X
H H
H
X= H, C 6H5
O
R1
R2
XNHNH2
MeCOOH
R1
R2
The groups R1 and R
2 may be H, Cl, di-Cl, Me or OMe.
Scheme 6. Conversion of chalcones to 2-Pyrazolines using hydrazine or phenylhydrazine
1.4.7 Conversion of Chalcones to Isoxazoles179
Kidwai M. et al (2006) reported the synthesis of six isoxazole derivatives via
Michael addition of hydroxylamine hydrochloride over chalcones under microwave
irradiations using K2CO3 as solid support. O
X
Y N O
Y
X
(a-f)
X Y
a:
b:
c:
d:
e:
f:
H H
p-CH3O
m-NO2
p-Me 2N
H
p-CH3O
H
H
H
p-Cl
p-Cl
+Anhydrous K2CO3
EtOH, MW 140 °CNH2OH
Scheme 7. Synthesis of isoxazole under MW irradiations
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Chapter -1 Introduction & Literature Survey
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The above reactions were highly regioselective irrespective of the nature of the groups
attached to the two rings in the chalcones.
1.4.8 Conversion of Chalcones to Flavanones180
Sagrera and Seoane prepared flavanones by MW irradiation under solvent-free
conditions. For this purpose, they used common household microwave oven and
examined various mineral supports and catalysts. Irradiating with 30% TFA over
silica gel, chalcones produced flavanones in high yields.
R2
OH
R3
R5
R6
R4
OR1
R2
O
R3
R5
R6
R4
OR1
30% TFA / silica gel
microwave, 9min
69 - 80%
Scheme 8. Synthesis of flavonones from o-hydroxychalcones under MW irradiations
1.4.9 Conversion of Chalcones to (±)-1-(5-aryl-3-pyridin-2-yl-4,5-
dihydro-pyrazol-1-yl)-2-imidazol-1-yl-ethanone181
Mamolo et al. prepared (±)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-pyrazol-1-
yl)-2-imidazol-1-yl-ethanone derivatives according to the following scheme.
Chalcones (1) first treated with hydrazine hydrate to give corresponding (±)-5-aryl-3-
(pyridin-2-yl)-4,5-dihydro-1H-pyrazoles (2). Upon stirring these pyrazoles (2) with
equimolar bromoacetyl chloride and triethylamine in benzene at r. t. for 4 h and
finally concentrating the mixture under reduced pressure the corresponding (±)-2-
bromo-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-pyrazol-1-yl)-ethanone derivatives (3)
were obtained. Ultimately, (3) were refluxed with imidazole (in 1:2 mole ratio) for 2
h, in acetonitrile. After long work up (±)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-
pyrazol-1-yl)-2-imidazol-1-yl-ethanone derivatives (4) were obtained in pure form.
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O
H
N
O
+ RN
O
R
(1)
NH2NH2.H2O
(2)
O
ClBr
NN
N
O
Br
R
NNH
NR
N
NH
NN
N
O
N N
R
(4)(3)
Scheme 9. Conversion of chalcones to (±)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-
pyrazol-1-yl)-2-imidazol-1-yl-ethanone
and finally tested for their in vitro antifungal activity. The compounds exhibited
moderate antifungal activity against strains of Candida parapsilosis, C.
pseudotropicalis and C. glabrata.
1.4.10 Conversion of Chalcones to 5-amino-1,3,4-thiadiazole-2-thiol
imines and imino-thiobenzyl182
Yusuf et al. synthesized a series of 5-amino-1,3,4-thiadiazole-2-thiol imines
and imino-thiobenzyl derivatives by treating different chalcones with 5-amino-1,3,4-
thiadiazole-2-thiols under reflux in absolute ethanol for 5-8 h. The reaction mixture
was concentrated in vacuum, and the crude product was recrystallized from methanol.
The starting material 5-amino-1,3,4-thiadiazole-2-thiol was prepared by refluxing
thiosemicarbazide with carbon disulphide.
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Chapter -1 Introduction & Literature Survey
35
S
NH
NH2
NH2
+ SS
N N
SNH2
SH
OR1
R2
N NN
S
SH
R1
R2
Cl
Cl
Cl
NN
N
S
S
R1
R2
NN
N
S
S
Cl
R1
R2
(1)(2)
(3i) (3ii)
R1 = H, OMe, (Me)2N, Cl, OH
R2 = H, Cl
Scheme 10. Synthesis of 5-amino-1,3,4-thiadiazole-2-thiol imines and imino-
thiobenzyl derivatives
1.4.11 Conversion of Chalcones to 2,4,6-trisubstituted pyrimidines183
Agarwal et al. reported the synthesis of 2,4,6-trisubstituted pyrimidines (3).
For this purpose chalcones (1), prepared by the reaction of 4-acetylpyridine with
different aldehydes, were treated with morpholine-4-carboxamidine hydrochloride
(2), which in turn was prepared by refluxing morpholine with S-methylisothiourea
sulfate in water. The chalcones (1) cyclized with morpholine-4-carboxamidine
hydrochloride (2) in the presence of sodium isopropoxide (which appeared by adding
sodium metal in isopropanol in situ) to yield first dihydropyrimidine (A) which
further oxidizes to give a series of 2,4,6-trisubstituted pyrimidines (3).
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Chapter -1 Introduction & Literature Survey
36
O
CH3
+ CHOR
O
R
+ NO
NH
NH2
. HCl
NH
NH2
SMe
2
.H2SO4
NH
O
N
N
NH
N
O
R
N
N
N
N
O
R
(1) (2)
(3)(A)
Scheme 11. Conversion of chalcones to 2,4,6-trisubstituted pyrimidines
1.4.12 Reaction of Chalcones with Diethyl Malonate184
Zhang et al. proposed the use of K2CO3 as an efficient catalyst in Michael
addition reactions of chalcones and azachalcones with equimolar amount of diethyl
malonate under high-speed vibration milling (HSVM) conditions.
X
O
+R
(1a-o) (2) (3a-o)
X = CH, N
R = H, 4-Me, 4-OMe, 4-NO 2, 3-NO 2, 4-CN, 4-Cl, 3,4-Cl, 3,4-(OCH 2O)-
CH2(COOEt) 2X
O
EtO2C CO2Et
R K2CO3 (10% equiv.)
HSVM
Scheme 12. Michael additionof diethyl malonate catalyzed by K2CO3 under
HSVM conditions
Amazing results were obtained in terms of yields. Except compounds 3c, 3i
and 3m all the other compounds were obtained in 98-99% yield. The yields of 3c, 3i
and 3m were 91%, 76% and 92% respectively.
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Chapter -1 Introduction & Literature Survey
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1.4.13 Reactions of Chalcones with Thiosemicarbazide185
Özdemir et al. synthesized pyrazoline derivatives of chalcones with
thiosemicarbazide. It was done by heating each chalcone with thiosemicarbazide (in
slight excess) in the presence of NaOH (double) in ethanol. The crude product (2) was
obtained by pouring the reaction mixture in ice cold water, and then filtration. It was
crystallized from proper solvent.
O
O
HAr
O
+OH-
O
Ar
O
NHNH2
NH2S
O
N N
Ar
S NH2
Ar = C6H5-, 2-furyl-
(1)(2)
Scheme 13. Reactions of chalcones with thiosemicarbazide
1.4.14 Conversion of Chalcones to Di- and Triphenylquinoline186
Qi et al. reported a seven step procedure for the synthesis of 2,5,7-
triphenylquinoline (8). In the second last (6th) step 5,7-diphenylquinoline (7) was
obtained by heating a mixture containing m-terphenylamine (3.7 mmol), nitrobenzene
(2.78 ml), FeSO4 (11 mmol), glycerol (60 mmol), conc. H2SO4 (3 ml) and glacial
acetic acid (3.33 ml) at 145 ºC for 4 h. After work up 33% yield of 5,7-
diphenylquinoline (7) was obtained. Finally, 5,7-diphenylquinoline (7) was added to a
solution of phenyl lithium in THF and the mixture was refluxed for 4 h.. The 2,5,7-
triphenylquinoline (8) was obtained (34.8%) after work up.
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Chapter -1 Introduction & Literature Survey
38
HPh
O
+ OH-
(1) (2)
CH3
O
Ph
OOO
OEt
O
COOEt
Ph
(3)
O
H2NOH.HCl
NOH
NH2
AcCl/Ac2O
Py
(4) (5) (6)
N N
PhLiGlycerol
PhNO2
(7) (8)
Scheme 14. Synthesis of 5,7-diphenylquinoline and 2,5,7-triphenylquinoline from
chalcones
1.4.15 Conversion of Chalcones to Chromones & Chromanones187
Prakash et al. reported the synthesis of 2,3-dimethoxy-3-hydroxy-2-(1-phenyl-
3-aryl-4-pyrazolyl)chromanones (5) by the oxidation of 3-hydroxy-2-(1-phenyl-3-
aryl-4-pyrazolyl)chromones (4) using IDB (iodobenzene diacetate) in MeOH, which
in turn were prepared by the cyclization of pyrazolyl derivatives of 2-
hydroxychalcone (3) with H2O2 in KOH─MeOH.
+
(1) (2)
CH3
OH
O
NN
O
Ph
H Ar
KOH-MeOH
THF
OH
O
N
N
Ar
Ph
(3)
H2O2 KOH-MeOH
N
N
O
O
OH
Ph
ArIBD
MeOH
N
N
O
O
OH
Ph
Ar
OMe
OMe
(4)(5)
Ar = a, C6H5; b, 4-MeC 6H4; c, 4-OMeC 6H4; d, 4-ClC 6H4; e, 4-BrC6H4; f, 4-FC 6H4; g, 4-NO 2C6H4
Scheme 15. Conversion of chalcones to chromones & chromanones using IBD
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Chapter -1 Introduction & Literature Survey
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1.4.16 Conversion of Chalcones to 5-aryl-1-isonicotinoyl-3-(pyridin-
2-yl)-4,5-dihydro-1H-pyrazole Derivatives188
Mamolo et al. prepared a series of 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-
dihydro-1H-pyrazole derivatives according to the scheme given below. Chalcones (1)
first treated with hydrazine hydrate to give corresponding 5-aryl-3-(pyridin-2-yl)-4,5-
dihydro-1H-pyrazoles (2). Solution of (2) in ethanol was mixed with isonicotinoyl
bromoacetyl chloride (in DCM) at r. t. To this solution triethylamine was added
dropwise and allowed to stir for another 3 h. The final product (3) was obtained by
filtration and recrystallized from ethanol.
O
H
N
O
+N
O(1)
(2)
NNH
N
(3)
NN
N
O
N
N
Cl
O
NH2NH2.H2O
R
R
R R
Scheme 16. Synthesis of 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-dihydro-1H-
pyrazole derivatives of chalcones
1.4.17 Conversion of Chalcones to Pyrazolines by Ultrasound
Irradiation189
Li et al. introduced an improved and efficient method for the ring pyrazoline
ring insertion reaction on chalcone moiety. Owing to the extensive use of ultrasound
in synthetic organic chemistry, they employed this technique to synthesize
pyrazolines. A series of 1,3,5-triaryl-2-pyrazolines was prepared by treating different
chalcones with phenylhydrazine hydrochloride in high yields of 83-96%. The reaction
was carried out at 28-36 ºC for 1.5-2 h in CH3COONa-CH3COOH aqueous soln. The
ultrasound frequency was adjusted at 25 kHz in most cases.
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Chapter -1 Introduction & Literature Survey
40
(1) (2)
O
Ar1 Ar2
+
NH NH2.HCl N
N
Ar1
Ar2
(3)
CH3COONa-CH3COOH
H2O/ U.S.
Ar1 Ar2
a. C6H5 4-CH3OC6H4
b. C6H5 4-CH3C6H4
c. C6H5 C6H5
d. C6H5 4-ClC6H4
e. C6H5 3-ClC6H4
f. C6H5 2-ClC6H4
g. C6H5 3-BrC6H4
h. C6H5 4-O2NC6H4
i. 4-ClC6H4 C6H5
j. 3-O2NC6H4 C6H5
Scheme 17. Synthesis of 1,3,5-triaryl-2-pyrazolines under ultrasonic irradiations
1.4.18 Reaction of Chalcones with Pyridine-2-carboxamidrazone190
Mamolo et al. reported the synthesis of three series of N1-[1-[3-aryl-1-
(pyridine-2-, 3-, or 4-yl)-3-oxo]propyl]-2-pyridinecarboxamidrazones (2a-t) by
stirring a mixture of different chalcones (1a-t) at r. t. in ethanol with 2-
pyridinecarboxamidrazone, which in turn was prepared by direct reaction of
hydrazine with 2-cyanopyridine.
+
(1a-t)
Het
O
H
O
Het
O
R R
N CN
NH2NH2
N
NH
NH NH2
ONH
Het
NH
NHN
R
(2a-t)
Het = 2-pyridyl, 3-pyridyl, 4-pyridyl
R = H, 3-Cl, 4-Cl, 3,4-Cl2, 3-Me, 4-Me, 4-Ph
Scheme 18. Synthesis of pyridine-2-carboxamidrazone from chalcones
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Chapter -1 Introduction & Literature Survey
41
1.4.19 Reaction of Chalcones with 4,5,6-Triaminopyrimidine191
Insuasty et al. synthesized a series of 4-amino-6-aryl-8-(1,3-benzodioxol-5-
yl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines (4a-f) and 4-amino-8-aryl-6-(1,3-
benzodioxol-5-yl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines (5a-f) by treatment
under microwave irradiation of equimolar quantity of 4,5,6-triaminopyrimidin 1 with
two series of chalcones 2a-f and 3a-f. DMF was used as a catalyst. Microwaves were
irradiated for 2-5 min at a power range of 100-300 W.
N
N
NH2
NH2
NH2
O
O
O
R
O
O
O
R(2a-f) (3a-f)
1
N
NH
N
N
NH2
O
O
R
N
NH
N
N
NH2
O
O
R(4a-f) (5a-f)
R = a, NO2; b, Cl; c, Br; d, H; e, Me; f, OMe
Scheme 19. Synthesis of novel derivatives of 8,9-dihydro-7H-pyrimido[4,5-
b][1,4]diazepines
1.4.20 Synthesis of Coumarinyl Derivatives of Chalcones192
Trivedi et al. reported an improved and rapid synthesis of coumarinyl
derivatives of chalcones. For this purpose, malonic acid was treated with substituted
phenols in the presence of ZnCl2 and POCl3, to yield substituted coumarins, which
were then acetylated using POCl3 and glacial acetic acid. Finally the prepared
acetylcoumarins were treated with different aromatic aldehydes to give the title
compounds. Chalcone synthesis was different in the way that CHCl3 was used as
solvent unlike conventional solvents MeOH and EtOH and a mild organic base
piperidine was used instead of NaOH or KOH.
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Chapter -1 Introduction & Literature Survey
42
+
OHC
R
(4a-i) and (5a-i)
OH
R4
R3
R2
R1
COOH
COOH
(1)
O
R1
R2
R3
R4
OH
O
glacial acetic acid POCl3
O
R1
R2
R3
R4
OH
O
COCH3
O
R1
R2
R3
R4
OH
O
O
R
(2)
(3)
CHCl3, piperidine, 80 °C
Anhydrous ZnCl2
POCl3, 70 °C
R = H, 4-H, 4-OMe, 3-OC6H5, 2-NO2, 3-NO2, 4-N(Me)2, 3-OMe and 4-OH, 3,4-di OMe
4 a-i , R1= Me, R
2= H, R
3= H, R
4= CH(Me)2
5 a-i , R1= H, R
2= Cl, R
3= Me, R
4= H
Scheme 20. Synthesis of coumarinyl derivatives of chalcones
1.5 Methods of Chalcone Synthesis
A variety of methods are available for the synthesis of chalcones. A few are
being discussed here, which are most efficient, convenient and give high yield in
shorter reaction time.
1.5.1 Conventional Method─Claisen-Schmidt Reaction193
Claisen-Schmidt condensation is a conventional and convenient method for
the synthesis of chalcones. In this reaction equimolar quantities of substituted
aromatic aldehydes are condensed with substituted aromatic ketones in aqueous
alcoholic alkali. The reaction is usually carried out in the temperature range of 20-
50ºC, and the reaction time is 12-15 hours. Some other condensing agents are also
employed e.g. alkali metal alkoxide, magnesium tert-butoxide, hydrogen chloride,
anhydrous aluminium chloride, boron trifluoride, phosphorus oxychloride, boric
anhydride, amino acids, borax and organometallic compounds (e.g. CdEt2 in butyl
ether)
1.5.2 Microwave Assisted Synthesis of Chalcones194
Reddy et al. reported the synthesis of chalcones by microwave irradiations
using domestic household oven (600 W) in high yields and very short reaction time as
compared to that needed under thermal conditions. In this reaction catalytic amount of
ZnCl2. The results are given in table 3.
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Chapter -1 Introduction & Literature Survey
43
(1) (2)
O
Ph CH3 +
CHO
R (3a-e)
ZnCl2
MW
O
Ph
R
R : a= H; b=Cl; c= OMe; d= Me; e= NO2
Scheme 21. Synthesis of chalcones under MW irradiations
Table 3. Experimental results of MW irradiation synthesis of chalcones
3 R Time (min) Yield (%)
a H 5 85
b Cl 3 82
c OCH3 3 90
d CH3 4 87
e NO2 5 85
1.5.3 Ultrasound Irradiation Synthesis of Chalcones195
Li et al. reported the synthesis of chalcones under ultrasound irradiation, using
catalyst pulverized KOH or KF-Al2O3. The results showed that the yield obtained in
case KOH was 52-97% while those in KF-Al2O3 was found to be 83-98%.
(1) (2)
+
(3a-k)
O
Ph Ar
Ar : a= C6H5; b= 4-MeOC 6H4; c= 3,4-(OCH 2O)C6H3; d= 3-O2NC6H4; e= 4-ClC 6H4
HAr
O
CH3Ph
O
f= 3-ClC 6H4; g= 4-MeC 6H4; h= 2,4-Cl 2C6H3; i= 4-O2NC6H4; j= 4-Me 2NC6H4; k= C6H5CH=CH
KF-Al2O3 or KOH
U. S.
Scheme 22. Synthesis of chalcones under ultrasonic irradiations
Moreover, this procedure needs less reaction time along with easier work-up. The
reaction temperatures were between 20-45 ºC
1.5.4 Synthesis of Chalcones Using a Solid Base Catalyst196
Kantam and coworkers introduced a new catalyst Mg-Al-OtBu hydrotalcite
(HT-OtBu), for the synthesis of chalcones. This new catalyst was designated as a solid
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Chapter -1 Introduction & Literature Survey
44
base. The advantage of this catalyst over others is that it gives higher yields and
proceeds with faster rates. The results are given in table 4.
(1) (2)
O
Ar2
CH3+
Ar1
O
H
(3a-l)
Ar2
Ar1
OHT-OtBu catalyst
Toluene, reflux
Scheme 23. Synthesis of chalcones HT-OtBu catalyst
Table 4. Experimental results of synthesis of chalcones using HT-OtBu catalyst
3 Ar1 Ar
2 Time (h) Yield (%)
a C6H5 C6H5 3.5 90
b C6H5 C4H3N 8.0 77
c C6H5 C8H8 5.0 88
d C6H5 4-MeC6H4 2.0 85
e C6H5 4-OMeC6H4 2.0 91
f 4-OmeC6H4 C6H5 1.5 92
g C4H3O C6H5 1.0 92
h 4-ClC6H4 C6H5 5.0 90
i C6H5 4-ClC6H4 2.0 87
j 3-OmeC6H4 C6H5 1.5 91
k 3-BrC6H4 C6H5 2.0 93
l 4-OphC6H4 C6H5 2.0 91
Other advantages of this procedure are; firstly there is no aldol-type by-
product has been observed, and secondly the catalyst can be recycled from the
reaction mixture by an easy procedure and can be reused at least three times.
1.5.5 Synthesis of Chalcones Using PTC197
Basaif et al. proposed a stereoselective synthesis of chalcones in water as
environmental friendly solvent. Excellent yields were obtained in the presence of a
phase transfer catalyst (PTC) cetyltrimethylammonium bromide (CTAB). Three
different series of chalcones were synthesized by employing three hetarylketones: 2-
Acetylpyrrole, 2-Acetylthiophene and 2-Acetylpyridine and a variety of aromatic
aldehydes. The yields were 62-95%.
(1a-c) (2)
O
Ar1
CH3
+Ar
2
O
H
(3a-h)
Ar1 Ar
2
O
(4a-h)
(5a-e)Ar1: a= 2-Acetylpyrrol; b= 2-Acetylthiophene; c= 2-Acetylpyridine
NaOH (2%), r. t.
CTAB
Scheme 24. Synthesis of chalcones using PTC
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Chapter -1 Introduction & Literature Survey
45
This method offers many significant advantages over the conventional
methods:
i) Faster rates
ii) Higher yields
iii) No side reactions
iv) Stereo-selectivity of product
v) Safe, neat and simple methodology
vi) Cheap and environmental friendly solvent
vii) Easier work-up and lower reaction temperature
viii) Alkoxides substituted aq. Alkali metal hydroxides
1.6 Aim of the Project
In the last two decades, chalcones have appeared as an effective class of biologically
active compounds. Research work is extensively being done throughout the world, in
order to search for the new biologically active chalcones. The aim of this project is to
synthesize novel biologically active heterocyclic chalcones, which might prove to be
more active and cheaper therapeutic agents than those of conventional ones. Literature
studies have strongly revealed the fact that chalcone derivatives (natural or synthetic)
possess a broad spectrum of biological activities including anti-inflammatory,198
antifungal,199
antioxidant,200
antimalarial,201
antituberculosis,202
analgesic,203
antitumor,204
anticancer,205
antiviral,206
anti-AIDS207
and antileishmanial agents.208
Structures of two chalcone drugs sofalcone209
and sophoradin210
are given in the
foolowing Figure 4.
OO
O
OH
O
CH3CH3 O
CH3CH3
OOH
OH
OH
CH3
CH3 CH3
CH3
CH3 CH3
Sofalcone (anti-ulcer) Sophoradin (a chinese herbal medicine)
Figure 4. Structures of chalcone based drugs
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Chapter -1 Introduction & Literature Survey
46
Quinolines and their derivatives, which represent a major class of
heterocycles,211
are widely found in natural products212
and drugs213-215
They exhibit
significant role in medicinal chemistry. Several quinoline derivatives have been
reported to exhibit bactericidal,216
antimalarial,217
antiallergenic,218
and anti-
inflammatory219
properties. Some of the famous antimalarial drugs, containing
quinoline ring system; available in the market are plasmoquine,220
primaquine and
chloroquine.221
Many quinoline derivatives are found to possess anticancer and
antitumor activities.222
A common anticancer drug (OSI-930) is based on quinolyl-
thienyl system (Figure 5).223
Among the quinolines, 2-chloro-3-formylquinolines find
an important place in synthetic organic chemistry, as these are key intermediates for
further β-annelation of a wide variety of ring systems and for the inter conversions of
many functional groups.224
Quinoline-based chalcones have been reported to possess
antimalarial activity.225
N
NHN
Cl N
NH
SNH
OO
F
F
F
Chloroquine (Antimalarial) OSI-930 (Anticancer)
Figure 5. Structures of quinoline based drugs
In the present work, various substituted 2-chloro-3-formylquinoline nuclei and
chalcone functionality have been incorporated in a single molecule (1a-k, 2a-k, 3a-s
and 4a-s).
Similarly piperidine nucleus is frequently recognized in the structure of
numerous naturally occuring alkaloids,226
pharmaceutical, agrochemicals and
synthetic intermediate with interesting biological, physical and pharmacological
properties like neuroleptic, antihypertensive, antiinflammatory, antitumor, anti-HIV
and anticonvulsant activities.227
A very large number of compounds have been
prepared for testing as local anestheties, the structure of which were patterned after
cocaine and contained the piperidine nucleus.228
Other reported biological and
enzyme inhibition activities of piperidine derivatives are antibacterial,229
antifungal,230
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Chapter -1 Introduction & Literature Survey
47
antimalarial,231
antioxidant232
antiestrogenic,233
antidepressant,234
anticancer235
and
cytotoxic activities.236
In view of the biological properties, a series of piperidyl
chalcones (9a-l) is also prepared. Two very common drugs used in the treatment of
alzheimer's disease237
and schizophrenia238
are given in the Figure 6.
N
N
N
O
N
O
O
O
Ampalex (alzheimer) CX-546 (schizophrenia)
Figure 6. Structures of two piperidine-based drugs
Thiophene and its derivatives find applications in the pharmaceutical area over
a wide range of drug types.239
They are of current interest due to their wide spectrum
of pharmacological properties. Some of the common biological activities shown by
thiophene derivatives include antibacterial,240,241
antifungal,240,241
anti-
inflammatory,242
anticancer243
and antitumor244
activities. The structures of some
thiophene-based drugs used as antiasthmatic245
(ketotifen), antifungal246
(tioconazole)
and non-steroidal anti-inflammatory247
drug (tenoxicam) are given in figure 7.
S
O
N
CH3
Cl
Cl
O
N
N
S
Cl
N OH
NH
O
SN
S
CH3
OO
Ketotifen (Antiasthmatic) Tioconazole (Antifungal) Tenoxicam (NSAID)
Figure 7. Structures of some thiophene based drugs
Looking at such a significant role of thiophene derivatives in the field of
pharmaceutical chemistry, we used a variety of substituted aetylthiophenes to be
condensed with various heteroaromatic aldehydes to form libraries of heterocyclic
chalcones.
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Chapter -1 Introduction & Literature Survey
48
On the other hand Pyrazoline derivat have been reported to possess a
widespread range of biological activities like antibacterial,248
antifungal,249
antidepressant,250
antitumor,251
antimicrobial,252
anti-inflammatory,253
molluscicidal
activity,254
antiamoebic,255
anticonvulsant256
activities. One of the most famous
pyrazole-based drugs used as a non-steroidal anti-inflammatory drug (NSAID) is
celecoxib257
and a poisoning treatment drug (i.e. antidote) is fomepizole258
(Figure 8).
Considerable attention has been focused on the pyrazoline family in the last two
decades. Among various pyrazoline derivativs, 2-pyrazolines seem to be the most
frequently studied pyrazoline type compounds.259
N
N
S
NH2
O
O
F F
F
NH
N
CH3
celecoxib (NSAID) fomepizole (antidote)
Figure 8. Structures of some thiophene based drugs
This precedent for broad bioactivity profiles for these different heterocyclic
pharmacophores led us to perceive that fusion of quinolyl and piperidyl chalcones
with pyrazole nuclei, may result in new bioactive molecules which might exhibit
enhanced biological activities. For this purpose, the prepared chalcones were refluxed
with hydrazine hydrate in ethanol to yield five series of new 2-pyrazoline derivatives
of chalcones (5a-k, 6a-k, 7a-k, 8a-k and 10a-l) based on quinolyl, piperidyl and
thienyl ring systems. In the end all the compounds were tested for their antimicrobial,
antileishmanial anti-HIV-1 and cytotoxic activities.
A short account of research work is being presented here in the field of
synthetic organic chemistry.
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Chapter -1 Introduction & Literature Survey
49
1.7 Plan of Work and Experimental Schemes
The synthesis of biologically active, novel heterocyclic chalcones consists of
the following phases:
I) Thorough literature survey, in order to design various experimental
schemes.
II) Purchase of the chemicals according to the proposed schemes.
III) Synthesis of the heteroaromatic precursors: substituted 2-chloro-3-
formylquinolines i.e. 1, 2, 3 and 4 (scheme-I, Figure 4) and 4-
piperidin-1-ylbenzaldehyde i.e. 9 (scheme-III, Figure 6).
IV) Condensation of the prepared precursors with various aromatic and
heteroaromatic ketones in the presence of a base to yield new
chalcones, as given in the scheme-I and scheme-III.
V) Pyrazoline ring insertion on the chalcone-moiety using hydrazine
hydrate in ethanol, as given in scheme-II (Figure 5) and scheme-IV
(Figure 7).
VI) Screening of all the prepared compounds (chalcones and their
pyrazoline derivatives) for various biological activities.
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Chapter -1 Introduction & Literature Survey
50
1.7.1 Scheme─I
(1) R1= CH 3 R
2R
3= H
NH2
R1
R2
R3 AcOH
o-H3PO4
NH
R1
R2
R3
O
CH3
POCl3
DMF
N
H
Cl
R3
R2
R1
O
(2) R2= CH 3 R
1R
3= H
(3) R3= CH 3 R
1R
2= H
(4) R3= OCH 3 R
1R
2= H
N
H
Cl
R3
R2
R1
O
NaOH/EtOH
r. t.N Cl
R3
R2
R1
O
Ar
(1a-k) R1= CH 3 R
2R
3= H
(2a-k) R2= CH 3 R
1R
3= H
(3a-s) R3= CH 3 R
1R
2= H
(4a-s) R3= OCH 3 R
1R
2= H
Ketones Ar Ketones Ar
a Thien-3-yl k 5-I-thien-2-yl
b 3-Me-thien-2-yl l 1H-pyrrol-2-yl
c 4-Me-thien-2-yl m 5-Me-furan-2yl
d 5-Me-thien-2-yl n 2,5-diMe-furan-3-yl
e 2,5-diMe-thien-3-yl o Benzofuran-2-yl
f 3-Cl-thien-2-yl p 2,3-diH-1,4-benzodioxin-6-yl
g 5-Cl-thien-2-yl q 1-Naphthyl
h 2,5-diCl-thien-3-yl r 2-Naphthyl
i 3-Br-thien-2-yl s 9-Anthryl
j 5-Br-thien-2-yl
+ ArCH3
O
Figure 9. Synthesis of quinolinyl chalcones
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Chapter -1 Introduction & Literature Survey
51
1.7.2 Scheme─II
N
Ar
O
ClR2
R1
R3
NH2NH
2.H
2O
EtOHN ClR
2
R1
NH N
ArR
3
(1a-k) R1= CH 3 R
2R
3= H
(2a-k) R2= CH 3 R
1R
3= H
(3a-k) R3= CH 3 R
1R
2= H
(4a-k) R3= OCH 3 R
1R
2= H
(5a-k)
(6a-k)
(7a-k)
(8a-k)
Ketones Ar Ketones Ar
a Thien-3-yl g 5-Cl-thien-2-yl
b 3-Me-thien-2-yl h 2,5-diCl-thien-3-yl
c 4-Me-thien-2-yl i 3-Br-thien-2-yl
d 5-Me-thien-2-yl j 5-Br-thien-2-yl
e 2,5-diMe-thien-3-yl k 5-I-thien-2-yl
f 3-Cl-thien-2-yl
Figure 10. Synthesis of 2-pyrazoline derivatives of chalcones
1.7.3 Scheme─III
NH
NaOH/EtOH
r. t.+ Ar
O
O
H
F+ N
O
H
N
O
H
N
O
Ar
(9)
(9) (9a-l)
Ketones Ar Ketones Ar
a Thien-2-yl g 3-Cl-thien-2-yl
b Thien-3-yl h 5-Cl-thien-2-yl
c 3-Me-thien-2-yl i 2,5-diCl-thien-3-yl
d 4-Me-thien-2-yl j 3-Br-thien-2-yl
e 5-Me-thien-2-yl k 5-Br-thien-2-yl
f 2,5-diMe-thien-3-yl l 5-I-thien-2-yl
K2CO3, CTAB
DMF, 100 °C
Figure 11. Synthesis of piperidyl chalcones
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Chapter -1 Introduction & Literature Survey
52
1.7.4 Scheme─IV
N
O
Ar
(10a-l)
N
Ar
NH N
+
(9a-l)
NH2 NH2EtOH
reflux
Ketones Ar Ketones Ar
a Thien-2-yl g 3-Cl-thien-2-yl
b Thien-3-yl h 5-Cl-thien-2-yl
c 3-Me-thien-2-yl i 2,5-diCl-thien-3-yl
d 4-Me-thien-2-yl j 3-Br-thien-2-yl
e 5-Me-thien-2-yl k 5-Br-thien-2-yl
f 2,5-diMe-thien-3-yl l 5-I-thien-2-yl
Figure 12. Conversion of piperidyl chalcones to 2-pyrazoline derivatives
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Chapter – 2
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Chapter -2 Experimental
53
Chapter 2
EXPERIMENTAL
2.1 General
All the chemicals (solvents and reagents) were purchased from foreign
companies (Merck, Wako, Sigma/Aldrich and Alpha Aesar), and were used as such
with no further purification and distillation. No local chemical has been used in the
research work. The purity of these chemicals was 98-99.9%.
2.1.1 Substrates and Reagents
Various substituted and unsubstituted aromatic ketones (Alpha Aesar and
Sigma/Aldrich), p-anisidine (Sigma/Aldrich), o-toluidine (Merck), m-toluidine
(Sigma/Aldrich), p-toluidine (Sigma/Aldrich), piperidine (Wako), p-
fluorobenzaldehyde (Wako), were used as received. The reagents used were:
Phosphoryl chloride (Sigma/Aldrich and Merck), Glacial Acetic Acid (Merck),
orthophosphoric Acid (Sigma/Aldrich), Aliquat (Wako) sodium hydroxide (Merck)
and hydrazine (Merck).
2.1.2 Solvents
Analytical grade solvents like N,N-Dimethylformamide (DMF), dimethyl
sulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), ethyl acetate (AcOEt)
chloroform (CHCl3) and n-hexane were used as such without further distillation.
2.1.3 Instruments
Melting points were obtained on Gallenkamp melting point apparatus and were
uncorrected.
IR spectra were recorded in KBr pellets on Perkin Elmer infrared spectrophotometer.
1H NMR spectra were recorded in CDCl3 on Brücker/XWIN NMR (400 MHz) and
TMSwas used as internal standard. Chemical shifts are given in δ (ppm).
Mass spectra were recorded on a Jeol MS Route instrument.
Elemental analyses were performed by C.S.I.C., Madrid Spain and were within ±
0.4% of predicted values for all the compounds.
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Chapter -2 Experimental
54
All the reactions were monitored with the help of pre-coated aluminium TLC plates
(0.2mm, 60 HF254, Merck).
2.2 Methods of Preparation of Precursors for Chalcones
2.2.1 N-acetylation of Substituted Anilines260
To 0.1 mol of substituted aniline, 0.2 mol of glacial acetic acid was added in a
250 ml flask. To this mixture, catalytic amount of orthophosphoric acid was added
and the mixture was refluxed for 5-6 hrs. At the completion of the reaction (TLC
monitoring), the mixture was poured in ice-cold water and stirred well. The crude
product was precipitated out at once. The precipitates were filtered and washed with
cold water. The pure product was obtained by recrystallization from boiling water.
2.2.2 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-A;
Conventional Thermal Method)261
Vilsmeier reagent was prepared by adding POCl3 (107.4 g, 64.4 mL, 0.70 mol)
dropwise in DMF (18.26 g, 19.2 mL, 0.25 mol) at 0 ºC with constant stirring. To this
solution was added the acetanilide (0.10 mol) and the mixture was stirred (15 min) at
room temperature. Then this mixture was stirred at 70-80 ºC for the time period as
mentioned in table-5. After the completion of the reaction (TLC monitoring), the
mixture was poured in ice cold water (500 mL) and stirred vigorously (30 min) at 0-
10 °C. The 2-Chloro-3-quinolinecarbaldehyde was precipitated out, which was
filtered off, washed with water (200 mL), dried and recrystallised from ethyl acetate.
2.2.3 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-B;
Microwave Irradiation Method)
Vilsmeier reagent was prepared by adding POCl3 (107.4 g, 64.4 mL, 0.70 mol)
dropwise in DMF (18.26 g, 19.2 mL, 0.25 mol) at 0 ºC with constant stirring. To this
solution was added the acetanilide (0.10 mol) and the mixture was stirred (15 min) at
room temperature. Then this mixture was subjected to microwave irradiation at 350
W for the time period as mentioned in table-5. After the completion of the reaction
(TLC monitoring), the mixture was poured in ice cold water (500 mL) and stirred
vigorously (30 min) at 0-10 °C. The 2-Chloro-3-quinolinecarbaldehyde was
precipitated out, which was filtered off, washed with water (200 mL), dried and
recrystallised from ethyl acetate.
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Chapter -2 Experimental
55
Table 5. A comparison of the methods producing chloroquinolinecarbaldehyde, in terms of yields & reaction kinetics
Thermal Condition Microwave Irradiation
Entry Acetanilide 2-Chloro-3-formylquinoline (70-80°C) (350W)
Reaction Yield Reaction Yield
(R) (R) Time/hr (%) Time/sec (%)
1 2-Me 8-Me 15.5 67 100 82
2 3-Me 7-Me 6 66 30 79
3 4-Me 6-Me 16 70 120 88
4 4-OMe 6-OMe 16 56 120 85
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Chapter -2 Experimental
56
2.2.4 Method for N-arylation of Piperidine 262 (9) (Scheme─III)
A mixture of piperidine (50 mmol, 4.25 g, 4.93 mL) and para-
fluorobenzaldehyde (50 mmol, 6.205g, 5.275 mL) in DMF (25 mL), was stirred at
100 ºC in the presence of K2CO3 (50 mmol, 6.9 g) and cetyl trimethylammonium
bromide (CTAB, 10 mg). After the completion of reaction (TLC monitoring), the
mixture was poured into ice-cold water (100 mL). Crude product 4-piperidin-1-
ylbenzaldehyde was precipitated out, which was filtered and recrystallized from
methanol.
2.3 General Method for the Synthesis of Quinolinyl
Chalcones (1a-k, 2a-k, 3a-s and 4a-s) (Scheme─I)
A mixture of quinolinecarbaldehyde (1, 2, 3 or 4, 10 mmol) and an aromatic
ketone (a-k or a-s, 10 mmol) in methanol (50 ml) was stirred at room temperature,
followed by dropwise addition of aq. NaOH (4 ml, 10%). The stirring was continued
for 2 h and the reaction mixture was then kept at 0°C (24 h). Subsequently, it was
poured onto ice-cold water (200 ml). The precipitates were collected by filtration,
washed with cold water followed by cold MeOH. The resulting chalcones (1a-k, 2a-
k, 3a-s and 4a-s) were recrystallised from CHCl3.
2.3.1 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-thien-3-ylprop-2-en-
1-one (1a)
N
O
S
Cl
CH3
Yield : 60%
State : Pale yellow solid
M.P. : 128-130°C
IR : υmax(KBr) cm-1
1649 (C=O), 1591 (C=C), 1561 (C=N
of quinoline ring).
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Chapter -2 Experimental
57
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.39 (1H, dd, H4', J = 5.1
Hz, 2.9 Hz), 7.46 (1H, d, Hα, J = 15.6 Hz), 7.47 (1H, t,
H6, J = 7.6 Hz), 7.60 (1H, d, H7, J=7.0 Hz), 7.69 (1H,
d, H5', J = 4.7 Hz, 1.1 Hz), 7.70 (1H, d, H5, J = 6.7 Hz),
8.20 (1H, d, Hβ, J = 15.7 Hz), 8.20 (1H, dd, H2', J = 2.8
Hz, 1.1 Hz), 8.42 (1H, s, H4).
MS : (m/z): 313 (M+, 1.9%), 111 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C17H12NOClS: C, 65.07; H, 3.85;
N, 4.46. Found: C, 65.04; H, 3.78; N, 4.44.
2.3.2 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (1b)
N
O
S
Cl CH3
CH3
Yield : 56%
State : Yellow solid
M.P. : 174-175°C
IR : υmax(KBr) cm-1
1654 (C=O), 1594 (C=C), 1563 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.66-2.76 (s, Me x 2), 7.02 (1H, d, H4', J =
4.9 Hz), 7.41 (1H, d, Hα, J = 15.4 Hz), 7.47 (1H, t, H6, J
= 7.6 Hz), 7.49 (1H, d, H5', J = 5.3 Hz), 7.59 (1H, d,
H7, J = 7.0 Hz), 7.71 (1H, d, H5, J = 8.0 Hz), 8.20 (1H,
d, Hβ, J = 15.4 Hz), 8.40 (1H, s, H4).
MS : (m/z): 327 (M+, 6.74%), 125 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.90; H, 4.27; N, 4.27.
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Chapter -2 Experimental
58
2.3.3 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (1c)
N
O
S
Cl
CH3CH3
Yield : 49%
State : Yellow solid
M.P. : 146-147°C
IR : υmax(KBr) cm-1
1655 (C=O), 1593 (C=C), 1565 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.33-2.76 (s, Me x 2), 7.31 (1H, s, H5'), 7.46
(1H, d, Hα, J = 15.5 Hz), 7.47 (1H, t, H6, J = 7.6 Hz),
7.60 (1H, d, H7, J = 7.0 Hz), 7.70 (1H, d, H5, J = 7.0
Hz), 7.71 (1H, s, H3'), 8.23 (1H, d, Hβ, J = 15.6 Hz),
8.42 (1H, s, H4).
MS : (m/z): 327 (M+, 5.02%), 292 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.85; H, 4.23; N, 4.22.
2.3.4 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (1d)
N
O
S
Cl
CH3
CH3
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Chapter -2 Experimental
59
Yield : 55%
State : Yellow solid
M.P. : 180-181°C
IR : υmax(KBr) cm-1
1652 (C=O), 1596 (C=C), 1563 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.57-2.75 (s, Me x 2), 6.86 (1H, d, H4',
J=3.1 Hz), 7.43 (1H, d, Hα, J = 15.6 Hz), 7.46 (1H, t,
H6, J = 7.7 Hz), 7.59 (1H, d, H7, J = 7.0 Hz), 7.69 (1H,
d, H5, J = 8.2 Hz), 7.72 (1H, d, H3' J = 3.8 Hz), 8.19
(1H, d, Hβ, J = 15.6 Hz), 8.40 (1H, s, H4).
MS : (m/z): 327 (M+, 5.56%), 125 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.86; H, 4.25; N, 4.25.
2.3.5 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dimethylthien-
3-yl)prop-2-en-1-one (1e)
N
O
S
Cl
CH3
CH3CH3 1
Yield : 67%
State : Yellow solid
M.P. : 138-140°C
IR : υmax(KBr) cm-1
1648 (C=O), 1585 (C=C), 1565 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.44-2.75 (s, Me x 3), 7.10 (1H, s, H4'), 7.33
(1H, d, Hα, J = 15.7 Hz), 7.46 (1H, t, H6, J = 7.7 Hz),
7.59 (1H, d, H7, J = 7.0 Hz), 7.68 (1H, d, H5, J = 8.1
Hz), 8.10 (1H, d, Hβ, J = 15.7 Hz), 8.37 (1H, s, H4).
MS : (m/z): 341 (M+, 7.71%), 139 (M
+−C12H9NCl, 100 %).
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Chapter -2 Experimental
60
CHN : Anal. Calculated for C19H16NOClS: C, 66.75; H, 4.72;
N, 4.10. Found: C, 66.66; H, 4.62; N, 4.02.
2.3.6 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (1f)
N
O
S
Cl Cl
CH3
Yield : 73%
State : Yellow solid
M.P. : 162-163°C
IR : υmax(KBr) cm-1
1650 (C=O), 1592 (C=C), 1570 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.07 (1H, d, H4', J = 5.3
Hz), 7.47 (1H, t, H6, J=7.7 Hz), 7.59 (1H, d, H7, J = 7.0
Hz), 7.60 (1H, d, H5', J = 5.3 Hz), 7.71 (1H, d, H5, J =
8.1 Hz), 7.82 (1H, d, Hα, J = 15.5 Hz), 8.24 (1H, d, Hβ,
J = 15.6 Hz), 8.42 (1H, s, H4).
MS : (m/z): 312 (M+−Cl, 40.18%), 145 (M
+−C12H9NCl, 100
%).
CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;
N, 4.02. Found: C, 58.59; H, 3.12; N, 3.98.
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Chapter -2 Experimental
61
2.3.7 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (1g)
N
O
S
Cl
Cl
CH3
Yield : 85%
State : Pale yellow solid
M.P. : 166-168°C
IR : υmax(KBr) cm-1
1656 (C=O), 1598 (C=C), 1572 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.02 (1H, d, H4', J=4.0
Hz), 7.39 (1H, d, Hα, J = 15.5 Hz), 7.48 (1H, t, H6, J =
7.6 Hz), 7.61 (1H, d, H7, J = 7.0 Hz), 7.68 (1H, d, H3', J
= 4.2 Hz), 7.70 (1H, d, H5, J = 8.1 Hz), 8.23 (1H, d, Hβ,
J = 15.6 Hz), 8.41 (1H, s, H4).
MS : (m/z): 312 (M+−Cl, 30.24%), 145 (M
+−C12H9NCl, 100
%).
CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;
N, 4.02. Found: C, 58.55; H, 3.13; N, 3.97.
2.3.8 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dichlorothien-3-
yl)prop-2-en-1-one (1h)
N
O
S
Cl
Cl
ClCH3
Yield : 69%
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Chapter -2 Experimental
62
State : White solid
M.P. : 120-121°C
IR : υmax(KBr) cm-1
1664 (C=O), 1596 (C=C), 1570 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.15 (1H, s, H4'), 7.45 (1H,
d, Hα, J = 15.7 Hz), 7.47 (1H, t, H6, J = 7.7 Hz), 7.61
(1H, d, H7, J = 6.8 Hz), 7.70 (1H, d, H5, J = 8.1 Hz),
8.17 (1H, d, Hβ, J = 15.7 Hz), 8.39 (1H, s, H4).
MS : (m/z): 383 (M+, 1.8%), 179 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C17H10NOCl3S: C, 53.35; H, 2.63;
N, 3.66. Found: C, 53.24; H, 2.55; N, 3.60.
2.3.9 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-3-
yl)prop-2-en-1-one (1i)
N
O
S
Cl Br
CH3
Yield : 86%
State : Yellow solid
M.P. : 210-212°C
IR : υmax(KBr) cm-1
1652 (C=O), 1592 (C=C), 1568 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.16 (1H, d, H4', J = 5.2
Hz), 7.47 (1H, t, H6, J = 7.6 Hz), 7.58 (1H, d, H5', J =
5.2 Hz), 7.60 (1H, d, H7, J = 7.1 Hz), 7.71 (1H, d, H5, J
= 8.0 Hz), 7.81 (1H, d, Hα, J = 15.6 Hz), 8.25 (1H, d,
Hβ, J = 15.5 Hz), 8.44 (1H, s, H4).
MS : (m/z): 393 (M+, 1.0%), 82 (M
+−C13H9NOClBr, 100 %).
CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.98; H, 2.77; N, 3.59.
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Chapter -2 Experimental
63
2.3.10 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-3-
yl)prop-2-en-1-one (1j)
N
O
S
Cl
Br
CH3
Yield : 71%
State : Off white solid
M.P. : 204-206°C
IR : υmax(KBr) cm-1
1653 (C=O), 1588 (C=C), 1566 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.17 (1H, d, H4', J = 4.0
Hz), 7.39 (1H, d, Hα, J = 15.6 Hz), 7.48 (1H, t, H6, J =
7.6 Hz), 7.61 (1H, d, H7, J = 7.1 Hz), 7.63 (1H, d, H3', J
= 4.0 Hz), 7.70 (1H, d, H5, J = 8.0 Hz), 8.23 (1H, d, Hβ,
J = 15.6 Hz), 8.41 (1H, s, H4).
MS : (m/z): 393 (M+, 2%), 82 (M
+−C13H9NOClBr, 100 %).
CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.93; H, 2.75; N, 3.55.
2.3.11 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (1k)
N
O
S
Cl
I
CH3
Yield : 86%
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Chapter -2 Experimental
64
State : Yellow solid
M.P. : 196-198°C
IR : υmax(KBr) cm-1
1649 (C=O), 1596 (C=C), 1565 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.36 (1H, d, H4', J = 3.8
Hz), 7.38 (1H, d, Hα, J = 15.6 Hz), 7.47 (1H, t, H6, J =
7.6 Hz), 7.51 (1H, d, H3', J = 3.9 Hz), 7.61 (1H, d, H7, J
= 7.0 Hz), 7.70 (1H, d, H5, J = 8.1 Hz), 8.23 (1H, d, Hβ,
J = 15.6 Hz), 8.41 (1H, s, H4).
MS : (m/z): 439 (M+, 1%), 82 (M
+−C13H9NOICl, 100 %).
CHN : Anal. Calculated for C17H11NOClSI: C, 46.44; H, 2.52;
N, 3.19. Found: C, 46.39; H, 2.42; N, 3.13.
2.3.12 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-thien-3-ylprop-2-
en-1-one (2a)
N
O
S
ClCH3
Yield : 65%
State : White solid
M.P. : 180-182°C
IR : υmax(KBr) cm-1
1649 (C=O), 1594 (C=C), 1565 (C=N
of quinoline ring);
1H-NMR : (CDCl3) δ: 2.57 (3H, s, Me), 7.39 (1H, dd, H4', J = 5.1
Hz, 2.9 Hz), 7.42 (1H, dd, H5, J = 8.2 Hz, 1.2 Hz), 7.45
(1H, d, Hα, J = 15.7 Hz), 7.69 (1H, dd, H5', J = 5.1 Hz,
1.0 Hz), 7.76 (1H, d, H6, J = 8.3 Hz), 7.79 (1H, s, H8),
8.19 (1H, d, Hβ, J = 15.6 Hz), 8.20 (1H, dd, H2', J = 2.9
Hz, 1.0 Hz), 8.42 (1H, s, H4);
MS : (m/z): 313 (M+, 1.86%), 111 (M
+−C12H9NCl, 100 %).
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Chapter -2 Experimental
65
CHN : Anal. Calculated for C17H12NOClS: C, 65.07; H, 3.85;
N, 4.46. Found: C, 65.03; H, 3.76; N, 4.43.
2.3.13 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (2b)
N
O
S
Cl CH3CH3
Yield : 51%
State : Pale yellow solid
M.P. : 208-210°C
IR : υmax(KBr) cm-1
1653 (C=O), 1594 (C=C), 1563 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.56-2.66 (s, Me x 2), 7.02 (1H, d, H4', J =
4.9 Hz), 7.40 (1H, d, Hα, J = 15.4 Hz), 7.42 (1H, dd, H5,
J = 8.2 Hz, 1.3 Hz), 7.49 (1H, d, H5' J = 4.9 Hz), 7.77
(1H, d, H6, J = 8.6 Hz), 7.78 (1H, s, H8), 8.18 (1H, d,
Hβ, J = 15.4 Hz), 8.40 (1H, s, H4).
MS : (m/z): 327 (M+, 10%), 125 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.92; H, 4.25; N, 4.25.
2.3.14 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (2c)
N
O
S
Cl
CH3
CH3
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Chapter -2 Experimental
66
Yield : 56%
State : Yellow solid
M.P. : 173-174°C
IR : υmax(KBr) cm-1
1655 (C=O), 1594 (C=C), 1564 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.33-2.56 (s, Me x 2), 7.31 (1H, s, H5'), 7.42
(1H, dd, H5, J = 8.2 Hz, 1.3 Hz), 7.44 (1H, d, Hα, J =
15.5 Hz), 7.71 (1H, s, H3'), 7.76 (1H, d, H6, J = 8.3 Hz),
7.79 (1H, s, H8), 8.21 (1H, d, Hβ, J = 15.6 Hz), 8.42
(1H, s, H4).
MS : (m/z): 327 (M+, %), 125 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.85; H, 4.24; N, 4.23.
2.3.15 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (2d)
N
O
S
Cl
CH3
CH3
Yield : 52%
State : Pale yellow solid
M.P. : 173-175°C
IR : υmax(KBr) cm-1
1652 (C=O), 1595 (C=C), 1563 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.56-2.57 (s, Me x 2), 6.86 (1H, d, H4', J =
3.3 Hz), 7.42 (1H, d, Hα, J = 15.6 Hz), 7.43 (1H, dd, H5,
J = 8.2 Hz, 1.2 Hz), 7.71 (1H, d, H3', J = 3.7 Hz), 7.75
(1H, d, H6, J = 8.3 Hz), 7.78 (1H, s, H8), 8.18 (1H, d,
Hβ, J = 15.6 Hz), 8.40 (1H, s, H4).
MS : (m/z): 327 (M+, 3.61%), 125 (M
+−C12H9NCl, 100 %).
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Chapter -2 Experimental
67
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.89; H, 4.26; N, 4.25.
2.3.16 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dimethylthien-
3-yl)prop-2-en-1-one (2e)
N
O
S
Cl
CH3
CH3
CH3
Yield : 70%
State : Yellow solid
M.P. : 183-185 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1590 (C=C), 1565 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.44-2.72 (s, Me x 3), 7.10 (1H, s, H4'), 7.32
(1H, d, Hα, J = 15.7 Hz), 7.41 (1H, dd, H5, J = 8.4 Hz,
1.2 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.78 (1H, s, H8),
8.08 (1H, d, Hβ, J = 15.7 Hz), 8.37 (1H, s, H4).
MS : (m/z): 341 (M+, 10.31%), 306 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C19H16NOClS: C, 66.75; H, 4.72;
N, 4.10. Found: C, 66.65; H, 4.68; N, 4.08.
2.3.17 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (2f)
N
O
S
Cl ClCH3
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Chapter -2 Experimental
68
Yield : 66%
State : Yellow solid
M.P. : 160-162 °C
IR : υmax(KBr) cm-1
1650 (C=O), 1591 (C=C), 1569 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.56 (3H, s, Me), 7.07 (1H, d, H4', J = 5.2
Hz), 7.28 (1H, dd, H5, J = 8.3 Hz, 1.1 Hz), 7.60 (1H, d,
H5', J = 5.2 Hz), 7.77 (1H, d, H6, J=8.6 Hz), 7.82 (1H,
d, Hα, J = 15.5 Hz), 7.96 (1H, s, H8), 8.23 (1H, d, Hβ, J
= 15.5 Hz), 8.42 (1H, s, H4).
MS : (m/z): 348 (M+, 1.8%), 145 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;
N, 4.02. Found: C, 58.53; H, 3.16; N, 3.97.
2.3.18 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (2g)
N
O
S
Cl
Cl
CH3
Yield : 80%
State : Pale yellow solid
M.P. : 170-171 °C
IR : υmax(KBr) cm-1
1656 (C=O), 1598 (C=C), 1570 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.52 (3H, s, Me), 6.92 (1H, d, H4', J = 4.1
Hz), 7.35 (1H, dd, H5, J = 8.3 Hz, 1.2 Hz), 7.39 (1H, d,
Hα, J = 15.6 Hz), 7.57 (1H, d, H3', J = 4.1 Hz), 7.64
(1H, d, H6, J = 8.3 Hz), 7.72 (1H, s, H8), 8.20 (1H, d,
Hβ, J=15.6 Hz), 8.39 (1H, s, H4).
MS : (m/z): 348 (M+, 2.41%), 145 (M
+−C12H9NCl, 100 %).
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Chapter -2 Experimental
69
CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;
N, 4.02. Found: C, 58.57; H, 3.14; N, 3.96.
2.3.19 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dichlorothien-
3-yl)prop-2-en-1-one (2h)
N
O
S
Cl
Cl
Cl
CH3
Yield : 63%
State : Off white solid
M.P. : 163 °C
IR : υmax(KBr) cm-1
1662 (C=O), 1596 (C=C), 1572 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.56 (3H, s, Me), 7.23 (1H, s, H4'), 7.42 (1H,
dd, H5, J = 8.3 Hz, 1.0 Hz), 7.45 (1H, d, Hα, J = 15.7
Hz), 7.76 (1H, d, H6, J = 8.3 Hz), 7.79 (1H, s, H8), 8.15
(1H, d, Hβ, J = 15.7 Hz), 8.39 (1H, s, H4).
MS : (m/z): 383 (M+, 1.7%), 346 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H10NOCl3S: C, 53.35; H, 2.63;
N, 3.66. Found: C, 53.26; H, 2.58; N, 3.67.
2.3.20 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-7-methylquinolin-3-
yl)prop-2-en-1-one (2i)
N
O
S
Cl BrCH3
Yield : 79%
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Chapter -2 Experimental
70
State : Yellow solid
M.P. : 164-165 °C
IR : υmax(KBr) cm-1
1652 (C=O), 1592 (C=C), 1568 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.57 (3H, s, Me), 7.16 (1H, d, H4', J = 5.16
Hz), 7.42 (1H, dd, H5, J = 8.3 Hz, 1.3 Hz), 7.58 (1H, d,
H5', J = 5.2 Hz), 7.78 (1H, d, H6, J = 8.6 Hz), 7.82 (1H,
d, Hα, J = 15.6 Hz), 7.79 (1H, s, H8), 8.23 (1H, d, Hβ, J
= 15.5 Hz), 8.43 (1H, s, H4).
MS : (m/z): 393 (M+, 1.5%), 82 (M
+−C13H9NOClBr, 100 %).
CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.94; H, 2.76; N, 3.56.
2.3.21 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-7-methylquinolin-3-
yl)prop-2-en-1-one (2j)
N
O
S
Cl
Br
CH3
Yield : 75%
State : Yellow solid
M.P. : 162-164 °C
IR : υmax(KBr) cm-1
1653 (C=O), 1588 (C=C), 1566 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.56 (3H, s, Me), 7.16 (1H, d, H4', J = 4.0
Hz), 7.38 (1H, d, Hα, J = 15.6 Hz), 7.42 (1H, dd, H5, J =
8.3 Hz, 1.0 Hz), 7.63 (1H, d, H3', J = 4.0 Hz), 7.76 (1H,
d, H6, J = 8.3 Hz),7.79 (1H, s, H8), 8.21 (1H, d, Hβ, J =
15.6 Hz), 8.40 (1H, s, H4).
MS : (m/z): 393 (M+, 1.5%), 82 (M
+−C13H9NOClBr, 100 %).
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Chapter -2 Experimental
71
CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.95; H, 2.79; N, 3.56.
2.3.22 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (2k)
N
O
S
Cl
I
CH3
Yield : 90%
State : Deep yellow solid
M.P. : 164-165 °C
IR : υmax(KBr) cm-1
1650 (C=O), 1596 (C=C), 1565 (C=N
of quinoline ring).
1H-NMR : (CDCl3) δ: 2.56 (3H, s, Me), 7.36 (1H, d, H4', J = 4.0
Hz), 7.37 (1H, d, Hα, J = 15.5 Hz), 7.42 (1H, dd, H5, J =
8.4 Hz, 1.2 Hz), 7.50 (1H, d, H3', J = 4.0 Hz), 7.76 (1H,
d, H6, J = 8.3 Hz), 7.79 (1H, s, H8), 8.21 (1H, d, Hβ, J =
15.6 Hz), 8.40 (1H, s, H4).
MS : (m/z): 439 (M+, 1.5%), 82 (M
+−C13H9NOICl, 100 %).
CHN : Anal. Calculated for C17H11NOClSI: C, 46.44; H, 2.52;
N, 3.19. Found: C, 46.44; H, 2.43; N, 3.18.
2.3.23 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-thien-3-ylprop-2-
en-1-one (3a)
N
O
S
Cl
CH3
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Chapter -2 Experimental
72
Yield : 72%
State : Pale yellow solid
M.P. : 183-185 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1592 (C=C).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.39 (1H, dd, H4', J=2.8
Hz), 7.44 (1H, d, Hα, J=15.7 Hz), 7.6 (1H, d, H7, J=8.6
Hz), 7.62 (1H, s, H5), 7.70 (1H, d, H5', J=4.7 Hz), 7.91
(1H, d, H8, J=8.5 Hz), 8.18 (1H, d, Hβ, J=15.8 Hz), 8.20
(1H, dd, H2', J=2.2 Hz), 8.36 (1H, s, H4).
MS : (m/z): 313 (M+, 7.9%), 278 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H12NOClS: C, 65.07; H, 3.85;
N, 4.46. Found: C, 65.02; H, 3.75; N, 4.41.
2.3.24 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (3b)
N
O
S
Cl CH3
CH3
Yield : 53%
State : Pale yellow solid
M.P. : 172-173 °C
IR : υmax(KBr) cm-1
1654 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 2.45-2.66 (s, Me x 2), 7.02 (1H, d, H4',
J=4.9 Hz), 7.40 (1H, d, Hα, J=15.4 Hz), 7.49 (1H, d,
H5', J=4.9 Hz), 7.58 (1H, dd, H7, J=8.6 Hz), 7.64 (1H,
s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.18 (1H, d, Hβ,
J=15.4 Hz), 8.35 (1H, s, H4).
MS : (m/z): 327 (M+, 25.8%), 292 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.89; H, 4.29; N, 4.25.
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Chapter -2 Experimental
73
2.3.25 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (3c)
N
O
S
Cl
CH3
CH3
Yield : 45%
State : White solid
M.P. : 150 °C
IR : υmax(KBr) cm-1
1656 (C=O), 1593 (C=C).
1H-NMR : (CDCl3) δ: 2.25-2.48 (s, Me x 2), 7.18 (1H, s, H5'), 7.44
(1H, d, Hα, J=15.5 Hz), 7.48 (1H, dd, H7, J=8.6 Hz),
7.51 (1H, s, H5), 7.71 (1H, s, H3'), 7.83 (1H, d, H8,
J=8.5 Hz), 8.21 (1H, d, Hβ, J=15.6 Hz), 8.41 (1H, s,
H4).
MS : (m/z): 328 (M+, 11.4%), 125 (M
+−C12H9NCl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.87; H, 4.24; N, 4.26.
2.3.26 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (3d)
N
O
S
Cl
CH3
CH3
Yield : 44%
State : Bright yellow solid
M.P. : 198 °C
IR : υmax(KBr) cm-1
1652 (C=O), 1596 (C=C).
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Chapter -2 Experimental
74
1H-NMR : (CDCl3) δ: 2.54-2.57 (s, Me x 2), 6.87 (1H, d, H4',
J=3.6 Hz), 7.42 (1H, d, Hα, J=15.6 Hz), 7.58 (1H, dd,
H7, J=8.6 Hz), 7.62 (1H, s, H5), 7.71 (1H, d, H3' J=3.8
Hz), 7.90 (1H, d, H8, J=8.6 Hz), 8.18 (1H, d, Hβ, J=15.6
Hz), 8.35 (1H, s, H4).
MS : (m/z): 327 (M+, 12.1%), 292 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NOClS: C, 65.95; H, 4.30;
N, 4.27. Found: C, 65.89; H, 4.27; N, 4.22.
2.3.27 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dimethylthien-
3-yl)prop-2-en-1-one (3e)
N
O
S
Cl
CH3
CH3
CH3
Yield : 67%
State : Pale yellow solid
M.P. : 128-130 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1585 (C=C).
1H-NMR : (CDCl3) δ: 2.44-2.72 (s, Me x 3), 7.10 (1H, s, H4'), 7.33
(1H, d, Hα, J=15.7 Hz), 7.58 (1H, dd, H7, J=8.6 Hz),
7.62 (1H, s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.08 (1H,
d, Hβ, J=15.7 Hz), 8.33 (1H, s, H4).
MS : (m/z): 341 (M+, 48.2%), 306 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C19H16NOClS: C, 66.75; H, 4.72;
N, 4.10. Found: C, 66.61; H, 4.63; N, 4.05.
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Chapter -2 Experimental
75
2.3.28 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (3f)
N
O
S
Cl Cl
CH3
Yield : 74%
State : Bright yellow solid
M.P. : 184-186 °C
IR : υmax(KBr) cm-1
1650 (C=O), 1592 (C=C).
1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 7.07 (1H, d, H4', J=5.2
Hz), 7.50 (1H, d, H5', J=5.2 Hz), 7.59 (1H, dd, H7,
J=8.5 Hz), 7.64 (1H, s, H5), 7.82 (1H, d, Hα, J=15.6
Hz), 7.90 (1H, d, H8, J=8.6 Hz), 8.22 (1H, d, Hβ, J=15.5
Hz), 8.37 (1H, s, H4).
MS : (m/z): 347 (M+, 4.2%), 312 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;
N, 4.02. Found: C, 58.54; H, 3.16; N, 3.99.
2.3.29 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (3g)
N
O
S
Cl
Cl
CH3
Yield : 89%
State : Bright yellow solid
M.P. : 180 °C
IR : υmax(KBr) cm-1
1656 (C=O), 1598 (C=C).
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Chapter -2 Experimental
76
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.03 (1H, d, H4', J=4.0
Hz), 7.39 (1H, d, Hα, J=15.6 Hz), 7.60 (1H, dd, H7,
J=8.6 Hz), 7.63 (1H, s, H5), 7.68 (1H, d, H3', J=4.0 Hz),
7.91 (1H, d, H8, J=8.5 Hz), 8.21 (1H, d, Hβ, J=15.6 Hz),
8.36 (1H, s, H4).
MS : (m/z): 347 (M+, 6.9%), 312 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;
N, 4.02. Found: C, 58.57; H, 3.13; N, 3.99.
2.3.30 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dichlorothien-
3-yl)prop-2-en-1-one (3h)
N
O
S
Cl
Cl
Cl
CH3
Yield : 53%
State : Pale yellow solid
M.P. : 128 °C
IR : υmax(KBr) cm-1
1664 (C=O), 1595 (C=C).
1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 7.15 (1H, s, H4'), 7.46 (1H,
d, Hα, J=15.7 Hz), 7.60 (1H, dd, H7, J=8.6 Hz), 7.63
(1H, s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.14 (1H, d, Hβ,
J=15.7 Hz), 8.34 (1H, s, H4).
MS : (m/z): 383 (M+, 5.7%), 346 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H10NOCl3S: C, 53.35; H, 2.63;
N, 3.66. Found: C, 53.22; H, 2.58; N, 3.62
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Chapter -2 Experimental
77
2.3.31 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-6-methylquinolin-3-
yl)prop-2-en-1-one (3i)
N
O
S
Cl Br
CH3
Yield : 64%
State : Bright yellow solid
M.P. : 189-191 °C
IR : υmax(KBr) cm-1
1650 (C=O), 1591 (C=C).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.16 (1H, d, H4', J=5.16
Hz), 7.58 (1H, d, H5', J=5.1 Hz), 7.59 (1H, dd, H7,
J=8.6 Hz), 7.65 (1H, s, H5), 7.83 (1H, d, Hα, J=15.5
Hz), 7.91 (1H, d, H8, J=8.6 Hz), 8.22 (1H, d, Hβ,
J=15.5 Hz), 8.38 (1H, s, H4).
MS : (m/z): 393 (M+, 5.1%), 356 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.96; H, 2.79; N, 3.58.
2.3.32 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-6-methylquinolin-3-
yl)prop-2-en-1-one (3j)
N
O
S
Cl
Br
CH3
Yield : 55%
State : Pale brown solid
M.P. : 160-161 °C
IR : υmax(KBr) cm-1
1653 (C=O), 1588 (C=C).
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Chapter -2 Experimental
78
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.10 (1H, d, H4', J=4.0
Hz), 7.17 (1H, d, H3', J=4.0 Hz), 7.38 (1H, d, Hα,
J=15.6 Hz), 7.60 (1H, dd, H7, J=8.5 Hz), 7.63 (1H, s,
H5), 7.91 (1H, d, H8, J=8.3 Hz), 8.21 (1H, d, Hβ, J=15.6
Hz), 8.36 (1H, s, H4).
MS : (m/z): 393 (M+, 10.9%), 358 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,
2.82; N, 3.57. Found: C, 51.98; H, 2.77; N, 3.56.
2.3.33 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (3k)
N
O
S
Cl
I
CH3
Yield : 87%
State : Pale yellow solid
M.P. : 178 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1596 (C=C).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.36 (1H, d, H4', J=3.9
Hz), 7.37 (1H, d, Hα, J=15.5 Hz), 7.50 (1H, d, H3',
J=3.9 Hz), 7.59 (1H, dd, H7, J=8.7 Hz), 7.62 (1H, s,
H5), 7.90 (1H, d, H8, J=8.5 Hz), 8.20 (1H, d, Hβ, J=15.6
Hz), 8.35 (1H, s, H4).
MS : (m/z): 439 (M+, 12.6%), 404 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NOClSI: C, 46.44; H, 2.52;
N, 3.19. Found: C, 46.41; H, 2.45; N, 3.17.
The ORTEP diagram of the compound 3k is given in the Figure 13 below.
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Chapter -2 Experimental
79
Figure 13. ORTEP-3 diagram of compound 3k with the numbering scheme. Displacement ellipsoids
are drawn at the 50% probability level, H atoms are represented by circles of arbitrary radii.
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Chapter -2 Experimental
80
Crystal Data:
C17H11ClINOS
Mr = 439.68
Monoclinic, P21/c
a = 17.112 (6) Å
b = 7.636 (3) Å
c = 13.174 (5) Å
β = 111.29 (2)°
V = 1603.9 (10) Å3
Z = 4
Mo Kα radiation
µ = 2.29 mm-1
T = 173 (2) K
0.26 X 0.07 X 0.06 mm
Data collection:
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.587, Tmax = 0.875
6042 measured reflections
3652 independent reflections
2663 reflections with I > 2σ(I)
Rint = 0.036
Refinement:
R[F2 > 2σ(F
2)] = 0.041
wR(F2) = 0.097
S = 1.03
3652 reflections
200 parameters
H-atom parameters constrained
Δρmax = 0.52 e Å-3
Δρmin = -0.63 e Å-3
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Chapter -2 Experimental
81
2.3.34 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1H-pyrrol-2-
yl)prop-2-en-1-one (3l)
N
O
NH
Cl
CH3
Yield : 70%
State : Bright yellow solid
M.P. : 214 °C
IR : υmax(KBr) cm-1
1654 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 2.47 (3H, s, Me), 6.24 (1H, dd, H4', J=3.5
Hz), 6.70 (1H, d, H3', J=3.5 Hz), 7.05 (1H, d, H5', J=4.2
Hz), 7.41 (1H, d, Hα, J=15.6 Hz), 7.57 (1H, dd, H7,
J=8.6 Hz), 7.63 (1H, s, H5), 7.91 (1H, d, H8, J=8.6 Hz),
8.18 (1H, d, Hβ, J=15.7 Hz), 8.35 (s, 1H, H4).
MS : (m/z): 295 (M+, 8.5%), 260 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H13N2OCl: C, 68.81; H, 4.42;
N, 9.44. Found: C, 68.72; H, 4.36; N, 9.40.
2.3.35 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-methyl-2-
furyl)prop-2-en-1-one (3m)
Yield : 95%
State : Deep yellow solid
M.P. : 158 °C
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Chapter -2 Experimental
82
IR : υmax(KBr) cm-1
1664 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 2.45-2.54 (s, Me x 2), 6.24 (1H, dd, H4',
J=3.4 Hz), 7.29 (1H, d, H3', J=3.5 Hz), 7.45 (1H, d, Hα,
J=15.7 Hz), 7.58 (1H, dd, H7, J=8.6 Hz), 7.63 (1H, s,
H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.22 (1H, d, Hβ, J=15.8
Hz), 8.38 (1H, s, H4).
MS : (m/z): 311 (M+, 8.3%), 276 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NO2Cl: C, 69.34; H, 4.53;
N, 4.49. Found: C, 69.32; H, 4.47; N, 4.48.
The ORTEP diagram of the compound 3m is given in the Figure 14 below.
Figure 14. ORTEP-3 diagram of compound 3m with the numbering scheme. Displacement ellipsoids
are drawn at the 50% probability level, H atoms are represented by circles of arbitrary radii.
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Chapter -2 Experimental
83
Crystal Data:
C18H14ClNO2
Mr = 311.75
Monoclinic, C2/c
a = 36.228 (10) Å
b = 7.372 (3) Å
c = 11.214 (5) Å
β = 99.70 (2)°
V = 2952 (2) Å3
Z = 8
Mo Kα radiation
µ = 0.27 mm-1
T = 173 (2) K
0.22 X 0.20 X 0.07 mm
Data collection:
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.944, Tmax = 0.982
6103 measured reflections
3355 independent reflections
2405 reflections with I > 2σ(I)
Rint = 0.038
Refinement:
R[F2 > 2σ(F
2)] = 0.044
wR(F2) = 0.110
S = 1.01
3355 reflections
200 parameters
H-atom parameters constrained
Δρmax = 0.25 e Å-3
Δρmin = -0.24 e Å-3
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Chapter -2 Experimental
84
2.3.36 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dimethyl-3-
furyl)prop-2-en-1-one (3n)
Yield : 92%
State : Deep yellow solid
M.P. : 145-147 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1596 (C=C).
1H-NMR : (CDCl3) δ: 2.29-2.62 (s, Me x3), 6.34 (1H, s, H4'), 7.22
(1H, d, Hα, J=15.9 Hz), 7.58 (1H, dd, H7, J=8.6 Hz),
7.61 (1H, s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.08 (1H,
d, Hβ, J=15.8 Hz), 8.31 (1H, s, H4).
MS : (m/z): 325 (M+, 38.1%), 290 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C19H16NO2Cl: C, 70.05; H, 4.95;
N, 4.30. Found: C, 69.99; H, 4.94; N, 4.22.
2.3.37 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methylquinolin-3-
yl)prop-2-en-1-one (3o)
Yield : 56%
State : Off white solid
M.P. : 162 °C
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Chapter -2 Experimental
85
IR : υmax(KBr) cm-1
1660 (C=O), 1592 (C=C).
1H-NMR : (CDCl3) δ: 2.47 (3H, s, Me), 7.28 (1H, t, Ar-H), 7.36
(1H, d, Hα, J=15.8 Hz), 7.42-7.53 (4H, m, Ar-H), 7.62
(1H, s, H5), 7.68 (1H, dd, H7, J=8.5 Hz), 7.83 (1H, d,
H8, J=8.6 Hz), 8.04 (1H, d, Hβ, J=15.6 Hz), 8.11 (1H, s,
H4).
MS : (m/z): 348 (M+, 12.5%), 313 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C21H14NO2Cl: C, 72.52; H, 4.06;
N, 4.03. Found: C, 72.49; H, 3.98; N, 4.01.
2.3.38 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-
benzodioxin-6-yl)prop-2-en-1-one (3p)
Yield : 46%
State : Off white solid
M.P. : 158-160 °C
IR : υmax(KBr) cm-1
1658 (C=O), 1595 (C=C).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 4.32 (4H, m, Dioxane
Ring), 6.96 (1H, d, Ar-H, J=8.8 Hz), 7.42 (1H, m, Ar-
H), 7.55 (1H, d, Hα, J=15.7 Hz), 7.58 (1H, dd, H7,
J=8.6 Hz), 7.62 (1H, s, H5), 7.70 (1H, m, Ar-H), 7.90
(1H, d, H8, J=8.6 Hz), 8.15 (1H, d, Hβ, J=15.7 Hz), 8.36
(1H, s, H4).
MS : (m/z): 365 (M+, 24.1%), 330 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C21H16NO3Cl: C, 68.95; H, 4.41;
N, 3.83. Found: C, 68.91; H, 4.36; N, 3.79.
The ORTEP diagram of the compound 3p is given in the Figure 15 below.
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Chapter -2 Experimental
86
Figure 15. ORTEP-3 diagram of compound 3p with the numbering scheme. Displacement ellipsoids
are drawn at the 50% probability level, H atoms are represented by circles of arbitrary radii.
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Chapter -2 Experimental
87
Crystal Data:
C21H16ClNO3
Mr = 365.80
Monoclinic, P21/c
a = 6.370 (3) Å
b = 38.735 (9) Å
c = 7.409 (4) Å
β = 114.93 (2)°
V = 1657.8 (12) Å3
Z = 4
Mo Kα radiation
µ = 0.25 mm-1
T = 173 K
0.18 X 0.16 X 0.14 mm
Data collection:
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.956, Tmax = 0.966
6971 measured reflections
2933 independent reflections
2256 reflections with I > 2σ(I)
Rint = 0.037
Refinement:
R[F2 > 2σ(F
2)] = 0.037
wR(F2) = 0.091
S = 1.03
2933 reflections
236 parameters
H-atom parameters constrained
Δρmax = 0.19 e Å-3
Δρmin = -0.23 e Å-3
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Chapter -2 Experimental
88
2.3.39 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1-naphthyl)prop-2-
en-1-one (3q)
Yield : 97%
State : Bright yellow solid
M.P. : 138 °C
IR : υmax(KBr) cm-1
1659 (C=O), 1587 (C=C).
1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 7.38 (1H, d, Hα, J=15.9
Hz), 7.53-7.60 (5H, m, Ar-H), 7.85 (1H, d, Ar-H, J=6.8
Hz), 7.90 (1H, d, H7, J=8.6 Hz), 7.93 (1H, s, H5), 8.02
(1H, d, H8, J=8.1 Hz), 8.04 (1H, d, Hβ, J=16.2 Hz), 8.37
(1H, s, H4), 8.39 (1H, d, Ar-H, J=8.3 Hz).
MS : (m/z): 357 (M+, 17.2%), 322 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C23H16NOCl: C, 77.20; H, 4.51; N,
3.91. Found: C, 77.13; H, 4.47; N, 3.85.
The ORTEP diagram of the compound 3q is given in the Figure 16 below.
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Chapter -2 Experimental
89
Figure 16. ORTEP-3 diagram of compound 3q with the numbering scheme. Displacement ellipsoids
are drawn at the 50% probability level, H atoms are represented by circles of arbitrary radii.
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Chapter -2 Experimental
90
Crystal Data:
C23H16ClNO
Mr = 357.82
Monoclinic, P21/c
a = 16.919 (8) Å
b = 7.146 (3) Å
c = 14.829 (5) Å
β = 103.29 (2)°
V = 1744.9 (13) Å3
Z = 4
Mo Kα radiation
µ = 0.23 mm-1
T = 173 K
0.14 X 0.12 X 0.05 mm
Data collection:
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.968, Tmax = 0.989
6886 measured reflections
3988 independent reflections
2575 reflections with I > 2σ(I)
Rint = 0.039
Refinement:
R[F2 > 2σ(F
2)] = 0.051
wR(F2) = 0.131
S = 1.01
3988 reflections
236 parameters
H-atom parameters constrained
Δρmax = 0.24 e Å-3
Δρmin = -0.29 e Å-3
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Chapter -2 Experimental
91
2.3.40 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2-naphthyl)prop-
2-en-1-one (3r)
Yield : 65%
State : Off white solid
M.P. : 138 °C
IR : υmax(KBr) cm-1
1654 (C=O), 1589 (C=C).
1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 7.35 (1H, d, Hα, J=16.1
Hz), 7.53-7.56 (2H, m, Ar-H), 7.60 (1H, dd, H7, J= 8.1
Hz), 7.63 (1H, s, H5), 7.86-7.93 (4H, m, Ar-H), 8.03
(1H, dd, H8, J=8.6 Hz), 8.06 (1H, d, Hβ, J=16.1 Hz),
8.44 (1H, s, H4), 8.46 (1H, s, Ar-H).
MS : (m/z): 357 (M+, 1.7%), 127 (M
+−C13H9NOCl, 100 %).
CHN : Anal. Calculated for C23H16NOCl: C, 77.20; H, 4.51; N,
3.91. Found: C, 77.18; H, 4.48; N, 3.91.
2.3.41 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methylquinolin-3-yl)prop-2-
en-1-one (3s)
Yield : 86%
State : Deep yellow solid
M.P. : 232-233 °C
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Chapter -2 Experimental
92
IR : υmax(KBr) cm-1
1662 (C=O), 1586 (C=C).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.32 (1H, d, Hα, J=16.1
Hz), 7.47-7.57 (4H, m, Ar-H), 7.60 (1H, dd, H7, J=8.5
Hz), 7.63 (1H, s, H5), 7.77 (1H, d, Hβ, J=16.1 Hz), 7.84
(1H, d, H8, J=8.6 Hz), 7.92-7.95 (2H, m, Ar-H), 8.05-
8.07 (2H, m, Ar-H), 8.31 (1H, s, H4), 8.56 (1H, s, Ar-
H).
MS : (m/z): 407 (M+, 83%), 177 (M
+−C13H9NOCl, 100 %).
CHN : Anal. Calculated for C27H18NOCl: C, 79.50; H, 4.45; N,
3.43. Found: C, 7979.46; H, 4.41; N, 3.39.
2.3.42 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-thien-3-ylprop-2-
en-1-one (4a)
N
O
S
Cl
O
CH3
Yield : 82%
State : Yellowish grey solid
M.P. : 182 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1593 (C=C).
1H-NMR : (CDCl3) δ: 3.94 (3H, s, OMe), 7.11 (1H, d, H5, J=2.6
Hz), 7.39 (1H, d, H4', J=2.9 Hz), 7.45 (1H, d, Hα,
J=15.7 Hz), 7.60 (1H, dd, H7, J=9.1 Hz), 7.69 (1H, d,
H5', J=4.6 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.17 (1H, d,
Hβ, J=15.9 Hz), 8.20 (1H, dd, H2', J=2.2 Hz), 8.36 (1H,
s, H4).
MS : (m/z): 329 (M+, 19.7%), 294 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H12NO2ClS: C, 61.91; H, 3.67;
N, 4.25. Found: C, 61.90; H, 3.61; N, 4.23.
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Chapter -2 Experimental
93
2.3.43 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-methylthien-2-
yl)prop-2-en-1-one (4b)
N
O
S
Cl CH3
O
CH3
Yield : 64%
State : Greenish yellow solid
M.P. : 180 °C
IR : υmax(KBr) cm-1
1654 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 2.67 (3H, s, Me), 3.94 (3H, s, OMe), 7.02
(1H, d, H4', J=4.9 Hz), 7.13 (1H, d, H5, J=2.6 Hz), 7.36
(1H, d, H8, J=9.2 Hz), 7.40 (1H, d, Hα, J=15.5 Hz), 7.49
(1H, d, H5', J=4.9 Hz), 7.58 (1H, dd, H7, J=8.6 Hz),
7.90 (1H, d, H8, J=9.2 Hz), 8.17 (1H, d, Hβ, J=15.4 Hz),
8.33 (1H, s, H4).
MS : (m/z): 343 (M+, 63.5%), 308 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NO2ClS: C, 62.88; H, 4.10;
N, 4.07. Found: C, 62.75; H, 4.02; N, 4.03.
2.3.44 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(4-methylthien-2-
yl)prop-2-en-1-one (4c)
N
O
S
Cl
CH3
O
CH3
Yield : 74%
State : Greenish yellow solid
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Chapter -2 Experimental
94
M.P. : 146 °C
IR : υmax(KBr) cm-1
1656 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 2.33 (3H, s, Me), 3.94 (3H, s, OMe), 7.02
(1H, d, H4', J=4.9 Hz), 7.12 (1H, d, H5, J=2.5 Hz), 7.31
(1H, s, H5'), 7.40 (1H, dd, H7, J=9.3 Hz), 7.44 (1H, d,
Hα, J=15.6 Hz), 7.70 (1H, s, H3'), 7.91 (1H, d, H8,
J=9.2 Hz), 8.19 (1H, d, Hβ, J=15.6 Hz), 8.35 (1H, s,
H4).
MS : (m/z): 343 (M+, 21.4%), 308 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NO2ClS: C, 62.88; H, 4.10;
N, 4.07. Found: C, 62.79; H, 4.04; N, 4.04.
2.3.45 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-methylthien-2-
yl)prop-2-en-1-one (4d)
N
O
S
Cl
CH3
O
CH3
Yield : 57%
State : Yellowish grey solid
M.P. : 152-153 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1588 (C=C).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 3.93 (3H, s, OMe), 7.06
(1H, d, H4' J=4.4 Hz), 7.11 (1H, d, H5, J=2.6 Hz ), 7.33
(1H, d, Hα, J=15.6 Hz), 7.42 (1H, dd, H7, J=9.2 Hz),
7.68 (1H, d, H3' J=4.4 Hz), 7.90 (1H, d, H8, J=9.2 Hz),
8.12 (1H, d, Hβ, J=15.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 343 (M+, 29.6%), 308 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NO2ClS: C, 62.88; H, 4.10;
N, 4.07. Found: C, 62.81; H, 4.03; N, 4.01.
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Chapter -2 Experimental
95
2.3.46 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-
dimethylthien-3-yl)prop-2-en-1-one (4e)
N
O
S
Cl
CH3
CH3
O
CH3
Yield : 94%
State : Off white solid
M.P. : 116 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1585 (C=C).
1H-NMR : (CDCl3) δ: 2.44-2.72 (s, Me x 2), 3.93 (3H, s, OMe),
7.09 (1H, s, H4'), 7.10 (1H, d, H5, J=2.9), 7.33 (1H, d,
Hα, J=15.7 Hz), 7.39 (1H, dd, H7, J=9.2 Hz), 7.90 (1H,
d, H8, J=9.2 Hz), 8.07 (1H, d, Hβ, J=15.7 Hz), 8.31 (1H,
s, H4).
MS : (m/z): 357 (M+, 56.4%), 322 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C19H16NO2ClS: C, 63.77; H, 4.51;
N, 3.91. Found: C, 63.62; H, 4.44; N, 3.85.
2.3.47 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-chlorothien-2-
yl)prop-2-en-1-one (4f)
N
O
S
Cl Cl
O
CH3
Yield : 67%
State : Greyish green solid
M.P. : 136-138 °C
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Chapter -2 Experimental
96
IR : υmax(KBr) cm-1
1651 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 3.94 (3H, s, OMe), 7.08 (1H, d, H4', J=5.2
Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.41 (1H, dd, H7,
J=9.2 Hz), 7.61 (1H, d, H5', J=5.2 Hz), 7.83 (1H, d, Hα,
J=15.5 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.22 (1H, d, Hβ,
J=15.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 363 (M+, 24.9%), 328 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NO2Cl2S: C, 56.06; H, 3.04;
N, 3.84. Found: C, 56.02; H, 3.01; N, 3.78.
2.3.48 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-chlorothien-2-
yl)prop-2-en-1-one (4g)
N
O
S
Cl
Cl
O
CH3
Yield : 95%
State : Yellowish grey solid
M.P. : 178-180 °C
IR : υmax(KBr) cm-1
1654 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 3.91 (3H, s, OMe), 6.95 (1H, d, H4', J=4.1
Hz), 7.11 (1H, d, H5, J=2.7 Hz), 7.36 (1H, dd, H7, J=9.2
Hz), 7.42 (1H, d, Hα, J=15.6 Hz), 7.50 (1H, d, H3',
J=4.1 Hz), 7.89 (1H, d, H8, J=9.2 Hz), 8.12 (1H, d, Hβ,
J=15.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 363 (M+, 13.7%), 328 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NO2Cl2S: 56.06; H, 3.04; N,
3.84. Found: C, 56.01; H, 2.98; N, 3.79.
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Chapter -2 Experimental
97
2.3.49 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-
dichlorothien-3-yl)prop-2-en-1-one (4h)
N
O
S
Cl
Cl
Cl
O
CH3
Yield : 96%
State : Greyish green solid
M.P. : 144 °C
IR : υmax(KBr) cm-1
1664 (C=O), 1591 (C=C).
1H-NMR : (CDCl3) δ: 3.94 (3H, s, OMe), 7.11 (1H, d, H5, J=2.7
Hz), 7.16 (1H, s, H4'), 7.41 (1H, dd, H7, J=9.2 Hz), 7.46
(1H, d, Hα, J=15.7 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.14
(1H, d, Hβ, J=15.7 Hz), 8.33 (1H, s, H4).
MS : (m/z): 397 (M+, 14.3%), 362 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H10NO2Cl3S: C, 51.21; H, 2.53;
N, 3.51. Found: C, 51.19; H, 2.42; N, 3.46.
2.3.50 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-6-methoxyquinolin-3-
yl)prop-2-en-1-one (4i)
N
O
S
Cl Br
O
CH3
Yield : 73%
State : Greyish green solid
M.P. : 148-150 °C
IR : υmax(KBr) cm-1
1650 (C=O), 1591 (C=C).
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Chapter -2 Experimental
98
1H-NMR : (CDCl3) δ: 3.94 (3H, s, OMe), 7.12 (1H, d, H5, J=2.7
Hz), 7.16 (1H, d, H4', J=5.1 Hz), 7.41 (1H, dd, H7,
J=9.2 Hz), 7.59 (1H, d, H5', J=5.1 Hz), 7.83 (1H, d, Hα,
J=15.6 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.22 (1H, d, Hβ,
J=15.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 408 (M+, 16.2%), 374 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NO2ClSBr: C, 49.96; H,
2.71; N, 3.43. Found: C, 49.92; H, 2.70; N, 3.33.
2.3.51 (2E)-1-(5-Bromothien-2-yl)-3-(2-chloro-6-methoxyquinolin-3-
yl)prop-2-en-1-one (4j)
N
O
S
Cl
Br
O
CH3
Yield : 84%
State : Yellowish grey solid
M.P. : 178 °C
IR : υmax(KBr) cm-1
1654 (C=O), 1589 (C=C).
1H-NMR : (CDCl3) δ: 3.91 (3H, s, OMe), 6.95 (1H, d, H4', J=4.1
Hz), 7.10 (1H, d, H5, J=2.6 Hz), 7.36 (1H, dd, H7, J=9.2
Hz), 7.42 (1H, d, Hα, J=15.6 Hz), 7.45 (1H, d, H3',
J=4.1 Hz), 7.89 (1H, d, H8, J=9.2 Hz), 8.13 (1H, d, Hβ,
J=15.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 409 (M+, 20.4%), 374 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H11NO2ClSBr: C, 49.96; H,
2.71; N, 3.43. Found: C, 49.87; H, 2.68; N, 3.41
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Chapter -2 Experimental
99
2.3.52 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-iodothien-2-
yl)prop-2-en-1-one (4k)
N
O
S
Cl
I
O
CH3
Yield : 91%
State : Yellowish grey solid
M.P. : 184 °C
IR : υmax(KBr) cm-1
1648 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 3.91 (3H, s, OMe), 6.92 (1H, d, H4', J=4.1
Hz), 7.10 (1H, d, H5, J=2.7 Hz), 7.36 (1H, dd, H7, J=9.2
Hz), 7.43 (1H, d, Hα, J=15.5 Hz), 7.46 (1H, d, H3',
J=4.1 Hz), 7.89 (1H, d, H8, J=9.2 Hz), 8.14 (1H, d, Hβ,
J=15.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 455 (M+, 11.2%), 237 (M
+−C12H9NOCl, 100 %).
CHN : Anal. Calculated for C17H11NO2ClSI: C, 44.81; H, 2.43;
N, 3.07. Found: C, 44.75; H, 2.39; N, 3.02.
2.3.53 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1H-pyrrol-2-
yl)prop-2-en-1-one (4l)
N Cl
NH
O
OCH3
Yield : 90%
State : Pale yellow solid
M.P. : 172 °C
IR: : υmaxυmax(KBr) 1648 (C=O), 1596 (C=C) cm
-1
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Chapter -2 Experimental
100
1H-NMR: : (CDCl3) δ: 2.47 (3H, s, OMe), 6.34 (1H, dd, H4', J=3.4
Hz), 6.64 (1H, d, H3', J=3.4 Hz), 7.0 (1H, d, H5', J=4.0
Hz), 7.44 (1H, d, Hα, J=15.5 Hz), 7.52 (1H, dd, H7,
J=8.6 Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.90 (1H, d, H8,
J=8.6 Hz), 8.20 (1H, d, Hβ, J=15.6 Hz), 8.34 (1H, s,
H4).
MS : (m/z) 311 (M+, 13.3%), 276 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C17H13N2O2Cl C, 65.28; H, 4.19;
N, 8.96. Found: C, 65.27; H, 4.11; N, 8.92.
2.3.54 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-methyl-2-
furyl)prop-2-en-1-one (4m)
N Cl
O
O
OCH3 CH3
Yield : 98%
State : Greenish yellow solid
M.P. : 168 °C
IR : υmax(KBr) cm-1
1664 (C=O), 1594 (C=C).
1H-NMR : (CDCl3) δ: 2.45 (3H, s, Me), 3.93 (3H, s, OMe), 6.24
(1H, dd, H4', J=3.0 Hz), 7.29 (1H, d, H3', J=3.4 Hz),
7.45 (1H, d, Hα, J=15.8 Hz), 7.40 (1H, dd, H7, J=9.1
Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.90 (1H, d, H8, J=8.2
Hz), 8.22 (1H, d, Hβ, J=15.8 Hz), 8.36 (1H, s, H4).
MS : (m/z): 327 (M+, 28.7%), 292 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H14NO3Cl: C, 65.96; H, 4.31;
N, 4.27. Found: C, 65.94; H, 4.31; N, 4.26.
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Chapter -2 Experimental
101
2.3.55 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-dimethyl-3-
furyl)prop-2-en-1-one (4n)
N Cl
O
O
OCH3
CH3
CH3
Yield : 69%
State : Pale yellow solid
M.P. : 122 °C
IR : υmax(KBr) cm-1
1649 (C=O), 1596 (C=C).
1H-NMR : (CDCl3) δ: 2.27-2.61 (s, Me x 2), 3.93 (3H, s, OMe),
6.97 (1H, s, H4'), 7.11 (1H, d, H5, J=2.7 Hz), 7.24 (1H,
d, Hα, J=15.9 Hz), 7.40 (1H, dd, H7, J=9.2 Hz), 7.90
(1H, d, H8, J=9.2 Hz), 8.12 (1H, d, Hβ, J=15.8 Hz), 8.36
(1H, s, H4).
MS : (m/z): 341 (M+, 22.5%), 306 (M
+−Cl,100 %).
CHN : Anal. Calculated for C19H16NO3Cl: C, 66.77; H, 4.72;
N, 4.10. Found: C, 66.74; H, 4.68; N, 4.09.
2.3.56 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methoxyquinolin-3-
yl)prop-2-en-1-one (4o)
N Cl
O
O
OCH3
Yield : 62%
State : Off white solid
M.P. : 158 °C
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Chapter -2 Experimental
102
IR : υmax(KBr) cm-1
1658 (C=O), 1587 (C=C).
1H-NMR : (CDCl3) δ: 3.87 (3H, s, OMe), 7.01 (1H, d, H5, J=2.7
Hz), 7.29 (1H, t, Ar-H) 7.36 (1H, d, Hα, J=15.8 Hz),
7.42-7.52 (4H, m, Ar-H), 7.67 (1H, d, H7, J=9.2 Hz),
7.82 (1H, d, H8, J=9.2 Hz), 8.06 (1H, d, Hβ, J=15.8 Hz),
8.10 (1H, s, H4).
MS : (m/z): 363 (M+, 10.5%), 328 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C21H14NO3Cl: C, 69.33; H, 3.88;
N, 3.85. Found: C, 69.31; H, 3.82; N, 3.81.
2.3.57 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,3-dihydro-1,4-
benzodioxin-6-yl)prop-2-en-1-one (4p)
Yield : 92%
State : Off white solid
M.P. : 163-164 °C
IR : υmax(KBr) cm-1
1658 (C=O), 1596 (C=C).
1H-NMR : (CDCl3) δ: 3.93 (3H, s, OMe), 4.34 (4H, m, Dioxane
Ring), 6.94 (1H, d, Ar-H, J=8.1 Hz), 7.12 (1H, d, H5,
J=2.6 Hz), 7.36 (1H, d, Ar-H, J=3.9 Hz), 7.50 (1H, d,
Hα, J=15.6 Hz), 7.58 (1H, dd, H7, J=9.1 Hz), 7.70 (1H,
m, Ar-H), 7.91 (1H, d, H8, J=9.2 Hz), 8.18 (1H, d, Hβ,
J=15.6 Hz), 8.35 (1H, s, H4).
MS : (m/z): 381 (M+, 7.5%), 346 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C21H16NO4Cl: C, 66.06; H, 4.22;
N, 3.67. Found: C, 66.02; H, 4.18; N, 3.63.
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Chapter -2 Experimental
103
2.3.58 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1-naphthyl)prop-
2-en-1-one (4q)
Yield : 90%
State : Pale yellow solid
M.P. : 162 °C
IR : υmax(KBr) cm-1
1659 (C=O), 1587 (C=C).
1H-NMR : (CDCl3) δ: 3.92 (3H, s, OMe), 7.09 (1H, d, H5, J=2.7
Hz), 7.38 (1H, d, Hα, J=15.9 Hz), 7.40 (1H, dd, H7,
J=9.2 Hz), 7.53-7.61 (3H, m, Ar-H), 7.83-7.92 (3H, m,
Ar-H), 7.98 (1H, d, H8, J=9.2 Hz), 8.03 (1H, d, Hβ,
J=16.1 Hz), 8.35 (1H, s, H4), 8.40 (1H, d, Ar-H, J=8.3
Hz).
MS : (m/z): 373 (M+, 57.0%), 338 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C23H16NO2Cl: C, 73.90; H, 4.31;
N, 3.75. Found: C, 73.87; H, 4.27; N, 3.72.
2.3.59 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2-naphthyl)prop-
2-en-1-one (4r)
Yield : 55%
State : Light grey solid
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Chapter -2 Experimental
104
M.P. : 140 °C
IR : υmax(KBr) cm-1
1659 (C=O), 1586 (C=C).
1H-NMR : (CDCl3) δ: 3.95 (3H, s, OMe), 7.15 (1H, d, H5, J=2.7
Hz), 7.41 (1H, dd, H7, J=9.2 Hz), 7.55-7.64 (2H, m, Ar-
H), 7.73 (1H, d, Hα, J=15.7 Hz), 7.89-8.00 (4H, m, Ar-
H), 8.11 (1H, dd, H8 J=9.2 Hz), 8.23 (1H, d, Hβ, J=15.7
Hz), 8.42 (1H, s, H4), 8.56 (1H, s, Ar-H).
MS : (m/z): 373 (M+, 34.9%), 338 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C23H16NO2Cl: C, 73.90; H, 4.31;
N, 3.75. Found: C, 73.88; H, 4.27; N, 3.71.
2.3.60 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methoxyquinolin-3-yl)prop-2-
en-1-one (4s)
Yield : 97%
State : Deep yellow solid
M.P. : 220-222 °C
IR : υmax(KBr) cm-1
1660 (C=O), 1588 (C=C).
1H-NMR : (CDCl3) δ: 3.92 (3H, s, OMe), 7.11 (1H, d, H5, J=2.7
Hz), 7.40 (1H, d, Hα, J=16.1 Hz), 7.47-7.56 (4H, m, Ar-
H), 7.84 (1H, dd, H7, J=7.2 Hz), 7.90-7.93 (2H, m, Ar-
H), 7.96 (1H, d, Hβ, J=16.1 Hz), 8.03 (1H, d, H8, J=7.4
Hz), 8.54 (1H, s, Ar-H) 8.06-8.08 (2H, m, Ar-H).
MS : (m/z): 423 (M+, 16.3%), 177 (M
+−C13H9NO2Cl, 100 %).
CHN : Anal. Calculated for C27H18NO2Cl: C, 76.50; H, 4.28;
N, 3.30. Found: C, 76.42; H, 4.27; N, 3.27.
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Chapter -2 Experimental
105
2.4 General Method for the Synthesis of 2-Pyrazolines263
(2.4.1─2.4.44) (Scheme─II)
A mixture of Chalcone (1a-k, 2a-k, 3a-k or 4a-k, 1.0 mmol) and hydrazine
hydrate (3.0 mmol) in ethanol (10 mL) was refluxed. The crude product was
precipitated out in the reaction flask within 8-15 min. Subsequently, it was poured
onto ice-cold water (50 ml). The precipitates were collected by filtration, washed with
cold water followed by cold EtOH to obtain 2-pyrazolines which were recrystallised
from EtOH (95%) to obtain pure compounds 5a-k, 6a-k, 7a-k and 8a-k.
2.4.1 2-Chloro-8-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-
5-yl)quinoline (5a)
S
N
NH
N
Cl
CH3
Yield : 72%
State : White solid
M.P. : 195-196 °C
IR : υmax(KBr) cm-1
3274 (N-H), 1595 (C=N of pyrazoline
ring), 1550 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.70 (3H, s, Me), 2.97 (1H, dd, J = 16.4, 9.4
Hz, 4-Ha), 3.75 (1H, dd, J = 16.4, 10.7 Hz, 4-Hb), 5.39
(1H, t, J = 9.9 Hz, 5-H), 7.32 (1H, dd, H4', J = 5.0 Hz,
2.8 Hz), 7.45 (1H, t, H6, J = 7.6 Hz), 7.55 (1H, d, H7, J
= 7.0 Hz), 7.60 (1H, d, H5', J = 4.6 Hz, 1.0 Hz), 7.67
(1H, d, H5, J = 6.6 Hz), 8.08 (1H, dd, H2', J = 2.7 Hz,
1.0 Hz), 8.39 (1H, s, H4).
MS : (m/z): 328 (M+, 100 %).
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Chapter -2 Experimental
106
CHN : Anal. Calculated for C17H14N3ClS: C, 62.28; H, 4.30; N,
12.82. Found: C, 62.22; H, 4.22; N, 12.78.
2.4.2 2-Chloro-8-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (5b)
S
N
NH
N
Cl CH3
CH3
Yield : 67%
State : White solid
M.P. : 130-131 °C
IR : υmax(KBr) cm-1
3277 (N-H), 1605 (C=N of pyrazoline
ring), 1552 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.63-2.73 (s, Me x 2), 2.86 (1H, dd, J =
16.3, 9.4 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.82 (1H, d, H4', J =
5.1 Hz), 7.45 (1H, t, H6, J = 7.6 Hz), 7.33 (1H, d, H5', J
= 5.1 Hz), 7.54 (1H, d, H7, J = 7.0 Hz), 7.69 (1H, d, H5,
J = 7.9 Hz), 8.38 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.22; H, 4.75; N, 12.23.
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Chapter -2 Experimental
107
2.4.3 2-Chloro-8-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (5c)
S
N
NH
N
Cl CH3
CH3
Yield : 71%
State : White solid
M.P. : 182 °C
IR : υmax(KBr) cm-1
3281 (N-H), 1595 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.30-2.72 (s, Me x 2), 2.87 (1H, dd, J =
16.3, 9.3 Hz, 4-Ha), 3.69 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H) 7.11 (1H, s, H5'), 7.44
(1H, t, H6, J = 7.5 Hz), 7.55 (1H, d, H7, J = 7.0 Hz),
7.69 (1H, d, H5, J = 7.0 Hz), 7.52 (1H, s, H3'), 8.37 (1H,
s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.20; H, 4.69; N, 12.25.
2.4.4 2-Chloro-8-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (5d)
S
N
NH
N
Cl
CH3
CH3
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Chapter -2 Experimental
108
Yield : 80%
State : Pale yellow solid
M.P. : 209-210 °C
IR : υmax(KBr) cm-1
3278 (N-H), 1592 (C=N of pyrazoline
ring), 1550 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.53-2.72 (s, Me x 2), 2.83 (1H, dd, J =
16.3, 9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.66 (1H, d, H4', J =
3.0 Hz), 6.86 (1H, d, H3' J = 3.4 Hz), 7.44 (1H, t, H6, J
= 7.6 Hz), 7.54 (1H, d, H7, J = 7.0 Hz), 7.62 (1H, d, H5,
J = 8.1 Hz), 8.33 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.23; H, 4.70; N, 12.27.
2.4.5 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-8-methylquinoline (5e)
S
N
NH
N
Cl
CH3
CH3
CH3
Yield : 88%
State : Brown solid
M.P. : 126-127 °C
IR : υmax(KBr) cm-1
3282 (N-H), 1609 (C=N of pyrazoline
ring), 1553 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.42-2.73 (s, Me x 3), 2.84 (1H, dd, J =
16.3, 9.7 Hz, 4-Ha), 3.68 (1H, dd, J = 16.3, 10.6 Hz, 4-
Hb), 5.30 (1H, t, J = 10.0 Hz, 5-H), 6.86 (1H, s, H4'),
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Chapter -2 Experimental
109
7.42 (1H, t, H6, J = 7.7 Hz), 7.54 (1H, d, H7, J = 7.0
Hz), 7.68 (1H, d, H5, J = 8.1 Hz), 8.34 (1H, s, H4).
MS : (m/z): 356 (M+, 100 %).
CHN : Anal. Calculated for C19H18N3ClS: C, 64.12; H, 5.10; N,
11.81. Found: C, 64.10; H, 5.08; N, 11.79.
2.4.6 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-8-methylquinoline (5f)
S
N
NH
N
Cl Cl
CH3
Yield : 81%
State : Yellowish brown solid
M.P. : 152 °C
IR : υmax(KBr) cm-1
3277 (N-H), 1610 (C=N of pyrazoline
ring), 1559 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 3.11 (1H, dd, J = 16.9,
10.2 Hz, 4-Ha), 3.94 (1H, dd, J = 16.9, 10.8 Hz, 4-Hb),
5.39 (1H, t, J = 10.4 Hz, 5-H), 6.87 (1H, d, H4', J = 5.4
Hz), 7.41 (1H, t, H6, J = 7.6 Hz), 7.54 (1H, d, H7, J =
7.0 Hz), 7.32 (1H, d, H5', J = 5.4 Hz), 7.65 (1H, d, H5, J
= 8.1 Hz), 8.37 (1H, s, H4).
MS : (m/z): 362 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.34; H, 3.58; N, 11.54.
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Chapter -2 Experimental
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2.4.7 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-8-methylquinoline (5g)
S
N
NH
N
Cl
Cl
CH3
Yield : 80%
State : Pale yellow solid
M.P. : 230-232 °C
IR : υmax(KBr) cm-1
3285 (N-H), 1603 (C=N of pyrazoline
ring), 1560 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 2.89 (1H, dd, J = 16.3,
10.1 Hz, 4-Ha), 3.62 (1H, dd, J = 16.3, 10.7 Hz, 4-Hb),
5.39 (1H, t, J = 10.3 Hz, 5-H), 6.85 (1H, d, H4', J = 4.2
Hz), 7.42 (1H, t, H6, J = 7.6 Hz), 7.56 (1H, d, H7, J =
7.0 Hz), 7.48 (1H, d, H3', J = 4.4 Hz), 7.63 (1H, d, H5, J
= 8.0 Hz), 8.35 (1H, s, H4).
MS : (m/z): 362 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.31; H, 3.56; N, 11.55.
2.4.8 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-8-methylquinoline (5h)
S
N
NH
N
Cl
Cl
Cl
CH3
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Chapter -2 Experimental
111
Yield : 75%
State : Yellowish brown solid
M.P. : 153 °C
IR : υmax(KBr) cm-1
3280 (N-H), 1615 (C=N of pyrazoline
ring), 1560 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 3.15 (1H, dd, J = 16.8,
10.0 Hz, 4-Ha), 4.00 (1H, dd, J = 16.8, 10.5 Hz, 4-Hb),
5.40 (1H, t, J = 10.3 Hz, 5-H), 6.96 (1H, s, H4'), 7.41
(1H, t, H6, J = 7.6 Hz), 7.56 (1H, d, H7, J = 6.8 Hz),
7.62 (1H, d, H5, J = 8.1 Hz), 8.35 (1H, s, H4).
MS : (m/z): 397 (M+, 100 %).
CHN : Anal. Calculated for C17H12N3Cl3S: C, 51.47; H, 3.05;
N, 10.59. Found: C, 51.41; H, 3.00; N, 10.56.
2.4.9 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-8-methylquinoline (5i)
S
N
NH
N
Cl Br
CH3
Yield : 77%
State : Pale yellow solid
M.P. : 166-168 °C
IR : υmax(KBr) cm-1
3279 (N-H), 1607 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 3.21 (1H, dd, J = 16.9,
10.2 Hz, 4-Ha), 4.10 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),
5.32 (1H, t, J = 10.4 Hz, 5-H), 6.86 (1H, d, H4', J = 5.5
Hz), 7.43 (1H, t, H6, J = 7.6 Hz), 7.21 (1H, d, H5', J =
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Chapter -2 Experimental
112
5.5 Hz), 7.54 (1H, d, H7, J = 7.1 Hz), 7.65 (1H, d, H5, J
= 8.0 Hz), 8.39 (1H, s, H4).
MS : (m/z): 407 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.14; H, 3.18; N, 10.29.
2.4.10 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-8-methylquinoline (5j)
S
N
NH
N
Cl
Br
CH3
Yield : 80%
State : Pale yellow solid
M.P. : 215-216 °C
IR : υmax(KBr) cm-1
3282 (N-H), 1597 (C=N of pyrazoline
ring), 1552 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 2.90 (1H, dd, J = 16.2, 9.9
Hz, 4-Ha), 3.61 (1H, dd, J = 16.2, 10.6 Hz, 4-Hb), 5.28
(1H, t, J = 10.3 Hz, 5-H), 6.87 (1H, d, H4', J = 4.2 Hz),
7.42 (1H, t, H6, J = 7.6 Hz), 7.55 (1H, d, H7, J = 7.1
Hz), 7.43 (1H, d, H3', J = 4.2 Hz), 7.63 (1H, d, H5, J =
8.0 Hz), 8.36 (1H, s, H4).
MS : (m/z): 407 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.19 H, 3.17; N, 10.28.
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Chapter -2 Experimental
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2.4.11 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-8-methylquinoline (5k)
S
N
NH
N
Cl
I
CH3
Yield : 82%
State : Pale yellow solid
M.P. : 178 °C
IR : υmax(KBr) cm-1
3280 (N-H), 1605 (C=N of pyrazoline
ring), 1550 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 2.90 (1H, dd, J = 16.3, 9.9
Hz, 4-Ha), 3.73 (1H, dd, J = 16.3, 10.6 Hz, 4-Hb), 5.31
(1H, t, J = 10.2 Hz, 5-H), 6.71 (1H, d, H4', J = 4.0 Hz),
7.42 (1H, t, H6, J = 7.6 Hz), 7.16 (1H, d, H3', J = 4.1
Hz), 7.56 (1H, d, H7, J = 7.0 Hz), 7.63 (1H, d, H5, J =
8.1 Hz), 8.36 (1H, s, H4).
MS : (m/z): 454 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSI: C, 45.00; H, 2.89;
N, 9.26. Found: C, 44.98; H, 2.81; N, 9.25.
2.4.12 2-Chloro-7-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-
5-yl)quinoline (6a)
S
N
NH
N
ClCH3
Yield : 80%
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Chapter -2 Experimental
114
State : White solid
M.P. : 180-181 °C
IR : υmax(KBr) cm-1
3275 (N-H), 1596 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.50 (3H, s, Me), 2.95 (1H, dd, J=16.3, 9.4
Hz, 4-Ha), 3.74 (1H, dd, J = 16.4, 10.6 Hz, 4-Hb), 5.38
(1H, t, J = 9.9 Hz, 5-H), 7.31 (1H, dd, H4', J = 5.0 Hz,
2.8 Hz), 7.40 (1H, d, H5, J = 8.1 Hz), 7.62 (1H, dd, H5',
J = 4.9 Hz, 0.9 Hz), 7.73 (1H, d, H6, J = 8.3 Hz), 7.75
(1H, s, H8), 8.08 (1H, dd, H2', J = 2.8 Hz, 1.0 Hz), 8.40
(1H, s, H4).
MS : (m/z): 327 (M+, 100 %).
CHN : Anal. Calculated for C17H14N3ClS: C, 62.28; H, 4.30; N,
12.82. Found: C, 62.24; H, 4.25; N, 12.80.
2.4.13 2-Chloro-7-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (6b)
S
N
NH
N
Cl CH3CH3
Yield : 78%
State : Yellow solid
M.P. : 160-161 °C
IR : υmax(KBr) cm-1
3285 (N-H), 1602 (C=N of pyrazoline
ring), 1559 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.53-2.62 (s, Me x 2), 2.84 (1H, dd, J =
16.3, 9.4 Hz, 4-Ha), 3.64 (1H, dd, J = 16.3, 10.4 Hz, 4-
Hb), 5.29 (1H, t, J = 9.9 Hz, 5-H), 6.82 (1H, d, H4', J =
5.0 Hz), 7.35 (1H, d, H5, J = 8.1 Hz), 7.35 (1H, d, H5', J
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Chapter -2 Experimental
115
= 4.9 Hz), 7.74 (1H, d, H6, J = 8.5 Hz), 7.76 (1H, s, H8),
8.39 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.14; H, 4.65; N, 12.29.
2.4.14 2-Chloro-7-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (6c)
S
N
NH
N
Cl CH3CH3
Yield : 83%
State : White solid
M.P. : 200 °C
IR : υmax(KBr) cm-1
3280 (N-H), 1599 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.30-2.50 (s, Me x 2), 2.85 (1H, dd, J =
16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.30 (1H, t, J = 9.9 Hz, 5-H), 7.11 (1H, s, H5'),
7.37 (1H, d, H5, J = 8.1 Hz), 7.51 (1H, s, H3'), 7.74 (1H,
d, H6, J = 8.3 Hz), 7.76 (1H, s, H8), 8.41 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.21; H, 4.69; N, 12.25.
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Chapter -2 Experimental
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2.4.15 2-Chloro-7-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (6d)
S
N
NH
N
Cl
CH3
CH3
Yield : 87%
Stat : Pale yellow solid
M.P. : 198°C
IR : υmax(KBr) cm-1
3275 (N-H), 1595 (C=N of pyrazoline
ring), 1558 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.52-2.54 (s, Me x 2), 2.85 (1H, dd, J =
16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.66 (1H, d, H4', J =
3.2 Hz), 6.85 (1H, d, H3', J = 3.5 Hz), 7.37 (1H, d, H5, J
= 8.1 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.76 (1H, s, H8),
8.40 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.23; H, 4.69; N, 12.31.
2.4.16 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (6e)
S
N
NH
N
Cl
CH3
CH3CH3
Yield : 86%
State : Off white solid
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Chapter -2 Experimental
117
M.P. : 116-117 °C
IR : υmax(KBr) cm-1
3279 (N-H), 1610 (C=N of pyrazoline
ring), 1556 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.36-2.65 (s, Me x 3), 2.82 (1H, dd, J =
16.2, 9.7 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.28 (1H, t, J = 10.0 Hz, 5-H), 6.86 (1H, s, H4'),
7.41 (1H, d, H5, J = 8.3 Hz), 7.72 (1H, d, H6, J = 8.3
Hz), 7.76 (1H, s, H8), 8.34 (1H, s, H4).
MS : (m/z): 356 (M+, 100 %).
CHN : Anal. Calculated for C19H18N3ClS: C, 64.12; H, 5.10; N,
11.81. Found: C, 64.08; H, 5.05; N, 11.76.
2.4.17 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-7-methylquinoline (6f)
S
N
NH
N
Cl ClCH3
Yield : 79%
State : White solid
M.P. : 166-167 °C
IR : υmax(KBr) cm-1
3288 (N-H), 1608 (C=N of pyrazoline
ring), 1560 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.52 (3H, s, Me), 3.15 (1H, dd, J = 16.9,
10.1 Hz, 4-Ha), 4.00 (1H, dd, J = 16.9, 10.8 Hz, 4-Hb),
5.39 (1H, t, J = 10.4 Hz, 5-H), 6.86 (1H, d, H4', J = 5.2
Hz), 7.21 (1H, d, H5, J = 8.3 Hz), 7.32 (1H, d, H5', J =
5.2 Hz), 7.76 (1H, d, H6, J = 8.6 Hz), 7.89 (1H, s, H8),
8.37 (1H, s, H4).
MS : (m/z): 362 (M+, 96.20%) 185 (M
+−C10H7NCl, 100 %).
CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.32; H, 3.61; N, 11.58.
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Chapter -2 Experimental
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2.4.18 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-7-methylquinoline (6g)
S
N
NH
N
Cl
Cl
CH3
Yield : 83%
State : Off white solid
M.P. : 205-207 °C
IR : υmax(KBr) cm-1
3284 (N-H), 1605 (C=N of pyrazoline
ring), 1560 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.50 (3H, s, Me), 2.87 (1H, dd, J = 16.2,
10.0 Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb),
5.36 (1H, t, J = 10.3 Hz, 5-H), 6.82 (1H, d, H4', J = 4.3
Hz), 7.28 (1H, d, H5, J = 8.3 Hz), 7.47 (1H, d, H3', J =
4.3 Hz), 7.65 (1H, d, H6, J = 8.3 Hz), 7.69 (1H, s, H8),
8.34 (1H, s, H4).
MS : (m/z): 362 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.34 H, 3.59; N, 11.52.
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Chapter -2 Experimental
119
2.4.19 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-7-methylquinoline (6h)
S
N
NH
N
Cl
Cl
ClCH3
Yield : 75%
State : Off white solid
M.P. : 178-179 °C
IR : υmax(KBr) cm-1
3282 (N-H), 1612 (C=N of pyrazoline
ring), 1561 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.52 (3H, s, Me), 3.11 (1H, dd, J = 16.7, 9.9
Hz, 4-Ha), 3.98 (1H, dd, J = 16.7, 10.5 Hz, 4-Hb), 5.39
(1H, t, J = 10.2 Hz, 5-H), 6.97 (1H, s, H4'), 7.35 (1H, d,
H5, J = 8.3 Hz), 7.72 (1H, d, H6, J = 8.2 Hz), 7.75 (1H,
s, H8), 8.33 (1H, s, H4).
MS : (m/z): 397 (M+, 100 %).
CHN : Anal. Calculated for C17H12N3Cl3S: C, 51.47; H, 3.05;
N, 10.59. Found: C, 51.45; H, 3.02; N, 10.54.
2.4.20 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-7-methylquinoline (6i)
S
N
NH
N
Cl BrCH3
Yield : 92%
Stat : White solid
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Chapter -2 Experimental
120
M.P. : 170-171 °C
IR : υmax(KBr) cm-1
3279 (N-H), 1608 (C=N of pyrazoline
ring), 1556 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 3.19 (1H, dd, J = 16.8,
10.1 Hz, 4-Ha), 4.06 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),
5.39 (1H, t, J = 10.4 Hz, 5-H), 6.95 (1H, d, H4', J = 5.5
Hz), 7.35 (1H, d, H5, J = 8.2 Hz), 7.21 (1H, d, H5', J =
5.5 Hz), 7.72 (1H, d, H6, J = 8.6 Hz), 7.74 (1H, s, H8),
8.38 (1H, s, H4).
MS : (m/z): 407 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.12; H, 3.14; N, 10.30.
2.4.21 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-7-methylquinoline (6j)
S
N
NH
N
Cl
Br
CH3
Yield : 76%
State : White solid
M.P. : 195 °C
IR : υmax(KBr) cm-1
3282 (N-H), 1600 (C=N of pyrazoline
ring), 1552 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.52 (3H, s, Me), 2.88 (1H, dd, J = 16.2, 9.9
Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 5.36
(1H, t, J = 10.3 Hz, 5-H), 6.86 (1H, d, H4', J = 4.2 Hz),
7.36 (1H, d, H5, J = 8.3 Hz), 7.43 (1H, d, H3', J = 4.2
Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.75 (1H, s, H8), 8.35
(1H, s, H4).
MS : (m/z): 407 (M+, 100 %).
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Chapter -2 Experimental
121
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.15; H, 3.19; N, 10.25.
2.4.22 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-7-methylquinoline (6k)
S
N
NH
N
Cl
I
CH3
Yield : 85%
State : White solid
M.P. : 212 °C
IR : υmax(KBr) cm-1
3281 (N-H), 1610 (C=N of pyrazoline
ring), 1550 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.52 (3H, s, Me), 2.87 (1H, dd, J = 16.2, 9.9
Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 5.36
(1H, t, J = 10.3 Hz, 5-H), 6.71 (1H, d, H4', J = 4.2 Hz),
7.15 (1H, d, H3', J = 4.2 Hz), 7.34 (1H, d, H5, J = 8.4
Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.75 (1H, s, H8), 8.35
(1H, s, H4).
MS : (m/z): 454 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSI: C, 45.00; H, 2.89;
N, 9.26. Found: C, 44.95; H, 2.85; N, 9.23.
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Chapter -2 Experimental
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2.4.23 2-Chloro-6-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-
5-yl)quinoline (7a)
S
N
NH
N
CH3
Cl
Yield : 75%
State : White solid
M.P. : 178-179 °C
IR : υmax(KBr) cm-1
3279 (N-H), 1599 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.50 (3H, s, Me), 2.91 (1H, dd, J = 16.2, 9.3
Hz, 4-Ha), 3.77 (1H, dd, J = 16.2, 10.4 Hz, 4-Hb), 5.38
(1H, t, J = 9.9 Hz, 5-H), 7.32 (1H, dd, H4', J=2.7 Hz),
7.56 (1H, d, H7, J=8.6 Hz), 7.60 (1H, s, H5), 7.63 (1H,
d, H5', J=4.7 Hz), 7.87 (1H, d, H8, J=8.5 Hz), 8.10 (1H,
dd, H2', J=2.2 Hz, 1.0 Hz), 8.34 (1H, s, H4).
MS : (m/z): 328 (M+, 100 %).
CHN : Anal. Calculated for C17H14N3ClS: C, 62.28; H, 4.30; N,
12.82. Found: C, 62.22; H, 4.22; N, 12.78.
2.4.24 2-Chloro-6-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (7b)
S
N
NH
N
CH3
Cl CH3
Yield : 70%
State : Off white solid
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Chapter -2 Experimental
123
M.P. : 179-180 °C
IR : υmax(KBr) cm-1
3274 (N-H), 1600 (C=N of pyrazoline
ring), 1557 (C=N of quinoline ring).
1H-NMR : (CDCl3) 2.42-2.64 (s, Me x 2), 2.84 (1H, dd, J = 16.2,
9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.2, 10.3 Hz, 4-Hb),
5.29 (1H, t, J = 9.8 Hz, 5-H), 6.84 (1H, d, H4', J=4.9
Hz), 7.34 (1H, d, H5', J=4.9 Hz), 7.54 (1H, dd, H7,
J=8.5 Hz), 7.64 (1H, s, H5), 7.88 (1H, d, H8, J=8.6 Hz),
8.34 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.22; H, 4.75; N, 12.23.
2.4.25 2-Chloro-6-methyl-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (7c)
S
N
NH
N
CH3
Cl CH3
Yield : 69%
State : White solid
M.P. : 210 °C
IR : υmax(KBr) cm-1
3284 (N-H), 1602 (C=N of pyrazoline
ring), 1560 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.22-2.46 (s, Me x 2), 2.86 (1H, dd, J =
16.3, 9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.3, 10.4 Hz, 4-
Hb), 5.29 (1H, t, J = 9.8 Hz, 5-H) 7.96 (1H, s, H5'), 7.14
(1H, s, H3'), 7.49 (1H, dd, H7, J=8.6 Hz), 7.60 (1H, s,
H5), 7.86 (1H, d, H8, J=8.6 Hz), 8.38 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.20; H, 4.69; N, 12.25.
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Chapter -2 Experimental
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2.4.26 2-Chloro-6-methyl-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (7d)
S
N
NH
N
CH3
Cl
CH3
Yield : 72%
State : Pale yellow solid
M.P. : 185-187 °C
IR : υmax(KBr) cm-1
3284 (N-H), 1603 (C=N of pyrazoline
ring), 1558 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.50-2.54 (s, Me x 2), 2.85 (1H, dd, J =
16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 5.30 (1H, t, J = 9.8 Hz, 5-H), 6.79 (1H, d, H4',
J=3.5 Hz), 7.07 (1H, d, H3' J=3.8 Hz), 7.56 (1H, dd,
H7, J=8.6 Hz), 7.61 (1H, s, H5), 7.88 (1H, d, H8, J=8.6
Hz), 8.34 (1H, s, H4).
MS : (m/z): 342 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.23; H, 4.70; N, 12.27.
2.4.27 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methylquinoline (7e)
S
N
NH
N
CH3
Cl
CH3
CH3
Yield : 79%
State : Yellowish brown solid
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Chapter -2 Experimental
125
M.P. : 117-119 °C
IR : υmax(KBr) cm-1
3278 (N-H), 1604 (C=N of pyrazoline
ring), 1559 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.42-2.66 (s, Me x 3), 2.82 (1H, dd, J =
16.3, 9.6 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3, 10.6 Hz, 4-
Hb), 5.29 (1H, t, J = 9.9 Hz, 5-H), 6.89 (1H, s, H4'),
7.59 (1H, dd, H7, J=8.6 Hz), 7.60 (1H, s, H5), 7.88 (1H,
d, H8, J=8.6 Hz), 8.36 (1H, s, H4).
MS : (m/z): 356 (M+, 100 %).
CHN : Anal. Calculated for C19H18N3ClS: C, 64.12; H, 5.10; N,
11.81. Found: C, 64.10; H, 5.08; N, 11.79.
2.4.28 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-6-methylquinoline (7f)
S
N
NH
N
CH3
Cl Cl
Yield : 75%
State : Pale yellow solid
M.P. : 170-172 °C
IR : υmax(KBr) cm-1
3286 (N-H), 1611 (C=N of pyrazoline
ring), 1562 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.50 (3H, s, Me), 3.14 (1H, dd, J = 16.9, 9.9
Hz, 4-Ha), 4.04 (1H, dd, J = 16.9, 10.7 Hz, 4-Hb), 5.35
(1H, t, J = 10.3 Hz, 5-H), 6.88 (1H, d, H4', J=5.2 Hz),
7.48 (1H, d, H5', J=5.2 Hz), 7.60 (1H, dd, H7, J=8.6
Hz), 7.64 (1H, s, H5), 7.87 (1H, d, H8, J=8.6 Hz), 8.36
(1H, s, H4).
MS : (m/z): 362 (M+, 100 %).
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Chapter -2 Experimental
126
CHN : Anal. Calculated. for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.34; H, 3.58; N, 11.54.
2.4.29 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methylquinoline (7g)
S
N
NH
N
CH3
Cl
Cl
Yield : 66%
State : Pale yellow solid
M.P. : 224-225 °C
IR : υmax(KBr) cm-1
3281 (N-H), 1605 (C=N of pyrazoline
ring), 1553 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.51 (3H, s, Me), 2.87 (1H, dd, J = 16.3, 9.8
Hz, 4-Ha), 3.70 (1H, dd, J = 16.3, 10.5 Hz, 4-Hb), 5.38
(1H, t, J = 10.3 Hz, 5-H), 6.94 (1H, d, H4', J=4.0 Hz),
7.60 (1H, dd, H7, J=8.6 Hz), 7.63 (1H, s, H5), 7.67 (1H,
d, H3', J=4.0 Hz), 7.88 (1H, d, H8, J=8.6 Hz), 8.38 (1H,
s, H4).
MS : (m/z): 362 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.31; H, 3.56; N, 11.55.
2.4.30 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methylquinoline (7h)
S
N
NH
N
CH3
Cl
Cl
Cl
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Chapter -2 Experimental
127
Yield : 69%
State : Pale yellow solid
M.P. : 178-180 °C
IR : υmax(KBr) cm-1
3274 (N-H), 1605 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 3.15 (1H, dd, J = 16.8,
10.0 Hz, 4-Ha), 4.00 (1H, dd, J = 16.8, 10.5 Hz, 4-Hb),
5.40 (1H, t, J = 10.3 Hz, 5-H), 7.15 (1H, s, H4'), 7.60
(1H, dd, H7, J=8.6 Hz), 7.63 (1H, s, H5), 7.90 (1H, d,
H8, J=8.6 Hz), 8.34 (1H, s, H4).
MS : (m/z): 397 (M+, 100 %).
CHN : Anal. Calculated for C17H12N3Cl3S: C, 51.47; H, 3.05;
N, 10.59. Found: C, 51.41; H, 3.00; N, 10.56.
2.4.31 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methylquinoline (7i)
S
N
NH
N
CH3
Cl Br
Yield : 81%
State : White solid
M.P. : 187-188 °C
IR : υmax(KBr) cm-1
3282 (N-H), 1612 (C=N of pyrazoline
ring), 1551 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 3.21 (1H, dd, J = 16.9,
10.2 Hz, 4-Ha), 4.10 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),
5.40 (1H, t, J = 10.4 Hz, 5-H), 7.16 (1H, d, H4', J=5.16
Hz), 7.58 (1H, d, H5', J=5.1 Hz), 7.59 (1H, dd, H7,
J=8.6 Hz), 7.65 (1H, s, H5), 7.91 (1H, d, H8, J=8.6 Hz),
8.38 (1H, s, H4).
MS : (m/z): 407 (M+, 100 %).
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Chapter -2 Experimental
128
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.14; H, 3.18; N, 10.29.
2.4.32 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methylquinoline (7j)
S
N
NH
N
CH3
Cl
Br
Yield : 83%;
State : Pale yellow solid
M.P. : 215-216 °C
IR : υmax(KBr) cm-1
3275 (N-H), 1598 (C=N of pyrazoline
ring), 1554 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 2.89 (1H, dd, J = 16.2, 9.9
Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.6 Hz, 4-Hb), 5.36
(1H, t, J = 10.3 Hz, 5-H), 7.10 (1H, d, H4', J=4.0 Hz),
7.17 (1H, d, H3', J=4.0 Hz), 7.60 (1H, dd, H7, J=8.5
Hz), 7.63 (1H, s, H5), 7.91 (1H, d, H8, J=8.3 Hz), 8.36
(1H, s, H4).
MS : (m/z): 407 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.19 H, 3.17; N, 10.28.
2.4.33 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-6-methylquinoline (7k)
S
N
NH
N
CH3
Cl
I
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Chapter -2 Experimental
129
Yield : 74%
State : White solid
M.P. : 192 °C
IR : υmax(KBr) cm-1
3282 (N-H), 1615 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 2.90 (1H, dd, J = 16.3, 9.9
Hz, 4-Ha), 3.73 (1H, dd, J = 16.3, 10.6 Hz, 4-Hb), 5.37
(1H, t, J = 10.2 Hz, 5-H), 7.36 (1H, d, H4', J=3.9 Hz),
7.50 (1H, d, H3', J=3.9 Hz), 7.59 (1H, dd, H7, J=8.7
Hz), 7.62 (1H, s, H5), 7.90 (1H, d, H8, J=8.5 Hz), 8.35
(1H, s, H4).
MS : (m/z): 454 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSI: C, 45.00; H, 2.89;
N, 9.26. Found: C, 44.98; H, 2.81; N, 9.25.
2.4.34 2-Chloro-6-methoxy-3-(3-thiophen-3-yl-4,5-dihydro-1H-
pyrazol-5-yl)quinoline (8a)
S
N
NH
N
MeO
Cl
Yield : 70%
State : Yellow solid
M.P. : 170-172 °C
IR : υmax(KBr) cm-1
3276 (N-H), 1596 (C=N of pyrazoline
ring), 1561 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.95 (1H, dd, J=16.3, 9.4 Hz, 4-Ha), 3.74
(1H, dd, J = 16.4, 10.6 Hz, 4-Hb), 3.94 (3H, s, OMe),
5.38 (1H, t, J = 9.9 Hz, 5-H), 7.11 (1H, d, H5, J=2.6
Hz), 7.39 (1H, d, H4', J=2.9 Hz), 7.60 (1H, dd, H7,
J=9.1 Hz), 7.69 (1H, d, H5', J=4.6 Hz), 7.91 (1H, d, H8,
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Chapter -2 Experimental
130
J=9.2 Hz), 8.20 (1H, dd, H2', J=2.2 Hz), 8.36 (1H, s,
H4).
MS : (m/z): 343 (M+, 100 %).
CHN : Anal. Calculated for C17H14N3ClS: C, 62.28; H, 4.30; N,
12.82. Found: C, 62.24; H, 4.25; N, 12.80.
2.4.35 2-Chloro-6-methoxy-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (8b)
S
N
NH
N
MeO
Cl CH3
Yield : 82%
State : Pale yellow solid
M.P. : 164-166 °C
IR : υmax(KBr) cm-1
3275 (N-H), 1607 (C=N of pyrazoline
ring), 1554 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.67 (3H, s, Me), 2.84 (1H, dd, J = 16.3, 9.4
Hz, 4-Ha), 3.64 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 3.94
(3H, s, OMe), 5.29 (1H, t, J = 9.9 Hz, 5-H), 7.02 (1H,
d, H4', J=4.9 Hz), 7.13 (1H, d, H5, J=2.6 Hz), 7.36 (1H,
d, H8, J=9.2 Hz), 7.49 (1H, d, H5', J=4.9 Hz), 7.58 (1H,
dd, H7, J=8.6 Hz), 7.90 (1H, d, H8, J=9.2 Hz), 8.33 (1H,
s, H4).
MS : (m/z): 356 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.14; H, 4.65; N, 12.29.
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Chapter -2 Experimental
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2.4.36 2-Chloro-6-methoxy-3-[3-(4-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (8c)
S
N
NH
N
MeO
Cl CH3
Yield : 81%
State : Pale yellow solid
M.P. : 180 °C
IR : υmax(KBr) cm-1
3287 (N-H), 1614 (C=N of pyrazoline
ring), 1564 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.33 (3H, s, Me), 2.85 (1H, dd, J = 16.3, 9.3
Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-Hb), 3.94
(3H, s, OMe), 5.30 (1H, t, J = 9.9 Hz, 5-H), 7.02 (1H,
d, H4', J=4.9 Hz), 7.12 (1H, d, H5, J=2.5 Hz), 7.31 (1H,
s, H5'), 7.40 (1H, dd, H7, J=9.3 Hz), 7.70 (1H, s, H3'),
7.91 (1H, d, H8, J=9.2 Hz), 8.35 (1H, s, H4).
MS : (m/z): 356 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.21; H, 4.69; N, 12.25.
2.4.37 2-Chloro-6-methoxy-3-[3-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl]quinoline (8d)
S
N
NH
N
MeO
Cl
CH3
Yield : 75%
State : Yellow solid
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Chapter -2 Experimental
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M.P. : 170 °C
IR : υmax(KBr) cm-1
3283 (N-H), 1597 (C=N of pyrazoline
ring), 1554 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 2.85 (1H, dd, J = 16.3, 9.3
Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-Hb), 3.93
(3H, s, OMe), 5.31 (1H, t, J = 9.9 Hz, 5-H), 7.06 (1H,
d, H4' J=4.4 Hz), 7.11 (1H, d, H5, J=2.6 Hz ), 7.42 (1H,
dd, H7, J=9.2 Hz), 7.68 (1H, d, H3' J=4.4 Hz), 7.90 (1H,
d, H8, J=9.2 Hz), 8.36 (1H, s, H4).
MS : (m/z): 356 (M+, 100 %).
CHN : Anal. Calculated for C18H16N3ClS: C, 63.24; H, 4.72; N,
12.29. Found: C, 63.23; H, 4.69; N, 12.31.
2.4.38 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methoxyquinoline (8e)
S
N
NH
N
MeO
Cl
CH3
CH3
Yield : 74%
State : White solid
M.P. : 122-124 °C
IR : υmax(KBr) cm-1
3281 (N-H), 1613 (C=N of pyrazoline
ring), 1558 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.44-2.72 (s, Me x 2), 2.82 (1H, dd, J =
16.2, 9.7 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3, 10.5 Hz, 4-
Hb), 3.93 (3H, s, OMe), 5.28 (1H, t, J = 10.0 Hz, 5-H),
7.09 (1H, s, H4'), 7.10 (1H, d, H5, J=2.9), 7.39 (1H, dd,
H7, J=9.2 Hz), 7.90 (1H, d, H8, J=9.2 Hz), 8.31 (1H, s,
H4).
MS : (m/z): 372 (M+, 100 %).
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Chapter -2 Experimental
133
CHN : Anal. Calculated for C19H18N3ClS: C, 64.12; H, 5.10; N,
11.81. Found: C, 64.08; H, 5.05; N, 11.76.
2.4.39 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-6-methoxyquinoline (8f)
S
N
NH
N
MeO
Cl Cl
Yield : 79%
State : Yellow solid
M.P. : 198-200 °C
IR : υmax(KBr) cm-1
3281 (N-H), 1696 (C=N of pyrazoline
ring), 1550 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 3.15 (1H, dd, J = 16.9, 10.1 Hz, 4-Ha), 3.94
(3H, s, OMe), 4.00 (1H, dd, J = 16.9, 10.8 Hz, 4-Hb),
5.39 (1H, t, J = 10.4 Hz, 5-H), 7.08 (1H, d, H4', J=5.2
Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.41 (1H, dd, H7,
J=9.2 Hz), 7.61 (1H, d, H5', J=5.2 Hz), 7.91 (1H, d, H8,
J=9.2 Hz), 8.36 (1H, s, H4).
MS : (m/z): 378 (M+, 100 %)
CHN : Anal. Calculated. for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.32; H, 3.61; N, 11.58.
2.4.40 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl]-6-methoxyquinoline (8g)
S
N
NH
N
MeO
Cl
Cl
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Chapter -2 Experimental
134
Yield : 57%
State : Off white solid
M.P. : 204-206 °C
IR : υmax(KBr) cm-1
3279 (N-H), 1615 (C=N of pyrazoline
ring), 1564 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.87 (1H, dd, J = 16.2, 10.0 Hz, 4-Ha), 3.71
(1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 3.91 (3H, s, OMe),
5.36 (1H, t, J = 10.3 Hz, 5-H), 6.95 (1H, d, H4', J=4.1
Hz), 7.11 (1H, d, H5, J = 2.7 Hz), 7.36 (1H, dd, H7,
J=9.2 Hz), 7.50 (1H, d, H3', J=4.1 Hz), 7.89 (1H, d, H8,
J = 9.2 Hz), 8.36 (1H, s, H4).
MS : (m/z): 378 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;
N, 11.60. Found: C, 56.34 H, 3.59; N, 11.52.
2.4.41 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl]-6-methoxyquinoline (8h)
S
N
NH
N
MeO
Cl
Cl
Cl
Yield : 87%
State : Yellow solid
M.P. : 190-191 °C
IR : υmax(KBr) cm-1
3279 (N-H), 1602 (C=N of pyrazoline
ring), 1555 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 3.11 (1H, dd, J = 16.7, 9.9 Hz, 4-Ha), 3.94
(3H, s, OMe), 3.98 (1H, dd, J = 16.7, 10.5 Hz, 4-Hb),
5.39 (1H, t, J = 10.2 Hz, 5-H), 7.11 (1H, d, H5, J=2.7
Hz), 7.16 (1H, s, H4'), 7.41 (1H, dd, H7, J=9.2 Hz), 7.91
(1H, d, H8, J=9.2 Hz), 8.33 (1H, s, H4).
MS : (m/z): 313 (M+, 100 %).
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Chapter -2 Experimental
135
CHN : Anal. Calculated for C17H12N3Cl3S: C, 51.47; H, 3.05;
N, 10.59. Found: C, 51.45; H, 3.02; N, 10.54.
2.4.42 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methoxyquinoline (8i)
S
N
NH
N
MeO
Cl Br
Yield : 81%
State : Pale yellow solid
M.P. : 157-159 °C
IR : υmax(KBr) cm-1
3280 (N-H), 1608 (C=N of pyrazoline
ring), 1559 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 3.19 (1H, dd, J = 16.8, 10.1 Hz, 4-Ha), 3.94
(3H, s, OMe), 4.06 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),
5.39 (1H, t, J = 10.4 Hz, 5-H), 7.12 (1H, d, H5, J=2.7
Hz), 7.16 (1H, d, H4', J=5.1 Hz), 7.41 (1H, dd, H7,
J=9.2 Hz), 7.59 (1H, d, H5', J=5.1 Hz), 7.91 (1H, d, H8,
J=9.2 Hz), 8.36 (1H, s, H4).
MS : (m/z): 423 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.12; H, 3.14; N, 10.30.
2.4.43 3-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-
chloro-6-methoxyquinoline (8j)
S
N
NH
N
MeO
Cl
Br
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Chapter -2 Experimental
136
Yield : 87%
State : White solid
M.P. : 203-205 °C
IR : υmax(KBr) cm-1
3287 (N-H), 1609 (C=N of pyrazoline
ring), 1550 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.88 (1H, dd, J = 16.2, 9.9 Hz, 4-Ha), 3.71
(1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 3.91 (3H, s, OMe),
5.36 (1H, t, J = 10.3 Hz, 5-H), 6.95 (1H, d, H4', J=4.1
Hz), 7.10 (1H, d, H5, J=2.6 Hz), 7.36 (1H, dd, H7, J=9.2
Hz), 7.45 (1H, d, H3', J=4.1 Hz), 7.89 (1H, d, H8, J=9.2
Hz), 8.36 (1H, s, H4).
MS : (m/z): 423 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;
N, 10.33. Found: C, 50.15; H, 3.19; N, 10.25.
2.4.44 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]-6-methoxyquinoline (8k)
S
N
NH
N
MeO
Cl
I
Yield : 69%
State : Yellow solid
M.P. : 216-218 °C
IR : υmax(KBr) cm-1
3280 (N-H), 1614 (C=N of pyrazoline
ring), 1551 (C=N of quinoline ring).
1H-NMR : (CDCl3) δ: 2.87 (1H, dd, J = 16.2, 9.9 Hz, 4-Ha), 3.71
(1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 3.91 (3H, s, OMe),
5.36 (1H, t, J = 10.3 Hz, 5-H), 6.92 (1H, d, H4', J=4.1
Hz), 7.10 (1H, d, H5, J=2.7 Hz), 7.36 (1H, dd, H7, J=9.2
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Chapter -2 Experimental
137
Hz), 7.46 (1H, d, H3', J=4.1 Hz), 7.89 (1H, d, H8, J=9.2
Hz), 8.36 (1H, s, H4).
MS : (m/z): 470 (M+, 100 %).
CHN : Anal. Calculated for C17H13N3ClSI: C, 45.00; H, 2.89;
N, 9.26. Found: C, 44.95; H, 2.85; N, 9.23.
2.5 General Method for the Synthesis of Piperidinyl
Chalcones (9a─l) (Scheme─III)
A mixture of 4-piperidin-1-ylbenzaldehyde (9) (10 mmol) and an aromatic
ketone (a-l, 10 mmol) in methanol (50 ml) was stirred at room temperature, followed
by dropwise addition of aq. NaOH (4 ml, 10%). The stirring was continued for 2 h
and the reaction mixture was then kept at 0 °C (24 h). Subsequently, it was poured
onto ice-cold water (200 ml). The precipitates were collected by filtration, washed
with cold water followed by cold MeOH. The resulting chalcones (9a-l) were
recrystallised from CHCl3.
2.5.1 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-2-ylprop-2-en-1-
one (9a)
O
S
N
2
3
4
5
6
1
7
8
9
10
11
12
2'
3'4'
5'1'
Yield : 80%
State : Orange red
M.P. : 141 °C
IR : υmax(KBr) 1652 (C=O), 1598 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.68 (6H, m, H3/H4/H5), 3.29-3.30 (4H,
m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.8 Hz ), 7.15 (1H, t,
H4', J = 4.2 Hz), 7.23 (1H, d, Hα, J = 15.2 Hz), 7.52
(2H, d, H8/H12, J = 8.8 Hz), 7.62 (1H, d, H3', J = 4.8
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Chapter -2 Experimental
138
Hz), 7.79 (1H, d, Hβ, J = 15.6 Hz), 7.82 (1H, d, H3', J =
3.6 Hz).
MS : (m/z) 297 (M+, 100 %)
CHN : Anal. Calculated for C18H19NOS: C, 72.69; H, 6.44; N,
4.71. Found: C, 72.62; H, 6.48; N, 4.68.
2.5.2 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-3-ylprop-2-en-1-
one (9b)
O
S
N
Yield : 85%
State : Orange
M.P. : 160 °C
IR : υmax(KBr) 1655 (C=O), 1596 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.68 (6H, m, H3/H4/H5), 3.29-3.31 (4H,
m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.8 Hz ), 7.21 (1H,
d, Hα, J = 15.2 Hz), 7.33 (1H, t, H4', J = 4.0 Hz), 7.51
(2H, d, H8/H12, J = 8.4 Hz), 7.64 (1H, d, H5', J = 4.8
Hz), 7.76 (1H, d, Hβ, J = 15.6 Hz), 8.10 (1H, s, H2').
MS : (m/z) 297 (M+, 100 %)
CHN : Anal. Calculated for C18H19NOS: C, 72.69; H, 6.44; N,
4.71. Found: C, 72.60; H, 6.40; N, 4.64 .
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Chapter -2 Experimental
139
2.5.3 (2E)-1-(3-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9c)
O
S
CH3N
Yield : 90%
State : Orange yellow
M.P. : 125 °C
IR : υmax(KBr) 1654 (C=O), 1590 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.68 (6H, m, H3/H4/H5), 2.56 (3H, s,
Me), 3.29-3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11, J =
8.4 Hz ), 7.12 (1H, d, H5', J = 5.2 Hz), 7.18 (1H, d, Hα, J
= 15.2 Hz), 7.52 (2H, d, H8/H12, J = 8.4 Hz), 7.60 (1H,
d, H4', J = 5.2 Hz), 7.78 (1H, d, Hβ, J = 15.2 Hz)
MS : (m/z) 311 (M+, 100 %)
CHN : Anal. Calculated for C19H21NOS: C, 73.27; H, 6.80; N,
4.50. Found: C, 73.22; H, 6.78; N, 4.44.
2.5.4 (2E)-1-(4-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9d)
O
S
CH3
N
Yield : 82%
State : Orange
M.P. : 110 °C
IR : υmax(KBr) 1652 (C=O), 1600 (C=C) cm
-1
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Chapter -2 Experimental
140
1H-NMR : (CDCl3) δ: 1.63-1.68 (6H, m, H3/H4/H5), 2.30 (3H, s,
Me), 3.29-3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11, J =
8.8 Hz ), 7.20 (1H, d, Hα, J = 15.2 Hz), 7.21 (1H, s,
H5'), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.63 (1H, s, H3', J
= 4.8 Hz), 7.77 (1H, d, Hβ, J = 15.2 Hz)
MS : (m/z) 311 (M+, 100 %)
CHN : Anal. Calculated forC19H21NOS: C, 73.27; H, 6.80; N,
4.50. Found: C, 73.32; H, 6.83; N, 4.48.
2.5.5 (2E)-1-(5-Methylthiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9e)
O
S
CH3
N
Yield : 79%
State : Yellowish Brown
M.P. : 90 °C
IR : υmax(KBr) 1656 (C=O), 1606 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.67 (6H, m, H3/H4/H5), 2.54 (3H, s,
Me), 3.28-3.30 (4H, m, H2/H6), 6.81 (1H, d, H4', J = 3.2
Hz), 6.87 (2H, d, H9/H11, J = 8.4 Hz ), 7.19 (1H, d, Hα, J
= 15.2 Hz), 7.51 (2H, d, H8/H12, J = 8.4 Hz), 7.64 (1H,
d, H3', J = 3.2 Hz), 7.75 (1H, d, Hβ, J = 15.6 Hz).
MS : (m/z) 311 (M+, 100 %)
CHN : Anal. Calculated for C19H21NOS: C, 73.27 H, 6.80; N,
4.50. Found: C, 73.21; H, 6.76; N, 4.53.
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Chapter -2 Experimental
141
2.5.6 (2E)-1-(2,5-Dimethylthiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9f)
O
S
CH3
CH3
N
Yield : 72%
State : Orange
M.P. : 115-117 °C
IR : υmax(KBr) 1650 (C=O), 1607 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.67 (6H, m, H3/H4/H5), 2.42-2.67 (3H,
s, 2xMe), 3.30-3.31 (4H, m, H2/H6), 6.86 (2H, d,
H9/H11, J = 8.8 Hz ), 7.10 (1H, s, H4'), 7.09 (1H, d, Hα,
J = 15.6 Hz), 7.48 (2H, d, H8/H12, J = 8.4 Hz), 7.67
(1H, d, Hβ, J = 15.6 Hz)
MS : (m/z) 325 (M+, 100 %)
CHN : Anal. Calculated for C21H27NOS: C, 73.86; H, 7.97; N,
4.10. Found: C, 73.82; H, 7.10; N, 4.12.
2.5.7 (2E)-1-(3-Chlorothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9g)
O
S
ClN
Yield : 82%
State : Crimson
M.P. : 85 °C
IR : υmax(KBr) 1658 (C=O), 1600 (C=C) cm
-1
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Chapter -2 Experimental
142
1H-NMR : (CDCl3) δ: 1.64-1.68 (6H, m, H3/H4/H5), 3.30-3.32 (4H,
m, H2/H6), 6.87 (2H, d, H8/H12, J = 8.8 Hz ), 7.02 (1H,
d, H5', J = 5.2 Hz), 7.51 (1H, d, H4', J = 5.2 Hz), 7.52
(2H, d, H9/H11, J = 8.8 Hz), 7.55 (1H, d, Hα, J = 15.6
Hz), 7.80 (1H, d, Hβ, J = 15.2 Hz)
MS : (m/z) 332 (M+, 48 %), 334 (M
++2, 12 %), 331 (M
+-1,
100 %)
CHN : Anal. Calculated for C18H18ClNOS: C, 65.15; H, 5.47;
N, 4.22. Found: C, 65.18; H, 5.43; N, 4.19.
2.5.8 (2E)-1-(5-Chlorothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9h)
O
S
Cl
N
Yield : 76%
State : Bright Yellow
M.P. : 162 °C
IR : υmax(KBr) 1656 (C=O), 1602 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.65-1.68 (6H, m, H3/H4/H5), 3.29-3.31 (4H,
m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.8 Hz ), 6.97 (1H,
d, H4', J = 4.0 Hz), 7.12 (1H, d, Hα, J = 15.2 Hz), 7.51
(2H, d, H8/H12, J = 8.4 Hz), 7.58 (1H, d, H3', J = 3.6
Hz), 7.77 (1H, d, Hβ, J = 15.2 Hz).
MS : (m/z) 332 (M+, 44 %), 33 (M
+-1, 100 %)
CHN : Anal. Calculated for C18H18ClNOS: C, 65.15; H, 5.47;
N, 4.22. Found: C, 65.27; H, 5.42; N, 4.26.
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Chapter -2 Experimental
143
2.5.9 (2E)-1-(2,5-Dichlorothiophen-3-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9i)
O
S
Cl
Cl
N
Yield : 62%
State : Yellowish Brown
M.P. : 84 °C
IR : υmax(KBr) 1654 (C=O), 1594 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.64-1.67 (6H, m, H3/H4/H5), 3.30-3.31 (4H,
m, H2/H6), 6.85 (2H, d, H9/H11, J = 8.8 Hz ), 7.11 (1H,
s, H4'), 7.13 (1H, d, Hα, J = 15.6 Hz), 7.48 (2H, d,
H8/H12, J = 8.4 Hz), 7.67 (1H, d, Hβ, J = 15.6 Hz)
MS : (m/z) 368 (M++2, 24 %), 365 (M
+-1, 100 %),
CHN : Anal. Calculated for C18H17Cl2NOS: C, 59.02; H, 4.68;
N, 3.82. Found: C, 58.70; H, 4.70; N, 3.75.
2.5.10 (2E)-1-(3-Bromothiophen-2-yl)-3-(4-piperidin-1-
ylphenyl)prop-2-en-1-one (9j)
O
S
BrN
Yield : 69%
State : Orange Red
M.P. : 93 °C
IR : υmax(KBr) 1655 (C=O), 1596 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.64-1.67 (6H, m, H3/H4/H5), 3.30-3.32 (4H,
m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.4 Hz ), 7.10 (1H,
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Chapter -2 Experimental
144
d, H5', J = 5.2 Hz), 7.48 (1H, d, H4', J = 5.2 Hz), 7.52
(2H, d, H8/H12, J = 8.8 Hz), 7.55 (1H, d, Hα, J = 15.6
Hz), 7.79 (1H, d, Hβ, J = 15.6 Hz)
MS : (m/z) 376 (M+, 100 %)
CHN : Anal. Calculated for C18H18BrNOS: C, 57.45; H, 4.82;
N, 3.72. Found: C, 57.54; H, 4.76; N, 3.76.
2.5.11 (2E)-1-(5-Bromothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-
2-en-1-one (9k)
O
S
Br
N
Yield : 88%
State : Deep Yellow
M.P. : 162 °C
IR: : υmax(KBr) 1650 (C=O), 1595 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.64-1.67 (6H, m, H3/H4/H5), 3.29-3.31 (4H,
m, H2/H6), 6.86 (2H, d, H9/H11, J = 8.4 Hz ), 7.11 (1H,
d, H4', J = 4.0 Hz), 7.12 (1H, d, Hα, J = 15.2 Hz), 7.50
(2H, d, H8/H12, J = 8.4 Hz), 7.54 (1H, d, H3', J = 3.6
Hz), 7.78 (1H, d, Hβ, J = 15.2 Hz).
MS : (m/z) 375 (M+-1, 100 %) 376 (M
+, 67 %)
CHN : Anal. Calculated for C18H18BrNOS: C, 57.45; H, 4.82;
N, 3.72. Found: C, 57.38; H, 4.16; N, 3.61.
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Chapter -2 Experimental
145
2.5.12 (2E)-1-(5-Iodothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-2-
en-1-one (9l)
O
S
I
N
Yield : 92%
State : Deep Yellow
M.P. : 142 °C
IR: : υmax(KBr) 1652 (C=O), 1602 (C=C) cm
-1
1H-NMR : (CDCl3) δ: 1.64-1.67 (6H, m, H3/H4/H5), 3.30-3.32 (4H,
m, H2/H6), 6.86 (2H, d, H9/H11, J = 8.4 Hz ), 7.31 (1H,
d, H4', J = 3.6 Hz), 7.11 (1H, d, Hα, J = 15.2 Hz), 7.50
(2H, d, H8/H12, J = 8.8 Hz), 7.43 (1H, d, H3', J = 4.0
Hz), 7.77 (1H, d, Hβ, J 15.2 Hz).
MS : (m/z) 423 (M+, 100 %)
CHN : Anal. Calculated for C19H22INOS: C, 51.94; H, 5.05, N,
3.19. Found: C, 52.04; H, 5.12; N, 3.26.
2.6 General Method for the Synthesis of 2-Pyrazolines of 4-
piperidin-1-ylbenzaldehyde (10a─l) (Scheme─IV)
A mixture of Chalcone (9a-l, 1.0 mmol) and hydrazine hydrate (3.0 mmol) in
ethanol (10 mL) was refluxed. After completion of the reaction (4-6 h, TLC
monitoring) the crude product was precipitated out when the reaction mixture was
poured onto ice-cold water (50 ml). The precipitates were collected by filtration,
washed with cold water followed by cold EtOH to obtain 2-pyrazolines which were
recrystallised from EtOH (95%) to obtain pure compounds 10a-l.
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Chapter -2 Experimental
146
2.6.1 1-[4-(3-Thiophen-2-yl-4,5-dihydro-1H-pyrazol-5-
yl)phenyl]piperidine (10a)
S
N
NNH
Yield : 65%
State : Red solid
M.P. : 132 °C
IR : υmax(KBr) 3313 (N-H) 1585 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.60-1.65 (6H, m, H3/H4/H5), 2.87 (1H, dd, J
= 16.3, 9.3 Hz, 4-Ha),3.30-3.31 (4H, m, H2/H6), 3.68
(1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.33 (1H, t, J = 9.8
Hz, 5-H), 6.85 (2H, d, H9/H11, J = 8.8 Hz ), 7.10 (1H, t,
H4', J = 4.2 Hz), 7.49 (2H, d, H8/H12, J = 8.8 Hz), 7.55
(1H, d, H5', J = 4.8 Hz), 7.75 (1H, d, H3', J = 3.6 Hz)
MS : (m/z) 311 (M+, 100 %)
CHN : Anal. Calculated for C18H21N3S: C, 69.42; H, 6.80; N,
13.49. Found: C, 69.35; H, 6.86; N, 13.56.
2.6.2 1-[4-(3-Thiophen-3-yl-4,5-dihydro-1H-pyrazol-5-
yl)phenyl]piperidine (10b)
S
N
NNH
Yield : 69%
State : Yellow solid
M.P. : 125 °C
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Chapter -2 Experimental
147
IR : υmax(KBr) 3312 (N-H) 1596 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.61-1.65 (6H, m, H3/H4/H5), 2.94 (1H, dd, J
= 16.4, 9.4 Hz, 4-Ha), 3.27-3.29 (4H, m, H2/H6), 3.71
(1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.39 (1H, t, J = 9.8
Hz, 5-H), 6.81 (2H, d, H9/H11, J = 8.7 Hz ), 7.23 (1H, t,
H4', J = 4.0 Hz), 7.42 (2H, d, H8/H12, J = 8.4 Hz), 7.51
(1H, d, H5', J = 4.8 Hz), 8.02 (1H, s, H2').
MS : (m/z) 311 (M+, 100 %).
CHN : Anal. Calculated for C18H21N3S: C, 69.42; H, 6.80; N,
13.49. Found: C, 69.47; H, 6.72; N, 13.44.
2.6.3 1-{4-[3-(3-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10c)
S
CH3N
NNH
Yield : 61%
State : Yellow solid
M.P. : 119-120 °C
IR: : υmax(KBr) 3307 (N-H) 1610 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.66 (6H, m, H3/H4/H5), 2.51 (3H, s,
Me), 2.81 (1H, dd, J = 16.1, 9.3 Hz, 4-Ha), 3.30-3.31
(4H, m, H2/H6), 3.62 (1H, dd, J = 16.1, 10.2 Hz, 4-Hb),
5.28 (1H, t, J = 9.8 Hz, 5-H), 6.81 (2H, d, H9/H11, J =
8.4 Hz ), 7.04 (1H, d, H5', J = 5.2 Hz), 7.42 (2H, d,
H8/H12, J = 8.4 Hz), 7.48 (1H, d, H4', J = 5.2 Hz).
MS : (m/z) 325 (M+, 100 %).
CHN : Anal. Calculated for C19H23N3S: C, 70.11; H, 7.12; N,
12.91. Found: C, 70.09; H, 7.07; N, 12.84.
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Chapter -2 Experimental
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2.6.4 1-{4-[3-(4-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10d)
S
CH3
N
NNH
Yield : 74%
State : Bright yellow solid
M.P. : 145 °C
IR : υmax(KBr) 3315 (N-H) 1602 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.66 (6H, m, H3/H4/H5), 2.26 (3H, s,
Me), 2.84 (1H, dd, J = 16.3, 9.3 Hz, 4-Ha), 3.30-3.32
(4H, m, H2/H6), 3.60 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb),
5.28 (1H, t, J = 9.9 Hz, 5-H), 6.77 (2H, d, H9/H11, J =
8.5 Hz ), 7.21 (1H, s, H5'), 7.43 (2H, d, H8/H12, J = 8.6
Hz), 7.54 (1H, s, H3', J = 4.8 Hz),
MS : (m/z) 325 (M+, 100 %).
CHN : Anal. Calculated C19H23N3S: C, 70.11; H, 7.12; N,
12.91. Found: C, 70.14; H, 7.07; N, 12.88.
2.6.5 1-{4-[3-(5-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10e)
Yield : 75%.
State : Orange red solid.
M.P. : 157 °C.
S
CH3
N
NNH
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Chapter -2 Experimental
149
IR : υmax(KBr) 3310 (N-H) 1589 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.67 (6H, m, H3/H4/H5), 2.53 (3H, s,
Me), 2.84 (1H, dd, J = 16.2, 9.1 Hz, 4-Ha), 3.30-3.32
(4H, m, H2/H6), 3.57 (1H, dd, J = 16.2, 10.0 Hz, 4-Hb),
5.23 (1H, t, J = 9.8 Hz, 5-H), 6.72 (1H, d, H4', J = 3.2
Hz), 6.77 (2H, d, H9/H11, J = 8.4 Hz ), 7.41 (2H, d,
H8/H12, J = 8.4 Hz), 7.51 (1H, d, H3', J = 3.2 Hz).
MS : (m/z) 325 (M+, 100 %).
CHN : Anal. Calculated for C19H23N3S : C, 70.11; H, 7.12; N,
12.91. Found: C, 70.03; H, 7.18; N, 12.97.
2.6.6 1-{4-[3-(2,5-Dimethylthiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10f)
S
CH3
CH3
N
NNH
Yield : 73%
State : Yellow solid
M.P. : 144 °C
IR : υmax(KBr) 3316 (N-H) 1582 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.66 (6H, m, H3/H4/H5), 2.39-2.60 (3H,
s, 2xMe), 2.77 (1H, dd, J = 16.3, 9.5 Hz, 4-Ha), 3.30-
3.32 (4H, m, H2/H6), 3.55 (1H, dd, J = 16.3, 10.2 Hz, 4-
Hb), 5.24 (1H, t, J = 10.0 Hz, 5-H), 6.78 (2H, d, H9/H11,
J = 8.7 Hz ), 7.02 (1H, s, H4'), 7.45 (2H, d, H8/H12, J =
8.4 Hz).
MS : (m/z) 339 (M+, 100 %).
CHN : Anal. Calculated for C20H25N3S: C, 70.76; H, 7.42; N,
12.38. Found: C, 70.69; H, 7.37; N, 12.37.
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Chapter -2 Experimental
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2.6.7 1-{4-[3-(3-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10g)
S
ClN
NH N
Yield : 65%
State : Yellowish brown solid
M.P. : 151 °C
IR : υmax(KBr) 3308 (N-H) 1597 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.66 (6H, m, H3/H4/H5), 3.12 (1H, dd, J
= 16.6, 10.2 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.96
(1H, dd, J = 16.7, 10.2 Hz, 4-Hb), 5.37 (1H, t, J = 10.2
Hz, 5-H), 6.80 (2H, d, H8/H12, J = 8.7 Hz ), 7.02 (1H, d,
H5', J = 5.2 Hz), 7.47 (1H, d, H4', J = 5.2 Hz), 7.49 (2H,
d, H9/H11, J = 8.8 Hz).
MS : (m/z) 346 (M+, 12 %), 311 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C19H24ClN3S : C, 62.50; H, 5.83;
N, 12.15. Found: C, 62.48; H, 5.76; N, 12.21.
2.6.8 1-{4-[3-(5-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10h)
S
Cl
N
NNH
Yield : 80%
State : Brown solid
M.P. : 147 °C
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Chapter -2 Experimental
151
IR : υmax(KBr) 3314 (N-H) 1606 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.64-1.68 (6H, m, H3/H4/H5), 2.86 (1H, dd, J
= 16.3, 10.1 Hz, 4-Ha), 3.29-3.30 (4H, m, H2/H6), 3.65
(1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 5.35 (1H, t, J = 10.3
Hz, 5-H), 6.86 (2H, d, H9/H11, J = 8.7 Hz ), 6.92 (1H, d,
H4', J = 4.0 Hz), 7.47 (2H, d, H8/H12, J = 8.4 Hz), 7.53
(1H, d, H3', J = 3.6 Hz).
MS : (m/z) 346 (M+, 18 %), 311 (M
+−Cl, 100 %).
CHN : Anal. Calculated for C18H20ClN3S: C, 62.50; H, 5.83; N,
12.15. Found: C, 62.42; H, 5.91; N, 12.09.
2.6.9 1-{4-[3-(2,5-Dichlorothiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10i)
S
Cl
Cl
N
NNH
Yield : 65%
State : Yellow solid
M.P. : 175 °C
IR : υmax(KBr) 3311 (N-H) 1605 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.66 (6H, m, H3/H4/H5), 3.14 (1H, dd, J
= 16.3, 10.0 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.95
(1H, dd, J = 16.4, 9.5 Hz, 4-Hb), 5.35 (1H, t, J = 10.3
Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8.5 Hz ), 7.09 (1H, s,
H4'), 7.46 (2H, d, H8/H12, J = 8.4 Hz).
MS : (m/z) 380 (M+, 100 %).
CHN : Anal. Calculated for C18H19Cl2N3S: C, 56.84; H, 5.04;
N, 11.05. Found: C, 56.74; H, 5.14; N, 11.09.
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Chapter -2 Experimental
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2.6.10 1-{4-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10j)
S
BrN
NH N
Yield : 77%
State : Yellowish brown solid
M.P. : 180 °C
IR : υmax(KBr) 3317 (N-H) 1600 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.66 (6H, m, H3/H4/H5), 3.14 (1H, dd, J
= 16.5, 10.2 Hz, 4-Ha), 3.25-3.28 (4H, m, H2/H6), 4.02
(1H, dd, J = 16.5, 10.6 Hz, 4-Hb), 5.35 (1H, t, J = 10.4
Hz, 5-H), 6.78 (2H, d, H9/H11, J = 8.4 Hz ), 7.05 (1H, d,
H5', J = 5.2 Hz), 7.46 (1H, d, H4', J = 5.2 Hz), 7.49 (2H,
d, H8/H12, J = 8.6 Hz).
MS : (m/z) 390 (M+, 100 %).
CHN : Anal. Calculated for C18H20BrN3S: C, 55.39; H, 5.16; N,
10.76. Found: C, 55.30; H, 5.20; N, 10.72.
2.6.11 1-{4-[3-(5-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10k)
S
Br
N
NNH
Yield : 78%
State : Brown solid
M.P. : 140 °C
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Chapter -2 Experimental
153
IR : υmax(KBr) 3305 (N-H) 1586 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.62-1.66 (6H, m, H3/H4/H5), 2.85 (1H, dd, J
= 16.2, 9.6 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.65
(1H, dd, J = 16.2, 9.6 Hz, 4-Hb), 5.32 (1H, t, J = 10.3
Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8. Hz ), 7.05 (1H, d,
H4', J = 4.0 Hz), 7.49 (2H, d, H8/H12, J = 8.4 Hz), 7.39
1H, d, H3', J = 3.6 Hz).
MS : (m/z) 390 (M+, 8%), 310 (M
+−Br, 100 %).
CHN : Anal. Calculated for C18H20BrN3S: C, 55.39; H, 5.16; N,
10.76. Found: C, 55.34; H, 5.14; N, 10.71.
2.6.12 1-{4-[3-(5-Iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-
yl]phenyl}piperidine (10l)
S
I
N
NNH
Yield : 72%
State : Yellowish brown solid
M.P. : 167 °C
IR : υmax(KBr) 3312 (N-H), 1608 (C=N) cm
-1
1H-NMR : (CDCl3) δ: 1.63-1.66 (6H, m, H3/H4/H5), 2.86 (1H, dd, J
= 16.3, 9.7 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.64
(1H, dd, J = 16.2, 10.1 Hz, 4-Hb), 5.29 (1H, t, J = 10.2
Hz, 5-H), 6.79 (2H, d, H9/H11, J = 8.4 Hz ), 7.15 (1H, d,
H4', J = 3.6 Hz), 7.50 (2H, d, H8/H12, J = 8.5 Hz), 7.32
(1H, d, H3', J = 4.0 Hz).
MS : (m/z) 437 (M+, 100 %).
CHN : Anal. Calculated for C18H20IN3S: C, 49.43; H, 4.61; N,
9.61. Found: C, 49.47; H, 4.55; N, 9.56.
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Chapter -2 Experimental
154
2.7 Protocols for Biological Studies
2.7.1 Antimicrobial Assay
The in vitro antimicrobial activity was done by the reported method.264
All
compounds (1a-k, 2a-k, 3a-s, 4a-s, 5a-k, 6a-k, and 9a-l) were screened for
antibacterial activity against Escherichia coli, Miicrococus luteus and Staphylococus
aureus using Chloramphenicol (1.00 mmol/ml) as standard. The antifungal activity
was investigated against Aspergellus flavus, Aspergellus niger and Curvuliaria lunata
using Flucanazole (1.00 mmol/ml) as standard. At the end of 24 h and 48 h for
bacteria and fungi respectively, the inhibition was recorded measuring the diameter of
the inhibition zone. Each experiment was repeated thrice and the average of the three
independednt determinations was recorded. The results are summarized in table 6.
2.7.2 Antileishmanial Assay
All compounds (1a-k, 2a-k, 3a-s, 4a-s, 5a-k, 6a-k and 9a-l) were tested for
the antileishmanial activity using L. major promastigotes as parasites for in vitro
screening. Parasites were cultured at 24C in Shaking incubator on M 199 medium
containing foetal bovine serum (10%); HEPES (25 mM), and penicillin and
streptomycin (0.22g each).265
Each compound (1 mg) was dissolved in DMSO (1 ml) and Amphotericin B
(1 mg) taken in DMSO (1 ml) was used as a positive control. Parasites were taken
from lag phase of their growth and were centrifuged at 3000 rpm for 3 minutes. The
parasite density was maintained at 2x106
cells/ml by diluting with fresh culture
medium. In 96-well plates, 180 l of medium was added in different wells. The
experimental compound (20 l) was added in medium and serially diluted. Parasite
culture (100 l) was added in all wells. In Negative controls, DMSO was serially
diluted in medium while the positive control contained varying concentrations of
standard antileishmanial compound i.e. Amphotericin B. The plates were incubated
for 72 h at 24 C. The culture was examined microscopically on an improved neubaur
counting chamber and IC50 values of compounds possessing antileishmanial activity
were calculated. All assays were run in duplicate. The results are summarized in table
7, 8 and 10.
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Chapter -2 Experimental
155
2.7.3 Determination of IC50 values of the titled compounds (1a-k, 2a-
k, 3a-s, 4a-s, 5a-k, 6a-k and 9a-l)
Prism windows-based software is used to run different biological screening
activity to find out IC50 / LD50.
In case of antileishmanial activity, after running the samples and calculating
the % of inhibition in serial dilution methods (It depends on the activity of the
compounds; some of them show in 4-6-7 or 10 dilution the inhibitory concentration).
After that we count the number of parasite in neubauer chamber (0,0025 mm2) and we
implement the result manually in the prism windows-based software.
2.7.4 Anti-HIV-1 Assay
The antiviral assays in human PBMCs were performed according to the
reported procedure.266,267
According to the procedure phytohemagglutinin- stimulated
human PBMCs were made infected with LAV-1 strain of HIV-1. The tested
compounds were then added to cultures. Uninfected and untreated PBMCs were
grown as controls in parallel at equivalent cell concentrations. The cultures were
incubated for 6 days after infection, in a humidified 5% CO2-95% air incubator at
37°C at which point all cultures were sampled for Anti-HIV-1 activity. The
supernatant was clarified, and the viral particles were then pelleted at 40,000 rpm for
30 min by using a rotor (70.1 Ti; Beckman Instruments, Inc., Fullerton, Calif.) and
suspended in virus-disrupting buffer. The RT assay was performed by a modification
of the method of Spira et al. in 96-well microdilution plates by using (rA)n . (dT)12-18
as the template primer. The RT results were expressed in disintegrations per minute
per milliliter of originally clarified supernatant. The results are summarized in table 9
and 11.
2.7.5 Cytotoxic Assay
The cytotoxic activity were also performed according to the literature
method.268,269
The compounds were evaluated for their potential toxic effects on
uninfected PHA-stimulated human PBM cell, CEM (T-lymphoblastoid cell line
obtained from American Type Culture Collection, Rockville, MD) and Vero (African
green monkey kidney) cells. Log phase Vero, CEM and PHA stimulated human PBM
cells were seeded at a density of 5×103, 2.5×103, and 5×104 cells/well, respectively.
All of the cells were plated in 96-well cell culture plates containing 10-fold serial
dilutions of the test drug. The cultures were incubated for 2, 3, and 4 days for Vero,
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Chapter -2 Experimental
156
CEM, and PBM cells, respectively, in a humidified 5% CO2–air at 37 ◦C. At the end
of incubation, MTT tetrazolium dye solution (cell titer 96, Promega, Madison, WI)
was added to each well and incubated overnight. The reaction was stopped with stop
solubilization solution (Promega, Madison, WI). The plates were incubated for 5 h to
ensure that the formazan crystals were dissolved. The plates were read at 570 nm
using an ELISA plate reader (Bio-Tek Instruments, Inc., Winooski, VT, Model EL
312e). The 50% inhibition concentration (IC50) was determined from the
concentration–response curve using the median effect method.270,271
The results are
summarized in table 9 and 11.
2.7.6 Determination of EC50 and EC90
The median effective concentrations (EC50s) and inhibitory concentrations
(IC50s) were derived from the computer-generated median effect plot of the dose
effect data, as described previously.272,273
From the slope of the dose-effect plot and
the EC50, the computer program also generated the 90% effective concentration
(EC90). The ratios of the drugs selected for the combination studies were based on the
relative potencies of the individual compounds. The combination index (CI) for the
combined effects of the drugs was also determined by using the same computer
program. For the analyses we used constant ratios of the drugs. The CI values were
determined from the median effect plot by using a conservative, mutually
nonexclusive equation. CI values of <1, 1, or >1 indicate synergism, additive ism, or
antagonism, respectively
2.8 X-Ray Crystallography
A colorless prismatic crystal of (3k, 3m, 3p and 3q) was coated with Paratone
8277 oil (Exxon) and mounted on a glass fiber. All measurements were made on a
Nonius KappaCCD diffractometer with graphite monochromated Mo-K radiation.
The data were collected274
using and scans. The data were corrected for Lorentz
and polarization effects and for absorption using multi-scan method.275
The structure was solved by the direct methods276
and expanded using Fourier
techniques.277
The non-hydrogen atoms were refined anisotropically. The H-atoms
were included at geometrically idealized positions and were not refined. The final
cycle of full-matrix least-squares refinement using SHELXL97278
converged with
unweighted and weighted agreement factors, R = 0.037 and wR = 0.086 (for 2933
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Chapter -2 Experimental
157
observed data with I > 2.0σ(I)), respectively, and goodness of fit, S = 1.01. The
weighting scheme was based on counting statistics and the final difference Fourier
map was essentially featureless. The figure was plotted with the aid of ORTEP-3 for
Windows.279
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Chapter – 3
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Chapter -3 Results & Discussion
158
Chapter 3
RESULTS AND DISCUSSION
3.1 Chemistry of Quinolyl Chalcones and their 2-
Pyrazoline Derivatives
3.1.1 Chemistry of Quinolyl Chalcones (1a-k, 2a-k, 3a-s and 4a-s)
All the chalcones were prepared by Claisen-Schmidt condensation reaction
between equimolar quantities of 6-OMe or 6/7/8-Me-substituted 2-Chloro-3-
formylquinolines with various aromatic and heteroaromatic ketones in methanol in the
presence of 10% NaOH solution. The product was precipitated out by stirring the
mixture at room temperature. The crude product was obtained by filtration and
washing first with water and then with cold methanol. It was then recrystallized from
EtOH to give pure compounds (1a-k, 2a-k, 3a-s and 4a-s). The general structure of
these chalcones is given below:
N
O
Ar
Cl
R1
R2
R3
Ketones Ar Ketones Ar
a Thien-3-yl k 5-I-thien-2-yl
b 3-Me-thien-2-yl l 1H-pyrrol-2-yl
c 4-Me-thien-2-yl m 5-Me-furan-2yl
d 5-Me-thien-2-yl n 2,5-diMe-furan-3-yl
e 2,5-diMe-thien-3-yl o Benzofuran-2-yl
f 3-Cl-thien-2-yl p 2,3-diH-1,4-benzodioxin-6-yl
g 5-Cl-thien-2-yl q 1-Naphthyl
h 2,5-diCl-thien-3-yl r 2-Naphthyl
i 3-Br-thien-2-yl s 9-Anthryl
j 5-Br-thien-2-yl
(1a-k): R2R
3 = H, R
1 = CH 3, Ar = a-k
(2a-k): R1R
3 = H, R
2 = CH 3, Ar = a-k
(3a-s): R1R
2 = H, R
3 = CH 3, Ar = a-s
(4a-s): R1R
2 = H, R
3 = OMe, Ar = a-s
1
3
2
45
6
7
8
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Chapter -3 Results & Discussion
159
All the prepared compounds were characterized by spectroscopic techniques
(NMR, IR, MS) and elemental analysis. The MS was employed only for the molecular
mass confirmation. For structure elucidation, 1H NMR spectroscopy was used. The X-
ray crystallographic study of 3k, 3m, 3p and 3q was also performed for the structure
confirmation. Elemental analyses were done after the recrystallization of the
compounds in appropriate solvents.
IR Spectra
Selected diagnostic bands of the IR spectra of the chalcones (1a-k, 2a-k, 3a-s
and 4a-s) showed useful information about the structure of the compounds. Two
significant stretching bands due to ethylenic group C=C and carbonyl group C=O
were observed at 1585-1598 and 1648-1664 cm-1
respectively, which are typical
stretching regions for chalcone moiety. The quinoline C=N stretching appeared at
1563-1572 cm-1
in all of the title compounds. The characteristic band for thiophene
(a-k derivatives) was observed at 750-700 cm-1
. The C─O─C stretching of furyl ring
in (3m-o and 4m-o) appeared at 1040-1075 cm-1
. In addition, the spectra of (3l and 4l)
showed a stretching band resulting from the NH stretching of the pyrrole moiety at
3215 cm-1
.
Mass Spectra
The molecular ion, observed in the mass spectra for all the chalcones,
confirmed their molecular masses. The base peak in the mass spectra of most of
compounds was obtained by the cleavage of C-Cl bond in 2-Chloroquinoline moiety.
1NMR Spectra
The 1H-NMR spectra of the chalcones (1a-k, 2a-k, 3a-s and 4a-s) reveal, that
the Cα-H and Cβ-H protons are so much deshielded that their signal is shifted
considerably downfield to such an extent that they appear in the aromatic region (δ
7.22-8.23). As a result, two very sharp doublets around 7.4 ppm for Hα and 8.2ppm
for Hβ, with a coupling constant 15.4-16.2 Hz for the trans chalcones were observed,
except (1f/1i, 2f/2i, 3f/3i and 4f/4i). Interestingly, Hα showed a doublet relatively in
the downfield at δ 7.82-7.83 in chalcones (1f/1i, 2f/2i, 3f/3i and 4f/4i). This was
attributed to an additional (-)I of the groups like Cl/Br in the vicinity i.e. on the 3‟
position of thiophene ring.
The thiophenyl protons appear in the region δ 6.24-8.20 ppm. The
unsubstituted thiophenyl derivatives (1a, 2a, 3a and 4a) show three signals, for
protons H2', H4' and H5'. The most deshielded of these is H2', which appears as
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Chapter -3 Results & Discussion
160
doublets of doublet at δ 8.20 ppm with J = 2.9, 1.0 Hz. This large δ value is due to the
presence of carbonyl oxygen atom in the vicinity, which increases Other two protons
H4' and H5' both appear as dd at δ 7.39
S
O
NCl
H2'
H4'
H
H
H5' R
(J = 5.1 and 2.9 Hz) and 7.70 ppm (J = 5.1 and 1.0 Hz) respectively. Similarly, 3-
substituted thiophenyl derivatives (1-4 b, f and i) show two doublets, representing H4',
H5' at δ 7.10 and 7.49 ppm respectively, with J = 4.9 Hz for both the protons. In case
of 5-substituted thiophenyl derivatives (1-4 d, g, j and k) two doublets appear at δ
6.87-7.36 and 7.51-7.72 ppm for protons H4' and H3' with J = 4.0 for both the protons.
For 4-substituted thiophenyl derivatives (1-4 c) two sharp singlets are observed at δ
7.31 and 7.71 ppm for H5' and H3' respectively. In case of disubstituted thiophenyl
derivatives (1-4 e and h) a sharp singlet appeared at δ 7.10 ppm.
The aromatic protons of quinolyl, thienyl, furyl, pyrrolyl, naphthyl and anthryl
rings appeared in the expected region δ 6.24-8.56 ppm.
X-Ray Crystallography
The E-configuration of chalcones was confirmed by X-ray structure of 3k,
3m, 3p and 3q and have already been reported.280-282
3.1.2 Chemistry of Pyrazolines of Quinolyl Chalcones (5a-k, 6a-k,
7a-k and 8a-k)
The pyrazoline derivatives of the synthesized chalcones were prepared by
refluxing them with hydrazine hydrate in ethanolic solution. The product was
precipitated within the reaction flask, which was filtered, washed (first with water and
then with cold ethanol), dried and ultimately recrystallized from ethanol.
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Chapter -3 Results & Discussion
161
N
Ar
O
ClR2
R1
R3
NH2NH
2.H
2O
EtOHN ClR
2
R1
NH N
ArR
3
(1a-k) R1= CH 3 R
2R
3= H
(2a-k) R2= CH 3 R
1R
3= H
(3a-k) R3= CH 3 R
1R
2= H
(4a-k) R3= OCH 3 R
1R
2= H
(5a-k)
(6a-k)
(7a-k)
(8a-k)
Ketones Ar Ketones Ar
a Thien-3-yl g 5-Cl-thien-2-yl
b 3-Me-thien-2-yl h 2,5-diCl-thien-3-yl
c 4-Me-thien-2-yl i 3-Br-thien-2-yl
d 5-Me-thien-2-yl j 5-Br-thien-2-yl
e 2,5-diMe-thien-3-yl k 5-I-thien-2-yl
f 3-Cl-thien-2-yl
IR Spectra
The formation of product (5a-k, 6a-k, 7a-k and 8a-k) was confirmed by the
disappearance of C=O peak at 1648-1664 cm-1
and appearance of characteristic ring
stretching bands of C=N at 1590-1500 cm-1
. In addition, another stretching band of N-
H at 3274-3288 cm-1
confirmed the ring closure at chalcone moiety. Moreover, the
absorption bands at 1020-1108 cm-1
were attributed to the C─N stretching vibrations,
which also confirmed the formation of desired pyrazoline ring in all the compounds.
Mass Spectra
The molecular ion M+, observed in the mass spectra for all the pyrazolines,
confirmed their molecular masses. The base peak, in all of the mass spectra (except
for 6f, where the quinoline nucleus fragments to give M+−C10H7NCl), was exhibited
by M+ itself.
1NMR Spectra
In proton NMR spectra, the disappearance of ethylenic protons between δ
7.22-8.23 ppm and appearance of a peak at δ 1.5 (±0.02) for CH2 in pyrazolines,
further confirmed the formation of proposed compounds. Th 1H-NMR signal for N-H
proton is so weak that it does not appear in the spectra. In the 1H-NMR spectra of the
pyrazolines (5a-k, 6a-k, 7a-k and 8a-k) reveal the presence of two doublets of
doublet signals due to CH2 protons Ha (upfield H of CH2) at δ 2.82-3.21 ppm region,
and Hb (downfield H of CH2) at 3.64-4.10 ppm. The CH proton appeared as a triplet
at δ 5.28-5.40 ppm region.
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Chapter -3 Results & Discussion
162
3.2 Chemistry of Piperidyl Chalcones and their 2-
Pyrazoline Derivatives
3.2.1 Chemistry of Piperidyl Chalcones (9a-l)
The precursor 4-piperidin-1-ylbenzaldehyde was prepared by N-arylation of
piperidine with 4-fluorobenzaldehyde in the presence of K2CO3 and CTAB, in DMF
as solvent. The 4-piperidin-1-ylbenzaldehyde was then condensed with various
thienyl ketones in alkaline medium with constant stirring at room temperature. The
title compounds (9a-l) were precipitated out within the reaction flask, which were
then filtered washed with water and then with cold methanol. The pure products were
obtained after recrystallization from methanol.
NH
NaOH/EtOH
r. t.+ Ar
O
O
H
F+ N
O
H
N
O
H
N
O
Ar
(9)
(9) (9a-l)
Ketones Ar Ketones Ar
a Thien-2-yl g 3-Cl-thien-2-yl
b Thien-3-yl h 5-Cl-thien-2-yl
c 3-Me-thien-2-yl i 2,5-diCl-thien-3-yl
d 4-Me-thien-2-yl j 3-Br-thien-2-yl
e 5-Me-thien-2-yl k 5-Br-thien-2-yl
f 2,5-diMe-thien-3-yl l 5-I-thien-2-yl
K2CO3, CTAB
DMF, 100 °C
IR Spectra
Selected bands of the IR spectra of the chalcones (9a-l) showed significant
information about their structures. Two typical stretching bands of chalcone moiety,
due to ethylenic group C=C and carbonyl group C=O were observed at 1590-1607
and 1650-1658 cm-1
respectively. The characteristic band for thiophene (a-l
derivatives) was observed at 750-700 cm-1
.
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Chapter -3 Results & Discussion
163
Mass Spectra
Very interesting mass spectra of compounds (9a-l) were obtained, in terms
that the base peak, in all the spectra was exhibited by M+ itself. This gives information
about the stability of the piperidyl chalcone nucleus. Molecular masses of compounds
(9a-l) were also confirmed by their mass spectra.
1NMR Spectra
The 1H-NMR spectra of the chalcones (9a-l) show that the Hα and Hβ protons
appear in the aromatic region (δ 7.09-7.79). As a result, two very sharp doublets
around 7.10 ppm for Hα and 7.79 ppm for Hβ, with a coupling constant 15.2-15.6 Hz
for the trans chalcones were observed. Here also, the signals of the Hα, for chalcones
(9g and 9j) appeared relatively in the downfield at δ 7.55. This again was attributed to
an additional (-)I of the groups like Cl/Br in the vicinity i.e. on the 3‟ position of
thiophene ring.
3.2.2 Chemistry of Pyrazolines of Piperidyl Chalcones (10a-l)
The pyrazoline derivatives of the synthesized piperidyl chalcones were
prepared by refluxing them with hydrazine hydrate in ethanolic solution. The product
(10a-l) was precipitated within the reaction flask, which was filtered, washed (first
with water and then with cold ethanol), and recrystallized from ethanol.
N
O
Ar
(10a-l)
N
Ar
NH N
+
(9a-l)
NH2 NH2EtOH
reflux
Ketones Ar Ketones Ar
a Thien-2-yl g 3-Cl-thien-2-yl
b Thien-3-yl h 5-Cl-thien-2-yl
c 3-Me-thien-2-yl i 2,5-diCl-thien-3-yl
d 4-Me-thien-2-yl j 3-Br-thien-2-yl
e 5-Me-thien-2-yl k 5-Br-thien-2-yl
f 2,5-diMe-thien-3-yl l 5-I-thien-2-yl
IR Spectra
The formation of product (10a-l) was confirmed by the disappearance of C=O
peak at 1650-1658 cm-1
and appearance of characteristic ring stretching bands of C=N
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Chapter -3 Results & Discussion
164
at 1610-1580 cm-1
. Moreover, an additional stretching band of N-H at 3305-3317 cm-1
confirmed the ring closure at chalcone moiety.
Mass Spectra
The molecular ion M+, observed in the mass spectra for all the pyrazolines,
confirmed their molecular masses. Again, the base peak, in all of the mass spectra
(except for 10g-h and 10k where the M+−Cl and M
+−Br gave the base peak,
respectively), was exhibited by M+ itself.
1NMR Spectra
The disappearance of signals between δ 7.22-8.23 ppm for olefinic protons in
the 1H NMR spectra and appearance of peaks at δ 2.77-3.14, 3.55-4.02, and 5.24-5.39
for CH2 (Ha and Hb respectively) and H-5 in pyrazoline ring, further confirmed the
formation of target compounds. The 1H-NMR spectra of pyrazolines (10a-l), show the
presence of two doublets of doublet signals due to CH2 protons, Ha (upfield H of CH2)
at δ 2.82-3.21 ppm region and Hb at 3.64-4.10 ppm. The CH proton appeared as a
triplet at δ 5.28-5.40 ppm region.
3.3 Biological Activities of Chalcones
The prepared chalcones were screened for various biological properties like
antifungal, antibacterial, antileishmanial, anti-HIV-1 and cytotoxicity.
Panels of Micro-organisms:
Bacteria: E. coli, M. luteus and S. aureus
Fungii: A. flaves, A. niger and C. lunata
Leishmania: L. major
Anti-HIV-1: Human PBM cells.
Cytotoxicity: Human PBM, CEM and VERO
The panel of the microorganisms was chosen following the literature (See
chapter 1). Actually, these are very common and highly pathogenic microorganisms
which are commonly found anywhere in the world, especially in Pakistan.
The results of these assays are tabulated below.
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Chapter -3 Results & Discussion
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3.3.1 Antimicrobial Studies of Quinolyl Chalcones (3a-s and 4a-s)
Table 6. Antimicrobial activity of compounds (3a-s and 4a-s) Antibacterial activity Zone of Antifungal activity Zone of
Inhibition in mm Inhibition in mm
Compound E. coli M. luteus S. aureus A. flaves A. niger C. lunata
3a 21 31 34 10 11 12
3b 16 23 25 8 10 11
3c 14 27 31 7 9 8
3d 13 22 26 4 10 9
3e 11 20 22 3 8 5
3f 30 28 30 20 15 11
3g 32 30 38 18 17 15
3h 36 35 39 13 15 10
3i 28 34 40 16 17 12
3j 20 22 31 10 9 10
3k 15 21 19 7 9 11
3l 36 33 37 10 11 14
3m 1 6 27 31 12 13 10
3n 11 17 15 3 5 6
3o 36 30 31 8 16 11
3p 37 30 39 11 12 15
3q 11 25 35 10 15 13
3r 15 17 25 11 10 11
3s 10 15 11 10 12 10
4a 22 32 35 11 12 13
4b 20 28 29 7 6 5
4c 16 23 37 10 11 9
4d 14 27 30 8 8 10
4e 12 22 24 4 7 6
4f 31 30 33 22 17 10
4g 33 32 39 20 21 18
4h 38 35 41 25 22 20
4i 37 34 40 12 14 11
4j 21 20 30 9 6 11
4k 14 18 12 6 8 10
4l 30 36 41 16 16 13
4m 18 30 32 10 10 11
4n 13 19 12 2 3 8
4o 37 34 33 11 17 18
4p 38 32 41 12 13 16
4q 12 27 37 13 16 14
4r 25 30 35 10 11 11
4s 17 20 13 11 13 12
Standarad 39 36 43 17 18 16
DMF +ve +ve +ve +ve +ve +ve +ve indicates microbial growth. Control: DMF (0.01% solution in distilled water). Standard for
antibacterial:
Chloramphenicol (1.00 mmol/ml). Standard for antifungal: Flucanazole (1.00 mmol/ml)
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Chapter -3 Results & Discussion
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Antibacterial Activity
Compounds 4h, and 4o-p, from substituted heteroaryl derivatives have shown
promising antibacterial activities (almost equivalent to standard) against all the three
bacterial strains i.e., E. coli, M. luteus and S. aureus. Among the two series of
compounds, unsubstituted thiophenyl derivatives (3a and 4a) exhibited almost
equivalent antibacterial activities to that of the standard (Table 6). Activity decreases
considerably by the substitution of methyl and halo groups at position 5 of thiophenyl
ring (3d, 4d, 3g, 4g, 3j, 4j, 3k and 4k; Table 6). Incorporation of chlorine at position
5 of thiophenyl ring (3g and 4g) enhanced the activity to a considerable extent; it is
further increased by the incorporation of another chlorine atom at position 2 (3h and
4h). However, incorporation of same groups at positions 3 and 4 (3b, 3c, 3f, 3i, 4b,
4c, 4f, and 4i) exhibited no difference in activity except of bromo derivatives. In case
of furanyl derivatives, incorporation of a second methyl group at position 2 (3n and
4n) considerably decreases the activity than of the mono substituted one (3m and
4m). In general, activity enhances by the substitution of aromatic rings with electron
withdrawing groups and is suppressed by the incorporation of electron donating
methyl groups. No systematic change has been observed in antibacterial activities for
the rest of the compounds (Table 6).
Antifungal Activity
Among the compounds under investigation, un-substituted thiophenyl
derivatives (3a and 4a) are found almost equivalent in their antifungal activities to the
standard. In general, activity decreases in the compounds having substitution at
position 2, 3 and 5 by the incorporation of electron donating methyl groups at
aromatic rings while it enhances by the substitution of electron withdrawing groups.
Among the electron withdrawing groups, activity increases with the electronegativity
of the substituent. However, such substitutions at position 4 (3c and 4c) displayed no
marked difference in the activities. No systematic change has been observed in
antibacterial activities for the rest of the compounds (Table 6).
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Chapter -3 Results & Discussion
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3.3.2 Antileishmanial Studies of Quinolyl Chalcones (3a-s and 4a-s)
Table 7. Antileishmanial activity of the series 3a-s and 4a-s (IC50 values)
Compounds IC50 µg/ml Compounds *IC50 µg/ml
3a 0.58±0.02 4a 0.59±0.01
3b 0.75±0.05 4b 0.82±1.25
3c 0.27±0.02 4c 0.84±0.35
3d 0.34±0.06 4d 0.61±0.05
3e 0.16±0.19 4e 0.93±0.08
3f 0.78±0.07 4f 0.68±0.56
3g 0.23±0.50 4g 0.23±0.50
3h 0.81±0.45 4h 0.69±0.06
3i 0.57±0.01 4i 0.79±0.78
3j 0.42±0.62 4j 0.32±0.62
3k 0.31±0.03 4k 0.41±0.03
3l 0.33±0.06 4l 0.33±0.06
3m 0.37±0.10 4m 0.27±0.10
3n 0.84±0.58 4n 0.29±0.03
3o 0.87±1.25 4o 0.22±0.19
3p 0.26±0.08 4p 0.46±0.08
3q 0.91±1.69 4q 0.57±0.02
3r 0.21±0.04 4r 0.31±0.04
3s 0.29±0.03 4s 0.39±0.03
Standard Drug
MIC(µg/ml±S.D)
(Amphotericin B)
0.56±0.20 Standard Drug
MIC(µg/ml±S.D)
(Amphotericin B)
0.56±0.20
Antileishmanial Activity
According to the results obtained, it is evident that unsubstituted thiophenyl
derivatives (3a and 4a) are almost equally active (IC50=0.58±0.02µg/ml for 3a and
IC50=0.59±0.01µg/ml for 4a), comparable to the standard, amphotericin B
(IC50=0.56±0.20µg/ml) while the activity enhances considerably by the substitution of
methyl and halo groups at position 5 of thiophenyl ring (3d, 4d, 3g, 4g, 3j, 4j, 3k and
4k; Table 7). Among the compounds, derivatized at position 5, chloro analogues (3g
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Chapter -3 Results & Discussion
168
and 4g) are the most active. However, incorporation of these functionalities at
position 3 of thiophenyl ring (3b, 4b, 3f, 4f, 3i and 4i) instead of position 5,
deactivates the compounds except of bromo derivative (3i) perhaps due to electronic
and steric reasons. Incorporation of methyl group at position 4 (3c) in category 3
increases the activity than its analogue 3b, derivatized at position 3
(IC50=0.75±0.05µg/ml for 3b and IC50=0.27±0.02µg/ml for 3c), while no prominent
difference in activities is observed by the same change in category 4 (4b and 4c
respectively, Table 7). Similarly, the replacement of two methyl groups at position 2
and 5 of thiophenyl ring (3e and 4e) by two chloro groups (3h and 4h), significantly
decreases the activity (by about 5 times) in category 3; reverse is observed in case of
category 4. In case of furanyl derivatives, incorporation of a second methyl group at
position 2 considerably decreases the activity (3n) than of the mono substituted one
(3m) in category 3, whereas in category 4 no marked difference is observed whether
one (4m) or two (4n) methyl groups are present on the furanyl ring. For the rest of the
compounds, no systematic change in anti-leishmanial activities is observed (Table 7).
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Chapter -3 Results & Discussion
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3.3.3 Antileishmanial Studies of Quinolyl Chalcones (1a-k and 2a-k)
and their 2-pyrazoline derivatives (5a-k and 6a-k)
Table 8. Antileishmanial activity of series 1a-k, 2a-k, 5a-k and 6a-k (IC50 values)
Antileishmanial Activity
According to the results obtained, among the two series of chalcones (1a-k
and 2a-k), the unsubstituted thiophenyl derivatives (1a and 2a) have prominent
Compounds IC50 µg/ml Compounds *IC50 µg/ml
1a 0.61±0.81 5a 0.67±0.09
1b 0.94±0.10 5b 0.78±0.23
1c 0.59±0.09 5c 0.74±0.09
1d 0.61±1.25 5d 0.89±0.10
1e 0.73±0.08 5e 0.93±0.16
1f 0.78±0.15 5f 0.84±0.07
1g 0.65±0.14 5g 0.75±0.02
1h 0.85±0.18 5h 0.79±0.03
1i 0.93±0.99 5i 0.94±0.20
1j 0.78±0.032 5j 0.93±0.20
1k 0.67±0.23 5k 0.77±0.02
2a 0.88±0.20 6a 0.94±0.02
2b 0.92±0.11 6b 0.76±0.05
2c 0.83±0.05 6c 0.87±0.08
2d 0.74±0.31 6d 0.89±0.03
2e 0.62±0.24 6e 0.76±0.19
2f 0.59±0.20 6f 0.78±0.07
2g 0.81±0.09 6g 0.83±0.50
2h 0.78±0.14 6h 0.71±0.45
2i 0.71±0.18 6i 0.85±0.18
2j 0.91±0.31 6j 0.93±0.62
2k 0.84±0.22 6k 0.88±0.27
Standard Drug
MIC(µg/ml±S.D)
(Amphotericin B)
0.56±0.20 Standard Drug
MIC(µg/ml±S.D)
(Amphotericin B)
0.56±0.20
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Chapter -3 Results & Discussion
170
difference in antileishmanial activities i.e. 1a is more active than 2a
(IC50=0.61±0.81µg/ml for 1a and IC50=0.88±0.20µg/ml for 2a), while the activity
decreases considerably by the introduction of methyl group at position 3 of thiophenyl
ring (1b and 2b; Table 8), but replacement of methyl group by halo groups (Cl and
Br) at position 3 (1f, 1i, 2f and 2i) enhances the activity except for 1i. Moreover, the
activity decreases in the order Cl>Br>Me. However, incorporation of these
functionalities at position 5 of thiophenyl ring (1d, 1g, 1j, 1k, 2d, 2g, 2j and 2k)
instead of position 3, activates the compounds except of 2g and 2j, perhaps due to
electronic and steric reasons. Among the compounds, derivatized at position 5, methyl
analogues (1d and 2d) are the most active and the order of activity is; Me>Cl>I>Br.
Incorporation of methyl group at position 4 (2c) in series 2 increases the activity a
little bit than its analogue 2b, derivatized at position 3 (IC50=0.92±0.11µg/ml for 2b
and IC50=0.83±0.05µg/ml for 2c), while very large difference in activities is observed
by the same change in series 1 (1b and 1c respectively, Table 8). Similarly, the
replacement of two methyl groups at position 2 and 5 of thiophenyl ring (1e and 2e)
by two chloro groups (1h and 2h), significantly decreases the activity in both the
series. Lastly, the order of activity by the incorporation of methyl group at three
different positions i.e. 3-, 4- and 5- of thiophenyl ring is; -5 > -4 > -3 in both the series
(1a-k and 2a-k).
It is clear from the Table 8, that the conversion of the two series of chalcones
(1a-k and 2a-k) to their corresponding 2-pyrazoline derivatives (5a-k and 6a-k), there
is an overall decrease in the antileishmanial activity. Moreover, the order of
antileishmanial activity w.r.t different substituents at different positions of thiophenyl
ring also changes. For instance, 3-substituted thiophenyl derivatives (5b, 5f, 5i, 6b, 6f
and 6i) exhibit the following order of activity; Me>Cl>Br. In case of 5-substituted
thiophenyl derivatives (5d, 5g, 5j, 5k, 6d, 6g, 6j and 6k), the activity decreases in the
order; Cl>I>Me>Br. Similarly, 2,5-Dichloro derivatives (5h and 6h) are more active
than the corresponding dimethyl ones (5e and 6e). Lastly, the order of activity by the
incorporation of methyl group at three different positions of thiophenyl ring is; -4 > -3
> -5 in both the series (5a-k and 6a-k).
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Chapter -3 Results & Discussion
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3.3.4 Anti-HIV-1 and Cytotoxic Studies of 2-Pyrazoline Derivatives
of Quinolyl Chalcones (5a-k and 7a-k)
Table 9. Anti- HIV-1 activity in human PBM cells and cytotoxicity (IC50, μM)
Anti- HIV-1 Activity in PBM cells Cytotoxicity (IC50, μM) in:
Code EC50, μM EC90, μM PBM CEM VERO
5a 8.5 21.0 20.2 39.7 26.0
5b 9.1 42.0 31.1 32.8 52.4
5c 7.7 34.5 13.4 30.4 52.6
5d 41.2 98.2 > 100 (0.8) ≥100 (45.3) 29.3
5e 14.5 42.4 42.2 42.1 41.0
5f 6.0 25.9 16.1 60.8 53.1
5g 66.9 ≥100 (72.5) >100 (1.7) > 100 (40.5) 58.8
5h 5.4 23.2 30.1 18.1 27.5
5i 7.3 28.0 17.1 29.1 25.5
5j 79.0 ≥100 (65.9) >100 (-11.0) 44.9 35.5
5k*
7a 22.7 77.6 44.1 44.0 28.6
7b 30.3 51.5 31.5 34.5 34.7
7c 3.4 18.4 49.7 8.8 >100 (38.7)
7d 26.3 64.2 50.5 33.4 32.9
7e 16.9 66.5 37.0 35.5 14.3
7f 14.5 43.6 >100 (1.6) 36.5 15.9
7g 5.5 68.3 29.6 16.3 27.2
7h 22.8 39.9 >100 (4.6) > 100 (35.5) 15.0
7i 3.7 20.0 13.4 31.1 32.6
7j*
7k* *Not Determined
Anti-HIV-1 and Cytotoxicity
The results show that unsubstituted thiophenyl derivative in series 5 displays
moderate activity while that in series 7 no activity has been observed. Incorporation
of Me/Cl/Br group at position 3 renders the resulting compound moderately active in
series 5, whereas in series 7 no activity is observed in 7b, weak activity in 7f and
moderate activity in 7i. If methyl group is present at position 4 then the resulting
compound (5c and 7c) showed moderate activity in both the series. Incorporation of
Me/Cl/Br group at position 5 imparts no antiviral activity in series 5 (5d, 5g and 5j)
whereas in case series 7 only Chloro substituted (7f) showed moderate activity. In
case of dimethyl-substituted thiophenyl derivatives (5e and 7e) weak activity is
observed, whereas dichloro-substituted thiophenyl derivatives (5h and 7h) exhibited
moderate activity in series 5 and no activity in series 7.
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Chapter -3 Results & Discussion
172
It is concluded that none of the compounds of the two series (5a-k and 7a-k)
have been proved to be good antiviral agent, although moderate activities have been
exhibited by a few ones (5a-c, 5f, 5h, 5i, 7c, 7g and 7i).
3.3.5 Antileishmanial Studies of Piperidyl Chalcones (9a-l)
The piperidine-based chalcones (9a-l) have not been proven to be good
antileishmanial agents. The results of the assays are given in the table 10.
Table 10. Antileishmanial activity of the series (9a-l) (IC50)
The compounds are classified into four categories as far as their
antileishmanial activities are concerned i.e. IC50 = 0.59-0.56 or below as significantly
active, 0.69-0.60 as good activity, 0.79-0.70 as moderately active and 0.95-0.80 as
low activity. On this basis, it is concluded that the piperidyl chalcones are inactive
towards leishmaniasis.
Compounds IC50 µg/ml
9a > 1.00
9b > 1.00
9c > 1.00
9d > 1.00
9e > 1.00
9f > 1.00
9g > 1.00
9h > 1.00
9i > 1.00
9j > 1.00
9k > 1.00
9l > 1.00
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Chapter -3 Results & Discussion
173
3.3.6 Cytotoxic Studies of Piperidyl Chalcones (9a-l) and their 2-
Pyrazoline Derivatives (10a-l)
Table 11. Anti-HIV-1 activity in human PBM cells (EC50 & EC90) and
cytotoxicity in PBM, CEM and Vero cells (IC50) of the series 9a-l and 10a-l
Anti-HIV-1 activity in Human PBM cells Cytotoxicity (IC50, µM) in:
Code EC50, μM EC90, μM PBM CEM VERO
ZDV 0.0029 ± 0.0020 0.026 ± 0.013 >100 14.3 56.0
1a 73.8 ≥100 >100 11.6 65.5
1b 56.0 ≥100 >100 32.1 34.4
1c 2.5 ± 1.8 19.6 ± 20.4 26.4 9.9 63.9
1d 11.6 23.1 68.8 33.3 56.3
1e 17.9 30.9 77.8 21.2 50.5
1f 11.6 ± 4.6 23.6 ± 4.9 38.2 16.6 42.3
1g 8.4 ± 7.8 29.0 ± 25.4 32.1 12.2 18.1
1h 35.4 ≥100 >100 41.5 32.4
1i 11.8 ± 2.9 24.7 ± 1.8 42.8 15.0 24.9
1j 5.8 ± 2.8 27.8 ± 16.8 39.3 12.5 18.0
1k 46.5 ≥100 >100 52.8 69.5
1l 11.6 ≥100 >100 22.0 56.5
2a 7.3 26.8 20.8 6.9 3.2
2b 11.3 ≥100 >100 27.0 29.5
2c 5.1 ± 3.9 15.5 ± 11.1 11.0 2.3 11.4
2d 13.0 24.9 24.4 16.3 31.6
2e 7.2 ± 0.5 52.9 ± 11.9 86.4 15.3 52.0
2f 16.9 ± 11.7 29.8 ± 12.9 77.5 20.1 83.4
2g 2.4 ± 1.4 13.1 ± 7.8 34.2 10.2 31.6
2h 75.3 >100 >100 >100 >100
2i 32.5 >100 59.0 37.7 53.9
2j 17.4 30.4 57.0 31.6 24.8
2k 9.0 ± 0.4 33.3 ± 17.5 80.0 21.5 25.8
2l 14.5 43.6 >100 36.5 15.9
Anti-HIV-1 Activity
According to the results obtained, it is evident that the unsubstituted
thiophenyl derivatives (9a and 9b) of chalcones (9a-l) have shown no anti-HIV
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Chapter -3 Results & Discussion
174
activity (EC50 >20 µM) while the activity enhances considerably by the substitution of
methyl and halo groups at position 3 of the thiophenyl ring (9c, 9g and 9j). However,
incorporation of these functionalities at position 5 of thiophenyl ring (9e, 9h, 9k and
9l) instead of position 3, the chloro and bromo derivatives (1h and 1k) displayed no
activity whereas methyl and iodo derivatives (9e and 9l) were proven to be weakly
active anti-HIV agents. Incorporation of methyl group at position 4 of thiophenyl ring
(9d) also exhibited weak activity. Moreover, the two disubstituted derivatives (9f and
9i) also showed weak activity. In short, in the chalcones series (9a-l), only three
compounds (9c, 9g and 9j) proved to be active anti-HIV-1 agents.
In case of pyrazoline derivatives (10a-l) the unsubstituted thiophenyl
derivatives (10a and 10b) showed enhanced activities (EC50 = 7.3 µM and 11.3 µM
respectively) as compared to their chalcones analogues (9a and 9b with EC50 = 73.8
µM and 56.0 µM respectively). The compounds 10c and 10g also proved to be active
anti-HIV agents like their starting analogues (9c and 9g), whereas the activity of 10j
(EC50 = 17.4 µM) decreased than that of 9j (EC50 = 5.8±2.8 µM). The compounds in
which methyl and halo groups are present at position 5 of thiophenyl ring (10e, 10h,
10k and 10l), only 10e and 10k displayed improved activity (EC50 = 7.2±0.5 µM and
9.0±0.4 µM respectively) than their corresponding chalcones (9e and 9k, EC50 = 17.9
µM and 46.5 µM respectively). Rest of the compounds (10d, 10f and 10i) showed no
or weak activities (Table 11).
Cytotoxic Activity
Among the compounds under investigation, the unsubstituted thiophenyl
derivatives (9a and 9b) of chalcones (9a-l) showed no toxicity against PBM cells. As
in case of anti-HIV assays, here also the activity enhances by the incorporation of
methyl and halo groups at position 3 of thiophenyl ring (9c, 9g and 9j). These three
compounds (i.e. 9c, 9g and 9j) were found to be active against PBM, CEM and Vero
cells, except that of 1c, which showed no toxicity against Vero cells only. Moreover,
both the disubstituted derivatives (9f and 9i) showed cytotoxicity against all three
types of cells (i.e. PBM, CEM and Vero cells). In rest of the compounds 9d, 9e, 9h,
9k and 9l exhibited no toxicity against PBM cells, 9k was non-toxic only against
CEM cells while 9d, 9e, 9k and 9l displayed no toxicity against Vero cells.
In case of pyrazoline derivatives (10a-l), only the compounds 10a, 10c, 10d and 10g
showed cytotoxicity against PBM cells. All of the pyrazoline derivatives (10a-l) were
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Chapter -3 Results & Discussion
175
active except 10h, while four compounds (10e, 10f, 10h and 10i) showed no cytotoxic
activity against Vero cells.
3.4 Achievements and Problems
The present study is a very petite effort in the field of research. However, we
have been successeful in achieving a few things, that could be a contribution for the
benefits of the human beings, e.g.,
Discovering some highly potent antileishmanial agents
Designing a new MW irradiated method for the synthesis of substituted 2-
chloro-3-formylquinoline derivatives in very high yields and very short
reaction times.
Synthesizing libraries of new chalcones and their 2-pyrazoline derivatives.
Besides these achievements, we also had to face some problems and difficulties, e.g.,
Failed to synthesize 2-chloro-3-acetylquinolines using DMA and POCl3, by
employing different methods like thermal, MW and US irradiation techniques.
Purification of the synthesized compounds was also a very tedious job.
Getting the required chemicals and reagents on the shelf took a long time i.e.
3-6 months or more.
Getting spectroscopic results in 1-3 months.
Obtaining some of the bio-assay results in approximately a year.
3.5 Conclusion
In summary, we have synthesized hybrids of chalcones and pyrazole nuclei,
which have potential biological activities.
All the synthesized chalcone derivatives were tested for a range of biological studies,
like antimicrobial, antileishmanial, anti-HIV and cytotoxic.
Antimicrobial Agents
Amongst the compounds tested for antibacterial study (3a-s and 4a-s), 3f-i, 3l,
3o-p, 4f-i, 4l, and 4o-p showed remarkable antibacterial activity. Especially,
compounds 3h, 3l, 3o-p, 4h-i, and 4o-p showed significant activity against E. coli and
3h-i, 4h-i and 4o against M. luteus while 3h-i, 3p, 4g, 4h-i, 4l and 4p were found
most active against S. Aureus. Compunds 3g, and 4g-h displayed more antifungal
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Chapter -3 Results & Discussion
176
activity, against all the fungi, than the standard flucanazole. The table 12 below
categorized the synthesized compounds in the form of significant active compounds.
Table 12. Significantly active antimicrobial agents (3a-s and 4a-s)
Activity Microbes Compounds
Antibacterial E. coli 3h, 3l, 3o-p, 4h-i, and 4o-p
M. luteus 3h-i, 4h-i and 4o
S. Aureus 3h-i, 3p, 4g, 4h-i, 4l and 4p
Antifungal A. Flaves 3f-g, 3i, 4f-h and 4l
A. Niger 3g, 3i, 4f-h and 4o
C. lunata 3g, 3p, 4g-h and 4o-p
Antileishmanial Agents
As far as antileishmanial activity is concerned, the chalcones (1a-k, 2a-k, 3a-
s, 4a-s and 9a-l) were tested for it. The compounds 3c-e, 3g, 3j-m, 3p, 3r-s, 4g, 4j-p,
and 4r-s exhibited significant antileishmanial activity, while others showed moderate
activity. The table 13 below categorized the synthesized compounds in the form of
significant active compounds, moderately active and weekly active.
Table 13 Categories of antileishmanial chalcones (1a-k, 2a-k, 3a-s, 4a-s and 9a-l)
Category Compounds
Significant 1c, 2f, 3a, 3c, 3d, 3e, 3g, 3i, 3j, 3k, 3l, 3m, 3p, 3r, 3s, 4a, 4g, 4j-s
Good 1a, 1d, 1g, 1k, 2e, 4d, 4f, 4h
Moderate 1e-f, 1j, 2d, 2h-i, 3b, 3f, 4i
Weak 1b, 1h-i, 2a-c, 2g, 2j-k, 3h, 3n-o, 3q, 4b-c, 4e, 9a-l
The above table 13, shows that the compounds 1c, 2f, 3a, 3c, 3d, 3e, 3g, 3i, 3j,
3k, 3l, 3m, 3p, 3r, 3s, 4a, 4g, and 4j-s were found potentially active antileishmanial
agents. It is also concluded that the piperidyl chalcones are inactive towards
leishmaniasis.
Furthermore, the conversion of chalcones (1a-k and 2a-k) to their
corresponding pyrazoline derivatives (5a-k and 6a-k), resulted in no significant
increase in their leishmanicidal properties (table 14).
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Chapter -3 Results & Discussion
177
Table 14. Categories of antileishmanial pyrazoline derivatives 5a-k and 6a-k
Category Compounds
Significant nil
Good 5a
Moderate 5b-c, 5g-h, 5k, 6b, 6e-f, 6h
Low 5d-f, 5i-j, 6a, 6c-d, 6g, 6i-k
From the above table 14, it is evident that only one compound displayed good activity
and none of the tested pyrazoline derivatives (5a-k and 6a-k) of chalcones (1a-k and
2a-k) exhibited significant antileishmanial activity.
Antiviral/Cytotoxic Activity
Amongst the compounds tested for anti-HIV-1 and cytotoxicity (5a-k, 7a-k,
9a-l and 10a-l), no compound was proved to be significantly active anti-HIV-1 and/or
cytotoxic agent. However, some of them showed moderate activity (table15).
Table 15. Categories of antiviral/cytotoxic compounds 5a-k, 7a-k, 9a-l and 10a-l
Category Compounds
Moderate 5a, 5b, 5c, 5f, 5h, 5i, 7c, 7g,7i, 9g, 9j, 10a, 10e, 10k,
Weak 5e,7e,7f, 9c, 9d, 9e, 9i, 9l, 10b, 10c,10h
Inactive 5d, 5g, 5j, 7a, 7b, 7d,7h, 9a, 9b, 9h, 9k, 9c, 10f, 10g, 10j
3.6 Future Perspectives
This research work has very great potential from pharmacological point of
view. Thats why we are planning to
Test our compounds for more biological activities like antiinflammatory,
antioxidant, antimalarial etc.
A few series have already been sent to University of Peshawar for enzymatic
activities studies, and many others for anti-HIV-1 and cytotoxic srudies.
We are also planning to synthesize pyrimidine, benzothiazine and isoxazole
derivatives of the prepared chalcones.
All of the prepared chalcones along with their derivatives and bio-assays will
be published in eminent journals, so as to lift up the name of the university (in
general) and that of the country (in particular) in the field of research.
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List of Publications
193
LIST OF PUBLICATIONS FROM THIS THESIS
1. Novel chalcones derived from 2-chloro-3-formyl-6-methylquinoline Umar Farooq Rizvi, Hamid Latif Siddiqui, Saeed Ahmad, Masood Parvez,
Acta Crystallogr. C, 64, 547 (2008).
2. Antimicrobial and Antileishmanial Studies of Novel (2E)-3-(2-Chloro-6-
methyl/methoxyquinolin-3-yl)-1-(Aryl)prop-2-en-1-ones
Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Masood Parvez, Matloob
Ahmad, Waseeq Ahmad Siddiqui Chem. Pharm. Bull. 58(3) 301—306 (2010)
3. (2E)-3-(2-Chloro-6-methyl-3-quinolyl)-1-(1-naphthyl)prop-2-en-1-one
Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Muhammad Zia-ur-
Rehman, Muhammad Azam and Masood Parvez, Acta Crystallogr. E, 66, 761
(2010).
4. (E)-3-(2-Chloro-6-methyl-3-quinolyl)-1-(2,3-dihydro-1,4-benzodioxin-6-
yl)prop-2-en-1-one
Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Tanvir Hussain,
Muhammad Azam and Masood Parvez, Acta Crystallogr. E, 66, 744 (2010).
5. Novel quinolyl-thienyl chalcones and their 2-pyrazoline derivatives with
diverse substitution pattern as antileishmanial agents against Leishmania
major Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Muhammad Nisar Ahmad,
Matloob Ahmad, Mujahid Hussain Bukhari Med. Chem Res. (Accepted and
Online published on 12th
April, 2011).
6. Anti-HIV-1 and Cytotoxicity Studies of Piperidyl-Thienyl Chalcones and
their 2-Pyrazoline Derivatives Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Melissa Johns, Mervi
Detorio, Raymond F. Schinazi, Med. Chem Res. (Submitted, May 2011).