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Synthesis, Characterization and Biological Activities of Isocoumarins, Triazoles, Thiadiazoles and Indolinones

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Synthesis, Characterization and Biological Activities of Isocoumarins, Triazoles, Thiadiazoles and Indolinones SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF ISOCOUMARINS, TRIAZOLES, THIADIAZOLES AND INDOLINONES A DISSERTATION SUBMITTED TO THE QUAID-I-AZAM UNIVERSITY ISLAMABAD IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY BY GHULAM QADEER Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan. 2008 SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITIES OF ISOCOUMARINS, TRIAZOLES, THIADIAZOLES AND INDOLINONES BY GHULAM QADEER Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan. 2008 Allah will exalt those who believe among you, and those who have knowledge to high ranks. Saying of Holy Prophet Hazrat Muhammad “Do you know who is the most beneficent? Allah is the most beneficent, than of the children of the man; I am the most beneficent and after me the most beneficent among them is the man who acquires knowledge and spreads it, he will come on the day of resurrection as a chief by himself”. My parents ACKNOWLEDGEMENT First of All I bow my head before “Almighty Allah” Who bestowed me the opportunity and potential to make material contribution to the already existing ocean of knowledge and all respects are for the Holy Prophet, Hazrat Muhammad who enabled us to recognize our Creator. It is a matter of great pleasure to express my obligations and sincere thanks to my teacher and research supervisor Prof. Dr. Nasim Hasan Rama, Department of Chemistry, Q. A. U. Islamabad, for his constant encouragement, keen interest and thought provoking guidance through out my research work. I am thankful to Prof. Dr S. Sakhawat shah, Chairman, Department of Chemistry, for providing necessary research facilities. Thanks to all the teachers of organic section for being a source of inspiration and enlightenment for me during my course work and stay in the department. I obliged to express my heartfelt thanks to Prof. Dr. Erik De Clercq, (Belgium) Dr. Lieve Naesens, (Belgium), Prof. Dr. Bob Hill (Scotland), Dr. Dra. Maria Luisa Garduño, (New Maxico), Dr. Wai Yeung-Wong (Hong Kong), Dr. Ales Ruzicka, (Czec republic) Dr. Yong Hong Li, (China) Dr. Fan Zhijin, (China), Dr. Sauli Vuoti, (Finland) Dr. M. Azad Malik, (U.K) James Rafetry (U.K) and Dr. Abdul Malik, H. E. J. Research institute, University of Karachi, Pakistan for their co-operation and generous help especially in the form of spectroscopic analysis, X-ray crystallography and bioassay. I ought to submit my thanks to my dear friends, who remember me in their prayers and hearts. I wish to acknowledge the support, co-operation and encouragement provided by Syed Jabbar Hussain Shah, Mazhar Ali Kalyar, Shahid Ashraf, Javeed Akhter (U.K), I do remember the company of my research fellows Dr. Muhammad Zareef, M. Arfan, Tasfeen Akhter, K. Ansar Yasin and Muhammad Sher. My acknowledgement remains incomplete if I don’t mention the help, encouragement and companionship of my lab fellows, Gul S. Khan, Naveed Umer, Taj-ud-din, Ahsan Farid, Obaid-ur-Rehman Abid, Tariq Mehmood Baber, Muhammad Hanif, Furrukh Iftikhar Ali, Muhammad Shahzad & Hakim Luqman. I am also heartily thankful to all the members of non-teaching staff of the department especially M. Sharif Chohan, Shamas Pervaiz Qureshi, Ali Zaman, Shamas Tabrez Qureshi, Muhammad Ilyas, M. Rashid, Muhammad Raza and Jumma Khan, for their help during the entire period of research work. My sincere thanks are due to my wife. Without her encouragement and excessive generosity I would not been able to complete the task. Lastly my special thanks are due to my parents, brothers, sisters and all of other relatives. It is due to their prayers that I have been successful in my educational career. May Almighty Allah shower his choicest blessings and prosperity on all those who assisted me in any way during completion of my thesis Thank you all, (GHULAM QADEER) CERTIFICATE This is to certify that this thesis submitted by Mr. GHULAM QADEER is accepted in its present form by the Department of Chemistry, Quaid-i-Azam University, Islamabad as satisfying the requirements for the Degree of Doctor of Philosophy in Organic Chemistry. SUPERVISOR --------------------------- (Prof. Dr. Nasim Hasan Rama) Departmet of Chemistry, Quaid-i-Azam University, Islamabad CHAIRMAN --------------------------------- (Prof. Dr. S. Sakhawat shah) Department of Chemistry, Quaid-i-Azam University, Islamabad Date: ABSTRACT The work presented in this thesis consists of the synthesis, characterization, and biological screening of heterocyclic compounds. For convenience, the work has been divided into two parts, part one is related to the compounds containing oxygen atom in the heterocyclic ring whereas part two refers to the compounds containing nitrogen and/ or sulphur atoms in the heterocyclic ring. Part one of this thesis is related to the synthesis, characterization and biological activity of some heterocyclic compounds containing oxygen in the ring. These compounds include some naturally and unnaturally occurring substituted isocoumarins and 3,4-dihydroisocoumarins. The synthesis of naturally occurring isocoumarin Thunberginol B is reported, in which 3,5-dimethoxyhomophthalic acid is a key intermediate for the synthesis of Thunberginol B. It was synthesized efficiently in five steps from 3,5-dimethoxybenzaldehyde via a series of reactions including synthesis of 3,5-dimethoxycinnamic acid, 3-(3′,5′- dimethoxyphenyl)propionic acid, cyclization of 3-(3′,5′-dimethoxyphenyl)propionic acid to 5,7-dimethoxy-1-indanone and oxidative decomposition of methyl 2- hydroxy-2-(5,7-dimethyoxy-1-oxo-1H-inden-2(3H)-ylidene)acetate to 3,5- dimethoxyhomophthalic acid. 3,4-Dimethoxybenzoylchloride was prepared from 3,4-dimethoxybenzoic acid on reaction with thionyl chloride which on condensation with 3,5-dimethoxyhomophthalic acid afforded 3-(3',4'- dimethoxyphenyl)-6,8-dimethoxyisocoumarin. Complete demethylation of 3-(3',4'- dimethoxyphenyl)-6,8-dimethoxyisocoumarin with hydrobromic acid in acetic acid gave 3-(3',4'-dihydroxyphenyl)-6,8-dihydroxyisocoumarin (Thunberginol B). In addition to above, some unnaturally occurring halogenated isocoumarins and their 3,4-dihydrodrivatives were also synthesized. The difluorophenyl- and dichlorophenylisocoumarins by condensation of homophthalic acid with an appropriate acid chloride. Alkaline hydrolysis of the isocoumarins yielded corresponding keto-acids, which on reduction give the corresponding racemic hydroxy-acids. 3,4-Dihydroisocoumarins were obtained from these racemic hydroxy-acids by cyclodehydration using acetic anhydride. All the synthesised compounds were identified using their IR, 1H NMR and mass spectral data. In many cases 13C NMR and elemental analysis data were employed to support the characterization. In each case, a plasible mass fragmentation pattern is suggested. The synthesized compounds were screened for their antifungal, antibacterial, herbicidal, insecticidal, fungicidal, anti- metastatic, brine shrimp lethality, antioxidant, anti -inflammatory, antiviral, anti- HIV, anti-HBV and anticancer activities and in some cases, very fascinating results were obtained which were then published in different international journals. These synthetic schemes have tremendous potential for further synthesis of novel biological active compounds. Part two of the thesis describes the synthesis and biological screening of some, hitherto unreported, isatin derivatives (Indolinones), 1,4-disubstituted thiosemicarbazides and their related 2,5-disubstituted-1,3,4-thiadiazoles and 4,5- disubstituted-3H-1,2,4-triazole-3-thiones. Indolinones were formed by the direct condensation of hydrazides with halogenated isatins. Triazoles were formed by intramolecular dehydrative cyclization of thiosemicarbazides in basic media while thiadiazoles were formed in acidic media, which is an intermediate during the synthesis of various heterocyclic compounds. Thiosemicarbazides were formed by aldol type condensation reaction of acid hydrazides and isothiocyanates. Isothiocyanates were formed by the reaction of anilines with carbon disulphide in ammonium hydroxide solution to yield ammonium dithiocarbamate, an intermediate which on oxidation with lead nitrate yield isothiocyanate. Acid hydrazides were formed by the reaction of esters of carboxylic acid with hydrazine hydrate and esters were formed by refluxing carboxylic acid in methanol in catalytic amount of carboxylic acids. As a result of these synthetic schemes, thirty new indolinones, ten disubstituted-1,3,4-thiadiazoles and twenty disubstituted 1,2,4-triazole-3-thiones were synthesized. The characterization of these synthesized compounds was carried out by IR, 1H NMR, 13C NMR, elemental analysis, Mass spectral data and XRD analysis. The synthesized compounds were screened for their antifungal, antibacterial, herbicidal, insecticidal, fungicidal, plant growth regulatory activity and antiviral activities. CONTENTS Acknowledgement I Abstract III Part one CHAPTER 1 INTRODUCTION 1.1 Nomenclature and structural types 1 1.2 Physical properties 5 1.3 Biological activities 5 1.4 Behavior towards human beings 12 1.5 Biosynthesis 14 1.6 Synthesis of isocoumarins and 3,4-dihydro- 18 isocoumarins 1.6.1 Synthesis involving metals 19 1.6.2 Oxidation of Indenes, Indanones and Indones 24 1.6.3 Oxidation of isochromans 26 1.6.4 Aldol type condensation between homophthalic 27 acids, esters or anhydrides and carbonyl compounds 1.6.5 Synthesis of isocoumarins via iodocyclization 32 1.6.6 Synthesis of isocoumarin by the use of new 33 technology 1.7 Interconverision
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