Thesis Entitled SYNTHESIS and characterization OF NEW ox AND NITROGEN HETEROCYCLIC COMPOUNDS WITH ITS BIOLOGICAL AND GROWTH PROMOTING PROPERTIES SUBMITTED TO THE MAHARAJA SAYAJIRAO UNIVERSITY OF BARODA FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY POONAM YADAV iO DEPARTMENT OF CHEMISTRY, FACULTY OF SCIENCE THE MAHARAJA SAYAJIRAO UNIVERSITY OF BARODA BARODA - 390 002, INDIA Prof. B.V. Kamath Department of Chemistry*, HEAD & Professor Centre of Advanced Studies in <T* >r% tvs e-mail: Faculty of Science, Vadodara 330 002 kamathbv 1 ©rediffmail.com India Tel: +31 -205-2705552 The Maharaja Sayajirao University of Baroda CHL/ -^3,/P^-D. ll. I APR 2011 CERTIFICATE This is to certify that the work presented in the thesis entitled “Synthesis and Characterization of New Oxygen and Nitrogen Heterocyclic Compounds with its Biological and Growth Promoting Properties”, submitted to the Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, for the award of Ph.D. degree by Ms. Poonam Yadav, is the original research work carried out by her under my guidance and supervision. Dr. Nalini V Purohit (Research Guide) Department of Chemistry, Faculty of Science, The Maharaja Sayajiroa University of Baroda, Vadodara - 390002. Department of Chemistry, Faculty of Science, The Maharaja Sayajiroa University of Baroda, Vadodara - 390002. | J om shree ganeshaya namaha J anant koti brahmand nayak rajadhiraj yogiraj parbrahma shree sachidanand sadguru shree sai nath maharaj kijai anant koti brahmand nayak rajadhiraj yogi raj parbrahma shr sachidanand sadguru shree swami samarth maharaj kijai Jj DECLARATION I state that the work presented in this entitled, “Synthesis and Characterization of New Oxygen and Nitrogen Heterocyclic Compounds with its Biological and Growth Promoting Properties”, comprises of independent investigations carried out by me under the guidance of Dr. Nalini V. Purohit, Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, and are true to the best of my knowledge. Wherever references have been made to the work of others, it has been clearly indicated with the source of information under the reference section. The work presented in this thesis has not been submitted elsewhere for the award of any other degree. AM YADAV I express my deep sense of gratitude to my research guide, Dr. Nalini V. Purohit, Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, for giving me the opportunity to do work under her guidance. Her excellent guidance throughout the progress of this work, her ingenuity, constant encouragement, keen knowledge and interest in the subject proved to be a constant source of inspiration for me. She provided encouragement, sound advice, good teaching, good company, and lots of good ideas in scientific field during my entire course of investigation. I thank her for this contribution towards my academic career. POONAM YADAV ACKNOWLEDGMENT It is always a pleasure to write an ‘acknowledgement’, for, more than anythinj^^e^ marks an end of hard work with the accompanying joys and frustrations. I would like to put on record my sincere thanks to the people who have contributed to this study in many ways. At the outset, I avail this opportunity to render my deep gratitude to The Maharaja Sayajirao University of Baroda, for its encouragement and full support for my research work in the field of Chemistry. I take this opportunity to express my sincere thanks to my research supervisor Dr. Nalini V. Purohit, Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, for her continuous guidance for my research work. Her patience, motivation, enthusiasm, immense knowledge and her logical way of thinking certainly became blessings for me. I take this privilege to thank Professor B. V. Kamath, Head, Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, for providing me the necessary facilities available in the department. I owe my most sincere gratitude to Professor Surekha Devi, former Head, Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, as I got valuable guidance and support for my research work. I am grateful to the non teaching staff members, mainly Mrs. Revathi Ganesh, Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, for their full cooperation during my research work. I am thankful to Sun Pharmaceutical Advance Research Centre (SPARC), Tandelja, Vadodara and SAIF, Punjab University, Chandigarh, for providing spectral analysis for my research work. I gratefully acknowledge Dr. Rajesh Sumple (MD), Medical Superintendent & Consultant & Physician, Laboratory Staff, Pramukh Swami Hospital, Vadodara; Ms. Darshee Bakshi, Navrachna University, Vadodara; Mr. G. Paramesh, Department of Chemistry, Gulbarga University; Prof. Arun Arya, Head, Department of Botany; Dr. Denni Mammen, Department of Chemistry; Prof. Anjana Desai and Ms. Aprana Shirsat, Department of Microbiology and Ms. Sarada, Department of Zoology, The M. S. University of Baroda, Vadodara, for their support in carrying out different biological screenings. I am especially grateful to my research colleagues and many thanks go in particular to Dr. K. Santhosh Kumar and Ms. Arti Bhadouria for their assistance, criticisms and useful insights through the course of my journey towards producing this thesis. I am thankful to all the Fellow lab mates of mine, especially Mr. Harish Talele, as I learnt a lot from them, which I am sure, will be useful in different stages of my life. The financial support obtained as a fellowship from University Grants Commission (UGC), New Delhi under “Research Fellowship in Science for Meritorious Students” scheme and Alembic Chemicals Works Ltd. for awarding “Maharaja Sayajirao HI Alembic Chemicals Works Ltd. Research Scholarship” is gratefully acknowledged. Finally, this thesis would not have been possible without the confidence, endurance and support of my family. My family has always been a source of inspiration and encouragement. I wish to thank my parents, Mr. L. S. Yadav & Mrs. Sheela Yadav whose love, teachings and support have brought me this far. I wish to thank my brother, Pankaj Yadav for his affection and lovable support. POONAM YADAV DEDICATED TO MY PARENTS INDEX • «^ s V <<' Introduction A cyclic organic compound containing all carbon atoms in ring formation is referred as a carbocyclic compound. If at least one atom other than the carbon forms a part of the ring system then it is designated as a heterocyclic compound. Their study is of great interest both from the theoretical as well as practical point of view. Of the large family of the heterocycles, isoeoumarins (Iif-2-benzopyran-l-one) are an important class of naturally occurring lactones that exhibit a wide range of biological activities. o In addition the isocoumarin ring system is a useful intermediate for the synthesis of hetero and carbocyclic compounds. The development of methods for the formation of several carbon-carbon and/or carbon-heteroatom bonds in one reaction is one of the most important goals of the synthetic chemist, because such processes allow the assembly of complex molecular structures from relatively simple precursors. So, the first step was to synthesize simple isoeoumarins and few phthalides from easily available starting materials and then using them as starting /building blocks in subsequent chapters. Objectives of the work: • To synthesise new isoeoumarins and phthalides with different substituent’s from simple precursors. • Introduction of different heterocyclic ring systems into isoeoumarins. • Biological screening of the synthesized compounds against various disease models. The structures of all the synthesized compounds have been established on the basis of their elemental analysis and spectral (IR, NMR, Mass) data for all the chapters. Chapter 2: Synthesis of some new isocoumarins and phthalides* Isocoumarins and phthalides have exhibited varied biological and physiological activities, o-acyl benzoic acids and o- aroyl benzoic acids are important starting materials in the synthesis of isocoumarins and phthalides. The synthetic pathway followed by J. N. Chatteijea et al has been employed to prepare the title compounds. Scheme I ^XOR R/Ar COOH R = CH3,C2H5,C3H7 Scheme II COR O ^^XOOHLA + Xxa Scheme III COCHO /^YC0Ar COOH R/Ar 4-alkyl-3-aroyl disubstituted isocoumarins were prepared by condensing different o-acyl benzoic acids with different bromo derivatives of substituted acetophenone in presence of anhy. K2CO3 and ethyl methyl ketone as solvent (Scheme I). Similarly 4-alkyl-3-acetyl isocoumarins were formed when chloroacetone was taken in place of bromo acetophenone in presence of base (Scheme II). Having taken o-aroyl benzoic acid instead of o-acyl benzoic acid and condensing it with different bromo acetophenone derivatives resulted in ring contraction and a mixture of phthalide and phenyl glyoxal were obtained rather than isocoumarins (Scheme HI). Purohit N V, Yadav Poonam & Rajput Santosh, Ind. Journal of Heterocyclic Chemistry, 2008,18,169. 2 % Some of the isocoumarins synthesized have been used as starting material for the synthesis of various heterocyclic compounds in subsequent chapters. Chapter 3: Section A: Synthesis of 3, 4-disubstituted nitro, aminyl benzoyl and amino carbonyl isocoumarins High throughput screening of the selected chemical libraries having a heterocyclic or carbocyclic