Doctor of Philosophy

Transcription

1 SYNTHESIS AND BIOLOGICAL ACTVITY OF NOVEL OXA-UNSATURATED CARBOCYCLE ANNULATED COUMARINS BY RING-CLOSING METATHESIS AND DIAZEPINES FROM 4-HYDROXYCOUMARINS ABSTRACT SUBMITTED TO OSMANIA UNIVERSITY FOR THE DEGREE OF Doctor of Philosophy IN CHEMISTRY by C. VENU Under the supervision of Dr. Y. Jayaprakash Rao DEPARTMENT OF CHEMISTRY OSMANIA UNIVERSITY HYDERABAD January

2 SYNTHESIS AND BIOLOGICAL ACTVITY OF NOVEL OXA-UNSATURATED CARBOCYCLE ANNULATED COUMARINS BY RING-CLOSING METATHESIS AND DIAZEPINES FROM 4-HYDROXYCOUMARINS THESIS SUBMITTED TO OSMANIA UNIVERSITY FOR THE DEGREE OF Doctor of Philosophy IN CHEMISTRY by C. VENU Under the supervision of Dr. Y. Jayaprakash Rao DEPARTMENT OF CHEMISTRY OSMANIA UNIVERSITY HYDERABAD January

3 Dedicated to my Beloved Parents

4 DECLARATION The research work embodied in this thesis has been carried out in the Department of Chemistry, Osmania University, Hyderabad, under the supervision of Dr. Y. JayaPrakash Rao, Department of Chemistry, University College of Science, Saifabad, Osmania University, Hyderabad. This work is original and has not been submitted in part or full, for any degree or diploma to this university or any other university. Date: (C. VENU)

5 CERTIFICATE This is to certify that Mr. C. Venu has carried out the research work presented in this thesis entitled Synthesis and biological activity of novel oxaunsaturated carbocycle annulated coumarins by ring-closing metathesis and diazepines from 4-hydroxycoumarins. This work has been carried out under my guidance and supervision at this Department and I hereby recommend the submission of this thesis for the award of degree of Doctor of Philosophy in Chemistry of Osmania University. Date: (Dr. Y. Jayaprakash Rao)

6 ACKNOWLEDGEMENTS It gives me great pleasure and profound privilege to place on record my deep sense of gratitude and indebtedness to my supervisor Dr. Y. Jayaprakash Rao whose constructive comments, unflagging optimism and scholarly guidance throughout the present work has driven me towards the success of this endeavor. I wish to express my grateful thanks to Prof. K. Nageshwar Rao, Dean, faculty of science, Department of Chemistry, Osmania University for his valuable help and encouragement during my research work. I wish to express my grateful thanks to Prof. Ch. Prasad Rao, Department of Chemistry, Osmania University for his valuable support and encouragement during my research work. It is pleasure to thank Prof. V. Uma, Head, Department of Chemistry, O.U. for providing facilities and encouragement to carry out the research work in Department and I acknowledge with pleasure the encouragement shown by, Prof. L.N. Sarada, Chairman, BOS in chemistry. I wish to express my thanks to Prof. G. Srimannarayana, Prof. G. L. David Krupadanam, Prof. P. Jaya Prasad Rao, Prof. V. Prabhakar Reddy, Prof. D. Ashok, Prof. T. Parthasarathy and Prof. Ch Kista Reddy Department of Chemistry, Osmania University for their assistance and encouragement during my research period. I acknowledge with pleasure the encouragement and support given by Dr. Y. Hemasri, Nizam College, Osmania University, Hyderabad.

7 I acknowledge with pleasure the encouragement and support given by Prof. Syed Rehman, Principal. University College of Science, Saifabad, Osmania University, Hyderabad. My sincere thanks to Dr. U.S. N. Murthy Division of Biology, IICT (Dy. Director, IICT) and K. Pranay, Hyderabad for their help in screening the compounds for antibacterial, antifungal and antioxidant activity. My sincere thanks to Dr. B.Venkateswara Rao, Dr. Ravi Kumar, Dr. Sridhar and Dr. Jagadeesh Babu, IICT, Hyderabad for their help in crystal study. My sincere thanks to Dr. A.C. Kunwar, NMR division, (Emeritus scientist), IICT, Hyderabad for their help in recording ROESY spectrum and analyzing the compounds. My sincere thanks to lab mates G. Thirupathi, E.Yadagiri Goud, E. Pravardhan, N. Shyam Prasad, G. Veerashankar, G. Madhu and K.Santosh Kumar. My sincere thanks to my friends Akula srinivas, K. Venu, N. Nagaraju, M. Ravikumar, G. Srinivas, Hari Prasad, Srinivas Yadav, Sunil Joshi, Vijay and Maruthi. I am deeply grateful to my parents, In-Laws and all other family members who have encouraged me at every stage of my career. level. My special tribute goes to my all teachers who have taught me to rise to this I remain inexplicably grateful to the Osmania University for providing facilities to carry out my research work. (C. VENU)

8 GENERAL METHODOLOGY EXPERIMENTAL AND INSTRUMENTATION Solvents were purified according to the procedure described in Vogel's text book of practical Organic Chemistry 3 rd Edition, London (1971). Petroleum ether of boiling range 60 o -80 o C was used. Silica gel G (ACME) and silica gel finer than 200, mesh (ACME), was used for thin layer and column chromatography respectively. All the melting points reported in the thesis were determined in polmon make instrument (Model No. MP-96). The melting points were uncorrected and reported in degrees centigrade. The IR spectra recorded on Perkin-Elmer Infrared model 337 and UV spectra on Schimadzu UV-VIS 1601 spectrophotometer. The 1 H NMR spectra were recorded at 300 and 500 MHz on varian Gemini Unity Spectrometer using TMS as internal standard and 400 Bruker MHz NMR spectrometer. 13 C NMR spectra were recorded at 75.5 MHz, 100 and 125 MHz on Varian Gemini Spectrometer. The mass spectra were recorded on Agilent 6310 ion trap and ESI (electron spray ionization) spectra were recorded on PE Sciex (API2000) mass spectrometer. X-ray data for the compound were collected at room temperature using a Bruker Smart Apex CCD diffractometer with graphite monochromated MoK radiation ( = Å) with ω-scan method. Copies of the original spectra are included in the thesis

9 GLOSSARY OF ABBREVIATIONS Py : Pyridine TBAB : Tetra butyl ammonium bromide DMF : N, N dimethylformamide TEA : Triethylamine TMSCl : Trimethylsilyl chloride Pd(0) : Tetrakis(triphenylphosphine)palladium(0) ACN : Acetonitrile DPPP : 1,3-Bis(diphenylphosphino)propane TFA : Trifluoroacetic acid THF : Tetrahydrofuran TBAF : Tetra-n-butylammonium fluoride DMSO : Dimethyl sulfoxide DIAD : Diisopropyl azodicarboxylate TPP : Triphenylphosphine DCM : Dichloromethane MeOH : Methanol AcOH : Acetic acid FDPP : Pentafluorophenyl diphenylphosphinate DIPEA/DIEA : N,N-Diisopropylethylamine BOP : (Benzotriazol-1- yloxy) tris(dimethylamino) phosphonium hexafluorophosphate HATU : 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate

10 EtOH : Ethanol PEG : Polyethylene glycol PTSA : p-toluenesulfonic acid DME : Dimethoxyethane DPPA : Diphenylphosphoryl Azide ESI MS : Electrospray ionization mass spectrum EI MS : Electron impact mass spectrum MS : Mass spectrum RCM : Ring closing metathesis TLC : Thin Layer Chromotography

11 CHAPTER-NO CONTENTS Page No CHAPTER I CHAPTER II Biological activity, synthesis and spectral characteristics of heterocyclic ring substituted and fused coumarins. Section-A: Synthesis of (Z)-2H-oxepino [3,2-c]chromen-6(5H)-ones Section-B: Synthesis of (Z)-2H-oxepino [3,2-c]chromene-2,6(5H)-diones Section-C: Synthesis of (Z)-3-vinyl-2H-oxepino [3,2-c]chromen-6(5H)-ones CHAPTER III Synthesis of membered dioxa-unsaturated CHAPTER-IV CHAPTER-V CHAPTER-VI carbocycle annulated coumarins. Synthesis of 5'-aryl-3'-vinyl-2',3'-dihydrospiro [chroman-3,4'-oxepino[3,2-c]chromene]-2,4,6'(5'h)- triones. Synthesis of diazepines Section-A: Synthesis of 7-(2-hydroxyphenyl)-2-phenyl- 4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-ones and 4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)- ones Section-B: Synthesis of novel 10-aryl-10,12- dihydro-6h-chromeno [4,3-e]pyrazolo[4,3-b] [1,4] diazepin-6-ones Section-A: Evaluation of the antibacterial and antifungal activity of substituted new synthetic coumarins and diazepines. Section-B: Anti-oxidant activity of substituted new synthetic coumarins ABSTRACT

12 LIST OF PAPERS PUBLISHED/COMMUNICATED 1. Combined claisen rearrangement and oxidative cyclization as a route to hydroxymethyl dihydrofuran-annulated coumarins (J. Heterocyclic chemistry, accepted, (2013) In print). 2. Synthesis of novel oxepin and 2-oxo-oxepin annulated coumarins via combined Claisen rearrangement and ring closing metathesis (Manuscript under preparation). 3. Unusual Tandem Ring Closing metathesis -Claisen rearrangementc enroute to spiro annulation of O-allyl bis coumarins (Manuscript under preparation).