CROSS METATHESIS APPROACHES FOR BROUSSONETINE C, G AND 12-C-GLYCOSYL- DODECANOIC ACIDS AND EXPLORATION OF CLICK REACTION IN CRYSTAL ENGINEERING BY KULBHUSHAN A. DURUGKAR Dr. C. V. RAMANA (RESEARCH GUIDE) ORGANIC CHEMISTRY DIVISION NATIONAL CHEMICAL LABORATORY PUNE–411008 APRIL–2009 Cross Metathesis Approaches for Broussonetine C, G & 12- C-Glycosyl-dodecanoic Acids and Exploration of Click Reaction in Crystal Engineering A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (IN CHEMISTRY) TO UNIVERSITY OF PUNE BY Mr. Kulbhushan A. Durugkar Dr. C. V. Ramana (Research Guide) ORGANIC CHEMISTRY DIVISION NATIONAL CHEMICAL LABORATORY PUNE–411008 April–2009 DEDICATED TO MY PARENTS DECLARATION The research work embodied in this thesis has been carried out at National Chemical Laboratory, Pune under the supervision of Dr. C. V. Ramana, Organic Chemistry Division, National Chemical Laboratory, Pune – 411 008. This work is original and has not been submitted in part or full, for any degree or diploma of this or any other University. Organic Chemistry Division National Chemical Laboratory Pune – 411008 April 2009 (Kulbhushan A. Durugkar) ~~~ '(~o?1T~~~~) m. ~ cqrcqr l1T1f ~ - 411 008. 'qT«f NATIONAL CHEMICAL LABORATORY ~ (Council of Scientific & Industrial Research) Dr. Homi Bhabha Road, Pune - 411 008. India. Dr. C. V. Ramana Phone: +91-20-25902577 +91-20-25902455 E-mail: vr.chelmri\aJ.ncl.res.in CERTIFICA TE The research work presented in thesis entitled "Cross Metathesis Approaches for Broussonetine C, G & 12-C-Glycosyl-dodecanoic Acids and Exploration of Click Reaction in Crystal Engineering" has been carried out under my supervision and is a bonafide work of Mr. Kulbhushan A. Durugkar. This work is original and has not been submitted for any other degree or diploma of this or any other University. Pune - 411008 Dr. C. V. Ramana April 2009 (Research Guide) W FAX WEBSITE Commu nication NCL Level DID : 2590 Director's Office: +91-20-25902601 www.ncl-india.org Channels NCL Board No. : +91-20-25902000 COA's Office: +91-20-25902660 EPABX : +91-20-25893300 COS&P's Office: +91-20-25902664 +91-20-25893400 Acknowledgements It gives me immense pleasure to express my deep sense of gratitude to my teacher and research guide Dr. C. V. Ramana, who has helped me a lot to learn and think more about chemistry. He has introduced me to the area of multistep synthesis, interdisciplinary areas like glyco-nanoparticle synthesis and crystal engineering. I thank him for an excellent and inspiring guidance, constant encouragement, sincere advice and unstinted support during all the times of my Ph.D. work. Working with him was a great pleasure and learning experience. I would like to thank our interdisciplinary collaborators Dr. B. L. V. Prasad and Dr. R. G. Gonnade for guidance and help. I am highly thankful to D. K. Mohapatra for his sincere efforts and patience in guiding me in my early days of research career. I would like to thank Dr. M. K. Gurjar, Dr. Hotha, Dr. HV Thulasiram, Mr. I. Shivakumar, Dr. M. N. Deshmukh, Dr. H. B. Borate, Dr. S. P. Chavan, Dr. U. R. Kalkote, Dr. R A Joshi, Dr. R. R. Joshi and Dr. Gajbhiye for timely help and discussions. I am thankful to my mentors at my school, college and University for their inspirational teaching, ethics and discipline. I gratefully acknowledge the training and support extended by my senior colleagues Dr. Sankar, Dr. Krishnakanth, Dr. Arindam, Dr. Joseph, Dr. Sridhar, Dr. Srinivas, Dr. Sidharth, Dr. Nagaprasad, Dr. Ekambram, Dr. Mahesh, Dr. Smriti, Dr. Sukhen, Dr. Manjusha, and Dr. Dhananjoy during the tenure of my Ph.D life. I would like to express thanks all my colleagues Ramdas, Tushar, Bhagwat, Bhargava, Sahoo, Sumanth, Gorakh, Sabita, Seetaram, Hasibur, Rita, Ramesh, Raghupathi, Nageswar, Anuj, Susheel, Kiran, Soumitra, Pradip, Chinmoy, Bhaskar, Indu, Abhijit, Srinivas, Sharad, Ganesh, Rosy, Debabrata, Mohabul, Giri, Rambabu, Sunil, Rahul, Pitambar, yogesh, Sridhar, Sachin, Vilas, Ajay, Mangesh, shyam, chandrababu, Suneel, Yadagiri and Senthil for their cooperation and friendly attitude. I am also thankful to my friends Nagendra, Vinod, Rameshwar, Shriram, Amol, Laxman, Namdev, Pandurang and Awadut for their continuous encouragement, help and whose companionship always kept my mood cheerful and with whom I shared golden moments. My sincere thanks to all other friends from NCL and SA for their co-operation specially Nilkant. A special thanks all “NCL-Chemistry” members for their cheerful company. Help from the spectroscopy, mass and microanalysis group is gratefully acknowledged. I sincerely thank Dr. Rajmohan and Mrs. Shanthakumari for their helpful discussions and cooperation. My sincere thanks to Dr. G. Pandey, Head, Division of Organic Chemistry for his cooperation and support. My honest thanks to Mrs. Raphel, Mrs. Kulkarni, and all other OCD office staff for their cooperation. It is impossible to express my sense of gratitude for my parents in mere words. Whatever I am and whatever I will be in future is because of their enormous blessings, commitments to my ambitions and their selfless sacrifices. Words fall short to thank my wife, Sphurti for her love and support at tough time. Finally I thank Director, National Chemical Laboratory; Pune for providing infrastructural facilities to complete my work successfully. Financial assistance from CSIR, New Delhi in the form of fellowship is gratefully acknowledged. Kulbhushan A. Durugkar DEFINATIONS AND ABBREVIATIONS Ac – Acetyl AcOH – Acetic acid Ac2O – Acetic anhydride AIBN – 2,2'-Azobisisobutyronitrile aq. – Aqueous Bn – Benzyl BnBr – Benzyl bromide BF3·Et2O – Boron trifluoride diethyl ether complex Boc – Tert-Butoxy carbonyl n-BuLi – n-Butyl lithium Cat. – Catalytic/catalyst Cbz – Benzyloxycarbonyl CM – Cross metathesis Conc. – Concentrated CuSO4 – Copper sulphate CSA – Camphor sulphonic acid m-CPBA – m-Chloroperbenzoic acid DCM – Dichloromethane DFT – Density functional theory DIBAL-H – Di-isobutly aluminium hydride DMF – N,N-Dimethylformamide DMAP – N,N'-Dimethylaminopyridine DMP – 2, 2-Dimethoxypropane DMSO – Dimethyl sulfoxide EtOH – Ethanol Et2O – Diethyl ether EtOAc – Ethyl acetate Et3N – Triethylamine IBX – Iodoxybenzoic acid Im – Imidazole KtOBu – Potassium tertiary butoxide LAH – Lithium aluminium hydride LDA – Lithium diisopropylamide LiN3 – Lithium azide Na2CO3 - Sodium carbonate NaN3 – Sodium azide NMR – Nuclear magnetic resonance Ms/Mesyl – Methanesulfonyl Me – Methyl ORTEP – Oak Ridge Thermal Ellipsoid Plot Pd/C – Palladium on Carbon Ph – Phenyl Py – Pyridine PTSA – Para-Toluenesulfonic acid RCM – Ring closing metathesis rpm – Rotations per minute rt – Room temperature sat. – Saturated TEMPO – 2,2,6,6-tetramethyl-1-piperidinyloxy free radical TFA – Trifluoro acetic acid Tf2O – Trifluoromethanesulphonic anhydride THF – Tetrahydrofuran TMSOTf – Trimethylsilyl trifluoromethanesulphonate TPP/PPh3 – Triphenylphosphine TsCl – para-Toluenesulphonyl chloride GENERAL REMARKS • 1H NMR spectra were recorded on AV–200 MHz, AV–400 MHz, and DRX– 500 MHz spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shifts have been expressed in ppm units downfield from TMS. • 13C NMR spectra were recorded on AV–50 MHz, AV–100 MHz, and DRX– 125 MHz spectrometer. • EI Mass spectra were recorded on Finngan MAT–1020 spectrometer at 70 eV using a direct inlet system. • The X-Ray Crystal data were collected on Bruker SMART APEX CCD diffractometer using Mo Kα radiation with fine focus tube with 50 kV and 30 mA. • Infrared spectra were scanned on Shimadzu IR 470 and Perkin-Elmer 683 or 1310 spectrometers with sodium chloride optics and are measured in cm–1. • Optical rotations were measured with a JASCO DIP 370 digital polarimeter. • Melting points were recorded on Buchi 535 melting point apparatus and are uncorrected. • All reactions are monitored by Thin Layer Chromatography (TLC) carried out on 0.25 mm E-Merck silica gel plates (60F–254) with UV light, I2, and anisaldehyde in ethanol as developing agents. • All reactions were carried out under nitrogen or argon atmosphere with dry, freshly distilled solvents under anhydrous conditions unless otherwise specified. Yields refer to chromatographically and spectroscopically homogeneous materials unless otherwise stated. • All evaporations were carried out under reduced pressure on Buchi rotary evaporator below 45 °C unless otherwise specified. • Silica gel (60–120), (100–200), and (230–400) mesh were used for column chromatography. CONTENTS Page No. Abstract i–xiii Chapter I: 1.1 Introduction 1 Section I: Cross metathesis approach for broussonetines C & G 1.2 Introduction 20 1.3 Present work 35 1.4 Experimental 52 1.5 Spectra 81 1.6 References 98 Section II: Synthesis of C-glycosides of dodecanoic acid employing cross metathesis and their application as new capping/reducing agents for silver nanoparticles synthesis. 1.7 Introduction 102 1.8 Present work 115 1.9 Experimental 127 1.10 Spectra 144 1.11 References 156 Chapter II: Section I: Cu(I) promoted one–pot “SNAr–Click reaction” of fluoronitrobenzenes. 2.1 Introduction 161 2.2 Present Work 170 2.3 Experimental 183 2.4 Spectra 201 2.5 References 216 Section II: “Click” synthesis of isomeric compounds for assessing the efficiency of bifurcated Cl···NO2 synthon. 2.6 Introduction 219 2.7 Present Work 231 2.8 Experimental 247 2.9 References 267 List of Publications 270 ABSTRACT ABSTRACT The thesis entitled “Cross Metathesis Approaches for Broussonetine C, G & 12-C- Glycosyl-dodecanoic Acids and Exploration of Click Reaction in Crystal Engineering”