NEW SYNTHETIC METHODOLOGIES FOR THIO- AND DETHIO- ACETALIZATION OF CARBONYL COMPOUNDS, AND DESILYLATION OF TERT-BUTYLDIMETHYLSILYL ETHERS A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by EJABUL MONDAL to the DEPARTMENT OF CHEMISTRY INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI North Guwahati, Guwahati -781 039 April, 2004 Dedicated to my late father TH-146_01612206 DEPARTMENT OF CHEMISTRY INDIAN INSTITUTE OF TECHNOLOGY, GUWAHATI INDIA CERTIFICATE-I This is to certify that Mr. Ejabul Mondal has satisfactorily completed all the courses required for the Ph. D. degree programme. These courses include: CH 603 Supra Molecules: Concept and Applications CH 611 Bio Inorganic Chemistry CH 627 New Reagents in Organic Synthesis CH 630 A Molecular Approach to Physical Chemistry Mr. Ejabul Mondal successfully completed his Ph. D. qualifying examination in May 8, 2003. (Dr. Jubaraj B. Baruah) Dr. Anil K. Saikia Head Secretary Department of Chemistry Departmental Post Graduate Committee I. I. T. Guwahati Department of Chemistry I. I. T. Guwahati TH-146_01612206 Indian Institute of Technology, Guwahati North Guwahati, Guwahati, 781 039, India Tel. No.: 0091-361-26902305 Fax No.: 0091-361-2690762 E. mail: [email protected] [email protected] Dr. Abu T. Khan Professor, Department of Chemistry ___________________________________________________________________________ CERTIFICATE – II Date: April , 2004 This is to certify that Mr. Ejabul Mondal has been working in my research group since March 30, 1999. At the beginning, he joined as a Junior Research Fellow in the CSIR project and later on, he has been registered as a self-sponsored Ph. D student on January 4, 2002 in the Department of Chemistry. Subsequently, he has been converted as regular registered Ph. D. student from August 15, 2002. I am forwarding his thesis entitled “NEW SYNTHETIC METHODOLOGIES FOR THIO- AND DETHIOACETALIZATION OF CARBONYL COMPOUNDS, AND DESILYLA-TION OF TERT-BUTYLDIMETHYL SILYL ETHERS” being submitted for the Ph. D. (Science) Degree of this Institute. I certify that he has fulfilled all the requirements according to the rules of this Institute regarding the investigations embodied in his thesis and this work has not been submitted elsewhere for a degree. (Dr. A. T. Khan) TH-146_01612206 STATEMENT I do hereby declare that the matter embodied in this thesis is the result of investigations carried out by me in the Department of Chemistry, Indian Institute of Technology Guwahati, India under the guidance of Professor Abu T. Khan. In keeping with the general practice of reporting scientific observations, due acknowledgements have been made wherever the work described is based on the findings of other investigators. Guwahati Ejabul Mondal April , 2004 TH-146_01612206 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI Ph. D. GRADE CARD Roll No.: 01612206 Department: Chemistry Name: Ejabul Mondal Semester I (Jan – May) 2002 Course Course Name Credit Grade CH 627 New Reagents in Organic Synthesis 6 AB Semester Performance Index (S. P. I): 9.00 Semester II (July-Nov.) 2002 Course Course Name Credit Grade CH 630 A Molecular Approach to Physical Chemistry 6 BC CH 611 Bio Inorganic Chemistry 6 AB CH 603 Supra Molecules: Concept and Applications 6 BC Semester Performance Index (S. P. I): 7.66 Cumulative Performance Index (C. P. I): 8.00 Date: April , 2004 Assistant Registrar (Academic) TH-146_01612206 ACKNOWLEDGEMENTS My sincere thanks to my Ph.D. supervisor Professor Abu T. Khan, Department of chemistry, IIT Guwahati for his able guidance, constant encouragements and moral supports at each and every step of my research work, which enables me to complete my thesis work. I am grateful to Professor M. K. Chaudhuri, Former Head, Department of Chemistry and Dean, Research and Development and Dr. B. K. Patel, Associate Professor, Department of chemistry, IIT Guwahati for their encouragements and moral supports during my continuing research work. I also express my sincere thanks to Dr. V. Manivannan and Dr. A. K. Saikia, Assistant Professor, Department of chemistry, IIT Guwahati as members of Doctoral Committee. I also acknowledge to all my present and former labmates Dr. Gopal Bose, Dr. Pankaj M. Bujar Barua, Dr. (Mrs.) P. Goswami, Miss Priti Rani Sahu, Samimul Islam, Subrata Ghosh, Md. Lokhman H. Chaudhuri, Ballav Moni Bora and Murshida Karim for their direct and indirect help. I am thankful to the RSIC, CDRI-Lucknow, RSIC-Shillong, Indian Institute of Chemical- Biology-Kolkata, Indian Institute of Technology Kanpur, Indian Association for the Cultivation of Science, Kolkata, Cental Marine Research Institute, Bhavanagar, Gujarat, and Indian Institute of Technology, Guwahati, for recording 1H NMR and 13 NMR. I also acknowledge all non-teaching staffs of our Department and library staff members of the IIT-Guwahati. I express my thanks to Dr. S. S. Dhar, Akhtarul Alam, and Subhabrata Das for their friendships during my staying at IIT Guwahati. I am highly grateful to the CSIR, New Delhi for my research fellowship and IIT Guwahati for providing general facilities to carry out my research works. Finally, I express my sincere gratitude to my beloved mother and my eldest sister for their constant encouragements and moral supports to complete my thesis work. Ejabul Mondal TH-146_01612206 SUMMARY This dissertation describes the successful efforts on the development of new synthetic methodologies in protection-deprotection chemistry for thio- and dethioacetalization of carbonyl compounds and desilylation of tert-butyldimethylsilyl ethers to the hydroxyl compounds. The thesis contains mainly three chapters. Each chapter is subdivided into two parts viz. Part I and Part II. In each of the Chapter, Part I describes a review of literature of the present work and its significance. Similarly, in each chapter of the Part II is subdivided into sections, which give an account of the work carried out by the candidate. Chapter I, Part I briefs the usefulness and importance of dithioacetals in organic synthesis as well as a survey of their preparations from the corresponding carbonyl compounds. In addition, it also highlights reasons for choosing the present research problem for investigation. In Chapter I, Part II consists of three sections viz., Section A, Section B and Section C, respectively. Each section describes a new synthetic protocol for thioacetalization of carbonyl compounds Section A gives a description of a new method for chemoselective thioacetalization of aldehydic compounds by using nickel(II) chloride as an efficient and useful catalyst. By applying this methodology, various aromatic and aliphatic aldehydes are smoothly converted into the corresponding acyclic and cyclic dithioacetals 25, 34, 66, 98, 99, 100, 101- 120 in good to high yields depending upon the substrates and thiol or dithiols used as indicated in the Table 1. A large number of other protecting groups such as acetyl (for example, 108 and 109), benzoyl (110), benzyl (107), allyl (106), TBS ether (105), esters (120) are stable during the reaction conditions. Moreover, a chemoselective thioacetlization of an aldehyde group in presence of a keto group in the same molecule, for substrate 129, is possible by our method. However, thioketalisation of ketones are unsuccessful even after prolonged reaction times. All the protected compounds are fully characterized by IR, 1H NMR 13C NMR and by elemental analyses, all are in full agreement with the expected products. Section B gives an account of a simple and practical synthetic protocol for thioacetalization of carbonyl compounds by using acetyl chloride under solvent free-conditions. TH-146_01612206 When a mixture of aldehyde or ketone (10 mmol) and dithiol (10 mmol) or thiol (22 mmol) was treated with a catalytic amount of acetyl chloride (72 L, 1 mmol or 144 L, 2 mmol for a ketone) at room temperature, it smoothly converted to the corresponding dithioacetal derivatives in good yields. The final products can be obtained either by direct recrystallisation or by distillation under reduced pressure depending upon the nature of the products. By applying this methodology, both cyclic as well as acyclic dithioacetals of various aldehydes and ketones were prepared in very good yields on reaction with the respective thiols or dithiols. It is important to mention that hydroxyl aldehydes can be easily protected to the desired dithioacetals (29 and 114) without acetylating the hydroxyl groups under the reaction conditions. More interestingly, highly acid sensitive substrates such as an ester aldehyde and 2-furaldehyde were also converted to the corresponding dithioacetals (120 and 134) in fairly good yields as mentioned in the Table 2. By applying our protocol, dithioacetalization of D-arabinose and a highly hindered ketone such as benzophenone can be protected to the corresponding dithioacetal derivatives 135 and 136, respectively in fairly high yield and shorter time. The protected dithioacetals are characterized by usual spectroscopic techniques. Section C elaborates an exceptionally simple and convenient synthetic protocol for thioacetalization of the carbonyl compounds by employing bromodimethylsulfonium + - bromide (Me2S BrBr ) as a new pre-catalyst under solvent-free conditions. When a mixture of carbonyl compounds (1 mmol) and thiol (2.2 mmol) or dithiol (1.1 mmol) was subjected with a catalytic amount of bromodimethylsulfonium bromide (0.05 mmol for aldehyde and 0.15 mmol for ketone) at room temperature, it converted readily to the corresponding