ENANTIOSELECTIVE SYNTHESIS OF PHORACANTHOLIDE I, MEXILETINE, ENCIPRAZINE, ESMOLOL, ATENOLOL, XIBENOLOL VIA α- AMINOXYLATION OF ALDEHYDE AND APPLICATION OF RECYCLABLE CATALYSIS IN ORGANIC TRANSFORMATION A THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY MOHSINKHAN YASEENKHAN PATHAN DR. SHAFEEK A. R. MULLA (RESEARCH GUIDE) CHEMICAL ENGINEERING AND PROCESS DEVELOPMENT DIVISION, NATIONAL CHEMICAL LABORATORY, PUNE- 411008, INDIA APRIL 2014 Mr. Yaseenkhan Sajjankhan Pathan Mrs. Farjana Yaseenkhan Pathan NATIONAL CHEMICAL LABORATORY DR. SHAFEEK A. R. MULLA Senior Scientist Ph.D. FMASc. AvH Fellow (Germany), JSPS Fellow (Japan) Chemical Engineering & Process Development Division Dr. Homi Bhabha Road, Pune – 411 008, India Tel.:+91-20-25902316, Fax:+91-20-25902676 E-mail : [email protected]/[email protected] CERTIFICATE Certified that the work incorporated in the thesis entitled “Enantioselective Synthesis of Phoracantholide I, Mexiletine, Enciprazine, Esmolol, Atenolol, Xibenolol via α- Aminoxylation of Aldehyde and Application of Recyclable Catalysis in Organic Transformation” was carried out by the candidate under my supervision. Such material as had been obtained from other sources has been duly acknowledged in the thesis. April 2014 (Dr. Shafeek. A. R. Mulla) Pune Research Guide NATIONAL CHEMICAL LABORATORY DECLARATION I here by declare that the thesis entitled “Enantioselective Synthesis of Phoracantholide I, Mexiletine, Enciprazine, Esmolol, Atenolol, Xibenolol via α-Aminoxylation of Aldehyde and Application of Recyclable Catalysis in Organic Transformation” submitted for the degree of Doctor of Philosophy in Chemistry to the University of Pune, has not been submitted by me to any other university or institution. This work was carried out at the National Chemical Laboratory, Pune, India. April 2014 Mohsinkhan Yaseenkhan Pathan Pune CE & PD Division, National Chemical Laboratory, Dr. Homi Bhabha Road Pune – 411 008, INDIA CONTENTS Page No. Acknowledgment ……………………………………………………… i Abbreviations ……………………………………………………… iii General Remarks ……………………………………………………… vi Abstract ……………………………………………………… vii CHAPTER I Enantioselective synthesis of (S)-Phoracantholide I and (R)- Mexiletine via α-aminoxylation of aldehyde catalyzed by L- proline Section I Enantioselective synthesis of (S)-Phoracantholide I 1.1.1 Introduction ………………………………………... 2 1.1.2 Review of literature ………………………………... 3 1.1.3 Present work ………………………………………. 7 1.1.3.1 Objectives ..………………………………………... 7 1.1.3.2 Proline-catalyzed α-aminoxylation ……………….. 8 1.1.3.3 Possible Mechanism for L-proline catalyzed asymmetric α-aminoxylation of aldehyde …………. 10 1.1.4 Results and discussion …………………………….. 11 1.1.4.1 Enantioselective synthesis of Phoracantholide I …... 12 1.1.5 Conclusion ………………………………………… 24 1.1.6 Experimental Section ……………………………… 24 Section II Enantioselective synthesis of (R)-Mexiletine 1.2.1 Introduction ………………………………………... 32 1.2.2 Review of literature ………………………………... 33 1.2.3 Present work ………………………………………. 40 1.2.3.1 Objectives ..………………………………………... 40 1.2.4 Results and discussion …………………………….. 40 1.2.4.1 Enantioselective synthesis of Mexiletine ………….. 41 1.2.5 Conclusion ………………………………………… 49 1.2.6 Experimental Section ……………………………… 50 1.2.7 References …………………………………………. 55 CHAPTER II Enantioselective synthesis of (S)-Enciprazine, (S)-Esmolol, (S)- Atenolol and (S)-Xibenolol via α-aminoxylation of aldehyde catalyzed by L-proline 2.1 Introduction ………………………………………... 61 2.2 Review of literature ………………………………. 63 2.3 Present work ………………………………………. 69 2.3.1 Objectives …………………………………………. 69 2.4 Results and discussion …………………………….. 70 2.4.1 Enantioselective synthesis of Enciprazine ………… 71 2.4.2 Enantioselective synthesis of Esmolol ……………. 79 2.4.3 Enantioselective synthesis of Atenolol ……………. 86 2.4.4 Enantioselective synthesis of Xibenolol ……...…… 94 2.5 Conclusion ………………………………………… 100 2.6 Experimental section ……………………………… 100 2.7 References …………………………………………. 112 CHAPTER III Synthetic methodologies in the presence of silica supported dodecatungstophosphoric acid (DTP/SiO2) Section I Highly efficient heterogeneous reusable silica supported dodecatungstophosphoric acid catalyzed one-pot multi- component synthesis of α-aminophosphonates and bis- α- aminophosphonates and their bioevaluation 3.1.1 Introduction ……………………………………… 116 3.1.2 Review of literature ………………………………. 117 3.1.3 Present work ………………………………………. 119 3.1.3.1 Objectives …………………………………………. 119 3.1.4 Results and discussion ……………………………. 120 3.1.5 Conclusion ………………………………………… 129 3.1.6 Experimental section ……………………………… 130 3.1.6.1 General Procedure for the preparation of DTP/SiO2-- 130 3.1.6.3 Antitubercular testing using XTT Reduction menadione assay protocol …………………………. 131 3.1.6.4 Cytotoxicity evaluation using MTT Reduction menadione assay protocol………………………… 132 3.1.7 Spectra …...………………………………………. 143 Section II A novel and efficient synthesis of azaarene-substituted 3- hydroxy-2-oxindoles via sp3 C-H functionalization of 2-methyl azaarenes and (2-azaaryl)methanes over heterogeneous, reusable silica-supported dodecatungstophosphoric acid catalyst 3.2.1 Introduction …………………………………… 167 3.2.2 Review of literature ………………………………. 169 3.2.3 Present work ………………………………………. 170 3.2.3.1 Objectives …………………………………………. 170 3.2.4 Results and discussion ……………………………. 171 3.2.5 Conclusion ………………………………………… 179 3.2.6 Experimental section ……………………………… 179 3.2.7 Spectra ….. ………………………………………. 196 Section III A facile and highly efficient one-pot multi-component synthesis of azaarene-substituted 3- substituted-2-oxindoles via sp3 C-H functionalization of 2-methyl azaarenes and (2- azaaryl)methanes over reusable silica-supported dodecatungstophosphoric acid catalyst 3.3.1 Introduction ……………………………………… 227 3.3.2 Present work ………………………………………. 229 3.3.2.1 Objectives …………………………………………. 229 3.3.3 Results and discussion ……………………………. 230 3.3.4 Conclusion ………………………………………… 236 3.3.5 Experimental section ……………………………… 237 3.3.6 Spectra ….. ………………………………………. 250 3.3.7 References ………………………………………… 276 CHAPTER IV Synthetic methodologies using ethylammonium nitrate (EAN) as an ionic liquid Section I Solvent free, highly efficient one-pot multi-component synthesis of 1-amido- and 1-carbamato-alkyl naphthols/phenols catalyzed by ethylammonium nitrate as reusable ionic liquid under neat reaction condition at ambient temperature 4.1.1 Introduction ……………………………………… 284 4.1.2 Review of literature ………………………………. 285 4.1.3 Present work ……………………………………… 288 4.1.3.1 Objectives …………………………………………. 288 4.1.4 Results and discussion ……………………………. 289 4.1.5 Conclusion ………………………………………… 296 4.1.6 Experimental section ……………………………… 297 4.1.6.1 A typical procedure for the synthesis of Ethyl ammonium nitrate (EAN) ionic liquid……………... 297 4.1.7 Spectra ……………………………………………. 308 Section II Efficient, rapid synthesis of bis(indolyl)methane using ethyl ammonium nitrate as an ionic liquid 4.2.1 Introduction ………………………………………... 332 4.2.2 Review of literature ………………………………. 333 4.2.3 Present work ……………………………………… 336 4.2.3.1 Objectives …………………………………………. 336 4.2.4 Results and discussion ……………………………. 336 4.2.5 Conclusion ………………………………………… 343 4.2.6 Experimental section ……………………………… 343 4.2.7 Spectra for selected compounds ……………... 351 4.2.8 References ………………………………………… 353 List of Publications ………………………………... 360 Acknowledgment All praise to Almighty Allah, the source of knowledge and wisdom within and beyond our comprehension and WHO bestowed His continuous boundless bounty upon me, blessed with courage of facing problems and obstacles, determination, and strength to complete this work. My deepest gratitude goes first to my research guide Dr. Shafeek A. R. Mulla for his constant support and encouragement during the course of Ph. D. work. It has been an intellectually stimulating and rewarding experience to work with him. We experienced together all the ups and downs of routine work, shared the happiness of success and the depression of failure. I would like to express my sincere gratitude and respect to Dr. V. V. Ranade, Deputy Director and Chair, CEPD Division, NCL. I also wish express deep sense of gratitude to Dr. B. D. Kulkarni, former Deputy Director and Head, CEPD, NCL. I would like to extend my special thanks to Dr. Sourav Pal, Director, NCL for allowing me to carry out research and extending all possible infrastructural facilities and permitting me to present this work in the form of a Ph.D. thesis. I thank NMR group and elemental analysis group for their help in obtaining the analytical data and also Dr. D. Sarkar and his group for the bioevaluation. I thank library staff, chemical stores, purchase staff, glass blowing section NCL for their cooperation. I thank CEPD office staff Mr. Raheja, Mr. Bhosale and Mr. Kakade for their cooperation. I thanks to Dr. C. G. Suresh, chair, Student Academic Office and staff Mrs. Puranik, Mrs. Kolhe, Mr. Pavithran and I also thank PG section of Pune University for their cooperation and help. I am extremely thankful to Dr. C. S. Gopinath, and Prof. A. K. Nikumbh, (Dept. of Chemistry, University of Pune) for their valuable help and suggestions during my research work. I also thank to Dr. A. Sudalai, Dr. Tarek Salama, Dr. Imran Rahman, Dr. M. S. Qureshi for their invaluable guidance and memorable suggestion and also to my college teachers Dr. R. P. Pawar, Head department of chemistry, Deogiri College, Aurangabad as well to Dr. W. N. Jadhav, Head department of chemistry, DSM college, parbhani for inspiring me towards