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Synthesis of New Chiral Phosphine Ligands and Their Applications in Asymmetric Catalysis

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Synthesis of New Chiral Phosphine Ligands and Their Applications in Asymmetric Catalysis Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Synthesis of New Chiral Phosphine Ligands and Their Applications in Asymmetric Catalysis von Murthy Narasimha Cheemala aus Eluru, India München 2007 Erklärung Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29. Januar 1998 von Herrn Prof. Dr. Paul Knochel betreut. Ehrenwörtliche Versicherung Diese Dissertation wurde selbständig, und ohne unerlaubte Hilfe erarbeitet. München, am 09. 07. 2007. Murthy Narasimha Cheemala Dissertation eingereicht am 09. 07. 2007 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Manfred Heuschmann Mündliche Prüfung am 25. 07. 2007 This work was carried out from August 2003 to April 2007 under the guidance of Prof. Knochel at the Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität, Munich. I would like to thank my supervisor, Prof. Dr. Paul Knochel, for giving me the opportunity of doing my Ph.D. in his group, for his invaluable support and kindness through this time, and for his guidance in the course of scientific research presented here. I am also very grateful to Prof. Dr. M. Heuschmann for agreeing to be my “Zweitgutachter”, as well as Prof. Dr. K. Karaghiosoff, Prof. Dr. H. R. Pfaendler, Prof. Dr. H. Langhals and Prof. Dr. I.-P. Lorenz for the interest shown in this manuscript by accepting to be referees. I thank Dr. Matthew Helm, Dr. Srinivas Reddy Dubbaka, Dr. Shohei Sase and Christina Despotopoulou for the careful corrections of this manuscript. I would like to thank the Ludwig-Maximilians-Universität for the financial support. I would like to thank also Prof. M. Periasamy, Prof. Dr. Lutz Ackerman, Prof. Dr. H. Ila and Prof. Dr. N. Sastry for their help, advices and suggestions for my research and career. Furthermore, I would like to thank all the students, diplomants and postdocs who came and went throughout my PhD for their suggestions, support and friendship which have made my time in Germany an enjoyable and worthwhile experience. I would especially like to thank Dr. Xiaoyin Yang, Dr. Wenwei Lin, Dr. Darunee Soorukram, Dr. Hongjun Ren, Dr. Gavryushin Andrei, Dr. Sylvie Perrone, Dr. Vicente del Amo, Dr. Felix Kopp, Dr. Ralf J. Kloetzing, Dr. Krasovskiy Arkady, Valeria Krasovskiy, Dr. Shohei Sase, Albrecht Metzger, Milica Gvozdenac, Guillaume Dunet, Christian Rauhut, Armin Stoll, Nadege Boudet, Johann Szeifert, Markus Hörn, Maud Gayral and all other members of the knochel group for the excellent time and friendly atmosphere during the working hours. I would also like to thank Vladimir Malakov, Beatrix Cammelade, Simon Matthe and Yulia Tsvik for their help in organizing everyday life in the lab, as well as the analytical team, Dr. D. Stephenson, Dr. C. Dubler, Dr. W. Spahl, B. Tschuk, and Dr. K. Polborn for their help. Finally none of this would have been possible without the constant love and encouragement of my family. I would like to thank them especially my parents, brother-in-law, brother and sisters for their great love, kind understanding and unquestioning support, as well as my friends (Abbas, Dr. Srinvasa Marimganti, Prativamayee, Panth, Rajesh, Kalyan, Rama, Thresen, Innus, Dr. Sabyasachi Mishra, Dr. Swarnalatha Kokatam, Hari) for their friendship and support throughout my time in Germany. Parts of this Ph. D. thesis have been published: 1.Korn, T. J.; Schade, M. A.; Cheemala, M. N.; Wirth, S.; Guevara, S. A.; Cahiez, G.; Knochel, P. “Cobalt-catalyzed cross-coupling reactions of heterocyclic chlorides with arylmagnesium halides and of polyfunctionalized arylcopper reagents with arylbromides, chlorides, fluorides and tosylates”. Synthesis 2006 , 24 , 4270. 2. Cheemala, M. N.; Knochel, P. “New P,N-Ferrocenyl Ligands for the Asymmetric Ir-Catalyzed Hydrogenation of Imines” Org. Lett. 2007 , accepted. 3. Cheemala, M. N.; Gayral, M.; Brown, J. M.; Rossen, K.; Knochel, P. “New Paracyclophane Phosphine for Highly Enantioselective Ru-Catalyzed Hydrogenation of Prochiral Ketones.” Manuscript in preparation . 4. Cheemala, M. N.; Knochel, P. “Synthesis of New Ferrocenyl P,N-ligands and their Applications in Asymmetric Catalysis” Manuscript in Preparation. 5. Cheemala, M.N.; Knochel, P. “Synthesis of new planar chiral ferrocenyl ligand through selective sulfoxide-lithium exchange” Manuscript in Preparation. To my parents Table of contents Introduction 1. General Introduction 1 1.1 Chiral P,P-Ligands 2 1.1.1 Ferrocenyl P,P-Ligands 4 1.2. Chiral P,N-Ligands 8 1.2.1 Ferrocenyl P,N-Ligands 10 2. Objectives 11 Results and Discussion 1. Synthesis of planar chiral ferrocenyl P,P-Ligands and their applications in asymmetric catalysis 13 1.1. Introduction 13 1.1.1. Chiral ferrocenyl ligands with planr chirality 13 1.1.2. Synthesis of 1,2-disubstituted ferrocenes via diastereoselective ortho -metallation 14 1.2. Synthesis of chiral planr ferrocenyl P,P-ligand 8 16 1.2.1. Diastereoselective ortho -lithiation 16 1.2.2. Optimization for the selective sulfoxide-lithium exchange 17 1.3. Applications in asymmetric catalysis 21 1.3.1. Rh-catalyzed hydrogenationof olefines 21 1.3.2. Pd-catalyzed asymmetric allylic alkylations 21 1.4. Conclusion 21 2. Synthesis of chiral ferrocenyl P,N-ligands and their applications in asymmetric catalysis 22 2.1. Introduction 22 2.2. Syntheis of P,N-ligands 9 and 10 24 2.2.1. Syntheis of ferrocenyl P,N-ligands 9 and 10 with pyridine ring as a N-donor 24 2.2.2. Syntheis of ferrocenyl P,N-ligands 9 and 10 with substituted pyridine ring as a N-donor 29 2.3. Applications in asymmetric catalysis 33 2.3.1. Pd-catalyzed allylic alkylations 34 2.3.2. Ir-catalyzed asymmetric hydrogenation of olefines 35 2.3.3. Ir-catalyzed asymmetric imine hydrogenation 37 2.4. Conclusion 49 3. Preparation of bisferrocenyl P,P ligands and their applications in asymmetric catalysis 49 3.1. Introduction 49 3.2. Synthesis of bisferrocenyl P,P-ligand 11 50 3.3. Applications in asymmetric catalysis 54 3.1. Rh-catalyzed hydrogenation of olefines 54 3.2. Pd-catalyzed asymmetric alkylations 54 3.4. Conclusion 55 4. Synthesis of new paracyclophane phosphines and their applications in asymmetric catalysis 55 4.1. Introduction 55 4.2. Synthesis of new paracyclophane phosphines 56 4.3. Applications in asymmetric catalysis 58 4.3.1. Rh-catalyzed asymmetric hydrogenation reactions 59 4.3.2. Ru-catalyzed hydrogenation of prochiral ketones 60 4.4. Conclusion 66 5. Summary and Outlook 67 Experimental Section 1. General Conditions 73 2. Typical Procedures 74 2.1. Typical procedure for the diastereoselective ortho-lithiation of ferrocene 14 (TP 1) 74 2.2. Typical procedure for the sulfoxide-lithium exchange on bromoferrocenes of type 17 using PhLi (TP 2) 75 2.3. Typical procedure for the preparation of ferrocenyl alcohols through the sulfoxide-lithium exchange (TP 3) 75 2.4. Typical procedure for the preparation of ferrocenyl ethers (TP 4) 75 2.5. Typical procedure for the desulfurizazion of the phosphine sulfides (TP 5) 75 2.6. Typical procedure for the preparation of ferrocenyl P,N-iridium complexes 46a-g and 47a-g (TP 6) 76 2.7. Typical procedure for the preparation of N-arylimines (TP 7) 76 2.8. Typical procedure for the Ir-catalyzed asymmetric hydrogenation of imines (TP 8) 76 2.9. Typical procedure for the preparation of chiral primary amines and lactams (TP 9) 76 2.10. Typical procedure for the ruthenium-diamine complexes 79a-c and 80a-c of paracyclophanephosphines (TP 10) 76 2.11. Typical procedure for the Ru-catalyzed hydrogenation of ketones (TP 11) 77 2.12. Typical procedure for the Pd(0)-catalyzed asymmetric alkylation on racemic 27 (TP 12) 77 2.13. Typical procedure for the Rh-catalyzed hydrogenation (TP 13) 77 3. Preparation of new planar chiral ferrocenyl P,P-ligand 8 77 4. Synthesis of chiral P,N-ligands 9 and 10 84 5. Preparation of iridium complexes 46a-g and 47a-g 108 6. Synthesis of N-arylimines 118 7. Asymmetric Hydrogenation of Imines 139 8. Synthesis of chiral primary amines and l actams 162 9. Synthesis of bisferrocenyl P,P-ligands 165 10. Synthesis of new paracyclophane based diphosphines 172 11. Preparation of ruthenium-diamine complexes 79a-c and 80a-c 174 12. Asymmetric hydrogenation of ketones and olefins 177 13. Data for the x-ray crystallographic analysis 189 14. Abbreviations 190 Introduction 1 1. General Introduction Molecular chirality plays a key role in science and technology. 1 Many organic compounds are chiral and many enantiomerically pure compounds are widely used in the preparation of cosmetics, flavours, pesticides, vitamins and pharmaceuticals. 2 There are many examples which stress the necessity for preparing enantiomerically pure compounds. For example, the market for single enantiomer drugs in 1996 was $ 73 billion, which increased to $ 96 billion in 1998 and to $ 123 billion in 2000. The market for enantiopure materials continues to increase 3; hence the search for efficient ways to access enantiomerically enriched compounds is still an active area of research to synthetic organic chemists. 4 To access enantiomerically pure compounds there are four main approaches. 1. Resolution of a racemic mixture 2. Synthesis from a chiral pool and synthesis using a chiral auxiliary 5 3. Synthesis using biocatalysts (enzymes, cell cultures and antibody) 6 4. Asymmetric catalysis using a man made chiral catalyst. Among this variety of methods, asymmetric catalysis has proved to be an ideal method to prepare naturally and nonnaturally occurring chiral compounds in large quantities by using small amounts of chiral catalyst. In the past three decades, many metal complexes using various chiral ligands have been found that catalyze various reactions with impressive enantioselectivities. However, despite the impressive progress in this area, the design of suitable chiral ligands for a particular application remains a formidable task.
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