Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Preparation and Reactions of Allylic Zinc Reagents and Transition Metal-Catalyzed Cross-Coupling Reactions von Guillaume Dunet aus Orléans, Frankreich 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 15.11.2007 Guillaume Dunet Dissertation eingereicht am 15.11.2007 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Manfred Heuschmann Mündliche Prüfung am 14.12.2007 This work was carried out from November 2004 to December 2007 under the guidance of Prof. Paul 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. I am also grateful to Prof. Dr. Manfred Heuschmann for agreeing to be my “Zweitgutachter”, as well as Prof. Dr. H. Zipse, Prof. Dr. H. Langhals, and Prof. Dr. K. Karaghiosoff for the interest shown in this manuscript by accepting to be referees. I thank Dr. Sylvie Perrone and Dr. Giuliano Clososki for the careful correction of this manuscript. I would like to thank the DFG for financial support. Special thanks to my actual and former lab mates: Hongjun, Genia, Pradipta, Subbu, Geogios, Matt, Tobias and Alex for the great time we spent together in the lab. I would like to thank Hongjun, Matt and Milica for the fruitful collaborations in the field of the allylmetal chemistry. I thank all past and present co-workers I have met in the Knochel’s group for the good times we had (especially parties). I would also like to thank Vladimir Malakhov, 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, I. Brück, H. Schulz and G. Käser for their help. Very special thanks to Sylvie for her support, and for making this stay in Munich a lot more entertaining :0)). Finally I would like to thank my family and my friends for their great support, throughout my time in Munich. Parts of this Ph.D. thesis have been published: 1. Dunet, G.; Knochel, P. “Iron-Catalyzed Cross-Coupling between Alkenyl and Dienyl Sulfonates and Functionalized Arylcopper Reagents” Synlett , 2006 , 3, 407-410. 2. Dunet, G.; Knochel, P. “Highly Stereoselective Cobalt-Catalyzed Allylation of Functionalized Diarylzinc Reagents” Synlett 2007 , 9, 1383. 3. Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. “Highly Diastereoselective synthesis of Homoallylic Alcohols Bearing Adjacent Quaternary Centers Using Substituted Allylic Zinc Reagents” J. Am. Chem. Soc. 2007 , 129 , 5376-5377. 4. Dunet, G.; Mayer, P.; Knochel,P. “Highly Diastereoselective Addition of Cinnamylzinc Reagents to α-Chiral Carbonyl Derivatives” Org. Lett. In press Après la pluie, le beau temps… 6 Table of Contents THEORETICAL PART ......................................................................................................................................... 9 1. Introduction ......................................................................................................................................... 10 1.1. Overview ......................................................................................................................................... 10 1.1.1. Allylic zinc reagents ...................................................................................................................... 10 1.1.2. Cross-coupling reactions .............................................................................................................. 21 1.2. Objectives ....................................................................................................................................... 29 3. LiCl-mediated preparation of allylic zinc reagents and their reaction with electrophiles .............................................................................................................................................. 31 3.1. Introduction .................................................................................................................................... 31 3.2. LiCl-mediated preparation of allylic zinc reagents ............................................................ 32 3.3. Diastereoselective reaction of allylic zinc reagents with aldehydes and ketones ...... 34 3.4. Reaction with α-chiral ketones ................................................................................................. 40 3.4.1. Reaction with α-chiral cyclohexanones......................................................................................... 40 3.4.2. Reaction with acyclic α-chiral ketones.......................................................................................... 45 3.4.3. Application to enantioenriched α-chiral ketones .......................................................................... 46 3.5. Direct “zinc-ene” reaction from allylic chlorides ............................................................... 47 3.6. Conclusion ...................................................................................................................................... 52 4. New transition metal-catalyzed cross-coupling reaction ............................................ 54 4.1. Highly stereoselective cobalt-catalyzed allylation of functionalized diarylzinc reagents .......................................................................................................................................................... 54 4.2. Iron-catalyzed cross-coupling between alkenyl and dienyl sulfonates and functionalized arylcopper reagents ........................................................................................................ 60 4.3. Nickel-catalyzed cross-coupling between aryl phosphates and arylmagnesium reagents .......................................................................................................................................................... 65 5. Summary and outlook .................................................................................................................... 70 5.1. LiCl-mediated preparation of allylic zinc reagents and their reaction with electrophiles ................................................................................................................................................. 70 5.2. Highly stereoselective cobalt-catalyzed allylation of functionalized diarylzinc reagents .......................................................................................................................................................... 72 7 5.3. Iron-catalyzed cross-coupling between alkenyl and dienyl sulfonates and functionalized arylcopper reagents ........................................................................................................ 73 5.4. Nickel-catalyzed cross-coupling between aryl phosphates and arylmagnesium reagents .......................................................................................................................................................... 74 EXPERIMENTAL PART .................................................................................................................................... 76 6. General considerations .................................................................................................................. 77 7. Preparation and reactions of allylic zinc reagents ......................................................... 81 7.1. Typical Procedures (TPs) ........................................................................................................... 81 7.1.1. Typical procedure for the formation of allylic zinc reagents from allylic chlorides or phosphates (TP1): ....................................................................................................................................................... 81 7.1.2. Typical procedure for the reaction of allylic zinc reagents with aldehydes, ketones or imines (TP2): ....................................................................................................................................................... 81 7.1.3. Typical procedure for the intramolecular “zinc-ene” reaction (TP3):......................................... 82 7.2. Experimental section :.................................................................................................................. 82 8. Cross-coupling reaction .............................................................................................................. 131 8.1. Typical Procedures (TPs) ......................................................................................................... 131 8.1.2. Typical procedure for the formation of diarylzinc reagents via an I/Zn-exchange (TP4): ......... 131 8.1.3. Typical procedure for the cobalt-catalyzed reaction of allylic chlorides or phosphates with diarylzinc reagents (TP5):......................................................................................................................... 131 8.1.4. Typical procedure for the iron-catalyzed cross-coupling between alkenyl sulfonates and arylcopper reagents (TP6): ......................................................................................................................