Direct Cross-Coupling Reaction of Simple Alkenes with Acrylates Catalyzed by Palladium Catalyst Yun-He Xu, Jun Lu, and Teck-Peng Loh J. Am. Chem. Soc., Article ASAP Current Literature Chenbo Wang @ Wipf Group Jan 17, 2009 Chenbo Wang @ Wipf Group Page 1 of 12 1/18/2009 Preparation of Diene Units with Cross-coupling Reactions: Classical Cross-coupling Reactions vs. Direct Cross-Coupling Reaction of Simple Alkenes The challenge: •Chemoselectivity: dimerization •Stereoselectivity: cis/trans •Difficulty in activating alkene C-H without a directing group •Product stability Chenbo Wang @ Wipf Group Page 2 of 12 1/18/2009 Construction of Diene Units in Natural Product Synthesis: Suzuki Reaction O O O PPh ,CBr ; Bu3SnH, Pd(PPh3)4; OMOM 3 4 OMOM 88% OMOM Ph O Ph O Ph O Br O Br Br OBn OBn 1. 2,5-dimethylhexa-2,4-diene, BH3.DMS, THF, OH O 2. H2O, then aq. CH2O, OH O 3. KHF , acetone, MeCN, H O; 99% OMOM 2 2 OMOM O O Br Br BF3K H N BnO Pd(PPh3)4, Cs CO O 2 3 OMOM OH N THF/H2O OH O OH O 42% OMe O O Oximidine II Molander, G. A. et al J. Am. Chem. Soc., 2004, 126, 10313 Chenbo Wang @ Wipf Group Page 3 of 12 1/18/2009 Construction of Diene Units in Natural Product Synthesis: Negishi Reaction Panek, S. J. et al J. Am. Chem. Soc. 2002, 124, 11368 Chenbo Wang @ Wipf Group Page 4 of 12 1/18/2009 Construction of Diene Units in Natural Product Synthesis: Stille and Heck Reaction OMe Bu3Sn O OMe SnBu3 1. Pd(MeCN)2Cl2,DMF/THF 2. CAN, THF/H2O CrCl , CHI ; 3. HF, CH CN; NH 2 3 3 NH 70% NH 54% over 3 steps O OMe OMe TBSO HO O O TBSO O O I HO OMe TIPSO O OMe TIPSO I OMe (+)-mycotrienol C H C H MeO OMe C8H17 8 17 8 17 1. KHMDS, PhNTf2;90% O 2. TsOH, actone/H2O; 80% OTf Pd(PPh3)4,K2CO3, MeCN; 50% 3. Ph3PCH3Br, KOtBu; 95% H H H H H H OO OO OO O O O Intermediate in the total synthesis of taxol Panek, J. S. et al J. Am. Chem. Soc. 1998, 120, 4123 Danishefsky, S. J. et al J. Am. Chem. Soc., 1996, 118, 2843 Chenbo Wang @ Wipf Group Page 5 of 12 1/18/2009 Alkene Dimerization Reaction: Previous Work Ishii, Y. et al Org. Lett. 2004, 6, 4623 and references therein Kohll, C. F. and Van Helden, R. Recl. Trav. Chim. Pays-Bas 1967, 86, 1930 Chenbo Wang @ Wipf Group Page 6 of 12 1/18/2009 The First Practical Example of Oxidative Alkene-alkene Oxidative Coupling Ishii, Y. et al Org. Lett. 2004, 6, 4623 Chenbo Wang @ Wipf Group Page 7 of 12 1/18/2009 Proposed Mechanism for Oxidative Alkene-alkene Oxidative Coupling Chenbo Wang @ Wipf Group Page 8 of 12 1/18/2009 Direct Cross-Coupling Reaction of Simple Alkenes with Acrylates: Optimization of Reaction Conditions Chenbo Wang @ Wipf Group Page 9 of 12 1/18/2009 Direct Cross-Coupling Reaction of Simple Alkenes with Acrylates: Substrate Scope Suitable substrate for this methodology: Chenbo Wang @ Wipf Group Page 10 of 12 1/18/2009 Direct Cross-Coupling Reaction of Simple Alkenes with Acrylates: Proposed Mechanism Chenbo Wang @ Wipf Group Page 11 of 12 1/18/2009 Summary • First example of direct cross-coupling reaction of simple alkenes with acrylates was reported. • This methodology is still at early exploratory stage. Substrate scope is very limited. • Future work: mechanistic study, a directing group for alkene C-H activation, milder conditions. Chenbo Wang @ Wipf Group Page 12 of 12 1/18/2009.