Dynamic Kinetic Asymmetric Allylation of Hydrazines and Hydroxylamines Ian Mangion,* Neil Strotman, Michael Drahl, Jason Imbriglio, and Erin Guidry Merck Research Laboratories, Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065 ian_mangion@merck.com Received May 27, 2009 ABSTRACT Hydrazines and hydroxylamines have been found to be excellent nucleophiles for the palladium-catalyzed dynamic asymmetric allylic amination of vinyl epoxide, with good yields and enantioselectivities of up to 97% ee. This method is applicable to acyclic and heterocyclic amines and was applied toward a five-step synthesis of (R)-piperazic acid. The central importance of new methods for the enantiose- lective synthesis of chiral amines has been demonstrated through numerous recent advances in asymmetric catalysis. 1 Despite the abundance of hydrazines and hydroxylamines in biologically active compounds, there are few general methods for their synthesis in a stereocontrolled fashion. 2 We became interested in dynamic kinetic asymmetric allylic allylation 3 as a broadly useful tool for the introduction of C-N stereogenicity. An intriguing recent report demon- strated the utility of imido carboxylates in the enantioselective amination of vinyl aziridines and epoxides. 4 We sought to demonstrate that hydrazines and hydroxylamines could display analogous reactivity, enabling access to new chiral synthons (Scheme 1). The Trost family of ligands (such as 1 and 2) have a well- documented ability to impart enantiodiscrimination for a number of different reactions involving palladium π-allyl (1) For recent examples, see: (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918. (b) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (c) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054. (2) (a) Fa ¨ssler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054. (b) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (c) Jin, X. L.; Sugihara, H.; Daikai, K.; Tateishi, H.; Jin, Y. Z.; Furuno, H.; Inanaga, J. Tetrahedron 2002, 58, 8321. (d) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 16178. (e) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (f) Imada, Y.; Nishida, M.; Kutsuwa, K.; Murahashi, S.-I.; Naota, T. Org. Lett. 2005, 7, 5837. (g) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641. (3) (a) Lloyd-Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. 1995, 34, 462. (b) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141. (c) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am. Chem. Soc. 2000, 122, 5968. (d) Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 509. (e) Hughes, D. L.; Palucki, M.; Yasuda, N.; Reamer, R. A.; Reider, P. J. J. Org. Chem. 2002, 67, 2762. (f) Lueseem, B. J.; Gais, H.-J. J. Org. Chem. 2004, 69, 4041. (4) Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T. Angew. Chem., Int. Ed. 2007, 46, 6123. Scheme 1. Asymmetric Allylation of Hydrazines ORGANIC LETTERS 2009 Vol. 11, No. 15 3258-3260 10.1021/ol901185d CCC: $40.75  2009 American Chemical Society Published on Web 07/09/2009