An Investigation into the Tether Length and Substitution Pattern of Arene-Substituted Complexes for Asymmetric Transfer Hydrogenation of Ketones Fung K. Cheung, † Changxue Lin, † Franco Minissi, † Adriana Lorente Criville ´, † Mark A. Graham, ‡ David J. Fox,* ,† and Martin Wills* ,† Asymmetric Catalysis Group, Department of Chemistry, UniVersity of Warwick, CoVentry, CV4 7AL, U.K., and Cancer & Infection Chemistry, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K. m.wills@warwick.ac.uk Received September 11, 2007 ABSTRACT A series of Ru(II) catalysts were prepared and tested in the asymmetric transfer hydrogenation of ketones. The catalyst containing a “4- carbon” tether gave the fastest rates of ketone reduction. This is due to both increased rate of regeneration of hydride “Ru-H” and increased rate of ketone reduction. Several classes of ketone were reduced in enantiomeric excesses of up to 97%. Substituents on the arene ring of the catalyst influence the reaction rate and enantioselectivity. Enantioselective ketone reduction is a pivotal reaction in asymmetric synthesis and catalysis. 1-3 Asymmetric transfer hydrogenation (ATH) of ketones using monosulfonated diamine complexes of Ru(II) was first reported by Noyori in 1995 2a and has since become one of the most widely studied and applied enantioselective reduction reactions. In our studies in this field, we recently reported the synthesis and applications of “tethered” catalysts 1 and 2 in which covalent linkages from the diamine to the η 6 -arene unit provide extra stability and a significant increase in rate (with 2) relative to “untethered” catalyst 3. 4 Using catalyst 2, acetophenone is fully reduced in 96% ee within 3 h at S/C ) 200, presumably through the established TS illustrated in Figure 1. 5,6 The high ee for the reduction of acetophenone derivatives arises from the stabilizing electrostatic interaction † University of Warwick. ‡ AstraZeneca. (1) (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (c) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem. ReV. 2004, 248, 2201. (d) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV. 1992, 92, 1051. (2) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562. (b) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521. (c) Matsumura, K.; Hashiguchi, Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738. (d) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119. (e) Haack, K. J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (3) (a) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226. (b) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (4) (a) Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986. (b) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127, 7318. (c) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem. 2006, 71, 7035. ORGANIC LETTERS 2007 Vol. 9, No. 22 4659-4662 10.1021/ol702226j CCC: $37.00 © 2007 American Chemical Society Published on Web 09/27/2007