1775 © Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1775–1779 S. A. M. Smith, R. H. Morris Paper Syn thesis An Unsymmetrical Iron Catalyst for the Asymmetric Transfer Hydrogenation of Ketones Samantha A. M. Smith Robert H. Morris* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada robert.morris@utoronto.ca R 1 R 2 O R 1 H OH [Fe] (0.02–0.2 mol%) KOt-Bu (0.1–0.4 mol%) * Fe P Ph 2 P Cy 2 N N Ph Ph Br + BPh 4 – H 40–99% conversion ee up to 99% R 2 i-PrOH, 28 °C C O Received: 12.12.2014 Accepted: 14.01.2015 Published online: 20.02.2015 DOI: 10.1055/s-0034-1380147; Art ID: ss-2014-c0753-st Abstract A new iron(II)(Ph 2 P–NH–N–PCy 2 ) complex with a dicyclohex- ylphosphino group trans to the NH group was found to catalyze the asymmetric transfer hydrogenation of a variety of ketones with high en- antioselectivity. Key words hydrogenation, iron catalysis, chirality, ketones, alcohols The reduction of ketones to give enantiopure alcohols is a very important transformation in organic synthesis as it provides valuable building blocks for the flavor, fragrance, fine chemical, and pharmaceutical industries. 1 Precious metals with expensive chiral ligands are generally required for the catalytic hydrogenation of ketones, but these metals are costly and potentially toxic. 2 Thus, there is a current re- search effort to find highly efficient and enantioselective catalysts based on earth-abundant metals for more eco- nomical and safer processes, without sacrificing activity and selectivity. Recently, iron has received significant atten- tion as a viable catalyst for both asymmetric transfer hydro- genation (ATH) 3 and direct hydrogenation (DH) 4 of polar double bonds. Asymmetric transfer hydrogenation takes place in the presence of a sacrificial reductant as the H + /H – source, as shown in Scheme 1, with isopropanol as the re- ductant. This transformation will be the focus of this paper. Scheme 1 General reaction scheme for the ATH of ketones Three iron(II) complexes (1–3 in Figure 1) of our iron catalysts for ATH have been synthesized and reported re- cently. 3m,4f Complex 1 was found to be highly active in the ATH of ketones with enzyme-like activity. Turnover fre- quencies (TOF) up to 200 s –1 and enantiomeric excess (ee) values of up to 90% were observed for the reduction of 3,4- bis(trifluoromethyl)acetophenone (K8 in Figure 2). Al- though complex 1 has unprecedented activity, there is room for improvement with respect to enantioselectivity. Complex 2 has lower activity, but provides higher enantio- meric excess values (up to 98%) for certain substrates. In some cases there is racemization of the product near the end of the reaction. Complex 3 has higher activity, but leads to lower enantioselectivity. Figure 1 Third generation iron(II) complexes previously reported by our group For the preparation of the catalyst, the incorporation of an N–H moiety in the tetradentate ligand required an inten- sive synthetic approach, where first an enantiomerically pure (S,S)-R 2 PCH 2 CH 2 NHCH(Ph)CH(Ph)NH 2 [(S,S)-P-NH- NH 2 ] ligand was synthesized and isolated, which then un- derwent an iron-templated Schiff base condensation with an α-diarylphosphinoacetaldehyde to produce the P–NH– N–P ligand on iron. Complexes 1–3 differ only by the aryl phosphine groups, and complex 3 is so far the only example with unsymmetrical phosphine donors. We propose that the use of a more sterically hindered phosphine, such as a dicyclohexylphosphino group on the ligand, may improve R 1 R 2 O R 1 R 2 OH [Fe] (0.02–0.2 mol%) KOt-Bu (0.1–0.4 mol%) * i-PrOH, 28 °C Fe P R 1 2 P R 2 2 N N Ph Ph C O Cl 1 + BF 4 – H 1: R 1 = R 2 = Ph 2: R 1 = R 2 = Xyl 3: R 1 = Ph, R 2 = p-Tol SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2015, 47, 1775–1779 paper Downloaded by: University of Toronto Libraries. Copyrighted material.