Enantioselective synthesis of a chiral fluoropiperidine via asymmetric hydrogenation of a vinyl fluoride Shane W. Krska * , Jeffrey V. Mitten, Peter G. Dormer, Dale Mowrey, Fouzia Machrouhi, Yongkui Sun, Todd D. Nelson * Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA article info Article history: Received 30 April 2009 Received in revised form 16 June 2009 Accepted 26 June 2009 Available online 2 July 2009 abstract Asymmetric hydrogenation of a vinyl fluoride derivative gives efficient access to enantioenriched 1,3,4- trisubstituted piperidine 1 with a stereogenic alkyl fluoride center. Extensive catalyst screening across transition metals and chiral ligands identified only one catalyst, a Rh/Walphos complex, that gives high conversion, enantioselectivity and chemoselectivity for olefin reduction over defluorination. The pres- ence of acid additives in the hydrogenation exerts a profound effect on reaction outcome. The results of deuterium labeling studies demonstrate that significant olefin isomerization accompanies the undesired defluorination side-reaction. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The asymmetric synthesis of chiral organofluorine compounds with stereogenic fluorine-bearing carbon atoms remains an active area of research. 1 By far the most commonly studied methods in- volve asymmetric fluorinations of carbonyl derivatives, often cat- alyzed by chiral transition metal complexes or Lewis bases. 1a–c The products of such transformations provide ready synthetic access to a number of useful enantioenriched fluorinated building blocks, among them 1,2-fluorohydrins. As part of a recent drug de- velopment program, we required a means to synthesize kilogram quantities of enantiopure 1 , a chiral 1,3-fluorohydrin (Scheme 1). Since the standard methodologies discussed above did not give efficient access to 1 , we envisioned a complementary approach involving the asymmetric hydrogenation of a fluorinated allylic alcohol 2. This report describes the successful identification of a chiral catalyst and conditions that give high chemo- and enan- tioselectivity in the asymmetric hydrogenation of 2, as well as the results of mechanistic experiments that shed light on the divergent pathways that comprise the catalytic reaction network. 2. Results The tetrahydropyridine substrate for the asymmetric hydroge- nation was obtained in a three step process from 3-fluoropyridine 3 (Scheme 2). Directed metallation of 3 and quench with DMF gave 3- fluoro-4-formylpyridine, 2 which was reduced in situ with sodium borohydride to the corresponding hydroxymethyl pyridine 4, iso- lated as a white crystalline solid in 79% yield. Alkylation of 4 with benzyl bromide gave crystalline pyridinium bromide 5, which was isolated in 93% yield. Reduction of 5 with sodium borohydride gave tetrahydropyridine 2, which was purified by column chromatog- raphy and used as the free base for catalyst screening studies. Compound 2 could also be crystallized in 70% yield as the hydro- chloride salt. N F Bn N F OH Bn OH 1 2 Scheme 1. Retrosynthesis of enantioenriched fluoropiperidine. N F OH N F OH Bn Br - + N F Bn BnBr acetone 93% 1. NaBH 4 , MeOH, 0 °C 2. HCl 70% N F 1. LDA, THF -78 °C 2. DMF -78 °C 3. NaBH 4 , 0 °C 78% OH 3 4 5 Cl - H + 2•HCl Scheme 2. Synthesis of vinyl fluoride. * Corresponding authors. Tel.: þ1 732 594 2636; fax: þ1 732 594 1499. E-mail addresses: shane_krska@merck.com (S.W. Krska), todd_nelson@merck.com (T.D. Nelson). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.06.105 Tetrahedron 65 (2009) 8987–8994 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet