Efficient asymmetric hydrogenation of pyridines.

Abstract

available and the reaction has the potential for the simultaneous creation of multiple stereocenters. Here we describe an efficient and unprecedented auxiliary-based method for the asymmetric hydrogenation of substituted pyridines (YR= N), which enables the stereoselective formation of piperidines with up to four new chiral centers in a single operation (Scheme 2a). The heterogeneous catalytic hydrogenation of pyridines is usually performed in acidic media. Protonation not only activates the pyridines for hydrogenation, it also suppresses catalyst poisoning by the resulting piperidines. We reasoned that single-point attachment of chiral oxazolidinones 4 for ease of introduction of the auxiliary in the 2-position of the pyridine would be ideal (Scheme 2a). Moreover, it occurred to us that whereas conformation 2 should be strongly preferred for unprotonated pyridines due to dipole-moment minimization, upon protonation hydrogen bonding between the pyridinium and the oxazolidinone moiety would favor conformation 5, in which the auxiliary is oriented coplanar with the pyridine ring but rotated by 1808. Indeed, on hydrogenation the iPr substituent shields one of the diastereotopic p-faces and selective hydrogen transfer to the opposite side leads to aminal 6 (Scheme 2b). Substrates 2 can be readily synthesized from oxazolidinones and the corresponding 2-bromoor chloropyridines 1 by copper catalysis (Scheme 2a). Gratifyingly, hydrogenation of pyridine 2d in acetic acid under a hydrogen atmosphere of 100 bar with PtO2 as the catalyst led to the formation of (S)-3-methyl piperidine (3d) in 85% ee. Different catalysts were screened, and Pd(OH)2/C was identified as the optimum catalyst, providing 3d in 98% ee (Table 1, entry 4). Importantly, the reaction does not stop at aminal 6d, but leads directly to piperidine 3d and oxazolidinone 4. Evidently traceless cleavage of the auxiliary occurs under the reaction conditions, thereby combining chirality transfer from and release of the auxiliary into a single operation. We were pleased to find that after treatment of the crude reaction mixture with hydrochloric acid, separation and purification of the less soluble piperidine hydrochloride 3d and the more soluble auxiliary could be achieved efficiently by simple extraction with ether/hexanes mixtures. The piperidinium hydrochloride 3d was obtained in 90% yield (98% ee) and 4 was recovered unchanged (93% yield, > 99% ee), allowing the recycling of the auxiliary. This method for the stereoselective synthesis of piperidines has been applied successfully to a large number of substrates, whereby the oxazolidinone with a tBu group often resulted in slightly improved ee values relative to those obtained with the iPr group (Table 1). Substituents in the 4, 5or 6-position of the 2-oxazolidinone-substituted pyridine can be used to create stereocenters at the corresponding positions (entries 1–7). Even multiple stereocenters can be generated, as exemplified by the stereoselective formation of diand trisubstituted piperidines in near-quantitative yield and excellent enantioselectivities (entries 9, 10). As far as we know this is the first highly asymmetric hydrogenation of an aromatic compound that selectively generates three stereocenters. Under milder conditions we even succeeded in the stereoselective synthesis (> 95:5) of aminal 6j, which bears four new chiral centers (entry 11). Furthermore, functional groups on the pyridine ring are well tolerated (entries 3, 5–6). The versatility of the process can be increased still further, since hydrogenation of 2d in the presence of acetaldehyde or acetic anhydride results in the formation of the corresponding (S)-N-ethylpiperidine 7 (entries 12, 13). The only present limitation concerns 3-substitution of the pyridine ring. A methyl substituent in the 3-position leads to a less reactive substrate, presumably because the oxazolidinone is rotated out of the plane of the pyridine ring thereby shielding both pfaces. Hydrogenation of 2h results in a nearly racemic product (entry 8). Finally, we were pleased to find that our method gives easy access to coniine (3b), the poisonous hemlock alkaloid, in excellent yield and enantiomeric excess (entry 2). Scheme 1. Stereoselective hydrogenation of (hetero)aromatic compounds (YR=CR, N).