Hydrogenation of enamines

Table 6.7 Enantioselective hydrogenation of enamines cata-lyzed by [(R,R,R)-(EBTHI)TiX2] [112],a)...

Until recently, the hydrogenation of enamines has scarcely been investigated. Results have been reported for model substrates 17 and 18, indicating that such transformations are possible in principle (Fig. 34.12). Substrate 17 was hydrogenated with Ir-diop with ee-values of 60-64% and with Rh-bdpch with 72% ee... 

Table 34.7 Selected results for the enantioselective hydrogenation of enamines (for structures, see Fig. 34.12) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

Hydrogenation of enamines in the presence of a chiral titanocene catalyst yields optically active amines in more than 90% enantiomeric excess, e.g. equation 80220. 

Kubryk, M. and Hansen, K.B. Apphcation of the Asymmetric Hydrogenation of Enamines to the Preparation of a Amino Acid Pharmacophore. Tetrahedron Asymmetry 2006,17, 205-209. 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

The proton NMR spectra of enamines have been examined for some time, " and represented the first reliable technique for assigning the regiochemistry of those enamines derived from unsymmetrical ketones, although of course there will be no vinylic hydrogen absorption for enamines upon formation of the TT-bond toward the side of the ketone that is disubstituted. Shown in Scheme 12 are shift values for the vinylic hydrogen of enamines derived from a variety of ketones and amines. ... 

Others. When applying these under appropriately designed conditions (0.3 mol% catalyst, 50 °C, 5-6 bar H2) the direct hydrogenation of enamine esters and enamine amides has been successfully conducted in excellent yields and optical purities without the need for the addition of an acyl group (see Fig. 2.14) [73]. 

Pfaltz systems represent promising beginnings for the asymmetric hydrogenation of enamines by discrete, cationic iridium catalysts, but both require more development before they can find wide use in amine synthesis. In particular, these systems are still highly substrate dependent, meaning that a new catalyst screening is necessary for each new substrate. 

Enantioselective Hydrogenation of Enamines with Monodentate Phosphorus Ligands... 

S Enantioselective Hydrogenation of Enamines tvith Monodentate Phosphorus Ligands rR u -R... 

The diversity requirement of chiral amines in the synthesis of natural products and chiral drugs is everlasting and the most studies about the catalytic asymmetric hydrogenation of enamines have dealt with simple substrates to date. Hence, it is necessary to explore highly efficient enantioselective protocol to provide more complex and also industrially useful chiral amines. We are confident that the easily accessible and changeable monodentate phosphorus hgands will find a wide appli cation in this field. 

Tire polymerized or linked monodentate phosphoramidites are no longer monodentate phosphorus hgands, but why were they also discussed in this chapter as monodentate phosphorus hgands in the asymmetric hydrogenation of enamines ... 

We (Novartis) reported ] an enantioselective synthesis of (2S,2 71)- zyf/iro-methylphenidate (3) utilizing Evans (S)-4-benzyl-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine intermediate (65 Scheme 16). Acylation of (S)-4-benzyl-V-phenylace-tyl-2-oxazolidinone (61) with the mixed anhydride 63, followed by deprotection of the V-Boc group with TFA, and neutralization of the reaction mixture with NaHCOs afforded the enamine intermediate 65. Hydrogenation of enamine 65 with 10% Pd-C in ethyl acetate furnished 66 in 95% yield with an excellent diastereoselectivity (97 5). Treatment of 66 with methanol in the presence of EnR afforded the desired... 

Only a few chiral catalysts based on metals other than rhodium and ruthenium have been reported. The titanocene complexes used by Buchwald et al. [109] for the highly enantioselective hydrogenation of enamines have aheady been mentioned in Section 3.4 (cf. Fig. 32). Cobalt semicorrin complexes have proven to be efficient catalysts for the enantioselective reduction of a,P-unsaturated carboxylic esters and amides using sodium borohydride as the reducing agent [ 156, 157]. Other chiral cobalt complexes have also been studied but with less success... 

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