Reduction of Cyclic Imines

During the study on enantioselective organocatalytic reductive amination, MacMillan et al. found that the pyruvic acid-derived cyclic imino ester could be efficiently reduced to yield the corresponding alanine amino ester with 97% ee and 82% yield 

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Another field where ATH catalysts have made an industrial impact is in the area of chiral amine synthesis by stereocontrolled reduction of imines. First demonstrated by Uematsu et the reduction of cyclic imines to yield chiral amines... 

Asymmetric reduction of cyclic imines. (Df a series of chiral sodium acyloxybo-rohydrides obtained from various chiral N-acyl-a amino acids, 1 affords the highest optical yields (70-86% ee) in the reduction of cyclic imines. 

The reduction of cyclic imines with this system was found to proceed under much milder conditions. For example, 2-phenylpyrroline was reduced at 80 psi of hydrogen to afford 2-phenylpyrrolidine in good yield and excellent enantiomeric excess (eq 4). 

The (S)-prolinate-borane complex (5)-(22) reduces ketones to the corresponding alcohols with optical yields up to 50%. The asymmetric reduction of cyclic imines (24) with chiral sodium triacyloxyborohydride (S)-(23) was utilized to prepare optically active alkaloids (25) with optical yields up to 86% (eq 9). ... 

Many cyclic amines are prepared by reduction of cyclic imines (see Section 1.20.3), or amides (see Section 1.20.4). Nitro-, amine- and carboxyl-substituted cyclic amines are formed by Mannich condensations (see Section 1.20.6). 

Enantioselective Reduction of Cyclic Imines (C=N Group Endocyclic)... 

Examination of the enantioselectivities in Table 7.5 indicates a striking difference in selectivity achieved in the reduction of cyclic (entries 1-8) vs. acyclic imines (entries 9-11). The former is very nearly 100% stereoselective. The simple reason for this is that the acyclic imines are mixtures of E and Z stereoisomers, which reduce to enantiomeric amines vide infra). The mechanism proposed for this reduction is shown in Scheme 7.11 [86]. The putative titanium(III) hydride catalyst is formed in situ by sequential treatment of the titanocene BINOL complex with butyllithium and phenylsilane. The latter reagent serves to stabilize the catalyst. Kinetic studies show that the reduction of cyclic imines is first order in hydrogen and first order in titanium but zero order in imine. This (and other evidence) is consistent with a fast 1,2-insertion followed by a slow hydrogenolysis (a-bond metathesis), as indicated [86]. Although P-hydride elimination of the titanium amide intermediate is possible, it appears to be slow relative to the hydrogenolysis. 

Sodium cyanoborohydride. 14. 28 Reduction of cyclic imines. 1 cyclic amines by reduction have apf the reducing agent is the possible pr synthesis of perhydro-l,2-oxazincs Macrolactone formation. [Pg.330]

Reduction of cyclic imines. More examples of stereoselective formation of cyclic amines by reduction have appeared in the literature. Another useful feature of the reducing agent is the possible preservation of the N-0 bond, which permits the synthesis of perhydro-l,2-oxazines and A-alkylation of hydroxylamines. ... 

The reduction of cyclic imines and oximes follows a trend similar to that of corresponding ketones. However, the tendency for attack from the most hindered side is in these cases attenuated. 4.5. 87 jn the case of oximes, while NaBFLt-MoOs attacks from the axial side, NaBH4-NiCl2 attacks from the equatorial side. An example of diastereoselective reduction of acyclic chiral imines is represented by the one-pot transformation of a-alkoxy or a,/8-epoxynitriles into anti vicinal amino alcohols (eq 17) or epoxyamines. The outcome of these reductions was explained on the basis of a cyclic chelated transition state. ... 

Nitrogen containing heterocycles can he reduced by NaBH3CN under acidic conditions. Two recent examples involved the stereoselective reduction of pyrazines to piperazines (eq 43) and pyrazinones to piperazinones (eq 44). The effectiveness of the ongoing use of sodium cyanoborohydride in reduction of cyclic imine derivatives was demonstrated by these reactions. In both cases only a single diastereomer of product was detected and isolated. 

On the other hand, Backvall, Privalov and co-workers proposed an inner-sphere reaction mechanism based on experimental studies and DFT calculations for the reduction of imines with Shvo s catalyst (370,371). The same group demonstrated that imines have to be protonated before being reduced by ruthenium Noyori s catalyst (372). But kinetic studies on the reduction of cyclic imine I (Fig. 94) reported by Blackmond and coworkers (373) conclude that the un-protonated imine is reduced by a Rh(III) catalyst of the Noyori-type catalyst (Fig. 95), using formic acid as the hydrogen transfer agent. 

Recently, Wills and co-workers (344) studied the application of ruthenium catalysts of the Noyori-type catalyst containing W-alkylated TsDPEN derivatives bearing alkyl groups of different size as the chiral ligand for the reduction of cyclic imine I (Fig. 94). The authors suggest that a viable model for the reduction of this imine (Fig. 96) could involve a protonated imine with a transition state allowing the CH-jt interaction between the aryl group of the iminium cation and the arene coordinated to the ruthenium. 

Secondary Amines.—The reduction of imines to the corresponding secondary amines can be effected by various methodologies. New additions are the sodium triacyloxyborohydrides (easily obtainable from sodium borohydride and AT-acyl derivatives of optically active amino-acids), which are used for the asymmetric reduction of cyclic imines. Also now available is a highly stereoselective reduction of N-benzylimines derived from substituted cyclohexanones, with alkali-metal borohydrides, in particular L-selectride. A fiuther addition is the first report of the reduction of aldimines by hydrogen transfer from propan-2-ol,... 

Asymmetric transfer hydrogenation of imines using HC02H/Et3N as a hydrogen donor and catalyzed by suitably designed chiral Ru(II)-complexes was developed by Noyori et al., and since then, it has become the method of choice in enantioselective reduction of cyclic imines. Using this protocol, several asymmetric syntheses of... 

Buchwald reported an important advance in enantioselective C=N reductions with the chiral titanocene catalyst 186 (X,X = l,l -binaphth-2,2 -diolate) [137]. The reduction of cyclic imines with 186 and silanes afforded products with high selectivity however, reductions of acyclic imines were considerably less selective. It was suggested that this arose from the fact that, unlike cyclic imines, acyclic imines are found as mixtures of equilibrating cis and trans isomers. An important breakthrough was achieved with the observation that in situ activation of the difluoride catalyst 187 (X = F) gave a catalytically active titanium hydride species that promotes the hydrosilylation of both cyclic and acyclic amines with excellent enantiomeric excess [138]. Subsequent investigations revealed that the addition of a primary amine had a beneficial effect on the scope of the reaction [138, 139]. A demonstration of the utility of this method was reported by Buchwald in the enantioselective synthesis of the alkaloid frans-solenopsin A (190), a constituent of fire-ant venom (Scheme 11.29) [140]. 

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