Titanocene imine reduction

Generally, amine products can be obtained with 91-99% ee. It is noteworthy that the ee of the product does not correspond to the E Z ratio of the starting imines. Imines 103 and 104 exist as 2.5 1 and 1.8 1 (E)/(Z) isomers, but titanocene-catalyzed reduction produces amines with 93% and 97% ee, respectively.105... 

Table 7.5. Examples of asymmetric imine reduction using Buchwald s chiral titanocene catalyst. Reactions were run at 45° and 80 psi, with 5 mol% s,S catalyst, unless noted otherwise.

Scheme 7.11. Proposed catalytic cycle for the titanocene catalyzed reduction of imines [86].

Figure 7.6. Transition structures for titanocene hydride imine reduction [86] (a) Front view of heterocycle reduction, (b) Top view of heterocycle reduction, (c) Front view of acylic imine reduction, (d) Top view of imine reduction.

The titanocene catalyzed asymmetric imine reduction may be used in kinetic resolutions of racemic pyrrolines [96]. The most efficient kinetic resolution was observed for 5-substituted pyrrolines, and the mechanistic postulate outlined above readily accomodates the experimental results, as shown by the matched pair transition structure in Scheme 7.12 [96]. Pyrrolines substituted at the 3- and 4-positions were reduced with excellent enantioselectivity, but kinetic resolution of the starting material was only modest [96]. 

A signifieant improvement in titanium-eatalysed imine reduction was realised with ethylene l,2-bis( / -4,5,6,7-tetrahydro-l-indenyl)titanocene difluoride (17) in the presence of phenylsilane. This eatalytie system was very aetive in the hydrosilylation of imines, and in this ease, elevated... 

The asymmetric hydrogenation of acyclic imines with the ansa-titanocene catalyst 102 gives the chiral amines in up to 92% ee.684,685 This same system applied to cyclic imines produces the chiral amines with >97% ee values.684,685 The mechanism of these reductions has been studied 686... 

The nature of the substituent directly attached to the N-atom influences the properties (basicity, reduction potential, etc.) of the C = N function more than the substituents at the carbon atom. For example, it was found that Ir-dipho-sphine catalysts that are very active for N-aryl imines are deactivated rapidly when applied for aliphatic imines [7], or that titanocene-based catalysts are active only for N-alkyl imines but not for N-aryl imines [8, 20, 21]. Oximes and other C = N-X compounds show even more pronounced differences in reactivity. 

Scheme 7.10. Titanocene catalyzed asymmetric reduction of imines [85], In the accompanying discussion, the catalyst shown is designated the S,S enantiomer, in accord with the CIP rules for describing metal arenes [88]. This is a different designation than that used by Buchwald, however. ...

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. 

Scheme 7.11 Asymmetric reduction of imines using titanocene hydride complex 16.

Titanium, Zirconium, Hafnium - The catalytic asymmetric hydrogenation of imines has been reported using a chiral titanocene catalyst. " An enantiopure titanocene catalyst has been used in the catalytic asymmetric hydrogaution of disubstituted enamines. Kinetic resolution of a racemic disubstituted pyrroline has been effected by asymmetric reduction with a chiral titanocene catalyst. Poly(methylhydrosiloxane) has been used as a stoichiometric... 

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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