Asymmetric hydrogenation of imines

Ir(cod)Cl]2 + bcpm + (a) nBu4NI or Nil3 2,3,3-trimethylindolenine Asymmetric hydrogenation of imines 722... 

One problem for the asymmetric hydrogenation of imine is (E)/(Z) isomerism of the substrate, which may have a significant effect on the enantioselectivity of the reaction. This problem was difficult to address because of the rapid interconversion of the E and Z isomers of the imines under reaction conditions (Fig. 6-8). 

For literature on the asymmetric hydrogenation of imines, see (a) Bakos, J. Toth,... 

Given the importance of chiral amines to synthetic chemistry as well as other fields asymmetric hydrogenation of imines has attracted wide interest but limited success compared to C=C and C=0 bond reduction. The first asymmetric hydrogenation of imines was carried out in the seventies with mthenium- and rhodium-based catalysts, followed later by titanium and zirconium systems [82]. Buchwald found that... 

Iridium-Catalyzed Asymmetric Hydrogenation of Olefins with Chiral N,P and C,N Ligands 73 Table 19 Asymmetric hydrogenation of imines... 

The Brintzinger-type C2-chiral titanocene catalysts efficiently promote asymmetric hydrogenation of imines (Figure 1.30). A variety of cyclic and acyclic imines are reduced with excellent enantioselectivity by using these catalysts. The active hydrogenation species 30B is produced by treatment of the titanocene binaphtholate derivative 30A with n-butyllithium followed by phenylsilane. 

Figure 1.30. Asymmetric hydrogenation of imines with a chiral titanocene catalyst.

The paramount significance of chiral amines in pharmaceutical and agrochemical substances drives the development of efficient catalytic asymmetric methods for their formation. In contrast to the high enantioselectivities observed in asymmetric reduction of both alkenes and ketones, only limited success has been achieved in the enantiose-lective hydrogenation of imines [118]. Currently, there are few efficient chiral catalytic systems available for the asymmetric hydrogenation of imines. 

Asymmetric hydrogenation of imines derived from trifluoropyruvate, in the presence of a chiral complex of palladium (ligand = (R)-BINAP), affords ethyl (/f)-trifluoroalaninate with ca. 90% The ee values strongly depend on the solvent,... 

SCHEME 76. Asymmetric hydrogenation of imines catalyzed by [lrHI2(diphosphine)]2. 

SCHEME 78. Titanocene-catalyzed asymmetric hydrogenation of imines. 

A new class of chiral phosphine-oxazolines act as ligands in iridium-catalysed asymmetric hydrogenation of imines, and of alkenes, giving ees up to 99%.51... 

Having learned this, Dupont workers [52] have added a temporary auxiliary donor atom to an unsaturated substrate in order to be able to steer adduct formation, and so the enantioselectivity of the hydrogenation. For example, asymmetric hydrogenation of imines or ketones was a reaction that yielded rather low enantiomeric excesses. However, by converting these first into acyl hydrazones the hydrazide oxygen can function as the secondary complexation function and now extremely high enantiomeric excesses can be obtained (Fig. 6.23). 

TTF in aqueous solution has been examined <07TL8430> and fabrication of thin crystals of [tetramethyltetraselenafulvalene]2+ PF6" within a confined electrode has been reported <07SM(157)492>. The synthesis, structures and electrochemistry of Cu and Co complexes of TTF-oxazolines 53 have been described <07ICA(360)233> and the crystal stmcture of the valine-derived TTF-oxazoline 54 has been determined while the corresponding phosphine 55 has proved to be an effective ligand for iridium-catalysed asymmetric hydrogenation of imines <07TA1877>. 

The catalysts are Tim hydrides which are generated in situ by reduction of enantio-merically pure L TiCl2 with butyllithium and PhSiH3 they are also highly effective in the asymmetric hydrogenation of imines and enamines.20 The lutetium ansa-metallocene complex (22-XVII) catalyzes the deuteration of 1-pentene (63% e.e.)21 Related samarium compounds hydrogenate imines.22... 

Other Reactions of Chiral Titanocene Derivatives. Buch-wald has recently reported the catalytic asymmetric hydrogenation of imines and unfunctionalized alkenes using chiral titanocene catalysts. 

Redaction of Imines. This catalyst system is very effective for the asymmetric hydrogenation of imines. For example, AL(1-cyclohexyl)ethylidenebenzylamine (as a mixture of anti and syn isomers) can be reduced in excellent yield and good enantiomeric excess (eq 3). The reaction must be conducted at high pressures in order to achieve maximum enantioselecdvity. This effect was found for several acyclic imines. 

Preparative Methods both enantiomers of the a-methyl sultam may be prepared on a multigram scale in optically pure form by asymmetric hydrogenation of imine (2a) followed by simple crystallization (eq 1). The (7 )-enantiomer of the a-f-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization. However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivati-zation of the racemic auxiliary (obtained in 98% yield from reaction of (2b) with Sodium Borohydride in MeOH) with 10-Camphorsulfonyl Chloride, separation of the resulting diastere-omers by fractional crystallization, and acidolysis. Prochi-ral imines (2a) and (2b) are readily prepared from inexpensive Saccharine by treatment with Methyllithium (73%) and t-Butyllithium (66%), respectively. 

Phosphines ligands that have chirality from ferrocenes have been implemented in the iridium-catalyzed asymmetric hydrogenation of imine with moderate enantioselectivities for Novartis s manufacture of metolachlor. Electronic modifications of these ferrocenyl ligands have increased the enantioselectivity and catalyst reactivity for Lonza s asymmetric hydrogenation processes of biotin and 2-substituted piperazines, intermediates for several pharmaceutical drugs. 

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