Reductive aldol coupling

Scheme 6 Complementary regioselectivities in direct aldol couplings of 2-butanone and corresponding hydrogen-mediated reductive aldol couplings of MVK...

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

Table 22.3 Use of phenyl vinyl ketone (PVK) in intermolecular hydrogen-mediated reductive aldol coupling.

To corroborate the proposed mechanism, the catalytic reductive aldol coupling of acrolein with phenyl glyoxal monohydrate was performed under 1 atmos. elemental deuterium. Exposure of the aldol product to excess hydrazine in situ results in formation of the pyridazine, which incorporates precisely one deuterium atom in a manner consistent with the general mechanism proposed in Scheme 22.4 (Scheme 22.9). 

Thus far, the use of acrylates and related acyl derivatives as nucleophilic partners in hydrogen-mediated reductive aldol coupling has been unsuccessful due to competitive conventional hydrogenation. Although the mechanistic basis of these results remains unclear, it may be speculated that for acrylates and struc-... 

Scheme 22.9 Intermolecular reductive aldol coupling of acrolein and phenyl glyoxal under a D2 atmosphere.a)...

Scheme 22.10 Attempted reductive aldol coupling of ethyl acrylate and related acyl derivatives.

Scheme 11.29 First enantioselective, reductive aldol couplings of vinyl ketones with aldehydes [48].

Hashimoto T, Ito J, Nishiyama H. Felkin-Anh selectivity in Rh(bisoxazolinylphenyl)-catalyzed reductive aldol coupling reaction asymmetric synthesis of stereotriads. Tetrahedron 2008 64 9408-9412. 

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