Imino Reformatsky reaction

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

The influence of a Lewis acid in favouring the ring closure was confirmed by the use of a catalytic amount of CpiTiCL in imino-Reformatsky reactions with a-bromoesters, -bromocrotonates and a-bromomethylacrylates the corresponding cis /9-lactams were obtained in excellent yields in THF at rt129. 

The joint effect of substituents and of temperature is clearly evident in imino-Reformatsky reactions of zinc dienolates197. At —78 °C, imines 194a-d react with crotonate derived zinc-dienolate 195, affording the products listed in Table 4. Imine substituents play a fundamental role in controlling the reaction regiochemistry. 

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, (g) ees of up to 92% have been achieved in the /i-amino ester product, using a recyclable A-methylcphedrinc as auxiliary. A nickel(II) salt and dimethylzinc are employed the latter serves as dehydrating agent, reductant, and coordinating metal. 

The first enantioselective one-pot, three-component imino Reformatsky reactions q have been reviewed 98 (—)-A, A-Dimethylami noisoborneol has been found to be an excellent ligand for the enantioselective addition of Reformatsky reagents to aromatic and aliphatic aldehydes 99 Enantioselectivities up to 93% ee have been obtained with sulfur-containing aldehydes. 

Scheme 4.32 Three-component imino-Reformatsky reaction.

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

Cozzi, R G., Rivalta, E. (2006). First enantioselective one-pot, three-component imino Reformatsky reaction. Pure and Applied Chemistry, 78, 287-291. 

Scheme 11.5 Imino-Reformatsky type three-component reaction.

Scheme 5.102 Enantioselective preparation of p-lactams 392 through imino difluoro Reformatsky reaction...

A partial reduction of O-protected chiral cyanohydrins is also possible by reaction with Reformatsky reagents (Blaise reaction). The primarily formed imino intermediates can be hydrolyzed under very mild conditions to give the enamines ( )-15, which yield by treatment with strong acids the tetronic acids (R)-16 (Scheme 9) [39,40]. 

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