α-Alkylation of Aldehydes by S_N1-Type Reaction of Alcohols

carbocations - α-alkylation - aldehydes

Significance

Alcohols capable of forming stabilized carbocations were used as the alkylating reagents for aldehydes. A catalytic amount of secondary amine salt 1 in Et₂O gave α-alkylated aldehydes 2 in moderate to good yields and good enantioselectivity with H₂O being the only byproduct. In this simple procedure the ammonium salt acts as an aminocatalyst but also as an acid to generate the carbocation from the alcohol.

Comment

The method reported is brilliant but still limited in the scope of the alkylating substrates. The otherwise problematic N-alkylation of the catalyst and the catalytically generated enamine is avoided here because of the reversibility of the ­reactions with stable carbocations (Mayr and co-workers Chem. Eur. J. 2003, 9, 2209). A similar approach using arylsulfonyl indoles to generate the stabilized carbocations was reported by ­Melchiorre and co-workers (Angew. Chem. Int. Ed. 2008, 47, 8707). In spite of these reports and the work by the MacMillan group (Science 2008, 322, 77), direct asymmetric introduction of the most useful, simple alkyl substituents to the α-position of the aldehydes remains to be solved.