Regioselective α-alkylation of extended enolates derived from enamines of β-keto esters. Studies relating to the synthesis of 2-substituted 2-alkoxycarbonylcycloalkanones

Abstract

Enamines 4a–c, 5a–c and 6 have been prepared (from the corresponding 5-, 6- and 7-ring cyclic β-keto esters) and converted into enolates of general structure 2. These extended enolates react with alkyl halides at the α-site exclusively and the resulting adducts, exemplified by 7, have been hydrolysed to the corresponding 2-substituted 2-alkoxycarbonylcycloalkanones. These results are discussed in the context of the regioselectivity that has been reported for related enolates which tend, depending on the structure, to show a preference for γ-selectivity in their reactions with electrophiles. The asymmetric variant of the alkylation sequence described has also been examined but only modest enantioselectivity (up to 33% e.e.) has been attained by incorporation of (S)-2-methoxymethylpyrrolidine 25, via enamine 26. Further progress was blocked by problems encountered in the synthesis of the requisite enamines when the more hindered C₂-symmetric amines, such as (2R,5R)-2,5-dimethylpyrrolidine 27, were used, thereby limiting the more general synthetic utility and scope of these extended enolates.