The effect of the N-substituent in electrophilic substitution reactions with acyclic nitrogen substituted carbonyl compounds

Abstract

The regioselectivity in the deprotonation of ketimines was examined. The studies examined the effect of the base, the deprotonation temperature and the nitrogen substituent on the formation of azaallyllithium reagents from ketimines. Deprotonations were performed using LDA or LDEA in THF at temperatures ranging from -78°C to ambient. Deprotonation of 2-butanone imines at -78°C using either LDA or LDEA, afforded predominantly 3-pentanone imines, upon methylation. Deprotonation at warmer temperatures afforded increasing amounts of 3-methyl-2-butanone imines, upon methylation. The rate of deprotonation of the E:Z equilibrium mixture of imines was found to be independent of the base concentration; however, the rate of deprotonation of isomerically pure (Z)-2-butanone imines was dependent on the base concentration. It was proposed that deprotonation by LDA at -78°C was rate limited by C=N bond isomerization. It was concluded that hindered dialkylamide bases, notably LDA, and, to a lesser extent, LDEA, preferentially deprotonate 2-butanone imines anti to the N-substituent. The deprotonation regioselectivity of isomerically pure 3-hexanone imines was examined, and found to range from 5:1 to 100:1 (anti:syn). The degree of selectivity depended upon the N-substituent. The deprotonation regioselectivity of (Z)-[1-¹³C]-3-pentanone imines was determined to range from 2.3:1 to 15:1 (preferentially anti), again depending on the N-substituent. Deprotonation with LDEA was found to be somewhat less selective than with LDA. It was observed that the initial formation of 2-azaallyllithium intermediate eliminated any regioselectivity in the formation of 1-azaallyllithium reagents from 3-pentanone benzyl imines. The relative kinetic and thermodynamic acidity of the benzylic, the methylene and the methyl position of the benzyl imines was determined. Transition state models were proposed to account for the regioselectivity observed. The asymmetric induction imparted by the chiral substituents in alkylations and aldol reactions with imidate esters was determined. The degree of diastereoselectivity obtained in alkylation reactions was determined to range from 34% to 98% de. Aldol reactions afforded predominantly threo aldol products. The diastereoselectivities ranged from 2.8:1 to 14:1, enantioselectivities ranged from 90% to 96% ee. Chelating substituents afforded a higher degree of asymmetric induction than nonchelating substituents. Transition state models were proposed to account for the stereoselectivity observed.