A comparison of secondary and tertiary amides as directors of ortho and adjacent benzylic lithiation and of asymmetric induction in ortho lithiated benzamides

Abstract

Comparisons are made between the influence of secondary and tertiary amides on ortho and adjacent benzylic metallations of benzamides. In the intramolecular competition offered by N,N-diethyl-N-ethylterephthalamide ( 1) the tertiary amide is the more effective director of ortho lithiation, while the secondary amide is better in the intermolecular competitions offered by the pairs N-ethyl-(9): N,N-diethylbenzamide( 10) and N-isopropyl-( 11):N,N-diisopropylbenzamide( 12). Both secondary and tertiary amides are found to direct metallation ortho to the amide in the 2-isopropylbenzamides 25 and 26; however, benzylic metallation is observed with secondary 2-ethyl- and 2-methylbenzamides 21 and 22 and with the tertiary 2-ethylbenzamide 19. Magnetic non-equivalence is noted for the anti-N-methylene group of 19. The reaction of an ortho lithio (S)-O-methyl-N-benzoylleucinol ( 34) with 1-naphthaldehyde-1-d gives, after lactonization, 3-(1-naphthyl-1-d)-phthalide with 10% enantiomeric excess. The phthalide can be obtained in high enantiomeric purity by separation of the diastereoisomers prior to cyclization. Control experiments establish that the observed asymmetric induction is attributable to diastereomeric transition states. The corresponding tertiary benzamide is ineffective in inducing asymmetry. Structural and mechanistic rationales are offered for these observations.