Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline with the 1-naphthyl Grignard reagent . Resolution of was achieved through chromatographic separation of the Noe-lactol derivatives and , providing of >99% ee and of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (62% ee) with Grignard reagent furnished , with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide . Reaction of optically enriched with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide , and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline in low enantiomeric purity (14% ee). The absolute configuration of was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide , with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, and , with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, and , in 53 and 60% ee, respectively. The free energy barriers to internal rotation in and have been determined, and the isoquinoline examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine , and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.