Regioselective addition of n-alkyllithiums to alpha,alpha '-disubstituted-1,8-naphthyridines: Synthesis of 6-amino-3-pyridinol analogs of alpha-tocopherol

Abstract

n-Alkyllithiums were added to alpha,alpha'-disubstituted-1,8-naphthyridines in non-polar solvents Such as Et2O-hexane mixtures. In polar solvents such as THF, alkyllithium acts as a base rather than a nucleophile. Regioselective addition was achieved for substrates capable of five-membered cyclic chelation of the (alkyl)lithium reagent. Substrates with a TBS-protected alcohol as the co-chelating moiety afforded the best combination of yield and regioselectivity. This methodology was Successfully employed in the preparation of two 6-amino-3-pyridinol analogs of pentamethyl-chromanol (PMC), an alpha-tocopherol derivative with its isoprenoid side chain truncated to a methyl group.