Regioselective Addition of n-Alkyllithiums to α,α′-Disubstituted-1,8-Naphthyridines: Synthesis of 6-Amino-3-Pyridinol Analogs of α-Tocopherol

Abstract

n-Alkyllithiums were added to α,α′-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 pentamethylchromanol (PMC), an α-tocopherol derivative with its isoprenoid side chain truncated to a methyl group.

Key words

1,8-naphthyridine - alkyllithium - chelation - solvent effects - α-tocopherol

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1

Current address: Department of Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

2

Current address: Department of Chemistry, Queen’s University, Kingston, Ontario, Canada.

18

Deprotection of TBS group in 16 resulted in unidentified by-product up to 50%.