Directed lithiation of 4‐halopyridines: Chemoselectivity, regioselectivity and application to synthesis

Abstract 4‐Chloro and 4‐fluoropyridines were ortho‐lithiated by n‐butyllithium‐TMEDA chelate or lithium diiso‐propylamide at low temperature. The resulting 3‐lithio 4‐halopyridines were reacted with electrophiles which led to various 3,4‐disubstituted pyridines. The versatility of this functionalization is enhanced by the 4‐halogen reactivity towards nucleophiles such as water, methylate and amines. Some of the 3,4‐disubstituted synthons were annelated to naphthyridine, xanthone and coumarin or condensed to Hantsch‐ester or to “chlotrimazol” analogues. Lithiation of 4‐fluoropyridine led in one step to 3,4‐pyridyne, which was trapped by cycloaddition with furans.