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

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.