Triazolopyridines via Selective Palladium-Catalyzed Monoarylation of Hydrazides

Significance

Reported is an efficient and convenient method for the synthesis of 3-substituted [1,2,4]triazolo[4,3-a]pyridines involving a palladium-catalyzed selective addition of acylhydrazides 2 to 2-chloropyridine (1) followed by dehydration under acidic conditions. Usually, under palladium or copper catalysis the acylhydrazides undergo reactions preferentially at the internal amide nitrogen (for Pd, see: J. B. Arterburn et al. Org. Lett. 2001, 3, 1351; for Cu, see: S. L. Buchwald and co-workers J. Am. Chem. Soc. 2001, 123, 7727). However, in this case, after optimization in the presence of Pd₂(dba)₃/Josiphos and NaHCO₃, a preferential monoarylation of the terminal nitrogen was achieved. After optimization of the selective palladium-catalyzed coupling (intermediate 3), a dehydrative cyclization under microwave irradiation (L. N. Aldrich et al. Tetrahedron Lett. 2009, 50, 212) was carried out to give the 3-substituted triazolopyridines 4 in moderate to good yields. A variety of benzoic hydrazides (with EDGs and EWGs), alkyl, cinnamic or heteroaromatic hydrazides were successfully used. This methodo­logy was unsuccessful for 2,4-dichloropyrines in order to establish 2- versus 4-regioselectivity (A. Abad et al. Synthesis 2005, 915).