Palladium-Catalyzed Chemoselective Monoarylation of Hydrazides for the Synthesis of [1,2,4]Triazolo[4,3-a]pyridines

Abstract

An efficient and convenient method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines was exemplified by the synthesis of 20 analogues bearing a variety of substituents at the 3-position. The methodology involves a palladium-catalyzed addition of hydrazides to 2-chloropyridine, which occurs chemoselectively at the terminal nitrogen atom of the hydrazide, followed by dehydration in acetic acid under microwave irradiation.

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

“…Amidrazones, the conjuncted products of imine and hydrazines, are a class of important reactants for the synthesis of various types of nitrogen-containing compounds with broad bioactive spectrum, interesting luminous and magnetic properties [44,45]. Their cyclization with carbonyl compounds is one of the most important pathways to access 1,2,4-triazole derivatives [46][47][48].…”

Process Research and Development for Heterocyclic p38 MAP Kinase Inhibitors

“…22 Initially we focused on benzhydrazides as nucleophiles. 11 In order to study the chemoselectivity (internal versus external nitrogen), we studied reactions with 2-chloropyridine (43) as a simplified model substrate (Scheme 11). The optimized conditions can be summarized as follows: hydrazide (1.5 equiv), NaHCO 3 (3 equiv), Josiphos (44; 2 mol%), and [Pd 2 (dba) 3 ] (1 mol%) in DMF at 100°C.…”

A Facile Synthesis of Amide Derivatives of [1,2,4]Triazolo[4,3-a]pyridine

“…2 depicts the synthetic route for the preparation hydrochloride salt of methyl- [1,2,4]triazolo [4,3-a]pyridin-3-ylmethyl-amine (7). 2-Chloro pyridine was treated with hydrazine hydrate (99 %) at 100 °C for 48 h to yield hydrazine derivative of pyridine (2) [2,5,7,9,17,18]. Compound 2 was selectively mono acylated with chloroacetyl chloride to afford amide derivative (3) of compound 2 [2,9,17,18].…”

“…2-Chloro pyridine was treated with hydrazine hydrate (99 %) at 100 °C for 48 h to yield hydrazine derivative of pyridine (2) [2,5,7,9,17,18]. Compound 2 was selectively mono acylated with chloroacetyl chloride to afford amide derivative (3) of compound 2 [2,9,17,18]. Further, compound 3 was cyclized with POCl3 with the elimination of water molecule to afford 3-chloromethyl- [1,2,4]triazolo[4,3-a]-pyridine (4) [4,17].…”

“…Compound 2 was selectively mono acylated with chloroacetyl chloride to afford amide derivative (3) of compound 2 [2,9,17,18]. Further, compound 3 was cyclized with POCl3 with the elimination of water molecule to afford 3-chloromethyl- [1,2,4]triazolo[4,3-a]-pyridine (4) [4,17]. Further, compound 4 is converted to methyl- [1,2,4]triazolo [4,3-a]pyridin-3-ylmethyl-amine (5) by treating with 2 M methyl-amine in methanol.…”