REACTIONS OF ACYLGLYCINES WITH HETEROARYLHYDRAZINES

Reactions of /V-acylglycmes with heteroarylhydrazines leading to acylamino substituted fused 1,2,4-triazoles and /V-{2-[2-(heteroaryl)hydrazino]-2-oxoethyl}benzamides have been investigated. Introduction Aminomethyl substituted heterocyclic compounds are useful compounds in heterocyclic synthesis. Their use in the synthesis of irrudazo[ 1,5-a]pyrazine, 3 pyrrolo[l,2-a]thieno[2,3-e][l,4]diazepine, pyrrolo[ 1,2-a][ 1,4]benzodiazepine, and 3a,4,5,7a-tetrahydro-5,7a-epoxyisoindoline, pyrrole, and other systems is well documented. Recently, we reported on a new procedure for the preparation of the benzoylaminomethyl substituted fused 1,2,4triazoles, possible precursors of the aminomethyl derivatives, based on the oxidative cyclization of N(heteroarylhydrazonoethyl)benzamides. ' Since these compounds might also be prepared from hippuric acid 1 and the corresponding hydrazines, as it had been done in the case of iV-[([l,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]benzamide 2, we decided to reinvestigate this possibility for their preparation. Results and Discussion Reactions of hippuric acid 1 with heteroarylhydrazines (2-hydrazinopyridine, 3-hydrazinopyridazine hydrochloride, 3-chloro-6-hydrazinopyridazine, 2-chloro-6-hydrazinopyrazine, 6-hydrazinoimidazo[l,2-6]pyridazine, 6hydrazino[l,2,4]triazolo[4,3-£>]pyridazine, and 6-hydrazinotetrazolo[l,5-&]pyridazine) were carried out by two procedures. In the procedure A, a mixture of equimolar amounts of 1 and heteroarylhydrazine was heated on an oil bath at 140-190°C under solvent-free conditions for 2-4 h. Upon cooling to room temperature the crude residue was suspended in 5% HCl and filtered. After addition of 1M NaOH to filtrate (pH=10) the separated solid was filtered off, and washed with water. In the procedure B, a mixture of 1 (0.5 mmol) and heteroarylhydrazine (0.5 mmol) in toluene or xylene (2 ml) was heated under reflux for 8-12 h. Upon cooling to room temperature the separated solid was filtered off, washed with the same solvent and ethanol. We found that besides 2-hydrazinopyridine, only two other hydrazines, 3-hydrazinopyridazine and 3-chloro-6hydrazinopyridazine, gave the benzoylaminomethyl substituted fused triazoles. Isolated products 2, 3, and 4 were identified by comparison with authentic samples (Scheme 1, Table 1). 321 Vol. 11, Nos. 3-4, 2005 Reactions of acylglycines with heteroarylhydrazines