Synthesis of 3‐Aminomethyl‐5R‐1,2,4‐Triazoles by Cyclization of Amidrazones: Multigram Approach and Revised Reaction Mechanism

A series of 3‐(aminomethyl)‐5 R ‐1,2,4‐triazoles is synthesized in gram‐scale quantities starting from N‐(cyanomethyl)phthalimide and carboxylic acid hydrazides. The intramolecular cyclization of amidrazones to give 1,2,4‐triazolines is the key step. The main side products are 1,3,4‐oxadiazoles formed by a concurrent intramolecular condensation. Their amount depends on the steric and electronic nature of the substituent in the initial carboxylic acid hydrazide. Additionally, aminomethyl‐1,2,4‐triazole is modified by the introduction of different substituents at positions 1, 2, and 4 of the heterocyclic scaffold. Quantum chemical calculations demonstrate a fine balance of activation energy values for the key stages in the formation of the two isomeric products. In contrast to the previously derived mechanism, the participation of water, not ammonia, is required as a factor reducing the activation barriers for both reaction pathways.