Aromatization and ring cyclization: A better understanding on the ring cyclization mechanism of 3‐amino‐6‐hydrazino‐1,2,4‐triazin‐5(2H)‐one reacted with acetic acid in N,N‐dimethylformamide

Abstract

In this paper we report that the title compound (3) reacts with excess N,N‐dimethylformamide (DMF) containing two equivalents of acetic acid to afford 6‐amino‐1,2,4‐triazolo[3,4‐f][1,2,4]triazin‐8(7H)‐one (1). When 3‐amino‐2‐benzyl‐6‐hydrazino‐1,2,4‐triazin‐5(2H)‐one (6), the N‐2 benzylated derivative of 3, is treated under the same conditions, ring cyclization does not occur; instead, 3‐amino‐2‐benzyl‐6‐(2‐formyl‐hydrazino)‐1,2,4‐triazin‐5(2H)‐one (7) is formed. Single‐crystal X‐ray analysis of a 3‐ethyl derivative of compound 1 reveals the predominant tautomeric structure to be the 7H‐tautomer (7H‐1). From these results, we propose a reasonable cyclization mechanism that incorporates two important points: (1) the tautomerism of the N‐2 hydrogen with the C‐5 oxo group aromatizes the 1,2,4‐triazine ring, and (2) the DMF is proto‐nated by acetic acid on the nitrogen atom, then deamination occurs where DMF is attacked by the 6‐hydrazino group of 3 or 6.

Aromatization and ring cyclization: A reasonable understanding on the ring cyclization mechanism of 3‐amino‐6‐hydrazino‐1,2,4‐triazin‐5(2H)‐one reacted with one‐carbon fragment reagents or nitrous acid

“…Compound 10 was treated with hot formic acid to give 3-amino-2-benzyl-6-(2-formylhydrazino)-1,2,4-triazin-5(2H)-one (11). The 1 H nmr spectrum revealed a conformer mixture of 11 in a ratio of about 2:1, and the same chemical shift was observed between the major conformer and the product from 10 reacted with DMF and acetic acid [12].…”

“…Compound 9 is identical in every respect with the corresponding compound in our previous report [12]. Hydrazination of 9 gave compound 10 successfully by nucleophilic heteroaromatic substitution (the hydrazination mechanism as illustrated in Scheme 2).…”

“…The ir spectra of the carbonyl groups on 11-14 (i.e., 1666, 1639, 1679 and 1642 cm -1 , respectively) suggested that these four compounds did not undergo acidolysis and the ring closure didn't occur, because the intense ir absorption at 1719-1725 cm -1 (the carbonyl absorption for fused triazines) indicated the occurrence of ring closure [6,7,12]. This result proved that if tautermerism of the 2H-5-one to the 5-ol on the hydrazino-1,2,4-triazine did not occur, no cyclization would be observed (Figure 1.…”

“…When 3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5(2H)-one (10), the N-2 benzylated derivative of 2, is treated under the same conditions, ring cyclization does not occur; instead, 3-amino-2-benzyl-6-substituted-1,2,4-triazin-5(2H)-ones (11,12,14) and 2-N-(2-amino-1-benzyl-4-oxo-1,2,4-triazin-5-yl)semicarbazide (13) are formed. Alternatively, when 3-amino-6-hydrazino-2-[(2-hydroxyethoxy)methyl]-1,2,4-triazin-5(2H)-one (16), a compound bearing the 2-[(2-hydroxyethoxy)methyl] side-chain at N-2 of 2 by an N-C-O bond, reacts with glacial acetic acid or nitrous acid, the side-chain is cleaved through acidolysis to affford the ring-closed compound 6-amino-3-methyl-1,2,4-triazolo [3,4-f] [1,2,4]triazin-8(7H)-one (3b) or compound 4, respectively.…”

“…These results inspired us to understand more about the actual mechanism for this ring cyclization of the compound 2 reacting with one-carbon fragment reagents to afford tautomeric heterobicycles (3). One of our previous study [12] has proved the hypothesis that the ring cyclization is dependent on the resonance of the 2H-5-one to the 5-ol on the 1,2,4-triazine ring ( Figure 1. type I structure).…”