Synthesis of new derivatives of pyrido[1,2-a]triazine

Abstract

One of the most useful methods for the annelation of the 1,3,5-thiadiazine ring is the double Mannich aminomethylation of 2-mercaptoazoles and -azines. This reaction is of a general nature and has been used successfully for the synthesis of derivatives of sym-triazolo[3,4-b][1,3,5]thiadiazine [1], thiazolo[3',4':1,5][1,2,4]triazolo[3,4-b][1,3,5]thiadiazine [2], imidazo[2,1-b][1,3,5]thiadiazine [3,4], 1,2,4-triazino[3,2-b][1,3,5]thiadiazine [4], and 1,3,5-thiadiazino[3,2-a]benzimidazole [5]. In the case of derivatives of pyridine2-thiolate the Mannich reaction does not proceed uniquely but leads to derivatives of pyrido[2,1-b][1,3,5]thiadiazine [6], 3,7-diazabicyclo[3.3.1]nonane (bispidine) [7], or 3,5,7,11-tetraazatricyclo[7.3.1.0]tridec-2-ene [8] depending on the structure of the aminomethyl substrate. We have studied the behavior of 6-amino-4-(het)aryl-2-thioxopyridine-3,5-dicarbonitriles 1 which are readily accessible by the reaction arylmethylenemalonitriles with cyanothioacetamide under Mannich reaction conditions. It was established that thione 1 readily and under mild conditions underwent aminomethylation with primary amines and HCHO to give pyrido[1,2-a]triazines 2. Thus the presence of an amino group in position 6 is regiondirecting , and the thione 1 behaves as an N,N-binucleophile rather than an N,S-binucleophile under Mannich conditions. The structures of compounds 2 were confirmed spectroscopically. Characteristic signals in the H NMR spectra are the broad peak of the N(1)H proton at 9.61-9.16 ppm and the signals of protons H-4 (6.04-5.36) and H-2 (5.06-4.44 ppm) which are resolved at 200 MHz as a pair of broadened pseudosinglets. Antihelminthics, fungicides [9], and antagonists of 5-hydroxytryptamine receptors [10] are found among the pyrido[1,2-a][1,3,5]triazines, but only a limited number of methods for the synthesis of derivatives of these heterocyclic systems is known.