Cyclocondensation of N-aryl-3-oxobutanethioamides with 5-amino-3-R-4-R1-pyrazoles

Abstract

We have recently shown that N-aryl-3-oxobutanethioamides react with such 2-aminoazoles (azines) as 3-amino-5-R-1,2,4-triazoles [1], 2-amino-5-R-pyridines [2], 2-amino-4-R-5-R 1 -thiazoles [3], and 5-aminotetrazole [4] via a [3+3] cycloaddition scheme to form two groups of compounds (pyrimidine-4-thione and 4-(arylamino)pyrimidine derivatives) the ratio of which depends on the basicity of the heterocyclic 1,3-dinucleopile and the acidity of the solvent [1][2][3][4].The aim of this work is to continue our investigation [1-4] and study of the regioselectivity of the cyclization of the N-aryl-3-oxobutanethioamides 1a-d with such 1,3-dinucleophiles as the 5-amino-3-R-4-R 1 -pyrazoles, viz 5-amino-3-methylpyrazole (2a), 5-amino-4-cyanopyrazole (2b), and 3-amino-2H-pyrazolo-[3,4-b]pyridine (2c) in the absence and the presence of a proton donor solvent. Such a course should prove an addition to the general results of preceding work [1][2][3][4], in particular the observation of the effect of the nucleophilicity of the 2-aminoazole and the acidity of the solvent on the regioselectivity of the process.Since the [3+3] cyclocondensation can occur at three reaction centers in the N-aryl-3-oxobutanethioamides 1a-d and at two in the 5-amino-3-R-4-R 1 -pyrazoles 2a-c the reaction products can be four groups of compounds i.e. 2(4)-methyl-7-R-8-R 1 -1,4(1,2)-dihydropyrazolo[1,5-a]pyrimidine-4(2)-thiones and 4(2)-arylamino-2(4)-methyl-7-R-8-R 1 -pyrazolo[1,5-a]pyrimidines.It was shown that two groups of compounds are the result of the reaction, i.e. the pyrimidine thiones 3a,b and the 4-(arylamino)pyrazolo[1,5-a]pyrimidines 4a-f. The structure of the dihydropyrazolo[1,5-a]pyrimidine thiones 3a,b was proved by thionation of the 2,7-dimethyl-1,4-dihydropyrazolo-[1,5-a]pyrimidin-4-one 5 (the structure of which had been proved using X-ray analysis [5]) to give the 2,7-dimethyl-1,4-dihydropyrazolo-[1,5-a]pyrimidine-4-thione (3a). Since the 5-amino-3-R-4-R 1 -pyrazoles are isoelectronic with 3-amino-__________________________________________________________________________________________

Heterocyclization of thioamides containing an active methylene group (review)

“…Whilst the reactions of 3-oxopropanethioamides with 1,2-dinucleophiles and 1,2-and 1,3-dielectrophilic reagents were investigated earlier, recently it was shown that they can also react with nitrogen-containing 1,3-dinucleophiles of heterocyclic [71,[76][77][78][79] and acyclic [80] structures.…”

“…It was established that N-aryl-3-oxobutanethioamides 144 undergo cyclization with 2-amino-5-R-pyridines [71], 3-amino-5-R-1,2,4-triazoles [76], 2-amino-4-R-5-R-thiazoles [77], 5-amino-3-R 1 -4-R 2 -pyrazoles [78], and 5-aminotetrazole [79] to form derivatives of 4-arylaminopyrimidine 145, 148, 150, and 151 and 4-pyrimidinethione 146, 147, 149, 152, and 153 [71,[76][77][78][79]. The reactions take place both in acetic acid [71,[76][77][78][79] and without a solvent [78][79][80].…”

“…The reactions take place both in acetic acid [71,[76][77][78][79] and without a solvent [78][79][80]. It was found [79] that the ratio of the derivatives of 4-arylaminopyrimidine and 4-pyrimidinethione depends on three factors, i.e., the basicity of the heterocycle in the initial 2-aminoazoles(azines), the nature of the substituent in the phenyl ring of the thioamides, and the protonating ability of the solvent.…”

A decade's overview of 2‐aminothiophenes and their fused analogs as promising anticancer agents

“…[17] Later, Gewald developed the synthesis of 2-aminthiophenes, which became a characteristic pathway. [18][19][20] Three versions of the gewald reaction were reported (Scheme 1). The first version includes the aminecatalyzed condensation of an α-mercaptoaldehyde or ketone with acetonitrile bearing an electron-withdrawing group.…”

“…[18,19,22,23] The third version was a two-step base-catalyzed synthesis that involves the formation of an α,β-unsaturated carbonitrile, which then reacts with sulfur for ring closure. [18,20] Other synthetic pathways for 2-aminothiophenes preparation have been reported in the literature. [20] Willgerodt-Kindler reaction is one of these pathways, which involves the preparation of 2-aminothiophenes from phenylbutanones in the presence of sulfur and amine solvent (Scheme 2).…”