Triazolo-pyrimidines, methylthio

The reactions of 5-methylthio-3-amino- or 3,5-diamino-l,2,4-triazole and diethyl 1-ethoxyethylidenemalonate in boiling ethanol in the presence of sodium ethylate for 1.5-3.5 hr gave l,2,4-triazolo[l,5-a]pyrimidin-7-ones (1123, R = MeS, NH2, R1 = Me) in 44% and 20% yields, respectively. The reaction of 5-methylthio-3-amino-l, 2,4-triazole (R = MeS) and 2-ethoxyethylidenemalonate in boiling pyridine for 4 hr gave 1,2,4-tria-zolo[l,5-a]pyrimidin-5-one (1122, R = MeS, R1 = Me) in 12% yield (61JCS3046). 

The 1,2,4-triazole ring of 2,3,5,6,7,8-hexahydro-l,2,4-triazolo[4,3-a] pyrimidin-3-ones (60) was constructed by cyclocondensation of the 1-ethoxycarbonyl-2-methylthio-l,4,5,6-tetrahydropyrimidine 58 with hydrazine (86JPR331), arylhydrazines [86H(24)93, 86KGS1350 88JPR753], or thiosemicarbazide (87KGS1540) (Scheme 24). 

Schiff bases (112) derived from 4-chlorobenzaldehyde and 1-substituted-5-amino-3-methylthio-l,2,4-triazoles (111) underwent cyclization with phe-noxyacetyl chloride or dichloroacetic acid in the presence of phosphoryl chloride and dimethylformamide to give the 7-(4-chlorophenyl)-fram-6,7-dihydro-3-methylthio-6-phenoxy-l-substituted-l,2,4-triazolo[4,3-a]pyrimidin-5-one 113 and l-substituted-6-chloro-7-(4-chlorophenyl)-3-methylthio 1,2,4-triazolo[4,3-a]pyrimidin-5-one 114, respectively (88JHC173) (Scheme 47). 

R1 = R2 = H) gave the triazolo[l,5-a]pyrimidines (125), but with 124 (R1 = R2 = Me) afforded the dioxo derivative 126, and with a-cyano- y-butyrolactones (127) or 2-amino-3-ethoxycarbonyl-5,6-dihydro-4//-thiopyran (129) gave the triazolopyrimidines 128 and 130, respectively (81JHC1287). Treatment of 4-ethoxymethylene-2-phenyl-5(4//)-oxazolone (131) with 5-amino-3-methylthio-l//-1,2,4-triazoles gave the triazolo[l,5-a]pyrimidi-none 132 and the [4,3-a] isomer 133 (93H955) (Scheme 24). 

Acid-catalyzed fusion of 7-methylthio-l,2,3-triazolo[4,5-d]pyrimidine (257) with l-0-acetyl-2,3,5-tri-0-benzoyl-D-ribofuranose (254) gave the... 

When 5-methylthio-7-amino-l,2,4-triazoIo[l,5-c]pyrimidine 65 was heated in hydrazine hydrate, 5-hydrazino-7-amino-l,2,4-triazolo[l,5-c]pyrimidine 66 was obtained and 66 underwent rearrangement to give isomer 67 (79KGS262). This a rare example of the retro-Dimroth rearrangement (Scheme 20). 

Reaction of Ai -[bis(methylthio)methylene]cyanamide (67) with the N]-acylamidrazones (68) at elevated temperature gave directly the corresponding l,2,4-triazolo[4,3-c]pyrimidines 69. Carrying out the reaction between 67 and 68 at ambient temperature in the presence of potassium carbonate afforded the 4-acylhydrazino-pyrimidines 70, which were dehy-dratively cyclized to 69 by heating in dimethylsulfoxide (92JHC1341) (Scheme 29). 

Synthetic routes leading to triazolo[l,5-c]pyrimidine sulfonanilides have been reviewed [4]. Scheme 2.4.1 shows a general synthetic route to the triazolo[l,5-cjpyrimidine sulfonanilides [5]. An appropriately substituted 4-hydrazino-2-methylthiopyrimidine is reacted with carbon disulfide followed by benzyl chloride to afford 3-benzylthio-5-methylthio-l,2,4-triazolo[4,3-c)pyrimidine (8). Compound 8 is then treated with methoxide to afford 2-benzylthio-5-methoxy-l,2,4-triazolo[l,5-c]pyrimidine (9). The benzyl sulfide (9) is oxidized to the sulfonyl chloride (10) by treatment with chlorine and water. The sulfonyl chlorides... 

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