1,3,4-Thiadiazoles, sulfonyl

Then, as described in U.S. Patent 2,55416, the 2-acetylamido-5-mercapto-1,3,4-thiadiazole is converted to the sulfonyl chloride by passing chlorine gas into a cooled (5°-10°C) solution in 33% acetic acid (66 parts to 4 parts of mercapto compound) used as a reaction medium. Chlorine treatment is continued for two hours. The crude product can be dried and purified by recrystallization from ethylene chloride. The pure compound is a white crystalline solid, MP l94°C,with decomposition, when heated rapidly. The crude damp sulfonyl chloride is converted to the sulfonamide by addition to a large excess of liquid ammonia. The product is purified by recrystallization from water. The pure compound is a white, crystalline solid, MP 259°C, with decomposition. The yield of sulfonamide was 85% of theory based on mercapto compound. 

Amino-5-ethyl-1.3,4-thiadiazole p-Acetylaminobenzene sulfonyl chloride... 

A somewhat different scheme is used to gain entry to the alternate symmetrical 1,3,4-thiadiazole ring system. Reaction of thiosemicarbazide with isovaleric acid affords the ring system (217) in one step. The reaction may be rationalized by positing acylation to intermediate 216 as the first step. Sulfonylation of the amino group of 217 with p-methoxybenzenesulfonyl chloride affords the oral... 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

In general, 3-hydroxy-l,2,4-thiadiazoles react with hard nucleophiles (acid chlorides, sulfonyl chlorides) at the oxygen atom, whereas soft nucleophiles (isocyanates, acid anhydrides) react at the N-2 position yielding 1,2,4-thiadiazolin-3-ones. Nucleophiles react at the N-4 position of 5-hydroxy-l,2,4-thiadiazoles <1996CHEC-II(4)307>. There have been no new publications on O-linked substituents since the publication of CHEC-II(1996). 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

Upon heating in dimethylformamide (DMF) at reflux temperature, the 4-thioureido-5-sulfonyl[l,2,4]triazoles 74 undergo cyclization to [l,2,4]triazolo[3,4-7][l,3,4]thiadiazoles 75 (Equation 15) <1983S411, 1988IJB576,... 

Acetyl azide, 0771 A-Azidocarbonylazepinc, 2728 Azidocarbonyl fluoride, 0339 Azidocarbonylguanidine, 0820 4-Azidocarbonyl-1,2,3-thiadiazole, 1069 Azidodithioformic acid, 0386 Benzene-l,3-bis(sulfonyl azide), 2210 Benzenesulfinyl azide, 2273 Benzenesulfonyl azide, 2274 Benzoyl azide, 2698... 

Reaction of 3-phenyl-1,2,4-thiadiazole-5-thiol (10) (R = Ph) with formaldehyde and with aryl-sulfonyl chlorides leads to N-4 derivatives (26) and (27) (Scheme 8) <89MI 408-01 >. 

Amino-1,2,4-thiadiazoles yield monoacylated derivatives of type (115) under the usual conditions, whereas 3-amino-1,2,4-thiadiazoles give both monoacyl and diacyl derivatives ((116) and (117), respectively) <84CHEC-I(6)463>. Treatment of 3-amino- and 5-amino-1,2,4-thiadiazoles with sulfonyl halides under basic conditions generally leads to low yields of sulfonamides. By... 

The 3-alkylthio groups in 1,2,4-thiadiazoles are difficult to replace. Thus, 3-alkylthio-l,2,4-thia-diazoles resist the action of aniline at 100°C, ammonia at 120°C, molten urea and ammonium acetate however, hydrazine attacks 3-methylthio-l,2,4-thiadiazole (142) forming 3-amino-1,2,4-triazole (143) (Equation (21)) <65AHC(5)119>. In contrast to 3-alkylthiogroups, 5-sulfonyl groups in... 

Reaction of chlorine with thio-l,2,4-thiadiazoles yields sulfonyl chlorides, sulfenyl chlorides, or chloro compounds, depending on the nature of the substrate and on the experimental conditions employed. Thus, treatment of (146) with one mole of chlorine yields the disulfide (147), whilst an excess of chlorine converts (147) into the sulfonyl chloride (148) and then further into the 3-chloro derivative (149) (Scheme 32) <82AHC(32)285>. 

Thiadiazole 5,5-dioxides (274) have been prepared by the cyclization of A(-halomethyl-sulfonyl amidines and guanidines (273) (Equation (41)) <84CHEC-I(6)463>. 

Amino-5-aryl-l,3,4-thiadiazole was treated with thionyl chloride in dry benzene to yield the N-sulfinylamine (93) an unstable compound, characterized by NMR and further derivatization. The sulfinylamine moiety caused an upheld shift on C(2) (4 6 ppm) comparable to a carbonyl or sulfonyl group, indicating the double-bond character of the N—S bond. Reaction of (93) with 2,3-dimethylbuta-1,3-diene yielded (94) via thermal cycloaddition <89JCS(P2)i855>. 

Amongst oxidizing reagents, arylsulfonyl chlorides in pyridine simultaneously cyclize and acylate amidinothiourea (and its 2V-phenyl and AT -diphenylhomologs), producing moderate yields of sulfonyl derivatives of 3,5-diamino-l,2,4-thiadiazoles in one step.116... 

The replacement of the reactive 5-chloro by a sulfonamido group in 1,2,4-thiadiazoles affords a convenient synthesis of the 5-sulfonamido heterocycles.92- 3,168-172 173 Thus, 5-halogeno compounds (171), on treatment with p-acetamidobenzenesulfonamide and potassium carbonate in diphenyl ether at 200°, afford the sulfonamido derivatives (170) in 70 % yields. Nitrobenzenesulfonamides do not react. This route is valuable, because the products are obtainable with difficulty by sulfonylation of the parent amine (see Section III,D, 1,A).8-8S-86-87 The superiority of route 171 -> 170 over route 169-y 170, though unusual in the heterocyclic field, recalls similar observations made in the synthesis of sulfonamidotriazines.174... 

The 3-amino isomers are more resistant towards reduction 3-amino-5-phenyl-l,2,4-thiadiazole is not affected by hydrogen sulfide or acidified potassium iodide, but does undergo decomposition under the influence of stannous chloride in acids or sodium in alcohol.126 Zinc in hydrochloric acid cleaves the heterocyclic nucleus completely, benzoic acid and hydrogen sulfide being the main products,126 while, under the same conditions, the 3-toluene-p-sulfonyl derivative yields benzal-dehyde and toluene-p-sulfonylguanidine.125... 

Proof for the formulation of the resulting derivatives as 5-sulfona-mido-l,2,4-thiadiazoles is provided by the series of reactions outlined in the appended scheme.81 The benzenesulfonyl derivative (211) of 5-amino-l,2,4-thiadiazole yields, on methylation, two monomethyl-ated products (212 and 213). Since the presence of the sulfonyl group (in 213) on the 5-imino group is shown by the alternative synthesis 214- 213, it follows that the sulfonyl group (in 211) is also attached to the exocyclic 5-amino group.81... 

Amino groups, on the other hand, are sulfonylated with less difficulty,126, 126 although here yields may again tend to be unsatisfactory.92 The synthesis of the sulfanilamido derivative from 3-amino-1,2,4-thiadiazole is described in the parent literature.184... 

The resemblance between 3-dialkylamino- and 3-alkyl-5-amino-1,2,4-thiadiazoles is again reflected by the fact that both yield monoacetyl derivatives attempted sulfonylation fails in the former case and gives low yields in the latter.6,87... 

The radioprotective action of 3,5-diamino-l,2,4-thiadiazole, its 3-toluene-p-sulfonyl derivative, and the corresponding 5-methyl-amino- and 5-anilino analogs has been determined.218 Administration of the parent compound results in 69% survival in mice after 900 r whole body X-radiation, a result that compares favorably with the effects of such established protectors as AET ([Pg.202]

Amino-2-n-butyl-l 3 4-thiadiazole p-Chlorobenzene sulfonyl chloride Hydrochloric acid... 

By contrast, however, 3,5-diamino-l,2,4-thiadiazoles are selectively converted into amides and sulfonamides in good yields. Thus, acetylation of 3,5-diamino-l,2,4-thiadiazole (53) with excess acetic anhydride yields the symmetrical derivative (133) whereas under similar conditions 3-amino-5-methylamino-l,2,4-thiadiazole and 3,5-diarylamino-l,2,4-thiadiazoles (65AHC(5)119) produce the monoacylated derivatives (134) and (135), respectively. Sulfonylation also results in the preferential formation of the 3-sulfonamides but reaction with excess reagent eventually produces the 3,5-disubstituted derivatives (136) and (137) in good yields (65AHC(5)119). 

Acetylation of 5-amino-3-dimethylamino-l,2,4-thiadiazole yields the expected 5-acety-lamino derivative but no product was obtained when sulfonylation was attempted. 3-Amino-5-phenyl-l,2,4-thiadiazole (15 R = Ph) forms the expected derivatives (138), (139) and... 

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