Thiadiazoles 3-alkylthio— from

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

Isothioureas similarly give, in neutral media, the corresponding 3-alkylthio-5-amino-l,2,4-thiadiazoles (65) in yields exceeding 70%.84"86 However, the attempted preparation of the parent 5-amino-3-mercap-to-l,2,4-thiadiazole from thiourea or dithioformamidine by this route yielded only intractable mixtures.85... 

The reaction has been extended to the synthesis of the analogous 3-alkylthio heterocycles (123) from the appropriate dithiobiurets (122).132 1-Substituted 2,4-dithiobiurets (125), unlike their monothio-biuret analogs (118), are unsuitable as precursors of 1,2,4-thiadiazoles, since in any oxidation the two thiol groups may be expected to react preferentially, resulting in the formation of cyclic disulfides (126). The formulation of such oxidation products as 1,2,4-thiadiazoles has indeed been discussed by Bambas1 however, the available evidence133 favors the cyclic disulfide structure.134... 

Alkoxy derivatives are attacked more rapidly by 2N hydrochloric acid, with liberation of sulfur, than are the 3-alkyl derivatives.88 3-Alkylthio groups also increase the sensitivity of 5-amino-l,2,4-thiadiazoles to hydrolysis the 3-phenylthio homolog, for example, tends to decompose on crystallization from boiling water.85... 

Amino-5-alkyl- or 5-phenyI-l,3,4-thiadiazoles are prepared most conveniently from thiosemicarbazide. For example, benzalthiosemicarbazone by oxidation with iron(III) chloride gives the 5-phenyl derivative. Thiosemicarbazide is also used in the synthesis of 2-amino-5-mercapto-l,3,4-thiadiazole by reaction with carbon disulfide. The product may be alkylated to yield the 5-alkylthio derivatives using a variety of alkylating agents (58MI11201). 

Amino-l,2,4-thiadiazoles are usually prepared by treating amidine hydrochlorides with halogen and thiocyanates to yield the 3-alkyl derivatives or treating alkylisothiouronium salts similarly to yield the 3-alkylthio derivatives (56CB2742). Diazonium salts derived from 5-amino-l,2,4-thiadiazole derivatives, which are prepared in acetic acid, are extremely reactive and are capable of coupling with m -xylene (60CB397). 

The preparations of 1,2,4-thiadiazoles and 1,2,4-thiadiazolidines from thioureas are well known and have been summarized in three reviews those of Bambas,188 Sherman,189 and Kurzer.170 Contained in these reviews are discussions of the controversies that surrounded some of the products, notably Hector s bases, which resulted from oxidation of substituted thioureas.171,172 Subjects covered in the above reviews, but too extensive to outline in detail here, are the oxidation of amidinothioureas to 3,5-diamino-1,2,4-thiadiazoles (71),173,174 the oxidation of phenylthiourea175 and of substituted amidinothioureas176 to 3,5-diimino-l,2,4-thiadiazolidines (72, Hector s bases), the reaction of thiopseudoureas with trichloromethanesulfenyl chloride to form 3-alkylthio-5-chloro-l,2,4-thiadiazoles (73),177 the reaction of thiopseudoureas with sodium thiocyanate and bromine178 and the oxidation... 

Reactions of 1,2,4-thiadiazoles with radicals and electron deficient species are virtually unknown. Catalytic and dissolving metal reductions usually result in S—N bond cleavage. For example, the 5-anilino-3-hydroxy derivative (51) gives a good yield of l-phenyl-2-thiobiuret (52) on Zn-HCl reduction (Scheme 27). Reduction of the diamino derivative (53) gives amidinothiourea (54) from which it may be prepared by oxidation (Scheme 28). Under similar conditions, cleavage of the 3,5-diphenyl derivative (55) results in loss of sulfur and formation of benzylbenzamidine (56 Scheme 29). Reduction of 5-alkylamino-or 5-arylamino-3-alkylthio derivatives (57) with H2S in pyridine-triethylamine or sodium in liquid ammonia yields 1-substituted dithiobiurets (58 Scheme 30). 

Cyanodithioimidocarbonate salts have become very useful reagents for the preparation of many 3,5-disubstituted 1,2,4-thiadiazoles. Dipotassium cyanodithioimidocarbonate (314) is readily prepared from cyanamide and carbon disulfide under alkaline conditions and is readily converted into the reactive thiadiazoles (315), (316), (317), (318) and (319), as shown in Scheme 112 (71JOC14). Alkylation of (314) produces derivatives of type (320) which react with chlorine or sulfuryl chloride to yield 5-alkylthio-3-chloro-l,2,4-thiadiazoles... 

Numerous examples of this series, many containing a 2-hetero substituent, were prepared by this route,152-156 chiefly because of their selective herbid-dal properties, and their potential value in the cultivation of grain and cotton. The structural types described included 170,152 171,155 and 172.156 The bis-l,2,4-thiadiazole system 173 was obtained from l-methyl-3- 1,2,4-thiadiazol-5-yl) urea.157 S-Alkylisothioureas give rise to 3-alkylthio-5-hydroxy-1,2,4-thiadiazoles.15 8... 

Finally, in order to confine the reactions of the cyanodithioimidocarbon-ates (280) to one Section, their participation in a synthesis of type E is now included the reaction concerned is their condensation with N-chloroamino compounds. Potassium S-alkylcyanodithioimidocarbonates (280) react with chloramine itself (produced in situ from aqueous ammonia and chlorine) to afford good yields of 3-amino-5-alkylthio-l,2,4-thiadiazoles (284).223,224... 

The action of trifluorobutenyl bromide (CF2=CFCH2CH2Br) on 3-phenyl-5-mercapto-l,2,4-thiadiazole and numerous analogs produces 5-(3,4,4-trifluoro-3-butenyl)thio derivatives (435), which are useful nema-tocides.344 The 5-alkylthio compound (436) is the product of the S-alkylation using l-(/ -chloro-2,4-dichlorophenetyl)imidazole.345 The formation of the monosulfide (437) from 3-isopropyl-5-mercapto-1,2,4-thiadiazole occurs under standard conditions.346... 

The interaction of dithiocarbazic esters and bromocyanogen in aqueous potassium bicarbonate produces good yields of 2-amino-5-alkylthio-1,3,4-thiadiazoles. The reaction is an extension of the known synthesis of the 5-alkoxy-analogues from alkoxythiocarbonylhydrazines and bromocyanogen. ... 

Alkylthio-l,3,4-thiadiazoles from dithiocarbazic acid esters and carboxylic acid dilorides... 

From dithiazoles. The alkylation of phenylthiuret (45) is attended by isomerization to 1,2,4-thiadiazole derivatives. Thus methylation or benzylation in alkaline media gives 5-imino-3-alkylthio-2-phenyl-l,2,4-thiadiazolines (46 R = Me or PhCHg, R = Ph, R = H), which can be independently synthesized by the oxidation of 2-5-alkyliso-l-phenyldithiobiuret (47 R = Me or PhCHg, R = Ph, R = H). Conversely, the dealkylation, by concentrated hydrochloric acid, of 3-t-butylthio-5-phenylimino-l,2,4-thiadiazoline (46 R = Bu R = H, R = Ph), obtained from (47 R = Bu , R = H, R = Ph), proceeds with the opposite isomerization, yielding (45) instead of the expected (46 R = R = H, R = Ph). Possible mechanisms of these reactions, and their significance for the structure of phenylthiuret, have been discussed. However, the issue is complicated by the fact that different alkyl halides produce different structural types of the 1,2,4-thiadiazole system. ... 

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