3- Hydroxy-1,2,4-thiadiazoles properties

Hydroxythiadiazoles exhibit marked acid properties (see Section 4.26.2.8) and exist essentially in the hydroxy form (68AHC(9)107). Alkylation with alkyl halides or sulfates and base in dipolar aprotic solvents usually forms ethers. In media where the oxygen atom is screened by solvation or by formation of ion pairs, mixtures of N- and O -alkylation products are formed. The reaction of 3-chloro-4-hydroxy-l,2,5-thiadiazole with epichlorohydrin catalyzed by piperidine in the absence of a solvent gave a mixture of N- and O-alkylated products in about equal amounts (72JMC651). Treatment of 3 - hydroxy-4-(A - morpholino) -... 

Thiadiazoles were first described in 1882 by Fischer and further developed by Busch and his coworkers. The advent of sulfur drugs and the later discovery of mesoionic compounds greatly accelerated the rate of progress in the field of thiadiazoles. Thiadiazoles carrying mercapto, hydroxy and amino substituents can exist in many tautomeric forms and this property is being intensively studied using modern instrumental methods. 

Most activity in this area has centered around the isolation of so-called pseudo-bases (82) in which the cyano group is replaced by a hydroxy group. Thus the pseudo-base is obtained, in addition to the normal Reissert compound, from S-nitroisoquinoline, " 3-methyl-5-nitroisoquinoline, 6-nitroquinoline, and phthalazine. Heating the pseudo-bases in alcohol gives rise to the ethers 83. A discussion of some of the chemistry and properties of the pseudo-bases has appeared. The formation of the pseudo-bases can be suppressed and that of the Reissert compounds increased by the use of a phase-transfer catalyst. Pseudo-bases have also been obtained in attempts to form Reissert compounds from 1,6-naphthyridine and 4,6-phenanthroline. 2-Phenyl-1,2,3-thiadiazole and benzoyl chloride in the presence of cyanide gave 84 and imidazo[l,5-a]pyrazines with acid chloride gave 85 in reactions analogous to the pseudo-base formation. 

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... 

Hydroxy-l,2,4-thiadiazoles readily form esters with phosphoric acid and its various analogs. Because of the pesticidal properties of these organo-phosphorus compounds, and their reported relatively low toxicity to warmblooded animals, a large volume of preparative work has been undertaken. The patent literature exemplifies almost the full range of possible phosphoric and phosphonic acid derivatives, and their thio analogs. For their production, a hydroxy-1,2,4-thiadiazole is condensed with the phosphoro- or phosphono-chloridic ester (426 or 429), in the presence of a base.332-336 Alternatively, a halogeno-1,2,4-thiadiazole is allowed to react with the appropriate free acid (424 or 427).337-341 The use of mercapto-l,2,4-thiadiazoles, or of the... 

Methoxybenzenesulphonamido-5-isobutyl-l, 3,4-thiadiazole (179) has hypoglycaemic properties, but produces neoplasms of the urinary bladder in rats, though not in dogs. This difference may possibly be due to the nature of the metabolites produced in the two species. These were isolated from urines by preparative t.l.c. and identified by their mass and n.m.r. spectra. Three metabolites are common to both dog and rat, viz. 2-p-hydroxy-benzenesulphonamido-5-isobutyl-l,3,4-thiadiazole, (180), and (182), derived... 

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