Thiadiazole rings

Without additional reagents 2,1,3-Thiadiazole ring from o-diamines... 

In the 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than at the 3-position, and this affects substituent reactions. 5-Halogeno derivatives, for example, approach the reactivity of 4-halogenopyrimidines. The 1,2,4-oxadiazole ring shows a similar difference between the 3- and 5-positions. 

Treatment of 5,7-diamino-l,3,4-thiadiazolo[3,2-n]pyrimidinium ehloride (25) with Vilsmeier reagent gave the 7-formamido-l,2,4-triazolo[l,5-c]pyrimidin-5-one (27) (90JHC851) (Seheme 42). Compound 27 has presumably been formed via rupture of the 1,3,4-thiadiazole ring of 25 and... 

Heating the 5-isocyano-l,3,4-thiadiazolo[3,2- ]pyrimidin-5-one 115 with 10% hydrochloric acid gave a mixture of the 5-imino-l,3,4-thiadiazolo[3,2- ]pyrimidin-7-one 116 (10%) and the l,2,4-triazolo[l,5-c]pyrimidine-5,7-dione 117 (35%) (91JHC489). Formation of 117 probably occurred through thiadiazole ring rupture of 116 and recyclizatioii with its imino function together with desulfurization (Scheme 43). 

There are nine possible isomeric compounds for the thiadiazoloquinoline based on the fusion of the thiadiazole ring on the faces a, ij and / and arrangement of the heteroatoms as shown in Fig. 10, from which only one, to the best of our knowledge, was reported 1,2,4-Thiadiazolo[4,5-a] quinolines. 

A rearrangement involving a fluctuating 1,2,3-thiadiazole ring has been found by Haddock et al. (1970) after diazotization of 7-amino-6-substituted 1,2,3-benzothia-diazoles (Scheme 6-46). 

The first A/ -oxides of the 1,2,4-thiadiazole ring system have been reported and were prepared by condensation of benzamidoximes (86) with 4,5-dichloro-l,2,3-dithiazohum chloride (87). A -labelling showed the compounds to be 4-oxides (88) and a mechanism was proposed for their formation. Alkyl amidoximes and arylamidoximes with electron-withdrawing substituents did not give A/ -oxides, but only the dithiazolone (89) and the dithiazolthione (90) <96CC1273>. 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

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... 

Perhaps the earliest reported method for the synthesis of the 1,2,3-thiadiazole ring system was the one described by Pechmann and Nold in which diazomethane was reacted with phenyl isothiocyanate. Of the four possible isomers that could be obtained from the reaction, 5-anilino-l,2,3-thiadiazole 62 (R1 Ph, R2 = H) was the only product formed (Equation 16) <1896CB2588>. This method continues to be used as a route to 5-amino substituted 1,2,3-thiadiazoles. 4,5-Disubstituted 1,2,3-thiadiazoles have been produced in excellent yield by reaction of l,l -thiocar-bonyl diimidazole with ethyl diazoacetate <1988SUL155>. 

The 1,2,3-thiadiazole ring system has been incorporated into a number of compounds which have antiviral activity. The thioamide 86 is a potent inhibitor of cytomegalovirus (CMV) <2004BML3401>. 

Thiadiazole has an absorption maximum at 229 nm (log e 3.7). The introduction of amino groups into the heteroaromatic nucleus results in a bathochromic shift. Thus, the maximum due to the 1,2,4-thiadiazole ring is moved to 247 nm in 5-amino and to 256nm in 3,5-diamino-l,2,4-thiadiazole <1996CHEG-II(4)307>. No new publications relating to the ultraviolet (UV) spectra of 1,2,4-thiadiazoles have appeared since the publication of CHEC-II(1996). 

X-Ray crystallographic studies on 1,2,4-thiadiazoles (see Table 1) show the 1,2,4-thiadiazole ring to be essentially planar. The X-ray structure of 4-phenyl-5-(/>-nitrophenyl)-3-(/>-methoxyphenyl)-A2-l,2,4-thiadiazoline 3 shows that the 1,2,4-thiadiazoline ring has a 30° fold around the S(l)-N(4) vector atoms S-l, N-2, C-3, and N-4 are nearly coplanar <1986JCM156>. 

Thiadiazole 1,1-dioxides are known they are not prepared by direct oxidation of the 1,2,4-thiadiazole ring, as ring cleavage occurs giving sulfate ion. They are only accessible by cyclization of precursors already incorporating the oxidized sulfur functions <1996CHEC-II(4)307>. 

Thiadiazoles have found applications as pharmaceuticals, fungicides, herbicides, bacteriocides, dyes, lubricant additives, and vulcanization accelerators. Cephalosporins incorporating a 1,2,4-thiadiazole ring into the side chain have good antibiotic and antimicrobial properties. 

An extensive coverage of the reactivity of substituents attached to the 1,2,5-thiadiazole ring carbon atoms exists in both CFIEC(1984) and CFIEC-II(1996). Recent developments are described in this section. 

The numbering of the 1,3,4-thiadiazole ring is given below. The present chapter is intended to update the previous work on the aromatic 1,3,4-thiadiazole 1, the nonaromatic A2-thiadiazolines 2, A3-thiadiazolines 3, the thiadiazoli-dines 4, the tautomeric forms 5 and 6, and the mesoionic systems 7. Reference is made to earlier chapters of CHEC(1984) and CHEC-II(1996) where appropriate. 

No examples of direct oxidation of the 1,3,4-thiadiazole ring sulfur to sulfoxide or sulfone have been reported. A3-l,3,4-Thiadiazoline 1-oxide and 1,1-dioxide, however, can be obtained by indirect methods that are reviewed in CHEC(1984) <1984CHEC(6)545>. 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

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