1.2.4- Thiadiazole ring, functionalized

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). 

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>. 

Compound 45 is susceptible to nucleophilic aromatic substitution at position 5 due to the highly electron-poor thiadiazole ring in addition to the effect of the ester functionality. 

Varying base allows to obtain a wide range of functionalized isoindoles fused with the thiadiazole ring or bearing substituents in the pyrrole ring [88]. 

On the other hand, reactivity of other functionalities linked to the thiadiazole ring is not affected by the presence of fluorinated moieties, therefore fluorinated 1,3,4-thiadiazoles behave as unfluorinated congeners. Also in this case, particular attention to fluorinated Ihiadiazoles which contain amino or methylthio groups has been given, due to their the industrial importance. 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

The nucleophilic attack of organometallic species occurs with cleavage of the N—S bond and eventual formation of an a-diketone. This reaction has been shown to proceed through an unsym-metrical diimine (17) (Scheme 2) <90JHC1861>. The 4-unsubstituted series (18) can be functionalized in this way. The diimine product of ring opening (19) can add a nucleophile at carbon (20) and then be recyclized to a 3,4-disubstituted 1,2,5-thiadiazole (21) (Scheme 3) <86H1131>. 

Renewed interest in 1,2,4-thiadiazoles is not merely part of the general intensive activity in contemporary heterocyclic chemistry. It is obviously desirable to compare this ring system with closely related important heterocycles (including thiazoles, oxazoles, pyrimidines, etc.), the chemistry of which is known in much greater detail. The iso-steric relationship between pyrimidine and 1,2,4-thiadiazole (but not with any of its isomers) foreshadows similarities in certain physical properties of the two series. The question of the biochemical function and physiological activity of heterocyclic compounds of this general pattern has also served to reinforce interest in the 1,2,4-thiadiazoles. 

Amino-1,2,4-thiadiazoles (16) are alkylated at the 4-position of the heterocyclic ring to produce salts of type (121) when heated with methyl iodide or reactive halides such as phenacyl bromide (77G1). The reaction is hindered when 3-substituents are present on the ring and when higher molecular weight alkyl, allyl or benzyl halides are used. By contrast, benzhydryl and trityl chlorides (which are harder electrophiles) alkylate (16) at the 5-amino function (presumably by an SN1 reaction) to produce products of type (122) as indicated in Scheme 53 (65AHC(5)119). 

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