Cyclic meso-ionic compounds. Part 23. Novel chemistry of 1,2,4-thiadiazoles and their transformation into meso-ionic 1,2,4-thiadiazolium derivatives

Abstract

Representatives of two new classes of meso-ionic heterocycles have been synthesised, the I ,2,4-thiadiazolium-3-olate (8) and the 1,2,4-thiadiazolium-3-tosylaminide (25). The reactions of 1,2,4-thiadiazoles and nucleophiles follow two general pathways : (i) reductive transformation to N-thiobenzoyl derivatives and (ii) elimination of elemental sulphur and the formation of N-benzoyl derivatives. A mechanistic rationale is proposed for the operation of pathways (i) and (ii). Earlier views on the oxidative formation of certain 1,2,4-thiadiazoles are corrected. A novel synthetic route to heterocycles containing sulphurnitrogen bonds is described. 1,2,4-Thiadiazoles are formed by oxidation of N-thiobenzoylureas and Nt hio benzoylg uanidines by bis (4met hoxyp hen yl) telluroxide.Four types of meso-ionic thiadiazoles can in principle exist as possible members of the type-A class of meso-ionic heterocycles.2 These are the conjugated mesomeric betaine derivatives of 1,2,3-thiadiazoles [(I) and (2)], 1,3,4-thiadiazoles (3), and 1,2,4-thiadiazoles (4). Meso-ionic heterocycles of the types (I), (2), and (3) have been extensively investigated.* Known representatives include the 1,2,3-thiadiazolium-4olates (1 ; X = 0), 1,2,3-thiadiazolium-5-olates (2; X = 0), 1,2,3-thiadiazolium-5-aminides (2; X = NR3), 1,2,3-thiadiazolium-5-thiolates (2; X = S ) , 1,2,3-thiadiazolium-5methylides (2; X = C Y Z ) , 1,3,4-thiadiazolium-2-0lates (3 ; X = 0), 1,3,4-thiadiazolium-2-aminides (3; X = NR3), 1,3,4-thiadiazolium-2-thiolates (3 ; X = S), and 1,3,4-thiadiazolium-2-methylides (3; X = CYZ). It is interesting to note that the pioneering investigations on the 1,3,4-thiadiazolium-2-thiolates (3; X = S) were carried out by Busch (1865Busch ( -1941, long before it was recognised that these compounds could be appropriately formulated with monocyclic meso-ionic structures.The claim to have prepared the first example of a mesoionic 1,2,4-thiadiazole (4; R' = Ph, R2 = Me, X = NH)

Thiadiazoles

“…Reaction of 3-amino-1,2,4-thiadiazole (396) with trimethyloxonium tetrafluoroborate occurs at N2 to yield the thiadiazolium salt, which, on basification, undergoes a Dimroth rearrangement to give the 5-methylamino derivative 397 (Scheme 14.108) [215]. Analogously, the sulfonamide 398 by reaction with methyl fluorosulfonate gives the N2 derivative 399, together with the mesoionic compound 400 (Scheme 14.109) [133]. Similar behavior has been observed for 3-hydroxy-5-phenyl-1,2,4-thiadiazole (401).…”

“…Similar behavior has been observed for 3-hydroxy-5-phenyl-1,2,4-thiadiazole (401). The reaction with dimethyl sulfate and sodium hydroxide leads to N2 methylated derivative 402; when methylation was carried out with toluene-4-sulfonate, 402 was obtained together with the meso-ionic compound 403 (Scheme 14.110) [133].…”

“…The fully saturated 1,2,4-thiadiazole system (1,2,4-thiadiazolidine) is present in a series of compounds endowed with important biological activities. Compounds 272 and 273 are characterized by interesting antibacterial, antifungal, anti-inflammatory, and analgesic activities [138,140] The synthesis and chemistry of two classes of meso-ionic 1,2,4-thiadiazoles (276, X ¼ O, X ¼ SO 2 C 6 H 4 Me-p) have also been reported [133]. …”

“…The tautomer 248, with the double bond between the a-nitrogen and the b-carbon, is the one with the lowest energy, lying 3.3 and 4.6 kcal mol À1 off the other forms, and thus is the more stable geometric structure [132]. Stable N-substituted D 4 -269 [133] and D 3 -thiadiazolines 270 [134] have been suggested as scaffolds for structure-activity investigation as N-S cysteine thiol trapping agents in enzyme systems [135]. The 5-amino-1,2,4-thiadiazolin-3-one 271, analog of cytosine, can exist in two stable tautomeric forms: lactam (oxo) 271a and lactim (enol) 271b.…”

Medicinal Chemistry and Properties of 1,2,4-Thiadiazoles

“…Similarly, the 1,2,4-thiadiazoline derivative (8) reacted with the sulfide nucleophile (9) to afford the disulfide compound (11) and the ring-opened product (12), via the disulfide intermediate (10) (Scheme 2) [16].…”