Functionalizations 1,2,3-thiadiazole

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

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). 

Therapeutic Function Carbonic anhydrase inhibitor, diuretic, treatment of glaucoma Chemical Name N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl] acetamide Common Name —... 

The heat of formation (AH ) for 1,2,4-thiadiazole has been reported <1990JPR885> while other thermodynamic functions (entropy, heat capacity, free energy) have not been reported. 

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>. 

Table 3 The net charges and condensed Fukui functions for 1,2,5-thiadiazole 1 with C2v symmetry <1997JMT67>...

A useful strategy for the formation of fused thiadiazoles is the annulation of suitably functionalized 1,2,5-thiadiazoles. Common routes involve the use of 3,4-difluoro-l,2,5-thiadiazole, 3,4-diamino-1,2,5-thiadiazole, l,2,5-thiadiazole-3,4-dicarbonyls, l,2,5-thiadiazole-3,4-dicarbonitrile, amino-1,2,5-thiadiazole-3-carboxamides and carboxamidines. These afford heteroarene-fused 1,2,5-thiadiazoles (which are covered in Volume 9). Below follows a brief description of fused thiadiazoles that fall within the scope of this chapter. 

In combination with the use of tetrasulfur tetranitride, trithiazyl trichloride, or any equivalent source of N-S-N , the technique of functionalizing a two-carbon source such as active methylene, alkene, or alkyne into thiadiazole (see Section 5.09.9.1.4) followed by reduction (see Section 5.09.5.6) provides a rapid route to 1,2-diamines. 

The chemical reactivity of 1,3,4-thiadiazole 1 was predicted using DFT by calculating the net atomic charges and the Fukui functions /+,/ , and f° (Table 2). 

Highly functionalized imidazo[2,l-A][l,3,4]thiadiazoles 166 react with bromine in acetic acid to give the corresponding monobrominated derivatives 167 (Equation 6) <2003IJC(B)1463, 2001IJC(B)303, 2003IJH33, 2002IJH125>. 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

The most widely used method for the preparation of [l,2,4]triazolo[3,4-A][l,3,4]thiadiazoles 85 employs 4-amino-5-thio-4/7-[l,2,4]triazoles 83 or 4-amino[l,2,4]-triazole-5(47T)-thiones 84 as starting materials. The reaction of the triazoles 83 or 84 with carbonic acid derivatives furnishes [l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles with a heteroatom substituent (N, O, S) at position 6 the O- and S-functions are formulated as 6-hydroxy and 6-thio derivatives 85a or as thiadiazol-(5/7)6-ones and -thiadiazole-(577)6-thiones 85b, respectively reaction with carboxylic acid derivatives provides the 6-substituted-[l,2,4]triazolo[3,4-4][l,3,4]-thiadiazoles 85c (Equation 20 Table 3). 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

An overall strategy for the synthesis of 1,2,5-thiadiazoles from the acyclic N-C-C-N grouping and sulfur monochloride was proposed in 1967 (1967JOC2823). The N-C function could vary over oxidation levels of amine, imine, cyanide, oxime and nitroso derivatives. Aliphatic and aromatic compounds having these functionalities in many combinations reacted with sulfur monochloride to form appropriately substituted or fused 1,2,5-thiadiazoles. Based on this model, a large... 

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). 

This method is also useful for the functionalization of substituents at C(5) during 1,2,3-thiadiazole formation (Equation (13)). The ratio of thiadiazoles and their sulfine derivatives is a function of both the acyl and alkylidine groups of the hydrazone starting materials <84JOC4773>. 

Alkylation of 5-amino-1,2,4-thiadiazoles (17) with methyl iodide leads to N-4 derivatives of type (18) which undergo a Dimroth rearrangement to (110) on warming in ethanol when R = H (Scheme 26). When R = methyl, phenyl, or benzyl the reaction is severly hindered <84CHEC-I(6)463>. In contrast, benzhydryl and trityl chlorides (which are harder electrophiles) alkylate (17) at the 5-amino function to give compounds of type (109) (Scheme 26). 

Amino-l,2,4-thiadiazoles fail to yield nitrosamines under the usual conditions but the more stable 5-nitrosamines (123) can be prepared easily (Scheme 29) <65ahc(5)H9>. The nitrosamino group in 5-nitrosamino-l,2,4-thiadiazoles (123) is fairly reactive and may be converted into various functional groups with the appropriate reagents <84CHEC-I(6)463>. 

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