1,2,3,-Thiadiazoles

3-Thiadiazoles (57) are produced by the reaction of fV-substituted hydrazones (58 R1, R2 = alkyl, aryl, H R3 = acetyl, ester, tosylate, etc.) with thionyl chloride.67 

Furukawa, O. Miyashita, and S. Shima, Chem. Pharm. Bull. 24, 970 (1976). 

Meso-ionic 1,2,3-Thiadiazoles.— The action of thionyl choride on the meso-ionic 3-aryl-4-carboxymethylsydnones (14) unexpectedly produces high yields of 3-aryl-4,5-dichloro-l,2,3-thiadiazolium salts (15), also obtainable from (16) with phosphorus oxychloride. On oxidation with hydrogen peroxide, the salts (15) are converted into novel meso-ionic 1,2,3-thiadiazoles of structure (17).  

Convtrsion into 1,2,3-Thiadiazoles. Diazotization of 5-amino-3-methyl-isothkzole, followed by treatment with aqueous thiourea and oxidation of the iitermediate thiol, yields the expected bis-(3-methylisothiazol-5-yl) disulphide. In contrast, 4-amino-3-methylisothiazole (70 = Me, 

R = H) is converted by the same sequence of reactions into 4-acetyl- 

3- thiadiazole (71), possibly by the mechanism outlined in the reaction scheme. 4-Aminoisothiazoles lacking the 3-methyl group [e.g. (70 Ri = R8 = H R = H, R = Me)] afford the corresponding 4-formyl- 

MetaUation.— In the course of a wider research programme on the metal-lation of five-membered heteroaromatic systems, Micetich has extended the work of Caton et al. on the lithiation of isothiazoles. Unlike 3,5-dimethylisoxazole, which undergoes chiefly lateral lithiation to the 5-lithiomethyl derivative capable of furnishing heteroarylacetic acids (HetCHa HetCHaLi - HetCHaCOaH), 3,5-dimethylisothiazole (72) is 

Saunders, The Aromatic Diazo-compounds and their Technical Applications , Edward Arnold and Co., London, 1949, pp. 324— 9 D. Kealy and H. Freiser, Talanta, 1966,13, 1381. 

A practical a-heteroarylation of simple esters or amides has been developed via nucleophilic aromatic substitution. Exposure of chlorothiadiazoles 317 and 319 to NaHMDS and tert-butyl acetate or iV-dimethylacetamide leads to the formation of functionalized 

Direct electrophilic silylation of thiadiazole 321 with bromotrimethylsilane (TMSBr) under basic conditions provides easy access to C-silyl thiadiazole 322, which can serve as a synthetic equivalent of an organometallic intermediate or a silyl-protected azole 06S 1279 . 

Reaction of A,A-dimcthylsullamoyl aziridines 323 and 325 with primary amines furnishes substituted 1,2,5-thiadiazolidine 1,1-dioxides 324 and 326, respectively, in a regioselective manner 06SL833 . Aziridine 325 is made from ( I /t,6,S ,Z)-bicyclo[4.2. l]non-3-en-9-one in two steps /V,/V-dimethylsulfamoyl imine formation using dimethylsulfamide and subsequent reaction with trimethylsulfoxonium ylide. The product from the reaction with 4-methoxy-benzyl amine can be subsequently manipulated (debenzylation and derivatization) to give the alternative nitrogen substitution pattern in a controlled manner. 

Cyclic sulfamides 326 serve as key intermediates in the synthesis of a series of potent and selective y-secretase inhibitors with potential for the treatment of Alzheimer s disease. 

Some typical rearrangements in this series have been reviewed in a different context, concerning 1,2,4-thiadiazole chemistry [82AHC(32)285]. 5-Amidinothiadiazoles 240, obtainable from the 5-amino-3-methyl-l, 2,4- 

In the case of the thiadiazole 240 (R = Me), the occurrence of a bond-switch is verified by N-labeling experiments. Thus, the reaction between the imidate 243 and NH3 gives a mixture of both thiadiazoles 244 and 245, which are characterized by N in the amidine side-chain or in the 

252 (Ar = Ph) reacts with carbon disulfide to give directly the dithiazole 

257 and alkynes also give addition products (89BCJ211). On the other hand, addition but no rearrangement products are obtained in a reaction between the imino-l,3,4-thiadiazoline 260 or iminothiazolines 261 with activated acetylenes. Generally, in the reaction of imino compounds 262 with activated acetylenes, rearrangement into thiazoles 259 via 266 is 

The moleeular geometry and eleetronie strueture of 3,4-diaza-l,6,6aiC -trithia-pentalene 85a has been studied and eompared with the nitrogen-free l,6,6aiC -trithiapentalene [98PS35]. Whereas Hartree-Foek ealeulations prediet 85b and 85c to be valenee isomers, DFT and MP2 ealeulations prediet the minimum to be of C2u symmetry eorresponding to 85a (Seheme 56). 

Consequently, structures 85b and 85c must be considered resonance structures rather than valence isomers. Hyperfine coupling constants were computed for a series of dithiazolyl radicals and related compounds [96MRC913]. An absolute mean deviation of 0.12 mT with respect to experimental data is reported for 10 sulfur hyperfine coupling constants obtained from UB3-LYP/TZVP calculations. 

According toB3-LYP/6-31G calculations, the triplet state of 88 is -5.1 kcal/ mol lower in energy than the zwitterionic singlet state. The order is reversed for the pyridine-bridged 89. Likewise, for l,l, 2,2, 3,3 -tetrathiadiazafulvalene, the state was found to be more stable than the state [99JA6657]. However, one should keep in mind that B3-LYP calculations often lead to an exaggerated stabilization of triplet states. 

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

Several cases of photochemically induced permutations of ring-atoms have been reported for six-membered ring heterocycles. However, these reactions are rarely useful for a synthetic strategy and in most cases such permutations have been investigated only for mechanistic purposes and academic questions [3, 5], 

4-thiadiazole, the lower electron supply from the sulfur compared to the oxygen equivalent accounts for the ortho meta para rate ratio in the phenyl ring of 1 3 2 in the 2-phenyl derivative (7.56) no substitution took place at the 5-position (53JPJ701). 

Nakamori, Y. Sato, and T. Kasai, Nippon Kagaku Kaishi, 1982, 98 Chem. Abstr., 1982, 96, 104 156). 

Bellesia, R. Grandi, U. M. Pagnoni, and R. Trave, Gazz. Chim. Ital., 1981, 111, 289. 

R = alkyl) have been obtained from a thermal rearrangement of the compounds (194 R = NR C02R, R = and various 5-substituted derivatives of 

Benzo-l,2,3-thiadiazole reacts with phenyl isothiocyanate to give the 2-phenylimino-l,3-benzodithiole (200), which was not isolated but converted into the quaternary ammonium salt with methyl iodide. A series of 4,6-dialkyl- 

3- thiadiazolo[4,5- /]pyrimidine-5,7-diones (201) has been prepared from the reactions of 6-hydrazino-uracils either with alkyl thiocyanates (to give the thiosemicarbazides, which cyclized on treatment with bromine) or with thionyl chloride.  

4- Thiadiazoles.—Synthesis. The reaction between benzoyl isothiocyanate and alkyl azides RN3 gives a mixture of the 1,2,4-thiadiazole (203 R = NRCOPh, R = SCOPh) and the 1,2,4-dithiazole (204). The oxidation of the aryl thioamides ArCSNH2 with nitrous acid gives a mixture of (203 R = R = Ar) and ArCN, but, when Ar was 2,6-dichlorophenyl, the aryl isothiocyanate was isolated.Oxidation of the substituted amidines, e.g. PhC(S)N=CPhNHPr, 

Lalezari, A. Shafiee, and S. Sadeghi-Milani, J. Heterocycl. Chem., 1979, 16, 1405. 

---

Although unsubstituted 1,2,5-thiadiazole is stable on heating at 220 °C, 3,4-diphenyl-1,2,5-thiadiazole 1,1-dioxide (26) decomposes into benzonitrile and sulfur dioxide at 250 °C (68AHC(9)107). 

In contrast to thiazoles, certain isothiazoles and benzisothiazoles have been directly oxidized to sulfoxides and sulfones. 4,5-Diphenyl-l,2,3-thiadiazole is converted by peracid into the trioxide (146). Although 1,2,5-thiadiazole 1,1-dioxides are known, they cannot be prepared in good yield by direct oxidation, which usually gives sulfate ion analogous to the results obtained with 1,2,4- and 1,3,4-thiadiazoles (68AHC 9)107). 

Isothiazoles are reductively desulfurized by Raney nickel, e.g. as in Scheme 31 (72AHC(l4)l). 1,2,5-Thiadiazoles are subject to reductive cleavage by zinc in acid, sodium in alcohol, or Raney nickel, e.g. Scheme 32 (68AHC(9)107). 

The above examples illustrate reactions at an electron-deficient carbon atom. Other 1,1-bielectrophiles allow the direct introduction of a heteroatom into the resultant heterocycle. The most widely applicable and versatile methods for the synthesis of 1,2,5-thiadiazoles and 1,2,5-selenadiazole rely on this approach. 

---