Hurd-Mori cyclization

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. ... 

The Hurd-Mori cyclization and Lalezari cyclization of a-methylene ketones are by far the most widely used routes to 1,2,3-thiadiazole and 1,2,3-selenodiazole, respectively.This approach has been applied in the synthesis of a variety of 1,2,3-thiadiazoles 129 (13JHC630) andl31 (13OT4038) from the corresponding hydrazones. Thiadiazoles 132, derived from 131, can be effectively converted to benzothiophene derivatives (see Section 5.5.4.2). 

Thiadiazoles encompass five-membered aromatic compounds with two nitrogen atoms and a sulfur atom. The chemistry of these class of molecules has been extensively studied and reviewed. The 1,2,3-thiadiazoles are known to display a wide variety of biological activities, and can be accessed by the Hurd-Mori cyclization of hydrazones with thionyl chloride. Although 1,2,3-thiadiazole belongs to a well-studied class of heterocycles, most of the substituted 1,2,3-thiadiazoles are synthesized from then-acyclic counterparts instead of functionalization of the 1,2,3-thiadiazole. 

Diazotization of aminothiophene and the Hurd-Mori reaction <1955JA5359> are two popular methods for synthesis of thieno[2,3- -l,2,3-thiadiazoles. Amine 128 gave only a poor yield of methyl thieno[2,3-/7]-l,2,3-thiadiazole-6-carbox-ylate 131a when subjected to acidic diazotization conditions (Scheme 14). The fully substituted thiophenes 129 and 126 underwent cyclization in much greater yields under similar conditions <1999M573>. Protected amines 127 and 130 also gave a better yield of the cyclized product than the unprotected amine 128 <1999JHC761>. 

Applications of Lalezari and Hurd-Mori reactions are also highlighted in the synthesis of a new class of 1,2,3-selenadiazoles 243 and 1,2,3-thiadiazoles 244 <07JHC1165>. Reaction of sulfonylacetate 241 with semicarbazide 237 gives semicarbazone 242, and oxidative cyclization of 242 with selenium dioxide in acetic acid at 60-70 °C furnishes selenadiazole 243. Compound 242 also undergoes Hurd-Mori reaction with excess thionyl chloride to give thiadiazole 244. 

The previously unreported 1,2,3-thiadiazole-4-thiolate (33) was synthesized by an extension of Hurd and Mori s cyclization procedure <88JHC1873> in which methyl dithiopropionate was converted to intermediate (32). This was cyclized with thionyl chloride to the 1,2,3-thiadiazole and the protecting group removed to give thiolate (33) (Scheme 10). 

Since the isolation of reaction intermediate (32 equation 30) by Hurd and Mori there has been no further work to illustrate the mechanism for its formation, nor has there been any further work to unravel the mechanism for its conversion to product under the reaction conditions. Only recently for hydrazone precursor (33), where R = Me and R1 = alkyl or aryl groups, it has been reported that cyclization predominates at the more reactive methylene site rather than the methyl site (81CB2938). Other workers have shown that when sulfur dichloride (SC12) is substituted for thionyl chloride, 1,2,3-thiadiazoles are still formed from a-methylene hydrazones. In several instances sulfur dichloride afforded products in higher yield than did thionyl chloride (81G289). 

---