Hurd-Mori reaction

The mechanism of the Hurd-Mori reaction has been discussed extensively in the review by Stanetty. The mechanism of the reaction was initially postulated by Hurd-Mori based on the isolation of intermediate 10. This intermediate was shown to transform into the desired thiadiazole upon heating in ethanol, either with or without acid. The reaction was thought to proceed via the four-membered intermediate 11, which would release the volatile ethylformate as a by-product. In 1995, Kobori and co-workers were able to isolate and determine crystallographically a very similar intermediate structure to 10 in their mechanistic studies of the reaction. ... 

The application of the Hurd-Mori reaction to the preparation of some potential fungicides from chiral hydrazones 50 and 52 shows that no racemization occurs under the reaction conditions... 

The Hurd-Mori reaction,where a tosylhydrazone is converted by thionyl chloride to the corresponding thiadiazole, involves the formation of a 1,2,3-thiadiazole-3,3-dioxide. In one example, this type of compound was isolated and subsequently deoxygenated with thiourea <1991PS175>. There have been no further reports of S-linked sulfoxide or sulfone derivatives of 1,2,3-thiadiazoles since the publication of CHEC-II(1996). 

Examples of the synthesis of 1,2,3-thiadiazoles using the Hurd-Mori reaction are prevalent in the most recent literature <2004RJ099, 2003JHC427, 2003JOC1947, 2003JHC925, 2003FA63, 2003JHC149>. 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

Reaction of 2-hydroxyacetophenones in the Hurd-Mori reaction led to a range of 4-(o-hydroxyaryl)-l,2,3-thiadia-zoles 56. Subsequent treatment of these derivatives with base and an alkyl halide led to the formation of 2-benzofuransulfanyl derivatives 57 (Scheme 6) <2000T3933>. 

The synthesis of the benzoimidazo[l,2- ][l,2,3]thiadiazole 61 can be explained using the same mechanistic model to that used for the Hurd-Mori reaction. The amino benzimidazole 58 when treated with thionyl chloride at reflux affords the benzoimidazo[l,2-r ][l,2,3]thiadiazole 61. If, however, the reactant 58 is treated with thionyl chloride at room temperature, the chloromethyl derivative 59 is formed. This derivative was then transformed into product 61 on reflux with thionyl chloride. The proposed mechanism for the formation of product 61 is for the initial formation of the sulfoxide 60, which then undergoes a Pummerer-like rearrangement, followed by loss of SO2 and HC1 to give the c-fused 1,2,3-thiadiazole 61 (Scheme 7) <2003TL6635>. 

An unexpected ring contraction reaction has been reported. The attempted hydrolysis of 3-methoxycarbonyl-177-thieno[2,3-< ][l,3,4]thiadiazine 4,4-dioxide 77 under acidic conditions gave the ring-contracted thieno[2,3-<7][l,2,3]thia-diazole 78 instead of the expected carboxylic acid (Equation 24). A similar mechanism to the Hurd-Mori reaction has been proposed for this transformation <2000JHC191>. 

Pyrrolidine semicarbazones 108a and 108b, treated with excess thionyl chloride (Hurd-Mori reaction) in chloroform, produced pyrrolothiadiazoles 109a and 109b, respectively (Equation 16). 

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>. 

Table 2 Effects of temperature on Hurd-Mori reaction...

As in the synthesis of thieno[2,3-,7]-l,2,3-thiadiazoles, thieno[3,2-.7 -l,2,3-thiadiazoles are made using diazotization of aminothio-substituted thiophenes and by Hurd-Mori reaction of hydrazones. Diazotization of compound 134 with NaN02 in AcOH/HCl at 0°C produced methyl thieno[3,2- / -l,2,3-thiadiazole-5-carboxylate 135 but in only low yield. Hydrazone tautomer 136 treated with excess SOCI2 in CH2CI2 at room temperature gave dimethyl thieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 137 and dimethyl 5,6-dihydrothieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 138 in a ratio of 3 2 (Equations 20 and 21) <1998H(48)259>. 

Tetrahydro[4,5]benzothieno[3,2-r/ [l,2,3]thiadiazole dicarboxylates 140a-c were prepared by the standard Hurd-Mori reaction of the corresponding semicarbazones 139a-c (Equation 22) <1998IJH259>. Compounds 141a-c, under similar reaction conditions, produced benzothieno[2,3- / -l, 2, 3 -thiadiazoles 142a-c (Equation 23) <1999IJB308>. 

Hurd-Mori reaction on hydrazone 147 produced methyl thieno[3,4-r/ -l,2,3-thiadiazole-6-carboxylate 148 along with methyl thieno[3,2-r7 -l,2,3-thiadiazole-5-carboxylate 135 and methyl 5,6-dihydrothieno[3,2-r7 -l,2,3-thiadiazole-5-carboxylate 149 in a ratio of 1 2.6 0.5 (72% combined yield). Conversion of compound 149 to the fully aromatized 135 is accomplished by treatment with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in refluxing benzene for 10 days (Scheme 15). A modified reaction mechanism for the Hurd-Mori reaction is also presented here <1998H(48)259>. 

Various common routes have been used for the synthesis of many of the compounds described. Those mentioned here follow on from those reported in the previous volume <1996CHEC-II(7)89>. The Hurd-Mori reaction of hydrazones with excess thionyl chloride is the most widely used method for preparation of 1,2 3-thiadiazoles <2005MOL367, 1998J(P1)853, 1998IJH259, 1999IJB308, 1998H(48)259>. 

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 Hurd-Mori reaction is frequently used in the synthesis of 1,2,3-thiadieizoles. For example, condensation of methyl ester of cyclopentanonopimaric acid 224 with semicarbazide gives semicarbazone 225, which, upon exposure to thionyl chloride, generates 1,2,3-thidiazolo terpenoid 226 <04RJOC99>. 

A series of tricyclic annelated 1,2,3-thiadiazoles (76) have been prepared using the Hurd-Mori reaction as the key step in the sequence. Thus, treatment of the oxoesters (74) with p-toluenesulphonyl hydrazine gave hydrazones (75), which upon reaction with thionyl chloride produced fully aromatised tricycles (76) <96JHC1759>. 

The most common, convenient and versatile preparation of the 1,2,3-thiadiazole ring system is undoubtedly the Hurd-Mori reaction. This was again widely reported in the literature during 2001 e.g., <01MI173,01JOC4045 and 01SL557>. 

The synthesis of fluorinated 1,2,3-thiadiazole was not widely investigated and is essentially related to the general scheme of the Hurd-Mori reaction [55], i.e. the treatment of hydrazone derivatives with thionyl chloride (Scheme 31). 

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