Hurd-Mori synthesis

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles s the most widely used method. The availability of aldehydes and ketones which can then be converted into their corresponding hydrazones and the high yields obtained on treatment of these hydrazones with thionyl chloride mean that this method should always be considered as the first choice. 

Thiadiazoles are prepared by cyclocondensation of tosylhydrazones derived from a-methylene ketones with thionyl chloride or sulfur dichloride Hurd-Mori synthesis) [148] ... 

The Hurd-Mori 1,2,3-thiadiazole synthesis is the reaction of thionyl chloride with the N-acylated or tosylated hydrazone derivatives 1 to provide the 1,2,3-thiadiazole 4 in one simple step. ... 

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. ... 

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>. 

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>. 

The most common, convenient and versatile synthesis of 1,2,3-thiadiazoles is undoubtedly the Hurd-Mori cyclisation of semicarbazones with thionyl chloride. This reaction was again widely reported in the literature during 2000 (e.g. <00ASJC687, 00JHC1325, 00T3933>. 

Sakya, S. M. Hurd-Mori 1,2,3-Thiadiazole Synthesis In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J. Corey, E. J. Wiley Sons Hoboken, NJ, 2005, 199—206. (Review). 

Scheme 12 shows synthesis of 1,2,3-thiadiazoles by the Wolff, Hurd-Mori and Pechmann-Nold methods. Pechmann s and Wolffs are the oldest of the methods. The Pechmann-Nold synthesis involves the [3 + 2] cycloaddition of diazo-compounds to isothiocyanates or thiocarbonyl compounds (modified Pechmann synthesis). The use of thiocarbonyl compounds in the [3 + 2] cycloaddition step has broadened the scope of this reaction and made the starting materials more readily accessible. Wolffs method requires the synthesis of diazoketones that are treated with a thionating reagent to produce 1,2,3-thiadiazoles. With the development of new methods of diazotransfer reactions, the diazoketone precursors have become easily attainable and with further attention to the thionating reagents, this reaction is also useful for the synthesis of 1,2,3-thiadiazoles. 

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>. 

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>. 

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 versatile synthesis of a series of novel 4-substituted 1,2,3-thiadiazoles 88 not easily obtained by other methods was described by Filippone et al. The final step in the preparation of 88 involved Hurd-Mori cyclisation of a-substituted hydrazones 87 using thionyl chloride at room temperature. Compounds of type 88 were attractive targets due to their potential use in medicinal and agricultural chemistry <01SL557>. 

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). 

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). 

In 1955, Hurd and Mori first described the preparation of 1,2,3-thiadiazole as an unexpected product from the reaction of the hydrazone 5 and thionyl chloride. The authors were attempting to prepare the six membered anhydride 7 in an analogous manner to the 5-membered anhydride 9, prepared from 8 using thionyl chloride. However, when the hydrazone 5 and thionyl chloride were mixed and heated at 60°C for 1 hour followed by cooling, the thiadiazole acid 6 precipitated out and was isolated by filtration. This serendipitous discovery led to a significant advance in the synthesis of thiadi azoles. 

The most common, convenient, and versatile synthesis of 1,2,3-thiadiazoles is the one discovered by Hurd and Mori in 1955 <1955JA5359>. This involves the reaction of thionyl chloride with acyl- or phenylsulfonylhydrazones or semicarbazones 54 that contain an a-methylene group this reaction affords a wide range of 1,2,3-thiadiazoles 55 (Equation 15). 

Although introduced over 40 years ago, Hurd and Mori s synthesis of 1,2,3-thiadiazoles remains the most widely used for the synthesis of 1,2,3-thiadiazoles. The simplicity of the method has contributed to its popularity. A variety of ketones and aldehydes have been converted into their corresponding hydrazones (tosyl and acyl), and thioamides have been converted into thio-carbazonate esters. The carbonyl derivatives are then treated with thionyl chloride to yield 1,2,3-thiadiazoles in high yields. When one is faced with the task of synthesizing new 1,2,3-thiadiazoles, Hurd and Mori s method should always receive attention. 

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