1,2,3-Thiadiazoles, synthesis using thionyl chloride

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. 

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>. 

Usually, N-sulfinyl compounds (59) behave as thionyl transfer reagents, similar to, but milder than, thionyl chloride. For example, o-diamines with A-sulfinylbenzeneamine (59 R = Ph) afford fused 1,2,5-thiadiazoles, as in Scheme 8a.77 The advantage of using Af-sulfinyl compounds, rather than thionyl chloride itself, is that concomitant chlorinations and oxidations are avoided. This is of particular importance in the synthesis of 2,1-benzisothia-zoles (Section V,B,6). Singerman s reagent, N-sulfinylmethanesulfonamide (60) is especially valuable 78 it was used very successfully in the synthesis of a series of benzobis(isothiazoles).79... 

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 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. 

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. 

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>. 

Synthesis of the benzo[l,2-c 3,4-c ]bis[l,2,5]thiadiazole (509) required cyclization of diamine (508). Nitration of (505) led to 4-nitro-2,1,3-benzothiadiazole (506) in 95% yield. Amination of (506) with hydroxylamine in basic medium led to compound (507), immediately reduced to the diamino derivative (508). Ring closure of (508) with thionyl chloride and pyridine led to the benzo[l,2-c 3,4-c ]bis[l,2,5]thiadiazole (509) in 89% yield. Compound (509) has been successfully used in the synthesis of several fused tetracyclic compounds (Scheme 40) <75JHC829>. 

Commonly known as DTBT, the structural unit of 4,7-di(thiophene-2-yl)benzo[c][l,2,5]thiadiazole has been extensively used to construct D-A copolymers of small bandgaps. Shown in Scheme 15.6, the synthesis of DTBT starts with the cyclization of 1,2-diaminobenzene under thionyl chloride to form the central unit, benzothiadiazole (BT). This BT unit is then brominated... 

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