Synthesis of sulfur-containing heterocycles via disulfide intermediates

Nitrogen- and sulfur-containing heterocyclic compounds are of great interest to the scientific community not only from a synthetic point of view but also from a biological perspective because these compounds frequently exhibit a wide range of biological activities. These heterocyclic scaffolds are often present in natural products, agrochemicals, and even commercially available drugs. While a range of synthesis methods are available for many heterocycles, certain scaffolds and substitution patterns lack generally applicable synthetic pathways. For example, there are many routes to prepare 1,2,4-triazole or benzothiazole derivatives; however, access to systems of 1,2,4-triazoles fused with benzothiazoles is provided mainly via one lengthy synthetic pathway. Among these tricyclic aromatic heterocycles are the neutral benzo4,5thiazolo2,3-c1,2,4triazoles, a structural motif that occurs in several bioactive molecules, as well as the benzo4,5thiazolo2,3-c1,2,4triazol-1-ium salts for which, to the best of our knowledge, only three articles with a combined total of five structures have been documented. On the other hand, more examples of synthetic pathways can be found for the neutral species; however, these methods have disadvantages such as long reaction times and limited substrate scopes. We explored novel and efficient methods for the synthesis of substituted benzo4,5thiazolo2,3-c1,2,4triazoles salts and the related neutral benzo4,5thiazolo2,3-c1,2,4triazoles. These tricyclic heterocycles are synthesized via the oxidation of a mercaptophenyl group to its corresponding disulfide, resulting in a C-S bond formation through an intramolecular ring closure. These new synthetic approaches are widely applicable to a variety of substituted 1,2,4-triazoles and triazolium salts. The desired products can be obtained after short reaction times in good to excellent isolated yields. Scaling up to several grams was possible and the final product could be isolated in similar or better yields. Additionally, the final tricyclic products could be further oxidized to sulfones, which are also valuable because of their medical importance.