Synthesis of Thiazolo[5,4-d]thiazoles in an Eco-Friendly L-Proline-Ethylene Glycol Mixture.

Abstract

The hazardousness of solvents used in synthetic organic chemistry is well established. In this context, it is relevant to search for safer and greener alternatives. Within the last decades, deep eutectic solvents have been considered as possible and promising alternatives. Consequently, this study aims at using deep eutectic solvents to synthesize an emerging class of heteroaromatic compounds named thiazolo[5,4-d]thiazoles, for which interest is growing in the field of organics, electronics, and biology. To address this challenge, we developed a straightforward synthetic protocol consisting of condensing dithiooxamide and aromatic aldehyde in deep eutectic solvents to yield the desired thiazolo[5,4-d]thiazole without further purification. The first hit was obtained with the well-known L-proline:glycerol (1:2) mixture at 130 °C. However, dithiooxamide is degraded under these conditions, leading to the formation of impurities that may arise from the consequent amount of reactive L-proline. Reaction conditions were optimized by modifying the deep eutectic solvent nature and proportions, applying various temperatures, changing the activation and heating source, or adding auxiliary oxidants. As a consequence, eight thiazolo[5,4-d]thiazoles were synthesized in equal or better yields (20 to 75%) than the reported procedure under safe and eco-friendly conditions in a mixture of L-proline and ethylene glycol (1:50) with sodium metabisulfite at 130 °C for one hour.