Deep-Eutectic Solvents as sustainable media for the Pd-catalyzed direct arylation of thienyl-derivatives with (hetero)aromatic bromides under air

Among all the components of a chemical reaction, the solvent choice is often dictated by the solubility of the reagents and/or the medium polarity, but rarely by safety, health, and environmental (SH&E) criteria. Nevertheless, solvents represent most of the waste at the end of a classic batch reaction for the preparation of fine chemicals, both in terms of flammability and toxicity issues. As an alternative to traditional volatile organic solvents (VOCs), Deep-Eutectic Solvents (DESs) drew the attention of academic and industrial researchers for the possibility of using inexpensive and environmentally benign components, and their unique physicochemical properties like low volatility and high thermal stability. Applications of DESs as reaction media in organic transformations are many and various but still limited to a few and particular examples in the field of Pd-catalyzed direct arylation (DA), a kind of cross-coupling reaction that does not require the employment of any preformed organometallic reagent, but usually employs toxic and volatile solvents like toluene or N,N-dimethylacetamide. For these reasons, we developed a general synthetic protocol for the DA reaction of 3,4-ethylenedioxythiophene (EDOT) and other substituted thiophenes with (hetero)aromatic bromides in a mixture of choline chloride/glycerol (1:2), under air and in non-anhydrous conditions, with moderate-to-high yields. This DA protocol was demonstrated to tolerate many functional groups, like aldehydes, ketones, nitriles, esters, carboxylic acids, and nitro-groups. The sustainability of the protocol was established through calculations of green metrics, such as Eco-scale and E-factor, and compared with the literature, when possible. Remarkably, such a procedure can be successfully applied for the simple preparation of conjugated organic compounds with potential applications in optoelectronics and photovoltaics.