Choline Chloride/Urea – Promoted Iodocyclization of 3-Alkynylthiophene-2-carboxamides: A Green Synthesis of 4-Iodo-7H-thieno[2,3-c]pyran-7-imines and Their Coupling Reactions in Deep Eutectic Solvents

A green approach to a previously unknown class of iodine-containing heterocycles, namely 4-iodo-7H-thieno[2,3-c]pyran-7-imines, by iodocyclization of readily available 3-alkynylthiophene-2-carboxamides in a deep eutectic solvent (DES) as both solvent and promoter, has been developed. We have found that, while the reaction with I₂ and K₂CO₃ as the base in a classical volatile organic solvent proceeded to a very limited extent, the iodocyclization was successful when performed under neutral conditions in choline chloride/urea (1/2 molar ratio). Moreover, the DES could be efficiently recycled several times without a significant decrease in the product yield. The promoting effect of the DES has been studied in detail using computational methods. The possibility to further decorate the newly synthesized iodinated heterocycles in a DES solvent (choline chloride/glycerol, 1/2 molar ratio, for Sonogashira reaction, and betaine/glycerol, 1/2 molar ratio, for Suzuki-Miyaura coupling) has been successfully assessed, and the solvent-catalyst system was recycled several times without appreciable loss of activity. A computational study on the effect of the betaine/glycerol system in the Suzuki–Miyaura cross-coupling has also been carried out, while the structures of representative products have been confirmed by X-ray diffraction analysis.