Recent Advances in the Gewald Reaction: A Valuable Tool for the Synthesis of Thiophene Derivatives

Since its first report in 1961, the Gewald reaction has evolved as a powerful tool for the construction of the 2-aminothiophene framework. Toward the synthesis of 2-aminothiophenes, in the past 4-5 decades, a plethora of publications have appeared in the scientific literature, but Gewald's strategy remains dominant among other methods due to its simplicity and the development of its different versions. This review showcases recent advances in Gewald methodologies for the fabrication of thiophene derivatives over the past one and a half decades, since the last update was reviewed. The present comprehensive manuscript, besides covering the traditional Gewald procedures, also exposes modern developments-for example, microwave and ultrasound-assisted synthesis, and the use of ionic liquids (ILs), deep eutectic solvents (DESs), and phase-transfer catalysts (PTCs). Herein, we have not only illustrated the details of the advancements in this still-emerging field, but have also illustrated its superiority, simplicity, and advantages in comparison with the existing methods.