Sustainable Synthesis of Tacrine and Analogues for Alzheimer’s Disease in Deep Eutectic Solvents: A Green Approach

N-heterocyclic compounds exhibit diverse pharmacological properties and serve as constituents of many biologically important molecules, including vitamins, nucleic acids, pharmaceuticals, antibiotics, and agrochemicals.1 Traditionally, the preparation of N-heterocyclic compounds relies on energy-intensive conditions with long reaction times (16–48 h), toxic volatile organic compounds (e.g., POCl3, toluene), and laborious work-up procedures based on volatile organic compounds (VOCs) (e.g., CHCl3, Et2O, MeOH).2 Unfortunately, these solvents significantly contribute to the environmental impact of chemical industries and laboratories, resulting in substantial waste generation.3 A promising solution to address these sustainability concerns lies in the adoption of Deep Eutectic Solvents (DESs), a new class of environmentally friendly solvents.4 Over the last decade, we have explored valuable sustainable methodologies for the synthesis of heterocycles with anti-inflammatory or antiproliferative properties, such as functionalized triazoles,5 pyrimidines, imidazoles,6 and tetrahydropyran derivatives.7 In this communication, we introduce a green synthetic protocol for the synthesis of tacrine and analogues, which are utilized in the treatment of neurological disorders, achieving yields of 90–95%. We employ Type I and IV Lewis Acid Lewis Acid DESs (LADESs) as solvent and catalyst (Figure 1). Quantitative metrics confirm the eco-friendliness of these novel approaches.