A general aqueous synthetic strategy towards 1-benzylTHIQs enabled by umpolung hydrazone

Abstract

Primarily found in the plants, 1-benzyltetrahydroisoquinoline (1-benzylTHIQ) alkaloids are a diverse class of N-heterocyclic natural products with biological activity against various infectious diseases and neurodegenerative pathologies. Traditionally, 1-benzylTHIQs are synthesized using commercially inaccessible pre-functionalized materials or hazardous organometallic reagents, making their synthesis challenging. Herein, we developed an environmentally benign synthetic strategy to synthesize 1-benzylTHIQs, which aligns with green chemistry principles. This method utilizes abundant, renewable aldehydes as sustainable alkyl carbanion equivalents, thereby eliminating the use of highly reactive or hazardous organometallic reagents. This reaction is catalyzed by ruthenium, using water as a greener solvent, eliminating the need for organic solvents, thereby reducing its environmental impact. Moreover, only N2 and H2O are produced as by-products, which minimizes waste generation. A diverse array of substituted 1-benzylTHIQs was synthesized, showing good functional group tolerance (without the need to protect the functional groups) and resulting in moderate to excellent yields. The sustainability of our method was further demonstrated through the synthesis of natural 1-benzylTHIQ-based alkaloids and late-stage functionalization of pharmacologically relevant molecules.