Title : General aqueous synthetic strategy towards 1-benzylTHIQs enabled by umpolung hydrazone
Abstract:
1-Benzyl tetrahydroisoquinolines (1-benzylTHIQs) are important structural motifs found in numerous bioactive natural products and pharmaceutical compounds. Despite their significance, conventional approaches to these compounds often rely on prefunctionalized starting materials, hazardous organometallic reagents, strong acids, and organic solvents, limiting their efficiency and sustainability. Developing practical and environmentally benign methods for the C1-functionalization of tetrahydroisoquinolines therefore remains an important challenge. Herein, we report a ruthenium-catalyzed umpolung strategy for the synthesis of 1- benzylTHIQs from readily accessible 3,4-dihydroisoquinolines (3,4-DHIQs) and aldehydederived hydrazones. This approach utilizes hydrazones as Hydrazone Organometallic Equivalents (HOME), enabling carbon–carbon bond formation without the preparation or use of preformed organometallic reagents. Under catalytic conditions in water, aldehyde hydrazones function as carbon nucleophile equivalents and undergo addition to 3,4-DHIQs to furnish structurally diverse 1-benzylTHIQ derivatives. The methodology offers several advantages in terms of sustainability and operational simplicity. Water serves as the reaction medium, avoiding the use of conventional organic solvents during the transformation. The use of hydrazones circumvents highly reactive and moisture-sensitive organometallic reagents and their associated metal-containing waste. Moreover, the transformation proceeds with the formation of nitrogen gas and water as benign by-products, contributing to efficient waste minimization. The reaction demonstrates broad substrate scope and good functional-group tolerance, enabling the synthesis of diverse substituted 1-benzylTHIQs in moderate to excellent yields without requiring protecting groups. The synthetic utility of this methodology was further demonstrated through the synthesis of naturally occurring 1-benzylTHIQ-based alkaloids and the late-stage functionalization of pharmacologically relevant molecules. Overall, this work establishes hydrazones as sustainable carbon nucleophile equivalents and provides an environmentally benign platform for accessing valuable C1-functionalized tetrahydroisoquinoline architectures.
