Employing Mechanochemistry in the Synthesis of N-Ibuprofen-Substituted 1,2,3,4-Tetrahydroisoquinolines ^†

Abstract

Mechanochemistry has emerged as a potential alternative for organic transformations, leveraging substrate availability, stability, and reduced solvent use. Its high efficiency and eco-friendly profile have garnered significant attention, particularly in the pharmaceutical industry, where it is hailed as the most promising environmentally friendly method for organic synthesis. This approach harnesses mechanical energy to stimulate or accelerate chemical changes, offering a green and effective means to obtain organic molecules. We employed an innovative green and eco-friendly approach—mechanochemical, solvent-free, and heterogeneously catalyzed—to synthesize a series of new biofunctional hybrid molecules, specifically derivatives of biologically active 1,2,3,4-tetrahydroisoquinoline alkaloids. Our method involves a mechanochemically driven intramolecular α-amidoalkylation reaction. To facilitate this reaction under acidic conditions, we successfully utilized polyphosphoric acid on silica as a heterogeneous catalyst. This approach enables the rapid and straightforward synthesis of novel compounds without the generation of byproducts or waste. All newly obtained bio-functional hybrid compounds were fully characterized via ¹H, ¹³C NMR, UV, and mass spectral data. In our quest for environmentally sustainable synthesis methods, we made a significant breakthrough by synthesizing a series of innovative N-ibuprofen-substituted 1,2,3,4-tetrahydroisoquinolines through solvent-free mechanosynthesis. These novel derivatives offer exciting prospects for studying their biological properties and investigating correlations between structure and activity.