Synthesis of N-Flurbiprofen-Substituted 1,2,3,4-Tetrahydroisoquinolines ^†

Abstract

Isoquinoline alkaloids constitute a substantial category of natural products, among which 1,2,3,4-tetrahydroisoquinoline (THIQ) holds significance. THIQ-based compounds, whether natural or synthetic, showcase a wide array of biological activities, demonstrating efficacy against diverse infectious pathogens and neurodegenerative disorders. Consequently, THIQ heterocyclic structures have garnered considerable interest within the scientific realm, driving the exploration and synthesis of novel THIQ derivatives with notable biological potential. In contrast, flurbiprofen falls under the category of nonsteroidal anti-inflammatory drugs (NSAIDs) and demonstrates both antipyretic and analgesic effects. Its potential extends beyond mere pain relief; it has been suggested for both local and systemic applications, such as inhibiting colon tumor growth and platelet aggregation. In our research, we focus on synthesizing novel N-flurbiprofen-substituted 1,2,3,4-tetrahydroisoquinolines. We explore novel methods for the amide cyclization, investigating the feasibility of utilizing new environmentally friendly reagents. Specifically, we examine the efficacy of strong protic acids that are immobilized on a silica gel as heterogeneous acid catalysts in intramolecular α-amidoalkylation reactions. These acid-supported silica gel systems are pivotal in acid-catalyzed synthetic processes, emerging as preferred options for producing novel organic compounds, aligning with eco-friendly practices. Our interest lies in applying this heterogeneous acid system on a silica gel as a “heterogeneous catalyst” to synthesize isoquinoline derivatives of flurbiprofen and elucidate the relationship between their structure and activity. When investigating the intramolecular α-amidoalkylation reaction, we conduct multiple experiments to determine the ideal reaction conditions. This involves altering solvents and acid reagents while considering the acid-catalyzed nature of the reaction. The novel compounds were successfully synthesized through an intramolecular α-amidoalkylation reaction. This synthesis method involved heating the reactants at 80 °C in dichloroethane, supplemented with a heterogeneous acid catalyst, PPA/SiO₂. The obtained compounds underwent full spectral characterization using ¹H and ¹³C NMR, IR spectroscopy, and mass analysis.