Orthogonal sp³ C₁–H and N–H Bond Functionalization of 1,2,3,4-Tetrahydroisoquinolines via the Ugi Four-Component Reaction

^◊ Ji-Min Yan and Qi-Fan Bai contributed equally to this work.

Abstract

A new protocol for orthogonal sp³ C₁–H and N–H bond functionalization of 1,2,3,4-tetrahydroisoquinolines has been established via the Ugi four-component reaction with aldehydes, isonitriles, and carboxylic acids. It was revealed that only the N–H bond could be functionalized when the reaction was performed in acetonitrile at room temperature; however, when the reaction was carried out in toluene at 80 °C, redox-neutral sp³ C₁–H bond functionalization of 1,2,3,4-tetrahydroisoquinolines was achieved. Differing from the common role of carboxylic acid as a promoter in redox-neutral amine α-functionalization, the carboxylic acid employed herein is also a reactant. The orthogonal process is compatible with various substrates and provides an appealing­ access to a library of structurally diverse 1,2,3,4-tetrahydro­isoquinolines.

Key words

sp³ C–H functionalization - Ugi reaction - redox-neutral reaction - 1,2,3,4-tetrahydroisoquinolines - iminium isomerization

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