Consecutive Four-Component Coupling-Addition Aza-Anellation <i>Pictet</i>–<i>Spengler</i> Synthesis of Tetrahydro-<i>β</i>-Carbolines: An Optimized <i>Michael</i> Addition and Computational Study on the Aza-Anellation Step

Abstract

Starting from acid chlorides, alkynes, tryptamines, and acryloyl chloride, 21 densely substituted tetrahydro-β-carbolines were prepared in a four-component, one-pot reaction. In this study, the aza-Michael addition step to generate intermediate enaminones was optimized in the presence of ytterbium triflate. Moreover, apart from acryloyl chloride, all reactants could be deployed in almost equimolar ratios, which increases the atom economy of the sequence. For mechanistic rationalization, the concluding aza-anellation was investigated by DFT calculations on potential intermediates and corresponding activation energies, revealing that the aza-anellation proceeds via ene reaction rather than via electrocyclization.

Keywords

• aza-<i>Michael</i> addition
• tetrahydro-<i>β</i>-carbolines
• catalysis
• one-pot reaction
• multicomponent reaction
• ytterbium (III) triflate