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

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 presence of ytterbium triflate. Moreover, apart all reactants could be deployed almost equimolar ratios, which increases atom economy sequence. For mechanistic rationalization, concluding aza-anellation investigated by DFT calculations on potential intermediates corresponding activation energies, revealing that proceeds via ene reaction rather than electrocyclization.