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 in the presence of ytterbium t...

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Bibliographic Details
Published in:Organics (Basel) 2023-09, Vol.4 (3), p.313-332
Main Authors: Ries, Kai, Aouane, Françoise A., Müller, Thomas J. J.
Format: Article
Language:English
Subjects:
aza-Michael addition
Catalysis
Chemicals
Chromatography
multicomponent reaction
Nitrogen
one-pot reaction
Solvents
Temperature
tetrahydro-β-carbolines
ytterbium (III) triflate
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Summary: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.
ISSN:2673-401X
2673-401X
DOI:10.3390/org4030025