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Consecutive Four-Component Coupling-Addition-Aza-Anellation-Pictet-Spengler Synthesis of Tetrahydro-Beta-Carbolines – Optimized Michael Addition and Computational Study on the Aza-Anellation Step
Ries, K.; Aouane, F.A.; Müller, T.J.J. 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. Organics2023, 4, 313-332.
Ries, K.; Aouane, F.A.; Müller, T.J.J. 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. Organics 2023, 4, 313-332.
Ries, K.; Aouane, F.A.; Müller, T.J.J. 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. Organics2023, 4, 313-332.
Ries, K.; Aouane, F.A.; Müller, T.J.J. 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. Organics 2023, 4, 313-332.
Abstract
Starting from acid chlorides, alkynes, tryptamines, and acroyl chloride, 21 densely substituted tetrahydro-beta-carbolines are prepared in a four-component one-pot reaction. In this study, the aza-Michael addition step to generate intermediate enaminones is optimized in the presence of ytterbium triflate. Moreover, apart from acroyl chloride, all reactants can be deployed in almost equimolar ratios, which increases the atom economy of the sequence. For mechanistic rationali-zation, the concluding aza-anellation was investigated by DFT calculations on potential inter-mediates and corresponding activation energies, revealing that the aza-anellation rather pro-ceeds via ene-reaction than via electrocyclization.
Chemistry and Materials Science, Organic Chemistry
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