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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

Kai Ries, Françoise A. Aouane, Thomas J. J. Müller

Organics · pp. 313–332 · Published 28 Jun 2023

10.3390/org4030025

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.

Michael reaction Tryptamines Chemistry Trifluoromethanesulfonate Organic chemistry Catalysis Biochemistry Tryptamine

References (38)

  1. 1 Anastas, 2009, Green Chemistry: Principles and Practice [DOI]
  2. 2 Li, 2008, Green chemistry for chemical synthesis [DOI]
  3. 3 Sheldon, 2011, Fundamentals of green chemistry: Efficiency in reaction design [DOI]
  4. 4 Martínez, J., Cortés, J.F., and Miranda, R. (2022). Green Chemistry Metrics, A Review. Processes, 10. [DOI]
  5. 5 Ganem, 2009, Strategies for Innovation in Multicomponent Reaction Design [DOI]
  6. 6 Ugi, 1994, Multicomponent reactions in organic chemistry [DOI]
  7. 7 2006, Multi-component syntheses of heterocycles by transition-metal catalysis
  8. 8 Antonchick, 2011, The Pictet-Spengler Reaction in Nature and in Organic Chemistry [DOI]
  9. 9 Rommelspacher, 1977, Pharmacological properties of tetrahydronorharmane (Tryptoline) [DOI]
  10. 10 Daugan, 2003, The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 1: 5,6,11,11a-Tetrahydro-1H-imidazo[1‘,5‘:1,6]pyrido[3,4-b]indole-1,3(2H)-dione Analogues [DOI]
  11. 11 Hermkens, 1992, Antiviral and antitumor structure-activity relationship studies on tetracyclic eudistomines [DOI]
  12. 12 Skoutaa, 2012, Design and synthesis of Pictet–Spengler condensation products that exhibit oncogenic-RAS synthetic lethality and induce non-apoptotic cell death [DOI]
  13. 13 Karpov, 2005, A diversity oriented four-component approach to tetrahydro-β-carbolines initiated by Sonogashira coupling [DOI]
  14. 14 Karpov, 2004, A novel one-pot four-component access to tetrahydro-β-carbolines by a coupling-amination-aza-annulation-Pictet-Spengler sequence (CAAPS) [DOI]
  15. 15 Kofler, L.A. (1954). Präparative Mikromethoden in der Organischen Chemie: Mikroskopische Methoden, Springer.
  16. 16 Karpov, 2003, Facile One-Pot Coupling-Aminovinylation Approach to Push-Pull Chromophores:  Alkyne Activation by Sonogashira Coupling [DOI]
  17. 17 Xiao, 2022, Iron-Catalyzed One-Pot Synthesis of Indole-Tethered Tetrasubstituted Pyrroles and Their Transformations to Indolizino[8,7-b]indole Derivatives [DOI]
  18. 18 Santhi, 2016, N-Iodosuccinimide-Promoted Rapid Access to Indeno[1,2-c]pyrroles via [3+2] Annulation of Enamine-alkynes [DOI]
  19. 19 Shvartsberg, 1993, The cyclization of vicinal 1-amino-2-acylvinylated derivatives of aromatic amines [DOI]
  20. 20 Ding, 2006, Expanding the Scope of Lewis Acid Catalysis in Water:  Remarkable Ligand Acceleration of Aqueous Ytterbium Triflate Catalyzed Michael Addition Reactions [DOI]
  21. 21 Srivastava, 2003, Bismuth Nitrate-Catalyzed Versatile Michael Reactions [DOI]
  22. 22 Epifano, 2011, Ytterbium Triflate Promoted One-Pot Three Component Synthesis of 3,4,5-Trisubstituted-3,6-dihydro-2H-1,3-oxazines [DOI]
  23. 23 Keller, 1996, Ytterbium triflate catalyzed Michael additions of β-ketoesters in water [DOI]
  24. 24 Kobayashi, 1994, Rare Earth Metal Trifluoromethanesulfonates as Water-Tolerant Lewis Acid Catalysts in Organic Synthesis [DOI]
  25. 25 Pfau, 1985, Enantioselective Synthesis of quaternary Carbon Centers through Michael-Type Alkylation of Chiral Imines [DOI]
  26. 26 Desmaele, 1992, The asymmetric Michael addition reaction using chiral imines [DOI]
  27. 27 Barta, 1994, Asymmetric Formation of Quaternary Centers through Aza-Annulation of Chiral. beta.-Enamino Esters with Acrylate Derivatives [DOI]
  28. 28 Maryanoff, 2004, Cyclizations of N-Acyliminium Ions [DOI]
  29. 29 Hoffmann, 1969, The Ene Reaction [DOI]
  30. 30 2014, Ene Reactions with Carbon Enophiles—Metallo-Ene Reactions
  31. 31 Cossy, 1997, Intramolecular Ene Reactions. Stereo- and Enantioselective Synthesis of Spirolactams through Thermolysis of Enamino Carboxamides [DOI]
  32. 32 Zhang, 1998, The aza-ene reaction of heterocyclic ketene aminals with enones: An unusual and efficient formation of imidazo[1,2-a] pyridine and imidazo[1,2,3-ij][1,8]naphthyridine derivatives [DOI]
  33. 33 Zhang, 1999, The aza-ene reaction of heterocyclic ketene aminals with enones: An efficient and simple synthetic route to fused di- and tri-heterocycles [DOI]
  34. 34 (2020). Spartan ‘18, V 1.4.5., Wavefunction.
  35. 35 Tasch, 2013, Masuda borylation–Suzuki coupling (MBSC) sequence of vinylhalides and its application in a one-pot synthesis of 3,4-biarylpyrazoles [DOI]
  36. 36 Arai, 2015, A new protocol for nickel-catalysed regio- and stereoselective hydrocyanation of allenes [DOI]
  37. 37 Liu, 2015, An Efficient Method for the Production of Terminal Alkynes from 1,1-Dibromo-1-alkenes and its Application in the Total Synthesis of Natural Product Dihydroxerulin [DOI]
  38. 38 Appleton, 2001, Novel tryptophan-derived dipeptides and bioactive metabolites from the sea hare Aplysia dactylomela [DOI]

Cited by 4

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