Skip to content
Research Article Open access CC BY 4.0

Synthesis of Indole-Based Derivatives Containing Ammonium Salts, Diamines and Aminoureas for Organocatalysis

Marcello Casertano, Brian G. Kelly, Malachi W. Gillick-Healy, Paolo Grieco, Mauro F. A. Adamo

Organics · pp. 15–15 · Published 2 Apr 2025

10.3390/org6020015

Abstract

Indole heterocycles have an established reactivity, and these compounds are H-bond donors via a peculiar non-basic NH. However, the indole core has been scarcely employed in organocatalysis, with only a few examples relevant to electrophilic halogenation reported. To expand the range of potential transformations achievable via indole catalysis, we have designed a set of new organic species incorporating an indole core, alongside three privelaged chiral moieties found in many known organocatalysts, namely a quaternary ammonium salt, a diamine and an amino-urea. Herein, we report an optimised synthetic route for the preparation of these potential catalytic species in an enantiomerically pure form. The syntheses are conceived to be modular and therefore will allow each of the three single organic catalysts to be expanded into families without alteration of the synthetic layout, therefore leading to a fast optimisation of new asymmetric procedures.

Organocatalysis Indole test Chemistry Ammonium Organic chemistry Catalysis Combinatorial chemistry Enantioselective synthesis

References (37)

  1. 1 Nagendra, 2013, Biomedical Importance of Indoles
  2. 2 Archana, 2019, Medicinal chemistry of indole derivatives: Current to future therapeutic perspectives [DOI]
  3. 3 James, 1959, Indole-3-aldehyde [DOI]
  4. 4 Heaney, 1974, 1-Benzylindole
  5. 5 Bergman, 1992, Efficient synthesis of 2-chloro-,2-bromo-, and 2-iodoindole [DOI]
  6. 6 Katritzky, 1995, Facile synthesis of 2-substituted indoles and indolo[3,2-b] carbazoles from 2-(benzotriazol-1-ylmethyl) indole [DOI]
  7. 7 Ximenes, 2001, The oxidation of indole derivatives catalysed by horseradish peroxidase is highly chemiluminescent [DOI]
  8. 8 Lynch, 2002, Intramolecular amidofuran cycloadditions across an indole pi-bond: An efficient approach to the aspidosperma and strychnos ABCE core [DOI]
  9. 9 Chaudhuri, 2013, Importance of indole NH hydrogen bonding in the organization and dynamics of gramicidin channels [DOI]
  10. 10 Chen, 2015, Indole-Catalyzed Bromolactonization in Lipophilic Solvent: A Solid− Liquid Phase Transfer Approach [DOI]
  11. 11 Shi, 2018, Environmentally benign indole-catalyzed position- selective halogenation of thioarenes and other aromatic [DOI]
  12. 12 Wong, 2020, Lipophilic indole mediated chemoselective a-monobromination of 1,3-dicarbonyl compounds [DOI]
  13. 13 Shi, 2019, Lipophilic Indole-Catalyzed Intermolecular Bromoesterification of Olefins in Nonpolar Media [DOI]
  14. 14 Bencivenni, G., Saraiva Rosa, N., Grieco, P., Gillick-Healy, M.W., Kelly, B.G., Twamley, B., and Adamo, M.F.A. (2022). Quaternary Ammonium Salts Interact with Enolates and Sulfonates via Formation of Multiple +N-C-H Hydrogen Bonding Interactions. Catalysts, 12. [DOI]
  15. 15 Bencivenni, 2021, Study of Ground State Interactions of Enantiopure Chiral Quaternary Ammonium Salts and Amides, Nitroalkanes, Nitroalkenes, Esters, Heterocycles, Ketones and Fluoroamides [DOI]
  16. 16 Salazar Illera, D., Pacifico, R., and Adamo, M.F.A. (2022). Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles. Catalysts, 12. [DOI]
  17. 17 Destro, 2020, Enantioselective Synthesis of 3, 4-Dihydropyran-2-ones via Phase-Transfer-Catalyzed Addition–Cyclization of Acetylacetone to Cinnamic Thioesters [DOI]
  18. 18 Piras, 2012, Phase transfer catalyzed enantioselective cyclopropanation of 4-nitro-5-styrylisoxazoles [DOI]
  19. 19 Baschieri, 2009, Catalytic Asymmetric Conjugate Addition of Nitroalkanes to 4-Nitro-5-styrylisoxazoles [DOI]
  20. 20 Pineda, 2024, A continuous flow approach for the desulfurative bromination of sulfides [DOI]
  21. 21 Canestrani, 2019, Sulphide as a leaving group: Highly stereoselective bromination of alkyl phenyl sulphides [DOI]
  22. 22 Alletto, 2020, Enantiospecific on-water bromination: A mild and efficient protocol for the preparation of alkyl bromides [DOI]
  23. 23 Canestrari, 2017, Desulfurative chlorination of alkyl phenyl sulfides [DOI]
  24. 24 Rakshit, 2008, Palladium-Catalyzed Oxidative Cyclization of N-Aryl Enamines: From Anilines to Indoles
  25. 25 Patil, 2011, Microwave-assisted synthesis of medicinally relevant indoles [DOI]
  26. 26 Nigam, 2024, Revolutionizing Indole Synthesis: A Microwave-Powered Approach
  27. 27 Huang, Y., Yang, Y., Song, H., Liu, Y., and Wang, Q. (2015). Synthesis of Structurally Diverse 2,3-Fused Indoles via Microwave-Assisted AgSbF6-Catalysed Intramolecular Difunctionalization of o-Alkynylanilines. Sci. Rep., 5. [DOI]
  28. 28 Bellavita, 2022, Microwave-Assisted synthesis of 2-methyl-1H-indole-3-carboxylate derivatives via Pd-catalysed heterocyclisation [DOI]
  29. 29 Kohler, 2010, Direct Carbon−Carbon Bond Formation via Soft Enolization: A Biomimetic Asymmetric Mannich Reaction of Phenylacetate Thioesters [DOI]
  30. 30 Bennani, 1997, trans-1,2-Diaminocyclohexane Derivatives as Chiral Reagents, Scaffolds, and Ligands for Catalysis: Applications in Asymmetric Synthesis and Molecular Recognition [DOI]
  31. 31 Kopyt, M., and Glowacki, M.P. (2022). Trans-1,2-Diaminocyclohexane and Its Derivatives in Asymmetric Organocatalysis. Chiral Building Blocks in Asymmetric Synthesis: Synthesis and Applications, Wiley VCH, GmbH.
  32. 32 Lee, 2007, Selective Mono-BOC Protection of Diamines [DOI]
  33. 33 Imperatore, C., Valadan, M., Tartaglione, L., Persico, M., Ramunno, A., Menna, M., Casertano, M., Dell’Aversano, C., Singh, M., and d’Aulisio Garigliota, M.L. (2020). Exploring the Photodynamic Properties of Two Antiproliferative Benzodiazopyrrole Derivatives. Int. J. Mol. Sci., 21. [DOI]
  34. 34 Casertano, M., Genovese, M., Piazza, L., Balestri, F., Del Corso, A., Vito, A., Paoli, P., Santi, A., Imperatore, C., and Menna, M. (2022). Identifying Human PTP1B Enzyme Inhibitors from Marine Natural Products: Perspectives for Developing of Novel Insulin-Mimetic Drugs. Pharmaceuticals, 15. [DOI]
  35. 35 Amarasinghe, 2012, The First Catalytic, Enantioselective Aza-Henry Reaction of an Unactivated Cyclic Imine [DOI]
  36. 36 Farah, 2015, Preparation of C2-Symmetric Biaryl Bisiminium Salts and Their Use as Organocatalysts for Asymmetric Epoxidation [DOI]
  37. 37 Berkessel, 2009, A simplified synthesis of Takemoto’s catalyst [DOI]

Cited by 0

No indexed citations yet.

Article metrics

Real usage data collected on this platform.

0

Page views

0

PDF downloads

0

Outbound clicks

0

Citations

Views by country

Approximate, from request IP at view time — not citizenship or institution. Countries with fewer than 5 views are grouped as "Other".

No views recorded yet.

Traffic sources

Referring site, by host.

No traffic recorded yet.

Views and downloads exclude known bots/crawlers. Citations combines this platform's own DOI-resolved index with each external source's own reported total — see Cited by above for individually listed citing works. Last refreshed 0 seconds ago.