Recent developments and perspectives in the copper-catalyzed multicomponent synthesis of heterocycles

Abstract

Heterocyclic compounds have become an inevitable part of organic chemistry due to their ubiquitous presence in bioactive compounds. Copper-catalyzed multicomponent synthesis of heterocycles has developed as the most convenient and facile synthetic route towards complex heterocyclic motifs. In this review, we discuss the advancements in the field of copper-catalyzed multicomponent reactions for the preparation of heterocycles since 2018.

Scheme 1. Synthesis of pyrrole derivatives from terminal alkynes, carbodiimides and malononitrile.

Scheme 2. Multicomponent synthesis of 1,3-dihydro-2H-pyrrol-2-one.

Scheme 3. One pot synthesis of poly-substituted pyrroles under solvent-free condition.

Scheme 4. Cu₂O-catalyzed three-component reaction for trisubstituted imidazole preparation.

Scheme 5. Copper-catalyzed synthesis of trisubstituted oxazoles.

Scheme 6. Possible mechanism of trisubstituted oxazoles synthesis [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2019].

Scheme 7. Regioselective synthesis of isoxazoles from a copper-promoted [3 + 2] cycloaddition.

Scheme 8. Construction of 5-((diarylphosphoryl)methyl)oxazolidin-2-ones via the copper(ii)-catalyzed phosphonocarboxylative cyclization reaction.

Scheme 9. Copper-mediated preparation of functionalized thiazoles.

Scheme 10. Four-component synthesis of N-propargyl oxazolidines.

Scheme 11. Expected mechanism of N-propargyl oxazolidine formation [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2019].

Scheme 12. Copper-catalyzed reaction of terminal alkynes, elemental sulfur and aziridines.

Scheme 13. PVC–EDA–Cu²⁺ complex catalyzed synthesis of 1,2,3-triazoles.

Scheme 14. Preparation of N¹- and N²-oxyalkylated 1,2,3-triazoles using copper catalyst.

Scheme 15. Expected mechanism of N¹-oxyalkylated 1,2,3-triazole formation [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2019].

Scheme 16. Plausible mechanism of synthesis of N²-oxyalkylated 1,2,3-triazoles [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2019].

Scheme 17. Construction of fully-substituted 1,2,3-triazoles from propiolic acids, azides, and arylboronic.

Scheme 18. Possible mechanism of substituted 1,2,3-triazoles synthesis [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2020].

Scheme 19. Synthesis of β-carbonyl 1,2,3-triazoles and triazole azido alcohols in water.

Scheme 20. One-pot synthesis of 1,2,3-triazoles and β-hydroxy 1,2,3-triazoles.

Scheme 21. Click reaction for the preparation of 1,2,3-triazoles under ultrasonic irradiation.

Scheme 22. Regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.

Scheme 23. Multicomponent synthesis of rufinamide from 2,6-difluorobenzyl bromide, NaN₃, and propiolamide.

Scheme 24. Formation of indole-fused oxazinone-1,2,3-triazole scaffolds using CuAAC-based multicomponent reaction.

Scheme 25. Four component reaction of aldehyde, malononitrile, ammonium acetate and acetophenone.

Scheme 26. Synthesis of iminolactone from aryl acetylene, enaminone and sulfonyl azide.

Scheme 27. Formation of multi-substituted pyrimidines using Cu(OAc)₂ catalyst.

Scheme 28. Photoinduced, three-component radical synthesis of highly functionalized aryl thienyl sulfides.

Scheme 29. Oxidative synthesis of imidazo fused heterocycles.

Scheme 30. Imidazo[1,2-a]pyridine derivatives synthesis in aqueous micellar media.

Scheme 31. Synthesis of C-3 sulfenylated imidazo[1,2-a]pyridine derivatives in the presence of CuI catalyst.

Scheme 32. Benzimidazole synthesis via oxidative cross-coupling.

Scheme 33. Cu-based one-pot three-component synthesis of benzothiazoles.

Scheme 34. MWCNTs@l-His/Cu(ii) complex catalyzed synthesis of pyrido[2,3-d:5,6-d′]dipyrimidines.

Scheme 35. CS/CuNPs catalyzed synthesis of quinoline derivatives.

Scheme 36. Copper-catalyzed synthesis of (a) quinazolin-4(H)-imines, (b) benzimidazo[1,2-c]quinazolines and (c) quinazolin-4(3H)-one.

Scheme 37. One pot synthesis of quinazolines via oxidative amination of methanol.

Scheme 38. Expected mechanism of quinazolines synthesis via oxidative amination of methanol [this figure has been reproduced from ref. with permission from Royal Society of Chemistry, copyright 2019].

Scheme 39. Copper-catalyzed oxidative multicomponent annulation for the synthesis of quinazolinones.

Scheme 40. Expected mechanism of quinazolinones synthesis [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2019].

Scheme 41. Asymmetric copper-catalyzed multicomponent synthesis of sulfonyl lactones.

Scheme 42. Plausible mechanism of sulfonyl lactone synthesis [this figure has been reproduced from ref. with permission from John Wiley & Sons, copyright 2018].

Scheme 43. Multi-component reaction of alkynes, sulfonyl azides and allylamines for the synthesis of 2,3-dihydro-1H-imidazo-[1,2-a]indoles.

Scheme 44. Enantio- and diastereoselective synthesis of 1,3-disubstituted isoindolines and tetrahydroisoquinolines.

Scheme 45. Preparation of trifluoromethyl-substituted carbamates through copper-catalyzed cascade cyclization of enynes.

Scheme 46. Multi-component cascade bis-heteroannulation reaction using (a) aromatic methyl ketoximes, (b) vinyl ketoximes.

Scheme 47. Preparation of 7,10-diaryl-7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-amine, 2H-indazoles, and quinazolines.

Scheme 48. Cu-based one-pot reaction cascade reaction of ethyl 2-azidoacetate, salicylaldehydes and arylacetylenes.

Scheme 49. Synthesis of 2,1-benzoisoxazole-containing 1,2,3-triazoles.

Scheme 50. Plausible mechanism for the synthesis of 2,1-benzoisoxazole-containing 1,2,3-triazoles synthesis [this figure has been reproduced from ref. with permission from American Chemical Society, copyright 2020].

Jaleel Fairoosa

Mohan Neetha

Gopinathan Anilkumar