Recent advances in the transition-metal-free synthesis of quinoxalines

Abstract

Quinoxalines, also known as benzo[a]pyrazines, constitute an important class of nitrogen-containing heterocyclic compounds as a result of their widespread prevalence in natural products, biologically active synthetic drug candidates, and optoelectronic materials. Owing to their importance and chemists' ever-increasing imagination of new transformations of these products, tremendous efforts have been dedicated to finding more efficient approaches toward the synthesis of quinoxaline rings. The last decades have witnessed a marvellous outburst in modifying organic synthetic methods to create them sustainable for the betterment of our environment. The exploitation of transition-metal-free catalysis in organic synthesis leads to a new frontier to access biologically active heterocycles and provides an alternative method from the perspective of green and sustainable chemistry. Despite notable developments achieved in transition-metal catalyzed synthesis, the high cost involved in the preparation of the catalyst, toxicity, and difficulty in removing it from the final products constitute disadvantageous effects on the atom economy and eco-friendly nature of the transformation. In this review article, we have summarized the recent progress achieved in the synthesis of quinoxalines under transition-metal-free conditions and cover the reports from 2015 to date. This aspect is presented alongside the mechanistic rationalization and limitations of the reaction methodologies. The scopes of future developments are also highlighted.

Fig. 1. Representative examples of natural products, drugs, and bioactive synthetic compounds containing quinoxaline ring.

Fig. 2. Various classical routes for the synthesis of quinoxalines derivatives.

Scheme 1. Efficient organocatalytic approach towards the rapid access of quinoxaline derivatives 3.

Scheme 2. One-pot reduction and subsequent tandem condensation to access diverse quinoxaline derivatives 7.

Scheme 3. Ammonium bifluoride catalyzed synthesis of various quinoxalines 9.

Scheme 4. Ionic liquid functionalized cellulose as an efficient catalyst for the rapid access to quinoxalines 12.

Scheme 5. Ultrasound irradiated catalyst-free synthesis of diverse quinoxaline derivatives 14 and 16.

Scheme 6. Visible light-mediated Rose Bengal catalyzed synthesis of different quinoxaline derivatives 19 and 20.

Scheme 7. The suggested mechanism to explain the formation of quinoxalines 20.

Scheme 8. Preparation of library of quinoxaline derivatives in ionic liquid.

Scheme 9. Camphor sulfonic acid-catalyzed synthesis of quinoxalines 29, 30, and 32.

Scheme 10. Catalyst-free oxidative cyclization of diamines and phenacyl bromide to access quinoxalines.

Scheme 11. Three-step synthesis of quinoxaline-sulfonamides based on a green catalyst-free strategy.

Scheme 12. Metal-free conventional as well as the microwave-assisted synthesis of quinoxaline hybrid 45.

Scheme 13. Visible light-induced electron-transfer and oxidative cyclization to access quinoxaline derivatives.

Scheme 14. Iodine catalyzed one-pot oxidation/cyclization to access quinoxalines 49.

Scheme 15. Transition-metal-free redox condensation reaction to access quinoxaline derivatives 52.

Scheme 16. Metal-free visible light-mediated domino synthesis of quinoxalines 56.

Scheme 17. I₂-catalyzed domino one-pot atom-economic approach to quinoxaline derivatives 58.

Scheme 18. NBS-promoted one-pot two-step green synthesis of quinoxalines 34.

Scheme 19. Metal-free one-pot synthesis of quinoxalines via C–α-CH₂-extrusion process.

Scheme 20. Metal-free domino protocol for the synthesis of quinoxalines via oxidative cyclization.

Scheme 21. Tandem Michael addition/azidation/cycloamination sequence toward the synthesis of quinoxalines.

Scheme 22. Visible-light induced photocatalytic cleavage of CC of enaminones to access quinoxalines.

Scheme 23. Halogen-bond-promoted construction of various quinoxaline derivatives under visible light irradiation.

Scheme 24. Visible light irradiated construction of different quinoxalines derivatives under metal-free conditions.

Scheme 25. One-pot tandem cyclization/metal-free N-arylation toward the synthesis of functionalized quinoxalines.

Fig. 3. Biologically active various pyrrolo/indolo[1,2-a]quinoxalines derivatives.

Scheme 26. Brønsted acid-catalyzed one-pot domino synthesis of pyrrolo[1,2-a]quinoxalines.

Scheme 27. Versatile activity of DMSO in the synthesis of quinoxaline.

Scheme 28. Acetic acid-catalyzed efficient synthesis of pyrrolo[1,2-a]quinoxalines through Pictet–Spengler reaction.

Scheme 29. TBHP catalyzed metal-free synthesis of quinoxalines based on in situ generated aldehydes.

Scheme 30. Metal-free diversity-oriented one-pot synthesis of fused quinoxaline derivatives from alkenes and alkynes.

Scheme 31. Transition-metal-free synthesis of fused quinoxalines from α-amino acid.

Scheme 32. Metal-free iodine catalyzed one-pot synthesis of imidazo[1,5-a]quinoxalines 105.

Scheme 33. Regioselective metal-free synthesis of imidazo[1,5-a]quinoxalines from ionic liquid supported 2-(1H-imidazol-1-yl)aniline.

Scheme 34. Synthesis of imidazo[1,5-a]quinoxalines 113 by using DMSO as solvent cum reagent in metal-free condition.

Scheme 35. Metal-free microwave-assisted one-pot preparation of library of imidazo[1,2-a]quinoxalines.

Scheme 36. Two-step synthesis of imidazo[1,2-a]quinoxalines in metal-free condition.

Scheme 37. Metal-free base promoted tandem cyclization approach toward the rapid access of fused quinoxalines.

Scheme 38. Ultrasound-assisted isocyanide-based multicomponent approach for the synthesis of quinoxalines 129.

Scheme 39. Application of triethylammonium thiolate salts as efficient reagents for the multicomponent synthesis of quinoxalines 134.

Scheme 40. One-pot two-step three-component synthesis of pyran-fused quinoxalines.

Scheme 41. PPh₃ catalyzed one-pot domino reaction to access spiro-fused quinoxaline 140.

Scheme 42. Ultrasound irradiated one-pot construction of several fused quinoxaline derivatives under metal-free condition.

Scheme 43. Microwave-assisted regio- and stereoselective one-pot four-component synthesis of spiro-fused quinoxalines.

Scheme 44. Acid-less Ugi-deprotection-cyclization-substitution sequence for the synthesis of quinolinone-fused quinoxalines.

Scheme 45. Catalyst-free regio- and diastereoselective one-pot synthesis of spiro-fused quinoxalines.

Scheme 46. Metal-free solvent-mediated diversity-oriented one-pot domino synthesis of various fused quinoxalines.

Biplob Borah

L. Raju Chowhan