Photochemical dearomative skeletal modifications of heteroaromatics

Abstract

Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field has evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance of photocatalysis and expansion of the activation mode, the last few years have witnessed impressive developments in innovative photochemical dearomatization methodologies, enabling skeletal modifications of dearomatized structures. They offer truly efficient and useful tools for facile construction of highly complex structures, which are viable for natural product synthesis and drug discovery. In this review, we aim to provide a mechanistically insightful overview on these innovations based on the degree of skeletal alteration, categorized into dearomative functionalization and skeletal editing, and to highlight their synthetic utilities.

Scheme 1. Selected examples of bioactive molecules or natural products synthesized by dearomatization. The cycles filled with light blue colour represent structures synthesized through dearomative skeletal modifications.

Scheme 2. State-of-the-art synthetic approaches for dearomative skeletal modifications of heteroarenes.

Scheme 3. Physiochemical properties of representative heteroarenes.

Scheme 4. Umpolung strategy enabled dearomative functionalization of bicyclic heteroarenes.

Scheme 5. Umpolung strategy enabled dearomative functionalization of indoles/thiophenes.

Scheme 6. Direct photoactivated hydrosilyation of bicyclic azoarenes.

Scheme 7. LMCT enabled radical addition to benzothiazole.

Scheme 8. Radical–radical coupling for dearomatization of electron deficient indoles.

Scheme 9. Nucleophilic radical addition to electron deficient indoles/benzothiopenes/benzofurans.

Scheme 10. Desulfuration enabled nucleophilic radical addition to electron rich benzothiophenes.

Scheme 11. Intramolecular radical addition to electron deficient indoles.

Scheme 12. Dearomative radical spirocyclization of electron rich thiophenes/furans/indoles.

Scheme 13. Dearomative radical spirocyclization of indoles for the synthesis of seleno/thiospiroindolenines.

Scheme 14. EDA complex induced dearomative radical spirocyclization of electron rich indoles.

Scheme 15. EnT promoted dearomative 4-exo-trig spirocyclization of indoles via intramolecular radical–radical cross coupling.

Scheme 16. Photoactive arenophile induced multiple dearomative functionalization of heteroarenes.

Scheme 17. Arenophile mediated dearomative multi-functionalization of pyridines.

Scheme 18. Direct visible light promoted dearomative triple elementalization of quinolines.

Scheme 19. (a) Photoredox catalysis with enzymatic catalysis for asymmetric dearomative 2,3-difunctionalization of indoles; (b) photoredox catalysis coupling with proline catalysis for enantioselective dearomative 2,3-difunctionalization of indoles.

Scheme 20. Cooperative photoredox catalysis and NHC catalysis for dearomative 2,3-difunctionalization of benzofurans.

Scheme 21. Cooperative EnT and NHC catalysis for dearomative 2,3-difunctionalization of indoles.

Scheme 22. Cooperative photoredox catalysis and chiral phosphate acid/base catalysis for dearomative 2,3-difunctionalization of indoles.

Scheme 23. Visible-light activated palladium catalysed dearomative 2,3-difunctionalization of indoles.

Scheme 24. Photoredox catalyzed cascade dearomative 2,3-difunctionalization of indoles using alkenes as a trapper.

Scheme 25. Photoredox mediated cascade dearomative 2,3difunctionalization of indoles utilizing CO₂ as a trap.

Scheme 26. Photoredox catalysed stepwise, cascade dearomative 3,7-difunctionalization of indoles.

Scheme 27. Photoredox catalytic cascade dearomative 2,3-difunctionalization of indoles for the synthesis of cyclopropane-fused indolines.

Scheme 28. Photoredox catalysed cascade dearomative 2,3-difunctionalization of indoles via [3,3] rearrangement.

Scheme 29. EnT facilitated cascade dearomative 2,3-difunctionalization of indoles/benzothiophenes/benzofuran by persistent iminyl radical trapping.

Scheme 30. EnT activated-intramolecular dearomative cycloaddition of inert pyridines/isoquinolines.

Scheme 31. EnT catalysed-intramolecular dearomative cycloaddition of inert (benzo)thiophenes/(benzo)furans.

Scheme 32. EnT promoted-intermolecular dearomative cycloaddition of inert bicyclic azoarenes.

Scheme 33. EnT catalysed-intermolecular dearomative [2π+2σ] cycloaddition of inert bicyclic azoarenes with bicyclo[2.1.1]butanes.

Scheme 34. Photoredox catalyzed dearomative [3+2] cycloaddition of isoquinoline N-oxide.

Scheme 35. Photoredox catalyzed dearomative [5+2] cycloaddition of quinoline for the synthesis of 1,3-diazepanes.

Scheme 36. Photochemical intermolecular triple-dearomative cycloaddition of furan and pyrrole for the synthesis of caged scaffolds.

Scheme 37. Direct photoactivated dearomative ring expansion of heterocycles by insertion of one C atom.

Scheme 38. Photochemical dearomative skeletal enlargement of pyridine for the synthesis of 1,2-diazepines by insertion of one N atom.

Scheme 39. Photoactivated arenophiles enabled dearomative ring expansion of heteroarenes.

Scheme 40. Photoredox catalysed dearomative ring expansion of furans.

Scheme 41. Photoredox catalysed dearomative ring expansion of (benzo)thiophenes by bicyclo[1.1.0]butane insertion.

Scheme 42. Direct UV light activated dearomative ring contraction of pyridiniums.

Scheme 43. Consecutive EnT catalysed ring contraction of quinolines.

Scheme 44. Photoredox catalysed dearomative ring cleavage of thiophenes/furans.

Scheme 45. Photoredox catalysed dearomative ring cleavage of indoles.

Scheme 46. Photochemical dearomative ring opening of pyridine N-oxide.

Scheme 47. Qualitative description of the development of dearomative skeletal modifications for different types of heteroarenes. The green-coloured circles mean the existence of initial well-developed research. The red-coloured circles represent the non-existence of well-developed research.

Peng Ji

Yueteng Zhang

Wei Wang