Recent Advances on the Synthesis of Nine-Membered N-Heterocycles

doi:10.6023/cjoc202206035

Abstract

Nine-membered N-heterocycle scaffolds are widely found in natural products and biologically active molecules. The rigid structure of the medium-sized ring plays important roles in the regulation of their biological and pharmacological activities. Therefore, nine-membered N-heterocycle is one of the most attractive medium-sized ring compounds. Because of the increasing entropy and ring extension of nine-membered ring skeleton, the synthesis of nine-membered N-heterocycles is still difficult; especially the effective control of substituent stereoselectivity for the nine-membered ring is one of the greatest challenging topics This review summarizes the novel synthetic strategies of nine-membered N-heterocycles and their applications in the synthesis of natural products and pharmaceutically active molecules containing nine-membered ring scaffold in recent years.

Key words: nine-membered N-heterocycles, medium-sized ring compounds, cyclization, cycloaddition, ring expansion

Cite this article

Xiaoting Qin, Ning Zou, Caimei Nong, Dongliang Mo. Recent Advances on the Synthesis of Nine-Membered N-Heterocycles[J]. Chinese Journal of Organic Chemistry, 2023, 43(1): 130-155.

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Fig. & Tab. 50

Figure 1. Some natural products containing nine-membered N- heterocyclic skeleton

Scheme 1. Intramolecular Heck cyclization to synthesize nine- membered N-heterocycles

Scheme 2. Intermolecular Ugi reaction/hydroarylation to form nine-membered N-heterocycles

Scheme 3. Aldimine condensation/1,6-HT/Mannich/cyclization cascade to construct polycyclic indole-3,4-fused nine-membered rings

Scheme 4. Mechanism of aldimine condensation/1,6-HT/Man- nich cascade to synthesize polycyclic indole-3,4-fused nine- membered ring

Scheme 5. Iron(III)-catalyzed alkyne-carbonyl metathesis for the synthesis of 6,7-dihydro-5H-dibenzo[c,e]azonines

Scheme 6. 1,4-Rearrangement and ring-expansion for the synthesis of nine-membered N-heterocycles

Scheme 7. The mechanism of 1,4-rearrangement and ring-expansion for the synthesis of nine-membered N-heterocycles

Scheme 8. Click reaction/[3,3]-rearrangement to construct nine-membered N-heterocycles

Scheme 9. Construction of nine-membered N-heterocycles by hydroalkoxylation/Claisen rearrangement

Scheme 10. Mechanism of the construction of nine-membered N-heterocycles by hydroalkoxylation/Claisen rearrangement

Scheme 11. Construction of benzo-nine-membered N-hetero- cycles by deprotonation/migration and ring expansion

Scheme 12. Iridium-catalyzed asymmetric allylation dearomati- zation/Mannich/hydrolysis cascade reaction to synthesize indole- fused medium-sized-ring compounds

Scheme 13. Construction of nine-membered N-heterocycles by tandem oxidation dearomatization and ring-expansion

Scheme 14. Electrochemical synthesis of benzo-nine-membered N-heterocycles

Scheme 15. Construction of nine-membered N-heterocycles by asymmetric bromination and ring-expansion

Scheme 16. Proposed mechanism for the formation of bridged nine-membered N-heterocycles by [6+3] cycloaddition

Scheme 17. Construction of benzofuran-fused nine-membered N-heterocycles by [5+4] cycloaddition

Scheme 18. Construction of benzofuran-fused nine-membered N-heterocycles by asymmetric [5+4] cycloaddition reaction

Scheme 19. Pd-catalyzed asymmetric [5+4] cycloaddition to form nine-membered N-heterocycles

Scheme 20. Palladium-catalyzed double-decarboxylative ring-expansion reaction to construct trifluoromethyl substituted nine-mem- bered N-heterocycles

Scheme 21. Pd-catalyzed [5+4] cycloaddition to form nine-membered N-heterocycles containing difluoro group

Scheme 22. Synergistic Pd(0)/Rh(II) dual catalytic [6+3] cycloaddition for the synthesis of nine-membered N-heterocycles

Scheme 23. Pd(0)-catalyzed [6+3] cycloaddition for the construction of nine-membered N-heterocycles

Scheme 24. [3+2] cycloaddition and [3,3]-rearrangement to form nine-membered N-heterocycles

Scheme 25. Mechanism for [3+2] cycloaddition of [3,3]-rearrangement to form nine-membered N-heterocycles

Scheme 26. Construction of nine-membered N-heterocycles by [3+2] cycloaddition/[3,3]-rearrangement

Scheme 27. Iron(III)/copper(II)-cocatalyzed cycloaddition/[3,3]-rearrangement/N—O bond cleavage cascade reaction for the synthesis of polysubstituted pyrrolizines

Scheme 28. Copper-catalyzed kinetic resolution of nine-membered N-heterocycles

Table 1. Yb(OTf)3 catalyzed cycloaddition and rearrangement to form nine-membered N-heterocycles

Scheme 29. Yb(OTf)3 and visible light relay catalyzed construction of aza-nine-membered endoperoxides

Scheme 30. AgNO3 catalyzed cycloaddition/rearrangement to form chiral nine-membered N-heterocycles

Scheme 31. Hydroalkoxylation and [4+2] cycloaddition to construct nine-membered N-heterocycles

Scheme 32. Insertion of carbene and Cope rearrangement to synthesize nine-membered N-heterocycles

Scheme 33. Mechanism for the carbene insertion and Cope rearrangement to construct nine-membered N-heterocycles

Scheme 34. Coupling cascade reaction to construct nine-membered N-heterocycles

Scheme 35. Ugi multicomponent reaction to construct nine-membered N-heterocycles

Scheme 36. C—H activation for the construction of nine-membered N-heterocycles

Scheme 37. Multi-component construction of nine-membered N-heterocycles

Scheme 38. Multi-component cascade construction of nine-membered diazoheterocycles

Scheme 39. Acylation/cleavage to construct nine-membered N- heterocycles

Scheme 40. Photocatalytic radical shift to construct nine-membered N-heterocycles

Scheme 41. Reaction mechanism of photocatalytic radical shift to construct nine-membered N-heterocycles

Scheme 42. Metal-free cascade cyclization for the construction of nine-membered N-heterocycles

Scheme 43. Application of intramolecular cyclization in the total synthesis of indole lactam alkaloids

Scheme 44. Application of intermolecular amination reaction in the total synthesis of serratine alkaloid

Scheme 45. Application of intramolecular Michael addition reaction in the total synthesis of natural product (–)-indolatam V

Scheme 46. Application of intramolecular condensation in total synthesis of alkaloid (–)-rhazinilam

Scheme 47. Application of intramolecular cyclization in the total synthesis of (±)-Isopalhinine A, (±)-Palhinine A, and (±)-Palhinine D

Scheme 48. Application of intramolecular nucleophilic cyclization in the total synthesis of huperzine H

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