Progress in Functionalization of N-α-Csp3—H Bond Catalyzed by Transition Metals

doi:10.6023/cjoc202404040

Abstract

Functionalization of C—H bonds is a very important research field in organic synthetic chemistry. In many C—H bonds located in different chemical environments, the induced effect of the nitrogen atom makes the α-C_sp3—H bond more active compared to other C_sp3—H bonds, and the regioselective functionalization of the α-C_sp3—H bond is also better achieved with the help of directing groups. Therefore, the functionalization of the α-C_sp3—H bond of nitrogen atoms is a very practical synthetic strategy, which provides more possibilities for the structural modification and development of drugs containing nitrogen atoms (such as nicotinamide and quinine). The current development of transition metal-catalyzed functionalization of the α-C_sp3—H bond of nitrogen atoms in the past twenty years is reviewed and the potential of this synthetic methodology in the future is looked forward.

Key words: nitrogen atom, C_sp3—H, functionalization, transition metal-catalyzed

Cite this article

Tengfei Zhang, Zhe Chang, Chunxia Chen, Jinsong Peng. Progress in Functionalization of N-α-C_sp3—H Bond Catalyzed by Transition Metals[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 168-188.

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Fig. & Tab. 55

Scheme 1. Natural products containing nitrogen atoms

Scheme 2. Ru-catalyzed alkylation reported by Chul-Ho Jun

Scheme 3. Ru-catalyzed alkylation reported by Shinji Murai

Scheme 4. Ru-catalyzed alkylation reported by Chae S. Yi

Scheme 5. Ru-catalyzed alkylation reported by Michael J. Krische

Scheme 6. Proposed mechanism of Ru-catalyzed 1,4-addition of N-α-Csp3—H to conjugated olefins

Scheme 7. Ru-catalyzed arylation reported by Dalibor Sames

Scheme 8. Proposed mechanism of Ru-catalyzed arylation of N-α-Csp3—H

Scheme 9. Ru-catalyzed arylation reported by Bert U. W. Maes

Scheme 10. Ru-catalyzed arylation reported by Bert U. W. Maes

Scheme 11. Ru-catalyzed C—H arylation reported by Min Zhang

Scheme 12. Proposed mechanism of Ru-catalyzed C—H arylation

Scheme 13. Rh-catalyzed N-α-carbonylation reported by Shinji Murai

Scheme 14. Rh-catalyzed α-carbonylation of alicyclic amines reported by Shinji Murai

Scheme 15. Rh-catalyzed α-alkylation of alicyclic amines reported by Huw M. L. Davies

Scheme 16. Rh-catalyzed intramolecular C—H alkylation of allylamines reported by Zhi Xiang Yu

Scheme 17. Rh-catalyzed N-α-Csp3—H alkylation of benzylamines reported by Michael Schnürch

Scheme 18. Rh-catalyzed N-α-Csp3—H arylation of cycloamines reported by Frank Glorius

Scheme 19. Rh-catalyzed N-α-Csp3—H amidation of alicyclic amines reported by In Su Kim

Scheme 20. Proposed Rh-catalyzed mechanism of N-α-Csp3—H amidation of alicyclic amines

Scheme 21. Pd-catalyzed N-α-Csp3—H arylation of alicyclic amines reported by Jin Quan Yu

Scheme 22. Pd-catalyzed asymmetric N-α-Csp3—H arylation of alicyclic amines

Scheme 23. Pd-catalyzed asymmetric N-α-Csp3—H arylation of alicyclic amines reported by Liu-Zhu Gong

Scheme 24. Pd-catalyzed intramolecular N-α-arylation reported by Zhi-Shi Ye

Scheme 25. Pd-catalyzed N-α-Csp3—H arylation of sulfonamides reported by Hang Shi

Scheme 26. Pd-catalyzed N-α-Csp3—H acetoxylation of amines reported by Jin Quan Yu

Scheme 27. Ir-catalyzed asymmetric N-α-alkylation of amines reported by Takanori Shibata

Scheme 28. Proposed mechanism of Ir-catalyzed asymmetric N-α-alkylation of amines

Scheme 29. Ir-catalyzed α-alkylation of aliphatic amines reported by Till Opatz

Scheme 30. Ir-catalyzed N-α-Csp3—H alkylation of alicyclic amines reported by Jin Quan Yu

Scheme 31. Ir-catalyzed N-α-Csp3—H alkylation of N-methylureas reported by Daisuke Yamauchi

Scheme 32. Ir-catalyzed N-α-Csp3—H alkylation of alicyclic amines reported by Jin Quan Yu

Scheme 33. Proposed Ir-catalyzed mechanism of N-α-Csp3—H alkylation of alicyclic amines

Scheme 34. Ir-catalyzed benzimidazole-directed N-α-Csp3—H alkylation of alicyclic amines reported by Takahiro Nishimura

Scheme 35. Ir-catalyzed intramolecular N-α-Csp3—H vinylation of unsaturated alicyclic amides reported by Dalibor Sames

Scheme 36. Ir-catalyzed N-α-Csp3—H vinylation of amides reported by Takanori Shibata

Scheme 37. Ir-catalyzed N-α-Csp3—H vinylation of 2-alkyl- aminopyridines reported by Takanori Shibata

Scheme 38. Cu-catalyzed N-α-Csp3—H alkylation of tetrahydroisoquinolines reported by Chao Jun Li

Scheme 39. Cu-catalyzed oxidative annulation of N-α-Csp3—H reported by Masahiro Miura

Scheme 40. Cu-catalyzed N-α-Csp3—H oxidative arylation reported by Yu hong Zhang

Scheme 41. Cu-catalyzed arylation mechanism of N-α-Csp3—H proposed by Yu hong Zhang

Scheme 42. Cu-catalyzed alkynylation of N-α-Csp3—H reported by Chao Jun Li

Scheme 43. Cu-catalyzed intramolecular etherification of N-α- Csp3—H reported by Christopher D. Maycock

Scheme 44. Cu-catalyzed hydroxylation of N-α-Csp3—H reported by De peng Zhao

Scheme 45. Cu-catalyzed oxidative cross-coupling for the introduction of ester group reported by Chao Jun Li

Scheme 46. Au-catalyzed N-α-Csp3—H alkynylation of alicyclic amines reported by Kazuya Yamaguchi

Scheme 47. Fe-catalyzed N-α-Csp3—H alkynylation of tertiary amines reported by Da yong Shi

Scheme 48. Ta-catalyzed N-α-Csp3—H alkylation of N-methyl secondary amines reported by Laurel L. Schafer

Scheme 49. Ta-catalyzed mechanism of N-α-Csp3—H alkylation proposed by Laurel L. Schafer

Scheme 50. Ni-catalyzed alkylation of N-α-Csp3—H reported by Hang Shi

Scheme 51. Proposed Ni-catalyzed N-α-Csp3—H alkylation mechanism

Scheme 52. Ni-catalyzed steroselective alkylation of N-α-Csp3—H reported by Li-Jun Xiao

Scheme 53. Ni-catalyzed vinylation of N-α-Csp3—H reported by Mengchun Ye

Scheme 54. Ni-catalyzed asymmetric vinylation of N-α-Csp3—H reported by Hang Shi

Scheme 55. Mn-catalyzed N-α-Csp3—H hydroxylation reported by M. Christina White

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过渡金属催化氮原子α位C_sp3—H键官能团化反应研究进展