Palladium-Catalyzed Intermolecular Functionalization of Unactivated Methylene C(sp3)—H Bonds

doi:10.6023/cjoc202406012

Abstract

Although transition metal-catalyzed methylene C(sp³)—H functionalization is a great challenge, it has made noticeable progress in recent years. This review specifically describes Pd-catalyzed intermolecular functionalization of unactivated methylene C(sp³)—H bonds. A variety of reactions, including arylation, alkylation, alkenylation/alkynylation, acetoxylation, amination, halogenation, borylation, and silylation reactions, have been discussed. Due to the inert properties, methylene C(sp³)—H functionalization reaction usually relies on the use of directing group strategies, which can not only control regioselectivity but also address low reactivity issue. Various directing groups, including strongly coordinating bidentate auxiliaries and weakly coordinating innate functional groups, have proven to be eﬀective for enabling methylene C(sp³)—H functionalization.

Key words: palladium catalysis, C—H activation, methylene C(sp³)—H activation, cross-coupling

Cite this article

Mingshun Mei, Yanghui Zhang. Palladium-Catalyzed Intermolecular Functionalization of Unactivated Methylene C(sp³)—H Bonds[J]. Chinese Journal of Organic Chemistry, 2025, 45(2): 620-640.

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Fig. & Tab. 54

Scheme 1. Intermolecular functionalization reactions of inert methylene C(sp3)—H bonds

Scheme 2. Directing group-assisted C(sp3)—H arylation

Scheme 3. 8-AQ-directed C(sp3)—H arylation reactions

Scheme 4. 8-AQ-directed enantioselective C(sp3)—H arylation reactions

Scheme 5. 8-AQ-directed C(sp3)—H arylation reaction with diaryliodonium triflates

Scheme 6. N,N-bidentate ligand-directed C(sp3)—H arylation reactions

Scheme 7. PIP-directed enantioselective C(sp3)—H arylation reactions

Scheme 8. β-C(sp3)—H arylation directed by 2,2-dimethyl aminooxyacetic acid

Scheme 9. 8-AQ-directed C(sp3)—H arylation reactions of aliphatic cycloalkanes

Scheme 10. 8-AQ-directed C(sp3)—H arylation reactions of glycosyl carboxamides

Scheme 11. PA-directed C(sp3)—H arylation reactions of cycloalkanes

Scheme 12. Mechanism of transient directing group-assisted C(sp3)—H functionalization

Scheme 13. TDG-Assisted β-C—H arylation of aliphatic aldehydes

Scheme 14. Ligand-controlled regioselective C—H arylation of aliphatic aldehydes

Scheme 15. Ligand-enhanced C—H diarylation of cyclohexanecarboxaldehyde

Scheme 16. TDG-assisted C—H arylation reactions of aliphatic ketones

Scheme 17. TDG-assisted C—H arylation reactions of linear aliphatic amines

Scheme 18. 1-Aminopyridinium-Ylide-directed β-C(sp3)—H arylation

Scheme 19. Amide-directed enantioselective arylation of methylene C—H bonds

Scheme 20. Mechanism of enantioselective C(sp3)—H arylation of cycloalkyl carboxamides

Scheme 21. Amide-directed remote C(sp3)—H arylation reactions of azacycloalkanes

Scheme 22. C(sp3)—H arylation reactions using carbon dioxide as a transient directing group

Scheme 23. Ligand-promoted β-methylene C(sp3)—H arylation of free aliphatic acids

Scheme 24. Ligand-promoted [2＋2] cycloaddition and double methylene C—H arylation reactions and proposed mechanism

Scheme 25. Ligand-promoted methylene C(sp3)—H arylation reactions of cycloalkanes

Scheme 26. Ligand-enabled double γ-C(sp3)—H functionalization of aliphatic acids: one-step synthesis of γ-arylated γ-lactones of this transformation

Scheme 27. Hydrogen-bond-acceptor ligands enable distal C(sp3)—H arylation of free alcohols

Scheme 28. 8-AQ-directed alkylation of C(sp3)—H bonds

Scheme 29. PA-directed alkylation of C(sp3)—H bonds with alkyl iodides

Scheme 30. Ligand-promoted site-selective cyanomethylation of C(sp3)—H bonds with acetonitrile

Scheme 31. PA-directed γ-C(sp3)—H alkenylation reactions of aliphatic cycloalkanes derivatives

Scheme 32. Tandem asymmetric C(sp3)—H alkenylation/aza-Wacker-type cyclization reaction

Scheme 33. C(sp3)—H alkenylation reactions of α-amino acids and peptides with glycosyl iodides

Scheme 34. Silver-free C(sp3)—H alkenylation reactions

Scheme 35. Methylene C(sp3)—H alkynylation reactions

Scheme 36. Alkynylation of methylene C(sp3)—H bonds in aliphatic chains and cycloalkanes

Scheme 37. Enantioselective methylene C(sp3)—H alkynylation reactions

Scheme 38. Carbonylation of methylene C(sp3)—H bonds to synthesize trans-disubstituted β-lactam derivatives

Scheme 39. Oxime ether-directed acetoxylation of methylene C(sp3)—H bonds

Scheme 40. 8-AQ-directed acetoxylation of methylene C(sp3)— H bonds

Scheme 41. Oxime ether-directed acetoxylation of methylene C(sp3)—H bond

Scheme 42. Diastereoselective β-C(sp3)—H acetoxylation of chiral amino acid derivatives

Scheme 43. Alkoxylation of methylene C(sp3)—H bonds with cyclic hypervalent iodine (I3＋) oxidants

Scheme 44. PIP-directed alkoxylation of methylene C(sp3)—H bonds

Scheme 45. Amination of methylene C(sp3)—H bonds

Scheme 46. Amide-directed fluorination of methylene C(sp3)—H bonds in amino acid derivatives

Scheme 47. PIP-directed fluorination of methylene C(sp3)—H bonds

Scheme 48. Oxime ether-directed fluorination of methylene C(sp3)—H bonds

Scheme 49. TDG-mediated fluorination of methylene C(sp3)— H bonds

Scheme 50. Amide-directed borylation of methylene C(sp3)—H bonds

Scheme 51. 8-AQ-directed silylation of methylene C(sp3)—H bonds in cycloalkanes

Scheme 52. 8-AQ-directed silylation of methylene C(sp3)—H bonds

Scheme 53. Pd(0)-catalyzed intermolecular methylene C(sp3)— H silylation by using NHC ligands

Scheme 54. Direct deuteration of methylene C(sp3)—H bonds

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钯催化惰性亚甲基C(sp³)—H键分子间官能团化反应

Palladium-Catalyzed Intermolecular Functionalization of Unactivated Methylene C(sp³)—H Bonds

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钯催化惰性亚甲基C(sp3)—H键分子间官能团化反应