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Review
. 2018 Jan 2;57(1):62-101.
doi: 10.1002/anie.201703743. Epub 2017 Dec 5.

Complementary Strategies for Directed C(sp3 )-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

John C K Chu  1 , Tomislav Rovis  2   1
Affiliations
Review

Complementary Strategies for Directed C(sp3 )-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

John C K Chu et al. Angew Chem Int Ed Engl. .

Abstract

The functionalization of C(sp3 )-H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3 )-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.

Keywords: C−H functionalization; carbenes; hydrogen atom transfer; nitrenes; transition metals.

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Figures

Figure 1
Figure 1
Challenges in C-H Functionalization
Figure 2
Figure 2
Use of a Directing Group in C-H Functionalization
Figure 3
Figure 3
Weaker Carbon-Metal Bonds with sp3 Carbons
Scheme 1
Scheme 1
Transition-Metal Catalyzed C-H Activation
Scheme 2
Scheme 2
Aryl Halides as Directing Groups
Scheme 3
Scheme 3
Nitrogen as Directing Group
Scheme 4
Scheme 4
Dehydrogenation and Cyclobutane Synthesis with Aryl Halides
Scheme 5
Scheme 5
Trapping of Putative Palladium-Alkyl Intermediates
Scheme 6
Scheme 6
Synthesis of 5-Membered Rings with Aryl Halides
Scheme 7
Scheme 7
Vinyl Halides as Traceless Directing Group
Scheme 8
Scheme 8
Generation of Aryl/Vinyl Palladium through Other Means
Scheme 9
Scheme 9
Oxime-Directed C-H Activation
Scheme 10
Scheme 10
Derivatization of Pyridines through C-H Activation
Scheme 11
Scheme 11
Use of Picolinamides for Amine Functionalization
Scheme 12
Scheme 12
Transannular C-H Activation of Alicyclic Amines
Scheme 13
Scheme 13
Sulfonamides as Directing Group for Functionalization of Amines
Scheme 14
Scheme 14
C-H Functionalization of Free Amines
Scheme 15
Scheme 15
In-situ Generated Imines as Directing Groups
Scheme 16
Scheme 16
Hydrazone-Directed C-H Activation
Scheme 17
Scheme 17
Formation of C-C Bonds with 8-aminoquinolines
Scheme 18
Scheme 18
Formation of C-X Bonds with 8-aminoquinolines
Scheme 19
Scheme 19
Formation of C-C Bonds with Perfluorinated Amides
Scheme 20
Scheme 20
Synthesis of Nitrogen-Heterocycles from Perfluorinated Amides
Scheme 21
Scheme 21
Formation of C-X Bonds with Perfluorinated Amides
Scheme 22
Scheme 22
C-H Functionalization with O-Methyl Hydroxamic acids and Carboxylic Acids
Scheme 23
Scheme 23
C-H Functionalization of Peptides
Scheme 24
Scheme 24
In-situ Generation of Directing Group from Carbonyl Groups
Scheme 25
Scheme 25
γ Functionalization of Carbonyl Compounds
Scheme 26
Scheme 26
C-H Activation of Alcohol Derivatives
Scheme 27
Scheme 27
Pyrazole-Directed C-H Activation
Scheme 28
Scheme 28
Ru-Catalyzed C-H Activation
Scheme 29
Scheme 29
Ir(I)-Catalyzed Borylation
Scheme 30
Scheme 30
Ir(III)-catalyzed C-H Amination and Arylation
Scheme 31
Scheme 31
Rh(III)-Catalyzed C-H Amination of Pyridines
Scheme 32
Scheme 32
Nickel(0)-Catalyzed [4+2] Cycloaddition
Scheme 33
Scheme 33
Nickel(II)-catalyzed C-H Functionalization
Scheme 34
Scheme 34
Synthesis of Nitrogen Heterocycles with Ni(II) Catalysis
Scheme 35
Scheme 35
Fe-Catalyzed Formation of C-C Bonds
Scheme 36
Scheme 36
Co-Catalyzed C-H Functionalization
Scheme 37
Scheme 37
Cu-Catalyzed C-H Functionalization
Scheme 38
Scheme 38
Hydrogen Atom Transfer
Scheme 39
Scheme 39
1,5 Hydrogen Atom Transfer
Scheme 40
Scheme 40
Generation of Nitrogen Radicals by Homolysis of N-X Bonds
Scheme 41
Scheme 41
In-situ Generation of N-X Bonds
Scheme 42
Scheme 42
γ, ε Functionalization with Nitrogen Radicals
Scheme 43
Scheme 43
Generation of Nitrogen Radicals by Reduction of Organic Azides
Scheme 44
Scheme 44
Catalytic Reduction of N-X Bonds
Scheme 45
Scheme 45
Generation of Nitrogen Radicals by Abstraction of Hydrogen
Scheme 46
Scheme 46
Generation of Nitrogen Radicals by Oxidation of N-H Bonds
Scheme 47
Scheme 47
Formation of C-C Bonds with Nitrogen Radicals
Scheme 48
Scheme 48
Reactivity of Oxygen Radicals
Scheme 49
Scheme 49
The Barton Reaction
Scheme 50
Scheme 50
Use of O-X Bonds for C-X Bonds Formation
Scheme 51
Scheme 51
Use of Excess Alkenes for C-H Alkylation
Scheme 52
Scheme 52
Generation of Oxygen Radicals by Reduction of O-X Bonds
Scheme 53
Scheme 53
Generation of Oxygen Radicals with Photoredox Catalysis
Scheme 54
Scheme 54
Generation of Oxygen Radicals by Oxidation of O-H Bonds
Scheme 55
Scheme 55
In-Situ Generation of O-I Bonds
Scheme 56
Scheme 56
Formation of Isoxazolines
Scheme 57
Scheme 57
Formation of γ-lactones through Carbonylation
Scheme 58
Scheme 58
Epoxides as Oxygen Radical Precursors
Scheme 59
Scheme 59
Norrish-Yang Cyclization
Scheme 60
Scheme 60
Initial report on 1,5 HAT with Vinyl Halides
Scheme 61
Scheme 61
Catalytic System for 1,5 HAT with sp3 C-H Bonds
Scheme 62
Scheme 62
Derivatization of Alcohols with Vinyl Radicals for 1,5 HAT
Scheme 63
Scheme 63
Generation of Vinyl Radicals through Radical Addition to Alkynes
Scheme 64
Scheme 64
Generation of Aryl Radicals from Aryl Triazenes
Scheme 65
Scheme 65
Metal Carbenoids and Nitrenoids
Scheme 66
Scheme 66
Rh(II)-Catalyzed Intramolecular C-H Insertion
Scheme 67
Scheme 67
Rh(II)-Catalyzed Intramolecular C-H Amination
Scheme 68
Scheme 68
Application of Intramolecular C-H insertion
Scheme 69
Scheme 69
Application of Intramolecular C-H Amination
Scheme 70
Scheme 70
Relative Stability of Pd-Alkyl Species
Scheme 71
Scheme 71
The Relative Reactivity of Primary and Secondary C-H Bonds
Scheme 72
Scheme 72
Pd-catalyzed C-H Activation of Tertiary C-H Bonds
Scheme 73
Scheme 73
Reactivity of 2° vs 3° C-H Bonds
Scheme 74
Scheme 74
Electronic Effects of Ligands on Regioselectivity
Scheme 75
Scheme 75
Sterics Effects of Ligands on Regioselectivity
Scheme 76
Scheme 76
Regioselectivity of C-H Amination
Scheme 77
Scheme 77
Transition-metal Catalyzed Activation of β, γ, δ C-H Bonds
Scheme 78
Scheme 78
Predominance of 1,5 HAT
Scheme 79
Scheme 79
1,8 Hydrogen Atom Transfer
Scheme 80
Scheme 80
Long-Range HAT
Scheme 81
Scheme 81
Effects of Geometry on 1,5 and 1,6 HAT
Scheme 82
Scheme 82
1,6 HAT Favored by Geometry and Bond Strengths
Scheme 83
Scheme 83
1,6 HAT with no C-H Bonds for 1,5 HAT
Scheme 84
Scheme 84
Regioselectivity of C-H Insertion
Scheme 85
Scheme 85
Asymmetric Activation of Secondary C-H Bonds
Scheme 86
Scheme 86
Asymmetric Activation of Primary C-H Bonds
Scheme 87
Scheme 87
Asymmetric Synthesis of Cyclopentanes
Scheme 88
Scheme 88
Asymmetric C-H Functionalization of Carbonyl Compounds
Scheme 89
Scheme 89
Enantioselective Aziridation
Scheme 90
Scheme 90
Diastereoselective C-H Activation
Scheme 91
Scheme 91
Use of Chiral Auxiliary in Chemistry of Alkyl Radicals
Scheme 92
Scheme 92
Lewis Acid-Catalyzed Asymmetric Addition of Alkyl Radicals
Scheme 93
Scheme 93
Use of Chiral Lewis Acid in HAT
Scheme 94
Scheme 94
Loss of Stereochemistry in HAT
Scheme 95
Scheme 95
Asymmetric C-H Insertion
Scheme 96
Scheme 96
Applications of Asymmetric C-H Insertion
Scheme 97
Scheme 97
Diastereoselective C-H Insertion
Scheme 98
Scheme 98
Diastereoselective C-H Amination
Scheme 99
Scheme 99
Retention of Stereochemistry in C-H Insertion and Amination
Scheme 100
Scheme 100
Scope of Different Strategies
Scheme 101
Scheme 101
Broadened Scope with Photoredox Catalysis for HAT
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References

    1. Cernak T, Dykstra KD, Tyagarajan S, Vachael P, Krska SW. Chem Soc Rev. 2016;45:546–576. - PubMed
    2. Wencel-Delord J, Glorius F. Nature Chem. 2013;5:369–375. - PubMed
    3. Chen DYK, Youn SW. Chem Eur J. 2012;18:9452–9474. - PubMed
    4. Yamaguchi J, Yamaguchi AD, Itami K. Angew Chem Int Ed. 2012;51:8960–9009. - PubMed
    5. Kakiuchi F, Chatani N. Adv Synth Catal. 2003;345:1077–1101.
    1. Siegbahn PEM. J Phys Chem. 1995;99:12723–12729.
    2. Martinho Simoes JA, Beauchamp JL. Chem Rev. 1990;90:629–688.
    1. Blanksby SJ, Ellison GB. Acc Chem Res. 2003;36:255–263. - PubMed
    1. Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. Chem Soc Rev. 2016;45:546–576. - PubMed
    2. Hartwig JF, Larsen MA. ACS Cent Sci. 2016;2:281–292. - PMC - PubMed
    1. Stoutland PO, Bergman RG, Nolan SP, Hoff CD. Polyhedron. 1988;7:1429–1440.

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