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C–H Functionalization

C–H functionalization has been called the holy grail of synthetic organic chemistry.1 Recent efforts across organic chemistry, organometallics, and catalysis have made serious inroads in both understanding the reactivity of C–H bonds and developing robust reactions taking advantage of this insight, suggesting that the time is right to widely introduce these tactics to the retrosynthetic lexicon.2-11 The reliable and predictable conversion of a C–H into a C–C, C–N, C–O, or C–X bond in a selective and controlled way is beneficial in terms of step economy and waste reduction.

Novel methods for C–H activation extend the number of sites that can be targeted in a given molecule, increasing the opportunity to elaborate it into a more complex product. In addition, it allows for completely different kinds of chemical bonds to be targeted in organic synthesis, particularly with high chemoselectivity. Combined with traditional functional-group chemistry, C–H functionalization considerably streamlines chemical synthesis for the construction of complex natural products and pharmaceutical compounds. While clearly there are advantages to the application of C–H functionalization logic,12 many curricula for organic chemistry have not yet been updated to reflect this approach and further information can be found in the C-H Functionalization Manual.

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A simple selectivity principle is covalent attachment of the C–H activating species to the substrate, with the geometry constraints inherent in the resultant intramolecular process limiting the potential C–H bonds to be activated.

Figure 1.General Strategy for Directed C–H Functionalization

Selectivity in Ir-Catalyzed C–H Borylation.

Figure 2.Undirected Sp2: Borylation

Undirected C–H Arylation of Heteroarenes

Figure 3.Undirected Sp2: Direct Arylation

Amine Tolerant Undirected C–H Hydroxylation

Figure 4.Undirected C–H Hydroxylation

Based Reactivity

Figure 5.Based Reactivity

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References

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Arndtsen BA, Bergman RG, Mobley TA, Peterson TH. 1995. Selective Intermolecular Carbon-Hydrogen Bond Activation by Synthetic Metal Complexes in Homogeneous Solution. Acc. Chem. Res.. 28(3):154-162. https://doi.org/10.1021/ar00051a009
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He J, Wasa M, Chan KSL, Shao Q, Yu J. 2017. Palladium-Catalyzed Transformations of Alkyl C?H Bonds. Chem. Rev.. 117(13):8754-8786. https://doi.org/10.1021/acs.chemrev.6b00622
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Wang D, Weinstein AB, White PB, Stahl SS. 2018. Ligand-Promoted Palladium-Catalyzed Aerobic Oxidation Reactions. Chem. Rev.. 118(5):2636-2679. https://doi.org/10.1021/acs.chemrev.7b00334
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Davies HML, Morton D. 2016. Recent Advances in C?H Functionalization. J. Org. Chem.. 81(2):343-350. https://doi.org/10.1021/acs.joc.5b02818
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Upp DM, Lewis JC. 2017. Selective C?H bond functionalization using repurposed or artificial metalloenzymes. Current Opinion in Chemical Biology. 3748-55. https://doi.org/10.1016/j.cbpa.2016.12.027
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Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. The medicinal chemist's toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev.. 45(3):546-576. https://doi.org/10.1039/c5cs00628g
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Yamaguchi J, Yamaguchi AD, Itami K. 2012. C?H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed.. 51(36):8960-9009. https://doi.org/10.1002/anie.201201666
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Lyons TW, Sanford MS. 2010. Palladium-Catalyzed Ligand-Directed C?H Functionalization Reactions. Chem. Rev.. 110(2):1147-1169. https://doi.org/10.1021/cr900184e
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Wencel-Delord J, Dröge T, Liu F, Glorius F. 2011. Towards mild metal-catalyzed C?H bond activation. Chem. Soc. Rev.. 40(9):4740. https://doi.org/10.1039/c1cs15083a
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Arockiam PB, Bruneau C, Dixneuf PH. 2012. Ruthenium(II)-Catalyzed C?H Bond Activation and Functionalization. Chem. Rev.. 112(11):5879-5918. https://doi.org/10.1021/cr300153j
11.
Engle KM, Mei T, Wasa M, Yu J. 2012. Weak Coordination as a Powerful Means for Developing Broadly Useful C?H Functionalization Reactions. Acc. Chem. Res.. 45(6):788-802. https://doi.org/10.1021/ar200185g
12.
Gutekunst WR, Baran PS. 2011. C?H functionalization logic in total synthesis. Chem. Soc. Rev.. 40(4):1976. https://doi.org/10.1039/c0cs00182a
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