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  • Directed C-H Activation: by Nicholas Massaro

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    Arianne
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    This document summarizes research on the directed C-H functionalization of aldehydes and ketones using amino acid directing groups. It first reviews previous work in this area, focusing on peptide C-H activation using directing groups. It then describes the authors' work optimizing the reaction using glycine as a directing group for benzaldehyde derivatives. The authors expanded the scope of the reaction to ketimines, overcoming challenges related to ketone reactivity. Finally, the authors achieved enantioselective C-H arylation of aldehydes and ketones using a chiral catalyst ligand.

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    This document summarizes research on the directed C-H functionalization of aldehydes and ketones using amino acid directing groups. It first reviews previous work in this area, focusing on peptide C-H activation using directing groups. It then describes the authors' work optimizing the reaction using glycine as a directing group for benzaldehyde derivatives. The authors expanded the scope of the reaction to ketimines, overcoming challenges related to ketone reactivity. Finally, the authors achieved enantioselective C-H arylation of aldehydes and ketones using a chiral catalyst ligand.

    Copyright:

    © All Rights Reserved
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    81 views11 pages

    Directed C-H Activation: by Nicholas Massaro

    Uploaded by

    Arianne
    This document summarizes research on the directed C-H functionalization of aldehydes and ketones using amino acid directing groups. It first reviews previous work in this area, focusing on peptide C-H activation using directing groups. It then describes the authors' work optimizing the reaction using glycine as a directing group for benzaldehyde derivatives. The authors expanded the scope of the reaction to ketimines, overcoming challenges related to ketone reactivity. Finally, the authors achieved enantioselective C-H arylation of aldehydes and ketones using a chiral catalyst ligand.

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    of 11

    Sp3 2-4 bonds

    to next exit

    Directed C-H
    Activation

    By Nicholas Massaro
    C—H Functionalization

    Usually
    Carbon is sp2 or sp3

    This type of catalytic cycle might seem familiar 

    Suzuki
    Kumada
    Stille
    Negishi
    Angew. Chem. Int. Ed. 2009, 48, 5094–5115
    Acc. Chem. Res., 2009, 42 (8), pp 1074–1086 2
    Directed C—H Functionalization
    Common Challenges

    • Design of new directing

    • sp2 C−H bonds to sp3 C−H bonds

    • Enhancement of the catalytic


    efficiency

    • earth-abundant catalysts

    J. Org. Chem., 2016, 81 (2), pp 343–350 3


    Functionalization of C(sp3)–H bonds using a transient directing group
    Science 15 Jan 2016: Vol. 351, Issue 6270, pp. 252-256 DOI: 10.1126/science.aad7893
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
    California 92037, United States
    Fang-Lin Zhang,* Kai Hong,* Tuan-
    Jie Li,* Hojoon Park, Jin-Quan Yu†

    Previous Work in this field


    J. AM. CHEM. SOC. 2008, 130, 7190–7191 Pd(II) catalyzed cross coupling of boronic acids
    Angew. Chem. Int. Ed. 2008, 47, 4882–4886 enantioselectivePd(II) catalyzed cross coupling of boronic acids
    Angew. Chem. Int. Ed. 2009, 48, 5094–5115 A review on these discoveries
    Science 327, 315–319 (2010). Ligand-Enabled Reactivity and Selectivity in Aryl C–H Olefination
    Science 343, 1216–1220 (2014). Ligand-Controlled C(sp3)–H Arylation with Amino Acids
    J. Am. Chem. Soc. 2014, 136, 16940−16946 Site-Selective C(sp3)−H Funct. of Di-, Tri-, and Tetrapeptides
    4
    Two Strategies for Directed C—H Activation

    Major drawback Concerns


    Not always suitable for complex molecules • Directing Group deactivating catalyst
    • Association/Dissociation Equilibrium
    of Directing Group
    Science 15 Jan 2016: Vol. 351, Issue 6270, pp. 252-256 DOI: 10.1126/science.aad7893
    5
    Pioneering to Present
    Other Research

    Previously Highlighted Research


    Selective Peptide C—H Activation

    This Work
    Further Exploiting Amino Acid
    Directing Groups

    Science 15 Jan 2016: Vol. 351, Issue 6270, pp. 252-256 DOI: 10.1126/science.aad7893
    6
    Initial Optimization

    • Benzaldehyde Derivatives
    • Glycine
    • Discovered rate mismatch
    • Expansion of Scope for Direct
    arylation of aldehydes

    Science 15 Jan 2016: Vol. 351, Issue 6270, pp. 252-256 DOI: 10.1126/science.aad7893
    7
    Expanding to Ketimines

    • Directed C(sp3) was only previously


    studied with oxime utilization
    • Directed arylation of ketones had
    multiple challenges
    • Ketimine vs aldimine
    • E/Z isomers
    • Tautomerization
    • Aliphatic aldehydes were not suitable

    • Achievements

    Science 15 Jan 2016: Vol. 351, Issue 6270, pp. 252-256 DOI: 10.1126/science.aad7893
    8
    Enantioselective C—H arylation

    • Sidechain Bulk influences er


    • Catalyst Ligand Ratio was changed

    Science 15 Jan 2016: Vol. 351, Issue 6270, pp. 252-256 DOI: 10.1126/science.aad7893
    9
    Thank you

    10
    Mechanism of the Week

    To a stirred solution of 2-iodo-m-xylene (23.2 mg, 0.100 mmol) in toluene (1 mL) was added
    Pd(OAc)2 (2.3 mg, 0.0102 mmol), Ad2PnBu (7.2 mg, 0.0201 mmol) and Cs2CO3 (97.7 mg, 0.300
    mmol) at room temperature and the reaction mixture was heated to 100 °C. After stirring for 10
    min, 1-isocyano-2(phenylethynyl)benzene 4 (0.200 mmol) in toluene (2 mL) was added for 3 h and
    stirred for 100 °C. After stirring for 1 h, the reaction mixture was neutralized by saturated aqueous
    solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried
    over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica
    gel column chromatography (hexane/EtOAc = 97/3) to give 4 (20.4 mg, 66%) as a colorless
    crystal. 11
    Org. Lett., 2012, 14 (16), pp 4270–4273

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