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Sp3 2-4 bonds

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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
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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
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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
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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
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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
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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
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Thank you

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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