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. 2017 Feb 1;8(2):1282-1287.
doi: 10.1039/c6sc03831j. Epub 2016 Oct 7.

Co/NHPI-mediated aerobic oxygenation of benzylic C-H bonds in pharmaceutically relevant molecules

Damian P Hruszkewycz  1 , Kelsey C Miles  1 , Oliver R Thiel  2 , Shannon S Stahl  1
Affiliations

Co/NHPI-mediated aerobic oxygenation of benzylic C-H bonds in pharmaceutically relevant molecules

Damian P Hruszkewycz et al. Chem Sci. .

Abstract

A simple cobalt(ii)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.

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Figures

Scheme 1
Scheme 1. Summary of major industrial radical autoxidation processes.
Scheme 2
Scheme 2. Recent work on aerobic benzylic oxygenation.
Scheme 3
Scheme 3. Simplified mechanism depicting C–H abstraction by phthalimido-N-oxyl (PINO) and radical oxygenation by O2.
Scheme 4
Scheme 4. Product-inhibition studies in Co/NHPI-catalyzed oxygenation. a1 mmol scale, orbital mixing. bGC yields with chlorobenzene as an internal standard.
Scheme 5
Scheme 5. Overcoming a limitation in Co/NHPI chemistry through the electrochemical generation of PINO.
Scheme 6
Scheme 6. Streamlined synthetic route toward AMG 579 via Co/NHPI-catalyzed benzylic oxygenation.
See this image and copyright information in PMC

References

    1. Teles H. J., Hermans I., Franz H. G. and Sheldon R. A., Oxidation in Ullmann's Encyclopedia of Industrial Chemistry, Electronic Release, Wiley-VCH, Weinheim, 2015.
    1. Partenheimer W. Catal. Today. 1995;23:69.
    2. Tomas R. A. F., Bordado J. C. M., Gomes J. F. P. Chem. Rev. 2013;113:7421. - PubMed
    3. Adamian V. A. and Gong W. H. in Liquid Phase Aerobic Oxidation Catalysis: Industrial Applications and Academic Perspectives, ed. S. S. Stahl and P. L. Alsters, Wiley-VCH, Weinheim, 2016, pp. 41–66.
    1. Weber M., Weber M. and Kleine-Boymann M., Phenol in Ullmann's Encyclopedia of Industrial Chemistry, Electronic Release, Wiley-VCH, 2004.
    1. Musser M. T., Cyclohexanol and Cyclohexanone in Ullmann's Encyclopedia of Industrial Chemistry, Electronic Release, Wiley-VCH, 2011.

    1. For metal-free conditions:

    2. Park K. K., Tsou L. K., Hamilton A. D. Synthesis. 2006:3617.
    3. Qi C., Jiang H., Huang L., Chen Z., Chen H. Synthesis. 2011:387.
    4. Zhang C., Xu Z., Zhang L., Jiao N. Tetrahedron. 2012;68:5258.
    5. Dos Santos A., El Kaim L., Grimaud L. Org. Biomol. Chem. 2013;11:3282. - PubMed
    6. Ren L., Wang L., Lv Y., Li G., Gao S. Org. Lett. 2015;17:2078. - PubMed
    7. Bao K., Li F., Liu H., Wang Z., Shen Q., Wang J., Zhang W. Sci. Rep. 2015;5:10360. - PMC - PubMed