Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 May 14;9(24):5360-5365.
doi: 10.1039/c8sc01756e. eCollection 2018 Jun 28.

Reagent-dictated site selectivity in intermolecular aliphatic C-H functionalizations using nitrogen-centered radicals

Anthony M Carestia  1 , Davide Ravelli  2 , Erik J Alexanian  1
Affiliations

Reagent-dictated site selectivity in intermolecular aliphatic C-H functionalizations using nitrogen-centered radicals

Anthony M Carestia et al. Chem Sci. .

Abstract

The site selectivities of intermolecular, aliphatic C-H bond functionalizations are central to the value of these transformations. While the scope of these reactions continues to expand, the site selectivities remain largely dictated by the inherent reactivity of the substrate C-H bonds. Herein, we introduce reagent-dictated site selectivity to intermolecular aliphatic C-H functionalizations using nitrogen-centered amidyl radicals. Simple modifications of the amide lead to high levels of site selectivity in intermolecular C-H functionalizations across a range of simple and complex substrates. DFT calculations demonstrate that the steric demand of the reacting nitrogen-centered radical is heavily affected by the substitution pattern of the starting amide. Optimization of transition state structures consistently indicated higher reagent-dictated steric selectivities using more hindered amides, consistent with experimental results.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Substrate versus reagent control in site-selective, intermolecular aliphatic C–H functionalizations involving nitrogen-centered radicals.
Fig. 2
Fig. 2. Reagent-dictated site selectivities (%) in C–H chlorinations of diverse substrates. Yields provided are for reactions using reagent 6. Reactions were performed in PhCF3 at 65 °C using (2 × 10 mol%) benzoyl peroxide as initiator with 1 equiv. of substrate, 0.5 equiv. of Cs2CO3, and 1–1.5 equiv. N-chloroamide. Yields and selectivities were determined by GC with dodecane as an internal standard or 1H NMR analysis. See ESI for further details regarding the distribution of minor products. a3 equiv. of substrate used. b5 equiv. of substrate used. cSecondary site selectivity includes all secondary chlorination products.
Fig. 3
Fig. 3. C–H chlorinations of complex natural products. See the ESI for reaction details. Yields and selectivities were determined by GC with dodecane as an internal standard or 1H NMR analysis. a3 equiv. of substrate used.
Fig. 4
Fig. 4. Similar reagent-dictated site selectivities are observed in C–H brominations and xanthylations. Combined yields and site selectivities determined by 1H NMR analysis.
Fig. 5
Fig. 5. OLEX2 structure of N-chloroamide 6.
Fig. 6
Fig. 6. Optimized structures of amidyl radicals 3′ and 6′, including their spin density plots and some relevant parameters.
Fig. 7
Fig. 7. Optimized structures of the TS for the reactive primary C–H abstraction of 3-methylpentane by 3′ (left) and 6′ (right).
See this image and copyright information in PMC

References

    1. Cernak T., Dykstra K. D., Tyagarajan S., Vachal P., Krska S. W. Chem. Soc. Rev. 2016;45:546–576. - PubMed
    2. Yan M., Lo J. C., Edwards J. T., Baran P. S. J. Am. Chem. Soc. 2016;138:12692–12714. - PMC - PubMed
    3. White M. C. Science. 2012;335:807–809. - PubMed
    1. Newhouse T., Baran P. S. Angew. Chem., Int. Ed. 2011;50:3362–3374. - PMC - PubMed
    2. Salamone M., Bietti M. Acc. Chem. Res. 2015;48:2895–2903. - PubMed

    1. ; For an example using a non-metal see:

    2. Liao K., Negretti S., Musaev D. G., Bacsa J., Davies H. M. L. Nature. 2016;533:230–234. - PubMed
    3. Gormisky P. E., White M. C. J. Am. Chem. Soc. 2013;135:14052–14055. - PubMed
    4. Gómez L., Canta M., Font D., Prat I., Ribas X., Costas M. J. Org. Chem. 2013;78:1421–1433. - PubMed
    5. Cook B. R., Reinert T. J., Suslick K. S. J. Am. Chem. Soc. 1986;108:7281–7286.
    6. Moteki S. A., Usui A., Zhang T., Alvarado C. R. S., Maruoka K. Angew. Chem., Int. Ed. 2013;52:8657–8660. - PubMed
    1. Narayan A. R. H., Jimenez-Oses G., Liu P., Negretti S., Zhao W., Gilbert M. M., Ramabhadran R. O., Yang Y.-F., Furan L. R., Li Z., Podust L. M., Montgomery J., Houk K. N., Sherman D. H. Nat. Chem. 2015;7:653–660. - PMC - PubMed
    2. Negretti S., Narayan A. R. H., Chiou K. C., Kells P. M., Stachowski J. L., Hansen D. A., Podust L. M., Montgomery J., Sherman D. H. J. Am. Chem. Soc. 2014;136:4901–4904. - PMC - PubMed
    3. Zhang K., El Damaty S., Fasan R. J. Am. Chem. Soc. 2011;133:3242–3245. - PubMed
    1. Schmidt V. A., Quinn R. K., Brusoe A. T., Alexanian E. J. J. Am. Chem. Soc. 2014;136:14389–14392. - PubMed
    2. Quinn R. K., Könst Z., Michalak S. E., Schmidt Y., Szklarski A. R., Flores A. R., Nam S., Horne D. A., Vanderwal C. D., Alexanian E. J. J. Am. Chem. Soc. 2016;138:696–702. - PMC - PubMed
    3. Czaplyski W. L., Na C. G., Alexanian E. J. J. Am. Chem. Soc. 2016;138:13854–13857. - PMC - PubMed