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Diverting Radical-Anionic C-H Amidation to a C-N/C-O Cascade for the Construction of Hydroxyisoindolines from Unprotected Amides

preprint
submitted on 04.09.2019 and posted on 06.09.2019 by Quintin Elliott, Gabriel dos Passos Gomes, Christopher Evoniuk, Igor Alabugin

An intramolecular C(sp3)-H amidation proceeds in the presence of t-BuOK, molecular oxygen, and DMF. The success of this reaction hinges on the deprotonation of a mildly acidic N-H bond and selective radical activation of a benzylic C(sp3)-H bond towards hydrogen atom transfer (HAT). DFT calculations suggest a thermodynamically favorable sequence of steps mediated by the generation of a radical-anion intermediate. As this intermediate starts to form a two-centered/three-electron (2c,3e)C-N bond, the extra electron is “ejected” into the π*-orbital of the aromatic core. The resulting cyclic radical-anion is readily oxidized by molecular oxygen to forge the C-N bond of the product. The transformation of a relatively weak reductant into a stronger reductant (i.e., “reductant upconversion”) allows one to use mild oxidants such as molecular oxygen. In contrast, the second stage of NH/CH activation forms a highly stabilized radical-anion intermediate incapable of electron transfer to molecular oxygen. Hence, the oxidation is impossible and an alternative reaction path opens via coupling between the radical anion intermediate and either superoxide or hydroperoxide radical. The hydroperoxide intermediate transforms into the final hydroxyisoindoline products under basic conditions. The use of TEMPO as an additive was found to activate less reactive amides. The combination of experimental and computational data outlines a conceptually new mechanism for the conversion of unprotected amides into hydroxyisoindolines proceeding as a sequence of C-H amidation and C-H oxidation.

Funding

PRF#57377-ND4

CHE-1465142

TG-CHE160006

History

Email Address of Submitting Author

gabriel.gomes@utoronto.ca

Institution

Florida State University

Country

United States of America

ORCID For Submitting Author

0000-0002-8235-5969

Declaration of Conflict of Interest

The authors declare no conflict of interest.

Version Notes

First version of this manuscript.

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