An intramolecular C(sp 3 )–H amidation proceeds in the presence of t -BuOK, molecular oxygen, and DMF. This transformation is initiated by the deprotonation of an acidic N–H bond and selective radical activation of a benzylic C–H bond towards hydrogen atom transfer (HAT). Cyclization of this radical–anion intermediate en route to a two-centered/three-electron (2c,3e) C–N bond removes electron density from nitrogen. As this electronegative element resists such an “oxidation”, making nitrogen more electron rich is key to overcoming this problem. This work dramatically expands the range of N-anions that can participate in this process by using amides instead of anilines. The resulting 10 7 -fold decrease in the N-component basicity (and nucleophilicity) doubles the activation barrier for C–N bond formation and makes this process nearly thermoneutral. Remarkably, this reaction also converts a weak reductant into a much stronger reductant. Such “reductant upconversion” allows mild oxidants like molecular oxygen to complete the first part of the cascade. In contrast, the second stage of NH/CH activation forms a highly stabilized radical–anion intermediate incapable of undergoing electron transfer to oxygen. Because the oxidation is unfavored, 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 conversion of unprotected amides into hydroxyisoindolines proceeding as a sequence of C–H amidation and C–H oxidation.
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Two Paths to Oxidative C−H Amination Under Basic Conditions: A Theoretical Case Study Reveals Hidden Opportunities Provided by Electron Upconversion**
Traditionally, cross‐dehydrogenative coupling (CDC) leads to C−N bond formation under basic and oxidative conditions and is proposed to proceed via a two‐electron bond formation mediated by carbenium ions. However, the formation of such high‐energy intermediates is only possible in the presence of strong oxidants, which may lead to undesired side reactions and poor functional group tolerance. In this work we explore if oxidation under basic conditions allows the formation of three‐electron bonds (resulting in “upconverted” highly‐reducing radical‐anions). The benefit of this “upconversion” process is in the ability to use milder oxidants (e. g., O2) and to avoid high‐energy intermediates. Comparison of the two‐ and three‐electron pathways using quantum mechanical calculations reveals that not only does the absence of a strong oxidant shut down two‐electron pathways in favor of a three‐electron path but, paradoxically, weaker oxidants react faster with the upconverted reductants by avoiding the inverted Marcus region for electron transfer.
more » « less- Award ID(s):
- 2102579
- NSF-PAR ID:
- 10370379
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Chemistry – A European Journal
- Volume:
- 28
- Issue:
- 60
- ISSN:
- 0947-6539
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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