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. 2020 Sep 30;2020(36):5828-5832.
doi: 10.1002/ejoc.201901784. Epub 2020 Aug 18.

Selectivity in the Addition of Electron Deficient Radicals to the C 2 Position of Indoles

Yi Li  1 , Roy J Vaz  2 , Steven H Olson  2 , Mark Munson  1 , Nick A Paras  2 , Jay Conrad  2
Affiliations

Selectivity in the Addition of Electron Deficient Radicals to the C 2 Position of Indoles

Yi Li et al. European J Org Chem. .

Abstract

The addition of electron deficient radicals to the C2 position of indoles has been described in the literature as opposed to electrophilic addition at the C3 position. Density functional theory calculations were used to understand the switch in regioselectivity from C3 to C2 for indole to undergo radical additions. Electron deficient radicals have a lower barrier for reaction at C2 and a lower energy radical intermediate that benefits from benzylic radical stabilization. Trifluoromethyl radical addition has a lower energy barrier than acetonitrile radical, and the C3 addition transition state is just 0.8 kcal/mol higher than C2. This is supported by experimental observations.

Keywords: density functional calculations; photocatalysis; radical reactions.

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Figures

Figure 1.
Figure 1.
A) Diagram of indole HOMO. B) Natural population analysis charges for indole. C) Divergent addition regiochemistry for electrophiles (C3) and D) electron deficient radicals (C2).
Figure 2.
Figure 2.
Examples of photoredox-mediated radical addition to the 2-position of indoles.
Figure 3.
Figure 3.
Transition state and intermediate energies (estimated ΔGf°) for the addition of acetonitrile radical to indole at either the C2 (2) or C3 (3) position using the M06-2X/CC-PVQZ(-g) method.
Figure 4.
Figure 4.
Transition state and estimated intermediate energies (estimated ΔGf°) for the addition of trifluoromethyl radical to indole at either the C2 (2) or C3 (3) position using the M06-2X/CC-PVQZ(-g) method.
Figure 5.
Figure 5.
Oxidation of radical intermediates to M06-2X/CC-PVQZ(-g) fully optimized cations followed by deprotonation and rearomatization to provide indole addition products 2d,h or 3d,h.
Figure 6.
Figure 6.
Spin density and relative energies in solution for 2b,f and 3b,f using the M06-2X/CC-PVQZ(-g) method.
Figure 7.
Figure 7.
A) Comparison of C2 or C3 trifluoromethyl substituted cations. B) Comparison of C2 or C3 protonation using the M06-2X/CC-PVQZ(-g) method.
See this image and copyright information in PMC

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