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. 2021 May 7;23(9):3389-3393.
doi: 10.1021/acs.orglett.1c00831. Epub 2021 Apr 15.

Photochemical Regioselective C(sp3)-H Amination of Amides Using N-Haloimides

Lei Pan  1 , Joseph Elmasry  1 , Tomas Osccorima  1 , Maria Victoria Cooke  1 , Sébastien Laulhé  1
Affiliations

Photochemical Regioselective C(sp3)-H Amination of Amides Using N-Haloimides

Lei Pan et al. Org Lett. .

Abstract

A metal-free regioselective C(sp3)-H amination of amides using N-haloimides in the presence of lithium tert-butoxide and visible light is presented herein. This photoexcited approach is straightforward, and it aminates a wide variety of amides under mild conditions without the use of photocatalysts, external radical initiators, or oxidants. A halogen-bonded intermediate between the tert-butoxide base and the N-haloimide is proposed to be responsible for the increased photoreactivity. Calculations show that the formation of this electron donor-acceptor complex presents an exergonic energy profile.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Amination of amides with N-bromophthalimide. Reaction conditions: 1a (0.2 mmol), 2 (1.0 mmol), LiOtBu (0.2 mmol), 1.0 mL of PhCl, room temperature around the reaction flask of 35 °C (heating caused by the LED lamp), overnight. Isolated yields.
Figure 2.
Figure 2.
Amination of amides by N-halosaccharins. Reaction conditions: 1b (0.2 mmol), 2 (1.0 mmol), LiOtBu (0.2 mmol), 1.0 mL of PhCl, room temperature around the reaction flask of 35 °C (heating caused by the LED lamp), overnight. Isolated yields.
Figure 3.
Figure 3.
Amination of Boc-protected amines. Reaction conditions: 1 (0.2 mmol), 4 (1.0 mmol), LiOtBu (0.2 mmol), 1.0 mL of PhCl, room temperature around the reaction flask of 35 °C (heating caused by the LED lamp), overnight. Isolated yields.
Scheme 1.
Scheme 1.
(A) Examples of FDA-Approved Drugs Containing the Amido Aminal Group, (B) Current Methods for Accessing the Amido Aminal Functional Group That Require the Use of Catalysts and Strong Oxidants at High Temperatures, and (C) Our Photoexcited C–H Activation under Mild Reaction Conditions
Scheme 2.
Scheme 2.
(A) Radical Trapping Experiments, (B) Control Experiments, and (C) Proposed Reaction Mechanism
See this image and copyright information in PMC

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