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. 2017 May 1;8(5):4044-4050.
doi: 10.1039/c6sc05697k. Epub 2017 Mar 24.

Direct Cα-heteroarylation of structurally diverse ethers via a mild N-hydroxysuccinimide mediated cross-dehydrogenative coupling reaction

Shihui Liu  1 , Aoxia Liu  1 , Yongqiang Zhang  1 , Wei Wang  1   2
Affiliations

Direct Cα-heteroarylation of structurally diverse ethers via a mild N-hydroxysuccinimide mediated cross-dehydrogenative coupling reaction

Shihui Liu et al. Chem Sci. .

Abstract

An important challenge in the Cα-heteroarylation of ethers is the requirement of a large excess amount of ethers (that are used as solvents in many cases) to achieve effective transformations. This drawback has significantly restricted the Cα-heteroarylation of ethers to the use of simple and easily accessible ether substrates. To overcome this limitation, a new, efficient, N-hydroxysuccinimide (NHS) mediated, mild and metal-free CDC strategy for the direct Cα-heteroarylation of diverse ethers has been developed. Different to our previous benzaldehyde mediated photoredox Cα-heteroarylation, we have identified NHS as a new and efficient mediator without using light. A distinct non-photoredox engaged hydrogen-atom-transfer (HAT) mechanism that used a nitrogen-centered radical cation produced from NHS is initially revealed. Notably, only 5-10 equivalents of ethers as coupling partners are used, which allows for structurally diverse and complex ethers to engage in this process, to create highly medicinally relevant Cα-heteroarylated ethers. Furthermore, more structurally diverse heterocyclics can serve as reactants for this process.

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Figures

Fig. 1
Fig. 1. Selected bioactive compounds that contain heteroaryl α-ether functionality.
Fig. 2
Fig. 2. Cα-heteroarylation of ethers via an oxidative CDC reaction.
Scheme 1
Scheme 1. Proposed mechanism.
See this image and copyright information in PMC

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