Transition-metal-free allylation of 2-azaallyls with allyl ethers through polar and radical mechanisms

Guogang Deng,Xiaodong Yang,Zhuo Chen,Patrick J Walsh,Shengzu Duan,Jing Wang,Hongbin Zhang,Wen Chen,Tongqi Liu

doi:10.1038/s41467-021-24027-6

Guogang Deng, Xiaodong Yang + Show 7 more

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https://doi.org/10.1038/s41467-021-24027-6

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Allylation of nucleophiles with highly reactive electrophiles like allyl halides can be conducted without metal catalysts. Less reactive electrophiles, such as allyl esters and carbonates, usually require a transition metal catalyst to facilitate the allylation. Herein, we report a unique transition-metal-free allylation strategy with allyl ether electrophiles. Reaction of a host of allyl ethers with 2-azaallyl anions delivers valuable homoallylic amine derivatives (up to 92%), which are significant in the pharmaceutical industry. Interestingly, no deprotonative isomerization or cyclization of the products were observed. The potential synthetic utility and ease of operation is demonstrated by a gram scale telescoped preparation of a homoallylic amine. In addition, mechanistic studies provide insight into these C(sp3)–C(sp3) bond-forming reactions.

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Allylation of nucleophiles with highly reactive electrophiles like allyl halides can be conducted without metal catalysts
We found that deprotonation of N-benzyl imines 1 generated semistabilized 2-azaallyl anions that readily undergo single electron transfer (SET) with a variety of electrophiles[85], generating 2-azaallyl anion intermediates that are persistent radicals[88]
Inspired by the work of Murphy and coworkers on organic super electron donors (SEDs)[89,90,91,92,93,94,95,96], we demonstrated that 2-azaallyl anions served as SEDs and enabled transitionmetal-free C−C bond formation via reduction of aryl or alkyl iodides followed by radical recombination with the resulting 2-azaallyl radical (Fig. 2a)

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Introduction

Allylation of nucleophiles with highly reactive electrophiles like allyl halides can be conducted without metal catalysts. Inspired by the work of Murphy and coworkers on organic super electron donors (SEDs)[89,90,91,92,93,94,95,96], we demonstrated that 2-azaallyl anions served as SEDs and enabled transitionmetal-free C−C bond formation via reduction of aryl or alkyl iodides followed by radical recombination with the resulting 2-azaallyl radical (Fig. 2a) This SED approach was further used for the preparation of benzofurylethylamines (Fig. 2b) and isochromene derivatives via SET from the 2-azaallyl anion, radical cyclization, and intermolecular radical–radical coupling reactions[97,98]. We describe coupling of 2-azaallyl species with allyl phenyl ether electrophiles to furnish SN2- and SN2ʹ-type allylation products in good yields This allylation approach enables the synthesis of homoallylic amines bearing various functional groups (38 examples, up to 92% yield).

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