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Deconstructive fluorination of cyclic amines by carbon-carbon cleavage

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Science  13 Jul 2018:
Vol. 361, Issue 6398, pp. 171-174
DOI: 10.1126/science.aat6365

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A silver cleaver splits cyclic amines

Carbon-carbon single bonds are fairly unreactive when they are not strained in a tight ring. Roque et al. now report that a silver salt can cleave C–C bonds in unstrained cyclic amines such as pyrrolidines and piperidines. Paired with an electrophilic fluorine source in aqueous solution, the silver first oxidizes the α carbon adjacent to the nitrogen. Ring-opening fluorination of the β carbon then proceeds by an apparent radical mechanism. The reaction offers a versatile means of introducing fluorine to structural motifs common in pharmaceutical research.

Science, this issue p. 171

Abstract

Deconstructive functionalizations involving scission of carbon-carbon double bonds are well established. In contrast, unstrained C(sp3)–C(sp3) bond cleavage and functionalization have less precedent. Here we report the use of deconstructive fluorination to access mono- and difluorinated amine derivatives by C(sp3)–C(sp3) bond cleavage in saturated nitrogen heterocycles such as piperidines and pyrrolidines. Silver-mediated ring-opening fluorination using Selectfluor highlights a strategy for cyclic amine functionalization and late-stage skeletal diversification, establishing cyclic amines as synthons for amino alkyl radicals and providing synthetic routes to valuable building blocks.

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