Research Article

Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts

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Science  19 Mar 2021:
Vol. 371, Issue 6535, pp. 1232-1240
DOI: 10.1126/science.abg0781

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Sequentially snipping off fluorines

It is often useful in pharmaceutical or agrochemical research to modify the properties of carbon compounds by appending one or more fluorine atoms. However, the methods used to prepare mono-, di-, or trifluorocarbon centers tend to differ from each other in inconvenient ways. Yu et al. developed a radical reaction that can successively remove one or two fluorine atoms from trifluoromethyl groups adjacent to amides or esters. The mechanism relies on a spin-center shift after attack at the carbonyl oxygen by a boryl radical.

Science, this issue p. 1232

Abstract

Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, the controllable replacement of one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe a general strategy for sequential carbon-fluorine (C–F) bond functionalizations of trifluoroacetamides and trifluoroacetates. The reaction begins with the activation of a carbonyl oxygen atom by a 4-dimethylaminopyridine-boryl radical, followed by a spin-center shift to trigger the C–F bond scission. A chemoselectivity-controllable two-stage process enables sequential generation of difluoro- and monofluoroalkyl radicals, which are selectively functionalized with different radical traps to afford diverse fluorinated products. The reaction mechanism and the origin of chemoselectivity were established by experimental and computational approaches.

  • Corresponding author. Email: houk{at}chem.ucla.edu (K.N.H.); yfwangzj{at}ustc.edu.cn (Y.-F.W.)

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