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A general method for the metal-free, regioselective, remote C–H halogenation of 8-substituted quinolines

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Abstract

An operationally simple and metal-free protocol for geometrically inaccessible C5–H halogenation of a range of 8-substituted quinoline derivatives has been established. The reaction proceeds under air, with inexpensive and atom economical trihaloisocyanuric acid as a halogen source (only 0.36 equiv.), at room temperature. Exceptionally high generality with respect to quinoline is observed, and in most instances, the reaction proceeded with complete regioselectivity. Quinoline with a variety of substituents at the 8-position gave, exclusively, the C5-halogenated product in good to excellent yields. Phosphoramidates, tertiary amides, N-alkyl/N,N-dialkyl, and urea derivatives of quinolin-8-amine as well as alkoxy quinolines were halogenated at the C5-position via remote functionalization for the first time. This methodology provides a highly economical route to halogenated quinolines with excellent functional group tolerance, thus providing a good complement to existing remote functionalization methods of quinolin-8-amide derivatives and broadening the field of remote functionalization. The utility of the method is further showcased through the synthesis of several compounds of biological and pharmaceutical interest.

Graphical abstract: A general method for the metal-free, regioselective, remote C–H halogenation of 8-substituted quinolines

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Publication details

The article was received on 19 Sep 2017, accepted on 02 Jan 2018 and first published on 05 Jan 2018


Article type: Edge Article
DOI: 10.1039/C7SC04107A
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY license
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    A general method for the metal-free, regioselective, remote C–H halogenation of 8-substituted quinolines

    D. R. Motati, D. Uredi and E. B. Watkins, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C7SC04107A

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