Issue 7, 2018

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
19 Sep 2017
Accepted
02 Jan 2018
First published
05 Jan 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 1782-1788

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, 9, 1782 DOI: 10.1039/C7SC04107A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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