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

Damoder Reddy Motati,Dilipkumar Uredi,E Blake Watkins

doi:10.1039/c7sc04107a

Damoder Reddy Motati, Dilipkumar Uredi + Show 1 more

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https://doi.org/10.1039/c7sc04107a

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Journal: Chemical Science	Publication Date: Jan 1, 2018
Citations: 109	License type: CC BY 3.0

Affiliation: Jackson Memorial Hospital

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.

Highlights

Approaches to the functionalization of unactivated carbonhydrogen (C–H) bonds is an area of great importance
Achieving site selectivity in C–H bond functionalization is a key challenge in organic synthesis due to the subtle differences in the reactivity of various C–H bonds within a given molecule
In continuation of our work on C–H bond activation/functionalization reactions;12a,20 we report an atom-economical, safe, inexpensive, air- and moisture-tolerant protocol for remote C5halogenation of an array of 8-substituted quinoline derivatives in high yields and with excellent regioselectivity at room temperature under metalfree conditions

Summary

Introduction

Approaches to the functionalization of unactivated carbonhydrogen (C–H) bonds is an area of great importance. In continuation of our work on C–H bond activation/functionalization reactions;12a,20 we report an atom-economical, safe, inexpensive, air- and moisture-tolerant protocol for remote C5halogenation (chlorination, bromination and iodination) of an array of 8-substituted quinoline derivatives in high yields and with excellent regioselectivity at room temperature under metalfree conditions. 1a was stirred with 0.36 equivalents of trichloroisocyanuric acid (TCCA) in acetonitrile to afford the desired product 2a in 98% yield in only 15 min (Table 1, entry 4).

Results

Conclusion