Wang W,
Yang X,
Dai R,
Yan Z,
Wei J,
Dou X,
Qiu X,
Zhang H,
Wang C,
Liu Y,
Song S,
*,
Jiao N.
*
Peking University, Beijing, Zhejiang University of Technology, Hangzhou, and Shanghai
Institute of Organic Chemistry, P. R. of China
Catalytic Electrophilic Halogenation of Arenes with Electron-Withdrawing Substituents.
J. Am. Chem. Soc. 2022; 13415-13425
DOI:
10.1021/jacs.2c06440
Key words
electrophilic halogenation - electron-deficient arenes - Brønsted acid catalysis -
hexafluoroisopropanol
Significance
Song, Jiao, and co-workers report a Brønsted acid-catalyzed electrophilic halogenation
of electron-deficient arenes by using readily available halogenation reagents and
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a hydrogen-bond activator. Numerous sensitive
electron-withdrawing substituents are tolerated under the reaction conditions, yielding
various aryl halides in moderate to excellent yields.
Comment
Experimental investigations provide support for an electrophilic mechanism in which
both 2-methyl-5-nitrobenzenesulfonic acid (m-NBSA) and HFIP synergistically activate the halogenating reagent. The authors have
developed an effective halogenation system for a broad scope of challenging electron-deficient
arenes with excellent functional-group tolerance. The potential of the method is demonstrated
by late-stage halogenation of bioactive molecules and by a successful application
in drug synthesis.
