Predictable site-selective functionalization: Promoter group assisted para-halogenation of N-substituted (hetero)aromatics under metal-free condition
- 21 October 2021
- journal article
- research article
- Published by Royal Society of Chemistry (RSC) in Organic & Biomolecular Chemistry
- Vol. 19 (44), 9675-9687
- https://doi.org/10.1039/d1ob02000e
Abstract
Herein, regioselective para-C-H halogenation of N-pyrimidyl (hetero)aromatics through SEAr (Electrophilic aromatic substitution) type reaction is disclosed. SEAr type reaction has been utilized for the C5-bromination of indolines (para-selective) with N-bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. Pyrimidyl group is identified as a reactivity tuner which also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge map also supports the observed p-selectivity. Post-functionalization of the title compound into corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, chlorzoxazone) to demonstrate the applicability of the developed protocol.Funding Information
- Council of Scientific and Industrial Research, India (MLP0159)
- University Grants Commission
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