期刊
CHEMICAL SCIENCE
卷 13, 期 42, 页码 12527-12532出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2sc04990b
关键词
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资金
- Sao Paulo Research Foundation - FAPESP [2021/09145-8]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) [001]
- European Union [862179]
This study describes a fast, safe, and scalable flow process for the preparation of C-4 alkylated pyridines, involving a photochemical hydrogen atom transfer event and inline removal of blocking group. The key role of benzophenone in the operative reaction mechanism has been revealed through a combination of experimental and computational studies.
The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselectivity, safety and/or scalability. Herein, we describe a fast, safe and scalable flow process which allows preparation of said C-4 alkylated pyridines. The process involves a photochemical hydrogen atom transfer (HAT) event to generate the carbon-centered radicals needed to alkylate the C-2 blocked pyridine. In a two-step streamlined flow process, this light-mediated alkylation step is combined with a nearly instantaneous inline removal of the blocking group. Notably, cheap benzophenone plays a dual role in the pyridine alkylation mechanism by activating the hydrocarbon feedstock reagents via a HAT mechanism, and by acting as a benign, terminal oxidant. The key role of benzophenone in the operative reaction mechanism has also been revealed through a combination of experimental and computational studies.
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