Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow

Autor(es)

Sanjose-Orduna, Jesus ; Silva, Rodrigo C. ; Raymenants, Fabian ; Reus, Bente ; Thaens, Jannik ; de Oliveira, Kleber T. ; Noel, Timothy

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL SCIENCE; v. 13, n. 42, p. 6-pg., 2022-10-10.

Resumo

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. (AU)

• Processo FAPESP: 21/09145-8 - Síntese de iminofosforanas a partir de nitroarenos por uma abordagem eletroquímica
• Beneficiário: Rodrigo Costa e Silva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado