Sanjosé-Orduna Jesús, Silva Rodrigo C, Raymenants Fabian, Reus Bente, Thaens Jannik, de Oliveira Kleber T, Noël Timothy
Flow Chemistry Group, Van't Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam Science Park 904 1098 XH Amsterdam The Netherlands
Departamento de Química, Universidade Federal de São Carlos SP 13565-905 Brazil.
Chem Sci. 2022 Oct 10;13(42):12527-12532. doi: 10.1039/d2sc04990b. eCollection 2022 Nov 2.
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 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.
吡啶的高效C-4选择性修饰是合成领域面临的一项重大挑战。目前的策略在杂芳烃的官能团耐受性电子活化、所需烷基自由基的温和生成、区域选择性、安全性和/或可扩展性方面至少存在一个缺点。在此，我们描述了一种快速、安全且可扩展的流动过程，该过程能够制备所述的C-4烷基化吡啶。该过程涉及光化学氢原子转移（HAT）事件，以生成将C-2位被保护的吡啶烷基化所需的碳中心自由基。在一个两步简化流动过程中，这种光介导的烷基化步骤与几乎瞬间的在线脱保护步骤相结合。值得注意的是，廉价的二苯甲酮在吡啶烷基化机制中发挥双重作用，通过HAT机制活化烃类原料试剂，并作为一种良性的终端氧化剂。通过实验和计算研究相结合，也揭示了二苯甲酮在反应机制中的关键作用。
