Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6323, United States.
J Am Chem Soc. 2017 Sep 6;139(35):12251-12258. doi: 10.1021/jacs.7b05899. Epub 2017 Aug 23.
Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a C-centered radical that can engage in the C-H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C-H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears.
在氧化条件下，1,4-二氢吡啶（DHPs）经历均裂裂解，仅形成可以参与杂环碱基和 1,4-醌的 C-H 烷基化的 C 中心自由基。DHPs 可从醛轻易制备，并且考虑到醛通常需要苛刻的反应条件才能参与此类转化，通常会得到烷基化和酰化产物的混合物，因此这种净脱羰烷基化方法变得特别有用。本方法在温和的反应条件下进行，仅需要过硫酸盐作为化学计量氧化剂，使得该方法适用于复杂分子的后期 C-H 烷基化。值得注意的是，结构复杂的药物制剂可以通过该方案进行官能化或制备，例如抗疟药阿托伐醌和抗泰勒菌的帕拉喹酮，从而证明了其适用性。机理研究表明，通过形成去芳构化中间体，可能存在自由基链过程，为这些自由基前体的反应性的控制因素提供了更深入的了解。
