Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA, 02139, USA.
Angew Chem Int Ed Engl. 2017 Jul 17;56(30):8823-8827. doi: 10.1002/anie.201704529. Epub 2017 Jun 20.
A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N-alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst-free conditions. This assembly-line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four-step, telescoped synthesis of measles therapeutic, AS-136A, in a total residence time of 31.7 min (1.76 g h ).
已经开发出一种快速且模块化的连续流动合成高度官能化的氟代吡唑和吡唑啉的方法。通过连续的反应器线圈使氟化胺流动，介导重氮烷烃的形成和[3+2]环加成，以缩合方式生成 30 多种唑类化合物。然后通过附加的反应器模块对吡唑核心进行顺序修饰，进行 N-烷基化和芳基化、脱保护和酰胺化，以短时间内引入广泛的分子多样性。连续流动合成能够在高温下安全处理重氮烷烃，并在无催化剂条件下使用芳基炔二极性试剂。这种装配线合成为农药和药物的合成提供了一种灵活的方法，通过三步、缩合合成麻疹治疗剂 AS-136A，总停留时间为 31.7 分钟（1.76 克/小时），证明了这一点。
