Rapid and Mild Nucleophilic Substitution of a Highly Active (Indol-2-yl)methyl Electrophile in a Microflow Reactor

Synthesis Pub Date : 2024-06-13 DOI:10.1055/s-0043-1775370
Shinichiro Fuse, Yuma Matsuura, Naoto Yamasaki
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Abstract

Indoles are common motifs in functional agricultural and pharmaceutical molecules. Heteroatom alkylation is the most frequently used chemical reaction in the pharmaceutical field. Developing protocols for the nucleophilic substitution of (indol-2-yl)methyl electrophiles is important for functionalizing indoles. There are few studies on the nucleophilic substitution at the 2′-position of the electrophiles without an electron-withdrawing group at the 1-position or substituents at the 2′- and 3-positions, where the existing approaches require high temperatures and long reaction times. In this study, we demonstrated rapid (7–12 s) and mild (25 °C) microflow nucleophilic substitution at the 2′-position of indole derivatives without an electron-withdrawing group at the 1-position and substituents at the 2′- or 3-positions. Comparable batch conditions resulted in a lower yield.

Abstract Image

在微流反应器中快速温和地亲核取代高活性(吲哚-2-基)甲基亲电子体
吲哚是功能性农业和医药分子中常见的基团。异原子烷基化是制药领域最常用的化学反应。开发(吲哚-2-基)甲基亲核取代亲电体的方案对于吲哚的功能化非常重要。在亲电体的 2′位上进行亲核取代的研究很少,因为在 1 位上没有抽电子基团,或在 2′和 3 位上没有取代基,现有的方法需要高温和较长的反应时间。在本研究中,我们证明了在 2′位上对吲哚衍生物进行快速(7-12 秒)、温和(25 °C)的微流亲核取代反应,而在 1 位上不含取电子基团,在 2′或 3 位上也不含取代基。类似的批次条件导致产率较低。
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