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Synthesis 2024; 56(17): 2663-2669
DOI: 10.1055/s-0043-1775370
DOI: 10.1055/s-0043-1775370
paper
Special Issue Flow Chemistry
Rapid and Mild Nucleophilic Substitution of a Highly Active (Indol-2-yl)methyl Electrophile in a Microflow Reactor
This work was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from Japan Agency for Medical Research and Development (AMED) under Grant Number JP23ama121044, and Moonshot R&D Program from Japan Science and Technology Agency (JST) under Grant Number JPMJMS2236.
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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1775370.
- Supporting Information
Publication History
Received: 09 April 2024
Accepted after revision: 17 May 2024
Article published online:
13 June 2024
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Nucleophilic substitution at the 2′-position of 2-(bromomethyl)-1-methyl-indole was reported, but the detailed procedure and the yield were not presented, see:
For recent selected reviews of continuous flow synthesis, see:
For selected publications on flash chemistry, see:
For pioneering and recent works on flow microsynthesis using highly reactive carbocations, see:
We also reported nucleophilic addition of alkyllithiums to indole-3-carbaldehydes and subsequent nucleophilic substitution at the 3′-position, see:
We recently reported highly electrophilic cation generation from diarylmethanols and furfuryl alcohols and their use for subsequent nucleophilic substitutions, see: