Chemoselective N‐Alkylation of Indoles in Aqueous Microdroplets

Abstract

Many reactions showmuchfaster kinetics in microdroplets than in the bulk phase.M ost reported reactions in microdroplets mirror the products found in bulk reactions. However,t he unique environment of microdroplets allows different chemistry to occur.I nt his work, we present the first chemoselective N-alkylation of indoles in aqueous microdroplets via athree-component Mannich-type reaction without using any catalyst. In sharp contrast, bulk reactions using the same reagents with ac atalyst yield exclusively C-alkylation products.The N-alkylation yield is moderate in microdroplets, up to 53 %. We extended the scope of the microdroplet reaction and obtained as eries of new functionalizedi ndole aminals, which are likely to have biological activities.This work clearly indicates that microdroplet reactions can show reactivity quite different from that of bulk-phase reactions,w hich holds great potential for developing novel reactivities in microdroplets.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Accelerated reactions of amines with carbon dioxide driven by superacid at the microdroplet interface

“…The protonated carbon dioxide and deprotonated amine reactions are of special interest because these forms of the reagents could arise from superacid/superbase reactions at the interface as discussed in the Introduction. 28 Previous reports 28,[30][31][32][33][34] have suggested that superacid (extreme pH) at the interface of organic droplets (and dielectric layers at the interface of water microdroplets) accelerate reactions. These results indicated the importance of water, even traces of water 28 in interfacial microdroplet chemistry.…”

“…[26][27][28] Most studies of reaction acceleration have been done in organic solvents but aqueous droplet reactions are also well represented. [29][30][31][32][33] Active species generated in the dielectric layer at the surface of water microdroplets include free radicals and hydrogen peroxide. 29,30,34 In very signicant work, the strong electric eld at the surface of aqueous droplets was recognized as playing a crucial role in reaction acceleration due to hydronium and hydroxide ion formation by ready autoionization of water at the surface.…”

Catalyst‐Free Accelerated Three‐Component Synthesis of Betti Bases in Microdroplets

“…It was surprisingly observed that several reactions in microdroplets followed a different pathway from the bulk. A typical example is chemoselective N ‐alkylated indoles in microdroplets without any catalysts in comparison with the formation of C ‐alkylated indoles in the corresponding bulk reactions [34] . Similar extraordinary transformation pathways including the formation of gold and N ‐heterocyclic carbenes, [35] cyclic reaction by dual Schiff reactions, [36] and ester hydrolysis [37] have also been discovered by microdroplet reactions.…”

“…Soon later Gnanamani et al. achieved chemoselective N ‐alkylation of indole in aqueous microdroplets through a three‐component Mannich‐type reaction [34] . In sharp contrast, the bulk reaction using the same reagents and catalysts only produces C ‐alkylation products.…”

Direct Liquid Extraction and Ionization Techniques for Understanding Multimolecular Environments in Biological Systems (Secondary Publication)

“…Studies of the change in reaction products against time (µs to ms) between the formation of the charged droplet and its introduction into the mass spectrometer showed that charged droplets help accelerate chemical reactions, including the formation of hydrazine 196) , the demetallation of chlorophyll 197) , Hantzsch synthesis 198) , catalyst-free Nalkylation of indole 199) , synthesis of ribonucleosides 200,201) , acid-induced unfolding of cytochrome c, hydrogendeuterium exchange in bradykinin 202) and angiotensin I 203) , and the Baeyer-Villiger reaction 204) . For more detailed descriptions, we refer the reader to comprehensive reviews [205][206][207] .…”