Dearomatization of 3-cyanoindoles by (3 + 2) cycloaddition: from batch to flow chemistry

Abstract

(3 + 2) Dearomatizing cycloaddition of 3-cyanoindoles occurs in smooth conditions with a non-stabilized azomethine ylide, to yield tricyclic indolines in only 1 min under microflow conditions using 3 equiv of the dipole precursor vs. 6 equiv. in a batch reactor.

Flow dearomatization of electron-poor 3-fluoromethylthioindoles by 1,3-dipolar cycloaddition

“…Expectedly, the 3thiomethylindole was the least electrophilic of the series (entry 8). These values are in full adequation with the experimental results, 12,13 and illustrate the usefulness of this parameter for further evaluation of the reactivity of electrophilic indoles in dearomatizing polar cycloadditions. In short, we have described the flow synthesis of a novel class of highly functionalized tricyclic indolines bearing valuable fluoromethylthio groups such as SCF 3 , SCF electron-rich azomethine ylide 1,3-dipole, these heteroarenes behave for the first time as electron-poor dipolarophiles.…”

“…Actually, the only examples described so far involved indoles bearing mesomeric attracting substituents such as a cyano or a methoxycarbonyl. 11,12 To the best of our knowledge, no purely inductive (I) group has been reported to be so electron-withdrawing to create an umpolung effect on the C2=C3 double bond of indoles. In this context, we wondered if the now popular trifluoromethylthio group, displaying a purely inductive attractive effect without the favourable assistance of a mesomeric attractive effect, could be sufficiently electron-withdrawing to enable the (3+2) cycloaddition with an electron-rich dipole such as the non-stabilized azomethine ylide 1 (Scheme 1).…”

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…Along with the Huisgen-type reactions, many other 1,3-dipolar cycloadditions have been developed in flow over the years. Flow conditions have found great utility in the synthesis of a diverse range of scaffolds such as pyrrolidines [476][477][478][479], pyrroles [480], pyrazoles [481][482][483], tetrazoles [484,485], isoxazoles [486][487][488], and bicyclic compounds [489][490][491].…”

Recent Dearomatization Strategies of Benzofurans and Benzothiophenes

“…Very recently, in 2020, Chataigner and co-workers developed a dearomative [3 + 2] cycloaddition of the 3-cyanobenzofurans 67 with in-situ generated azomethine ylide 41 (from 43 through flow technique) for the synthesis of tricyclic systems 68 (Scheme 15). [20] Scheme 11. Proposed mechanism.…”