Verification of preparations of (1H-indol-3-yl)methyl electrophiles and development of their microflow rapid generation and substitution

Abstract

Although highly reactive (1H-indol-3-yl)methyl electrophiles such as (1H-indol-3-yl)methyl halides are potential precursors for the synthesis of various indole derivatives, some researchers have reported difficulties in their preparation due to concomitant undesired dimerization/oligomerization. Nevertheless, there have been some reports on the preparation of (1H-indol-3-yl)methyl halides. To resolve this contradiction, all the previously reported preparations of (1H-indol-3-yl)methyl halides were examined. However, we could not reproduce any of these preparations, and we revised several structures of indole derivatives. Here we show the rapid (0.02 s) and mild (25 °C) generation of an (1H-indol-3-yl)methyl electrophile that enables the rapid (0.1 s) and mild (25 °C) nucleophilic substitution in a microflow reactor. Eighteen unprotected indole analogues can be successfully synthesized using the developed microflow nucleophilic substitution with various nucleophiles.

One‐Flow Synthesis of Substituted Indoles via Sequential 1,2‐Addition/Nucleophilic Substitution of Indolyl‐3‐Carbaldehydes

“…Although the rapid generation of 2 from the highly reactive indolylmethyl electrophiles 5 containing a good leaving group Y, such as halogen and OSO 2 R, can potentially prevent the undesired dimerization/oligomerization (Scheme 1b), the preparation of 5 that does not contain an electron‐withdrawing group (usually at the 1 or 2 position of the indole ring) is difficult [7] . We also experimentally confirmed the instability of 5 in a recent study [8] …”

“…[7] We also experimentally confirmed the instability of 5 in a recent study. [8] Scheme 1. Nucleophilic substitution at the 3'-position of indoles.…”

“…We have also realized microflow syntheses by harnessing their advantages over batch syntheses [11] . Recently, we achieved the rapid in situ generation of 5 via the activation of alcohols by PBr 3 (0.02 s) and their rapid coupling with nucleophiles (0.1 s) in a microflow reactor [8] . A variety of substituted indoles containing a secondary carbon at the 3’‐position were obtained in high yields using this method (Scheme 1b).…”

Micro-flow heteroatom alkylation via TfOH-mediated rapid in situ generation of carbocations and subsequent nucleophile addition

“…9 Recently, we reported the rapid generation of a highly active indolylmethyl electrophile and its nucleophilic substitution in a micro-flow reactor. 10 Here, we report a micro-flow rapid in situ generation of carbocations using strong Brønsted acid in the absence of nucleophiles and the subsequent rapid addition of nucleophiles that led to the high yielding coupling with the carbocations (Scheme 1d). This approach enables the use of basic nucleophiles, including aliphatic amines.…”

Rapid in situ generation of 2-(halomethyl)-5-phenylfuran and nucleophilic addition in a microflow reactor

“…10 We recently reported the rapid generation of highly active indolylmethyl electrophile VII from alcohol VI and PBr 3 , its nucleophilic substitution in a microflow reactor (Scheme 1c). 11 We also demonstrated the rapid formation of highly electrophilic carbocation X from diarylmethanol derivatives IX and TfOH, and the subsequent addition of nucleophiles (Scheme 1d). 12…”