2‑Lithiomethylindoles: Untapped Anions for the Synthesis of 2‑Functionalized Indoles

TL;DR

This paper introduces a new method for making 2-functionalized indoles using 2-lithiomethylindoles, which are efficient and versatile in synthesizing a wide range of indole derivatives.

Contribution

The study presents a novel and general protocol for the synthesis of 2-functionalized indoles using 2-lithiomethylindoles as untapped anions.

Findings

The use of nBuLi at room temperature provides optimal conditions for α-lithiation of 1,2-dimethylindoles.

The method allows for the synthesis of a broad range of C2-functionalized indoles with good yields.

Deep eutectic solvents enable the reactions under air- and moisture-tolerant conditions, making the process greener and simpler.

Abstract

Optimal conditions for the metalation via α-lithiation
of
1,2-dimethylindoles were established with nBuLi at
room temperature, providing the most effective protocol. The resulting
organolithium reagents bearing the structure of 2-lithiomethylindole
were efficiently trapped with diverse electrophiles, including Weinreb
amides, ketones, alkyl bromides, and epoxides, affording a broad range
of C2-functionalized indoles in good yields. The methodology proved
general and was successfully applied to 2-methylindoles bearing different
substituents at the benzenoid ring, C3, and on the nitrogen atom,
as well as to 2-benzylindoles, giving access to new functionalized
indole derivatives. Importantly, deep eutectic solvents enabled these
transformations under air- and moisture-tolerant conditions, highlighting
their greener and operationally simple character. The synthetic utility
of the method was further demonstrated through subsequent derivatizations,
exemplified by the two-step preparation of 2,4-disubstituted carbazoles.

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