Fluoromethoxymethylation of Nitrogen Heterocyclic Compounds with Fluoromethyl Iodide

Abstract

The fluoromethoxymethylation of nitrogen heterocyclic compounds with fluoromethyl iodide has been reported for the first time. In this reaction, a number of unexplored fluoromethoxymethylated nitrogen heterocyclic compounds including indoles, carbazoles, and 1H-indazoles were efficiently formed. Mechanistic studies indicated that this transformation consists of electrophilic monofluoromethylation, rapid hydrolysis, and another electrophilic monofluoromethylation. This method makes it possible to synthesize complex bioactive molecules containing a CH2OCH2F group, which have the potential to be a new series of fluorine-containing chemical entities for medicinal chemists.

Monofluoromethylation of N-Heterocyclic Compounds

“…A control experiment, consisting of the fluoromethylation of the previously obtained NCH2OH derivative, indirectly confirms this mechanism. Pyrrole, imidazole and benzotriazole do not react with ICH2F under the conditions considered [64].…”

“…Fluoriodomethane allows for the N-fluoromethoxymethylation of a wide range of aromatic heterocycles in the presence of KOH. The reaction proceeds well with indoles, carbazoles, 1H-indazoles and pyrazoles with yields of 46-81% [64] (Scheme 9).…”

The synthetic versatility of fluoroiodomethane: recent applications as monofluoromethylation platform

“…In 2020, the same authors reported, for the first time, a protocol for the fluoromethoxymethylation of nitrogenated heterocycles. 51 According to optimized conditions, the transformation was performed using potassium hydroxide as the base, and a mixture of acetonitrile/water (1 : 1) as the solvent. The presence of water was found to be crucial for the success of the process.…”

Fluoroiodomethane: A CH2F‐Moiety‐Delivering Agent Suitable for Nucleophilic‐, Electrophilic‐, and Radical‐Harnessed Operations

“…In 2020 Yi reported the first fluoromethoxymethylation of different nitrogen‐centered heterocyclic compounds with fluoroiodomethane (Scheme 23). [78] The screening of the reaction conditions indicated KOH as the optimal base and a mixture of MeCN/H 2 O (1:1) as the solvent. The protocol showed broad applicability with indoles bearing both electron‐donating and electron‐withdrawing substituents.…”