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Powerful Electrophilic Trifluoromethylating Reagent - Umemoto's Reagent II

The trifluoromethyl group has unique properties such as high electronegativity, metabolic stability and lipophilicity. The installment of a trifluoromethyl group is one of the significant functionalizations and is utilized for development in various fields, like pharmaceuticals, agricultural chemicals and material science.
S-(Perfluoroalkyl)dibenzothiophenium salt [D5335], which has been developed by Umemoto et al., is useful as an electrophilic trifluoromethylating reagent. This reagent is applicable for many reactions under basic conditions such as trifluoromethylation of β-ketoesters at the α-position, direct trifluoromethylation of indoles at the 2-position, and hydroxytrifluoromethylation of styrene derivatives using photoredox catalysts.

Advantages

・White Solid with Ease of Handling
・High Trifluoromethylating Ability
・Applicable to Various Nucleophiles Such as β-Ketoesters, Indoles and Phosphines

Application

 

Trifluoromethylation of β-ketoesters at the α-position
To a DMF (10 mL) solution of methyl 1-oxo-2-indanecarboxylate (1 mmol), potassium carbonate (3 mmol) and tetrabutylammonium iodide (0.05 mmol) is added D5335 (1.5 mmol) at room temperature, and the mixture is stirred at room temperature for 3 hours. The reaction solution is porured into water (30 mL) and extracted with ethyl acetate(30 mL x 3). The combined organic layer is dried over MgSO4. After concentration under reduced pressure, the residue is purified with silica gel column chromatography to give methyl 1-oxo-2-(trifluoromethyl)indanecarboxylate in 91% yield (234 mg).

Direct trifluoromethylation of indoles at the 2-position
To a DMF (2 mL) solution of 3-methylindole (0.5 mmol) and N-methylmorpholine (0.75 mmol) is added D5335 (0.6 mmol) at room temperature, and the mixture is stirred at room temperature for 6 hours. The reaction solution is porured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer is dried over MgSO4. After concentration under reduced pressure, the residue is purified with silica gel column chromatography to give 3-methy-2-(trifluoromethyl)lindole in 69% yield (82 mg).

Reference

  • T. Umemoto, B. Zhang, T. Zhu, X. Zhou, Y. Li, PCT Int. Appl. WO 2016107578, 2016.