Direct α-Trifluoromethylthiolation of Carboxylic Acids Enabled by Boron Catalysis

Abstract

A boron-catalyzed direct α-trifluoromethylthiolation of carboxylic acids was developed. Catalytically generated boron enediolates reacts with electrophilic SCF₃ reagent, N-SCF₃-phthalimide, to provide α-SCF₃ carboxylic acids without the need of substrate pre-activation. The method is applicable to direct modification of bioactive carboxylic acids. Data science analyses provided suitable models for substrate classification as well as yield prediction.

Key words

carboxylic acid - boron catalyst - trifluoromethylthiolation - data science - drug modification - fluorine compounds

Publication History

Received: 13 March 2023

Accepted after revision: 11 April 2023

Accepted Manuscript online:
11 April 2023

Article published online:
15 May 2023

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• 14 General Procedure for α-Trifluoromethylthiolation of Carboxylic Acids Carboxylic acid (0.1 mmol, 1.0 equiv) was added to a 4 mL vial and then brought into the glove box. (AcO)₄B₂O (2.7 mg, 0.1 equiv), THF (1 mL), DBU (35.7 μL, 2.4 equiv), and N-(trifluoromethylthio)phthalimide (37.1 mg, 1.5 equiv) were sequentially added. The vial was sealed and removed from the glove box, and the resulting solution was stirred for 2 h at room temperature (23–28 ℃). MeI (37.4 μL, 6.0 equiv) was consequently added, and the reaction mixture was left stirred for another 2 h. Then, the reaction was worked up by adding 2 mL of 2:1:1 solution of brine, water, and 4 M HCl, followed by extraction with EtOAc (3 times). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. To this crude product was added tetrabromoethane (11.6 μL, 0.1 mmol) and hexafluorobenzene (34.6 μL, 0.3 mmol) as the standards for the determination of NMR yield. The residue was then purified by silica gel chromatography on a Biotage Isolera One using a dry-load method.