Silver(I) Oxide Catalyzed C/S–H Trifluoromethylation of Arenes and Heteroarenes with Sodium Trifluoromethanesulfinate

Abstract

We present a general and scalable approach for the C(sp²)–H or S–H trifluoromethylation of arenes and heteroarenes. This method employs bench-stable CF₃SO₂Na as the CF₃ source, with Ag₂O serving as the catalyst and K₂S₂O₈ as the oxidant. Notably, the protocol features broad functional-group compatibility, mild conditions, and high regioselectivity. Furthermore, it is applicable to biologically relevant molecules such as caffeine, pentoxifylline, ganciclovir triacetate, and mercaptopurine.

Key words

silver catalysis - trifluoromethylation - sodium trifluoromethanesulfinate - late-stage functionalization

Publication History

Received: 28 February 2025

Accepted after revision: 07 April 2025

Article published online:
09 May 2025

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• 31 Trifluoromethylation of C–H and S–H Bonds of (Hetero)arenes; General Procedure An oven-dried 20 mL borosilicate glass vial equipped with a magnetic stirrer bar was charged with the appropriate substrate 1 (0.5 mmol), Ag₂O (10 mol%), CF₃CO₂Na (2.0 equiv.), K₂S₂O₈ (3.0 equiv.), and DMSO (4 mL), and the resulting mixture was stirred at r.t. (28 °C) for 24 h. When the reaction was complete, ice-cold H₂O (30 mL) was added and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phase was washed with sat. brine (2 × 10 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel (230–400 or 60–200 mesh)]. 1,3,7-Trimethyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione [8-(Trifluoromethyl)caffeine] (2a)¹⁷ Prepared by the general procedure from 1a (0.5 mmol, 97.1 mg) and purified by column chromatography [silica gel (60–200 mesh), hexane–EtOAc (3:1)] to give a white solid; yield: 102.2 mg (78%). ¹H NMR (400 MHz, CDCl₃): δ = 4.14 (s, 3 H), 3.57 (s, 3 H), 3.40 (s, 3 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –62.41 (s, CF₃). ¹³C NMR (151 MHz, CDCl₃): δ = 155.6, 151.4, 146.6, 139.0 (q, J _C–F = 40.8 Hz), 118.3 (q, J _C–F = 270.3 Hz), 109.8, 33.3, 30.0, 28.3.