Potassium Alkoxide as an Efficient Catalyst for Nucleophilic Perfluoroalkylation: Attempt at Anion-Controlled Enantioselective Insertion of a Trifluoromethyl Group

Abstract

Potassium alkoxide was found to be a highly active catalyst for the nucleophilic trifluoromethylation of carbonyl compounds. The catalytic system was successfully applied to the reactions of both aldehydes and ketones, affording the corresponding trifluoromethylated products in high yields at low catalyst loadings (0.1–0.01 mol%) in several solvents, such as THF, toluene, and CH₂Cl₂. In addition, the potassium salt of a Ru(II) complex bearing an (S)-2,2′-bis[bis(3,5-dimethylphenyl)phosphinyl]-1,1′-binaphthalene [(S)-XylBINAP] ligand and two l-threoninate ligands, prepared in situ, catalyzed the enantioselective trifluoromethylation of aromatic aldehydes, although the ee values were not satisfactory (less than 20%).

Key words

trifluoromethylation - potassium tert-butoxide - ruthenium catalysis - trifluoromethyltrimethylsilane - asymmetric catalysis - carbonyl compounds

Publication History

Received: 25 June 2022

Accepted after revision: 01 August 2022

Accepted Manuscript online:
01 August 2022

Article published online:
09 September 2022

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• 24 [1-(4-Bromophenyl)-2,2,2-trifluoroethoxy]-(trimethyl)silane (2a): Typical Procedure All manipulations were performed under an argon atmosphere by using standard Schlenk techniques. 4-Bromobenzaldehyde (1a; 186 mg, 1.00 mmol) was added to a 20 mL Schlenk flask, which was then subjected to three cycles of a vacuum–argon replacement procedure. THF (900 μL) and Me₃SiCF₃ (173 mg, 1.22 mmol) were added to the reaction vessel, and the resulting solution was degassed by a freeze-drying cycle with purging by argon. The resulting mixture in the flask was placed in a water bath at 30 °C and a 10 mM solution of tBuOK in THF (100 μL) was added. When the reaction was complete [TLC, hexane–EtOAc (5:1)], the reaction was terminated by direct purification by column chromatography (silica gel, EtOAc) to give colorless oil; yield: 325 mg (0.99 mmol, 99%).
• 25 H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 8.4 Hz, 2 H, Ar–H), 7.34 (d, J = 8.4 Hz, 2 H, Ar–H), 4.88 (q, J = 6.4 Hz, 1 H, F₃CCH), 0.1 (s, 9 H, SiMe₃). ¹³C NMR (100 MHz, CDCl₃): δ = 134.5, 131.5, 129.2, 123.9 (q, J = 280.8 Hz), 123.3, 72.7 (q, J = 32.5 Hz), –0.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –78.4 (d, J = 5.6 Hz).
• 26 (1S)-[1-(4-Bromophenyl)-2,2,2-trifluoroethoxy]-(trimethyl)silane (2a): Typical Procedure A 10 mM solution of KHMDS in toluene (125 μL) was added to a solution of Ru catalyst 4a (1.3 mg, 1.2 μmol) in tBuOMe (625 μL) at –78 °C for 10 min. Then, Me₃SiCF₃ (67 mg, 0.47 mmol) was added and the mixture was stirred at –78 °C for 15 min. A solution of 4-bromobenzaldehyde (1a; 46 mg, 0.25 mmol) in tBuOMe (500 μL) was poured into the catalyst mixture at –78 °C, and the mixture was allowed to warm to –40 °C. When the reaction was completed, it was terminated by direct purification by column chromatography (silica gel, EtOAc) to give a colorless liquid; yield: 67 mg (0.20 mmol, 82%). TBAF was then added for desilylation of 2a to determine the ee value by chiral GC (Chirasil-Dex-CB; 140 °C): t _R (major): 23.7 min [(S)-alcohol; 59.6%], t _R (minor): 25.8 min [(R)-alcohol; 40.4%].²⁷
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