Palladium‐Catalyzed Decarbonylative Trifluoromethylation of Acid Fluorides

Abstract While acid fluorides can readily be made from widely available or biomass‐feedstock‐derived carboxylic acids, their use as functional groups in metal‐catalyzed cross‐coupling reactions is rare. This report presents the first demonstration of Pd‐catalyzed decarbonylative functionalization of acid fluorides to yield trifluoromethyl arenes (ArCF3). The strategy relies on a Pd/Xantphos catalytic system and the supply of fluoride for transmetalation through intramolecular redistribution to the the Pd center. This strategy eliminated the need for exogenous and detrimental fluoride additives and allows Xantphos to be used in catalytic trifluoromethylations for the first time. Our experimental and computational mechanistic data support a sequence in which transmetalation by R3SiCF3 occurs prior to decarbonylation.


Reagents and starting materials
Unless otherwise stated, all reagents and starting materials were commercially available and used as received. Triethyl(trifluoromethyl)silane (96 %) was purchased from ChemPur. (Me 4 N)SCF 3 was prepared according to the reported literature procedure. 1

Solvents.
Dichloromethane and toluene were purified by the Pure Solvent PS-MD-5 solvent drying system from Innovative Technology. n-Hexane and ethyl acetate were technical grade.

Experimental Techniques.
The work-up of all reactions and the isolation of products were carried out in a fume hood using standard techniques. Whether a reaction was performed under an argon or air atmosphere is specified in the experimental procedure.

Characterization.
All 1 H NMR, 13 C NMR and 19 F NMR spectra were recorded at ambient temperature either on Varian V-NMRS 600 or Varian V-NMRS 400 spectrometer. Chemical shifts (δ) are quoted in parts per million (ppm) and were referenced to the residual solvent peak for the 1 H and 13 C NMR spectra. In some of the 13 C NMR spectra there is a peak at 83.3 ppm; this is an artifact from the spectrometer.
Coupling constants (J) are given in Hz. The resonance multiplicity is described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and br (broad). 19 F NMR spectra were recorded using the F-H decoupled pulse sequence from the Varian program library.   Found: 200.06384. The 19 F NMR data is in agreement with that reported in the literature, 4 no other data has been previously reported for this compound.

4-Phenoxybenzoyl fluoride 1f:
Method A, the reaction was performed on a 1.04 mmol scale (rather than 0.52 mmol). The title compound was obtained after filtration through a pad of silica (3)(4) cm in a Pasteur pipette) using 10% ethyl acetate in hexane in 99% yield (223 mg) as a pale yellow oil. 1
* If the acyl fluoride was a liquid it was added to the reaction mixture after the addition of toluene.

4-Methyl-4'-(trifluoromethyl)-1,1'-biphenyl 2o:
The title compound was obtained after purification using flash column chromatography on silica gel using hexane (R f = 0.56) in 30% yield (22 mg Me Two-step conversion of carboxylic acids to trifluoromethyl arenes General method: Step One: Carboxylic acid (0.4 mmol, 1 equiv.), (Me 4 N)SCF 3 (77 mg, 0.44 mmol, 1.1 equiv.) and dichloromethane (2 mL) were added to a 10 mL sample tube under an argon atmosphere. The tube was sealed and the reaction mixture was stirred at room temperature for 2 hours. Hexane (1 mL) was then added to the reaction mixture, and the mixture filtered through a pad of celite (3-4 cm in a Pasteur pipette) and the solvent removed under reduced pressure. The obtained material was further purified as outlined below, before being taken on to the second step.
Step Two: [(cinnamyl)PdCl] 2 (8 mg, 0.016 mmol, 0.04 equiv.), Xantphos (28 mg, 0.048 mmol, 0.12 equiv.) and potassium phosphate (17 mg, 0.08 mmol, 0.2 equiv.) were added to a 20 mL pressure tube under an argon atmosphere. The acyl fluoride was then transferred to the pressure tube by rinsing the vial containing the compound first with 1 mL of toluene and then 0.2 mL toluene (to ensure that all of the acyl fluoride was transferred to the pressure tube). Triethyl(trifluoromethyl)silane (160 µL, 0.8 mmol, 2 equiv.) was then added, the tube was sealed and the reaction mixture was heated with vigorous stirring at 170 °C for 16 hours. The reaction mixture was then allowed to cool to room temperature, 4-(trifluoromethoxy)anisole (60 µL, 0.4 mmol, 1 equiv.) was added as an internal standard and the mixture filtered through a pad of celite (3-4 cm in a Pasteur pipette). The crude reaction mixture was then analyzed using GC-MS and 19 F NMR spectroscopic analysis.
Step Two: The title compound was obtained after purification using flash column chromatography on silica gel using 5% ethyl acetate in hexane (R f = 0.33) in 35% yield (28.5 mg) as a colourless oil. Characterization data is the same as that reported on page 9.

1-Phenoxy-2-(trifluoromethyl)benzene 2e:
Step One: The crude material was purified using flash column chromatography on silica gel using 5% ethyl acetate in hexane (R f = 0.42) to give a colourless oil. Step Two: The title compound was obtained after purification using flash column chromatography on silica gel using hexane (R f = 0.29) in 55% yield (52.3 mg) as a colourless oil. Characterization data is the same as that reported on page 9. 2-Phenyl-4-(trifluoromethyl)quinoline 2l: Step One: The crude material was filtered through a pad of silica (3)(4)

Computational details
All calculations were performed using the Gaussian 09 software. 17 The frequency calculations and structure optimizations were performed using ωB97XD with the 6-31G (d) basis set for C, O, H, F       just the Xantphos fragment and 3) just the PhCO-Pd-X (X = F or CF 3 ) fragment (see Figure S3 for       Interac(on energy / kcal mol -1

Reaction development and control reactions
Examination of different additives and CF 3 sources

(16 h)
61.79 58.43 60.11 (1.68) a As the timer was started as soon as the tubes were added to the heating block there will be a period of time in which the reaction mixture warms to 170 °C; based on when the reaction mixture started vigorously bubbling this is estimated to be between 1-2 minutes. As such, the actual reaction times at 170 °C will be slightly less than that shown here, thus the ArCF 3 product 2d forms in less than 5 minutes. b The error shown in parentheses is half the range of the duplicate experiments