Hydrofluorination of Alkynes Catalysed by Gold Bifluorides

We report the synthesis of nine new N-heterocyclic carbene gold bifluoride complexes starting from the corresponding N-heterocyclic carbene gold hydroxides. A new methodology to access N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I) fluoride starting from N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I) hydroxide and readily available potassium bifluoride is also reported. These gold bifluorides were shown to be efficient catalysts in the hydrofluorination of symmetrical and unsymmetrical alkynes, thus affording fluorinated stilbene analogues and fluorovinyl thioethers in good to excellent yields with high stereo- and regioselectivity. The method is exploited further to access a fluorinated combretastatin analogue selectively in two steps starting from commercially available reagents.


General procedure for the synthesis of [[Au(NHC)(L)](HF 2 )] Method A:
An oven-dried round-bottomed flask was charged with [Au(NHC)OH] (1 equiv.), THF (0.08 M) and pyridine (0.3 equiv.). The flask was closed with a septum, placed under an atmosphere of nitrogen and stirred vigorously at room temperature. Pyridine hydrofluoride (1 equiv.) was then added dropwise. The reaction mixture was stirred at room temperature for 4 h and then concentrated at low temperature, until the product started to precipitate. At that point, hexane (10-15 mL per 0.1 mmol) was added to form a white precipitate. The solid was collected by filtration on a Büchner funnel, washed with hexane and then dried in vacuo.

Method B:
An oven-dried round-bottomed flask was charged with [Au(NHC)OH] (1 equiv.), THF (0.08 M) and the indicated ligand (1 equiv.). The flask was closed with a septum, placed under an atmosphere of nitrogen and stirred vigorously at room temperature. Triethylamine trihydrofluoride (0.7 equiv.) was then added dropwise. The reaction mixture was stirred at room temperature for 4 h and then concentrated at low temperature, until the product started to precipitate. At that point, hexane (10-15 mL per 0.1 mmol) was added to form a white precipitate. The solid was collected by filtration on a Büchner funnel, washed with hexane and then dried in vacuo.

[[Au(IPr)(pyridine)](HF 2 )] (4a)
Prepared according to the general procedure to afford the desired product as a white microcrystalline solid.  6.02;N,5.97. Found: C,54.55;H,6.12;N,5.90. Crystals suitable for X-ray diffraction analysis were grown by layering a concentrated THF solution at -20 o C with hexane overnight.
Crystals suitable for X-ray diffraction analysis were grown by a slow vapour diffusion of hexane into a concentrated solution of 4a in THF at room temperature.

General procedure for the synthesis of [Au(IPr)F]
A vial was charged with [Au(IPr)OH] (1 equiv.) and KHF 2 (1.05 equiv.) in benzene (0.3 M) and the reaction mixture was stirred at room temperature for 4 h. Once complete, the solvent was removed in vacuo. The residue was dissolved in THF and filtered through celite (the celite was washed with THF). The filtrate was concentrated in vacuo until the product started to precipitate. At that point, hexane (10-15 mL per 0.1 mmol) was added to form a white precipitate. The solid was collected by filtration on a Büchner funnel, washed with hexane and then dried in vacuo. The desired product was obtained as a white microcrystalline solid   7, 146.3, 134.9, 130.8, 124.6, 123.4, 29.2, 24.5, 24.2 ppm. 19  Catalyst 2e and 2f proved to be the best catalysts for this reaction. However, due to the better availability and easier synthesis of the IPr* ligand in our lab contrary to the IPr* Tol counterpart, catalyst 2e was chosen for further optimisation. DCM was clearly the best solvent. However toluene was also kept for the temperature screening performed later on (see table 4). HOTf ( TFA (1.0) 12 a Conversions determined by 1 H NMR. b Disappearance of starting alkyne after 24 h; sideproduct formation observed.
Ammonium tetrafluoroborate was chosen for further optimisation.
The reaction mixture was stirred while adding the corresponding aryl halide (6 mmol, 2 equiv.) and the 2-butynedioic acid (3 mmol, 1 equiv.), followed by the addition of 1, 8diazabicyclo(5.4.0)undec-7-ene (6 mmol, 2 equiv.). The reaction mixture was then stirred at 110°C for 6 hours. Afterwards, the reaction mixture was directly poured into saturated aqueous ammonium chloride and extracted with Et 2 O. The combined organic phases were washed with brine, dried over MgSO 4 and filtered. The solvent was removed under vacuum and the residue was purified by flash column chromatography (silica gel, pentane or pentane/EtOAc mixture or EtOAc were used as eluent).

Procedure for 10a-b:
A flame-dried Schlenk was charged with phenylacetylene (6 mmol, 1.2 equiv.) and THF (0.2 M) under argon. The reaction mixture was cooled at -78°C, followed by a dropwise addition of n-Butyllithium (1.6 M in hexanes, 5.5 mmol, 1.1 equiv.). The solution was allowed to warm to room temperature before adding the alkyl bromide (5 mmol, 1 equiv.) and tetrabutylammonium iodide (0.5 mmol, 0.1 equiv.). The reaction mixture was then stirred overnight at 80°C. Afterwards, the mixture was cooled at 0°C and then poured into a saturated aqueous ammonium chloride solution and extracted with Et 2 O. The combined organic phases were washed with brine, dried over MgSO 4 and filtered. The solvent was removed under vacuum and the residue was purified by flash column chromatography (silica gel, pentane was used as eluent).
The indicated gold bifluoride catalyst (0.01 mmol, 0.02 equiv.) and NH 4 BF 4 (0.75 mmol, 1.5 equiv.) were then added. DCM (0.7M) was added, followed by a dropwise addition of triethylamine trihydrofluoride (1.5 mmol, 3 equiv.). The reaction mixture was then stirred at the indicated temperature (50 o C for symmetrical alkynes or rt for asymmetrical alkynes) and time (24 hours for symmetrical alkynes or 5 days for asymmetrical alkynes). After total consumption of the starting material, the reaction mixture was directly purified by flash column chromatography (silica gel, pentane or pentane/EtOAc mixture were used as eluent).

Benzyl(hex-1-yn-1-yl)sulfane (11a)
1-Hexyne (2.0 mL, 17.4 mmol, 1.0 equiv.) was dissolved in diethyl ether (40 mL) and the resulting mixture cooled to -78 ºC. Butyllithium (1.6 M in hexanes, 10.9 mL, 17.4 mmol, 1.0 equiv.) was slowly added dropwise with stirring, and the mixture stirred at -78 ºC for a further 15 minutes. Molecular sulphur (556.8 mg, 17.4 mmol, 1.0 equiv.) was then added portionwise at -78 ºC, and the resulting mixture was stirred for a further hour and allowed to warm to room temperature. The mixture was then cooled to 0 ºC, benzyl bromide (2.1 mL, 17.4 mmol, 1.0 equiv.) was added dropwise, and the resulting mixture was stirred for 16 hours and allowed to warm to room temperature. It was then treated with a sat. aq. solution of sodium hydrogen carbonate (20 mL), the layers were separated and the aqueous layer was extracted with diethyl ether (3 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to furnish a yellow oil.
Purification by silica gel column chromatography, eluting with hexane, furnished the title compound as a slightly yellow oil (2.7 g, 78% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 7.37 - These data are in good agreement with the literature values. [6] Benzylthioethynyl trimethylsilane Trimethylsilyl acetylene (5.5 mL, 39.0 mmol, 1.0 equiv.) was dissolved in diethyl ether (50 mL) and the resulting mixture was cooled to -78 ºC. Butyllithium (1.6 M in hexanes, 24.0 mL, 39.0 mmol, 1.0 equiv.) was slowly added dropwise with stirring, and the mixture was stirred at -78 ºC for a further 15 minutes. Molecular sulphur (1.25 g, 39 mmol, 1.0 equiv.) was then added portionwise at -78 ºC, and the resulting mixture was stirred for a further hour and allowed to warm to room temperature, after which the sulphur had completely dissolved to yield an orange colour. The mixture was then cooled to 0 ºC, benzyl bromide (4.6 mL, 39.0 mmol, 1.0 equiv.) was added dropwise, and the resulting mixture was stirred for 16 hours and allowed to warm to room temperature. The resulting turbid mixture was concentrated under reduced pressure to yield a yellow paste, which was extracted with hexane (30 mL) and filtered. This procedure was repeated three times, and the combined hexane layers were concentrated under reduced pressure to furnish the title compound (orange oil, 7.7 g, 89% yield). The material obtained was used in the next synthetic step without any further purification. 1 H NMR (500 MHz, CDCl 3 ) δ 7.35-7.30 (m, 5H), 3.94 (s, 2H), 0.14 (s, 9H).
These data are in good agreement with the literature values. [7]

4-Phenylbutyl-thioethynyl trimethylsilane
Trimethylsilyl acetylene (3.5 mL, 24.9 mmol, 1.1 equiv.) was dissolved in diethyl ether (30 mL) and the resulting mixture was cooled to -78 ºC. Butyllithium (1.6 M in hexanes, 15.6 mL, 24.9 mmol, 1.1 equiv.) was slowly added dropwise with stirring, and the mixture was stirred at -78 ºC for a further 15 minutes. Molecular sulphur (797 mg, 24.9 mmol, 1.1 equiv.) was then added portionwise at -78 ºC, and the resulting mixture was stirred for a further hour and allowed to warm to room temperature, after which the sulphur had completely dissolved to yield an orange colour. The mixture was then cooled to 0 ºC and a solution of 4phenylbutyl bromide (4.83 g, 22.7 mmol, 1.0 equiv.) in dry diethyl ether (10 mL) was added dropwise, the resulting mixture was then stirred for 16 hours and allowed to warm to room temperature. It was then washed with a sat. aq. solution of sodium hydrogen carbonate (2 x 10 mL), brine (10 mL), dried over magnesium sulfate, and filtered and concentrated under reduced pressure. The material obtained was purified by silica gel flash column chromatography, eluting with hexane, to furnish the title compound as a colourless oil ( These data are in good agreement with the literature values. [8]

4-Phenylbutyl ethynyl sulfane (11c)
4-Phenylbutyl-thioethynyl trimethylsilane (500 mg, 1.9 mmol, 1.0 equiv.) was dissolved in a 3:1 mixture of tetrahydrofuran and methanol (5 mL These data are in good agreement with the literature values. [8] Thio enols: Hydrofluorination reactions General procedure for the hydrofluorination reactions A plastic vial was charged with the corresponding alkyne (1 equiv.) under argon. The indicated gold bifluoride catalyst (0.05 equiv.) was then added. DCM (0.7M) was added, followed by a dropwise addition of triethylamine trihydrofluoride (1.5 mmol, 3 equiv.). The reaction mixture was then stirred at room temperature until total consumption of the starting material. Afterwards, DCM was added followed by a sat. aq. solution of NaHCO 3 . The two layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo. The MHz, CDCl 3 ) δ -80.9. These data are in good agreement with the literature values. [8] (1-fluorovinyl)(4-phenylbutyl)sulfane (12c) These data are in good agreement with the literature values. [8]