Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper–N-Heterocyclic Carbene Complex

A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.


General Procedure A: Optimization of Propargylic Fluorination Protocol
Propargylic electrophile (0.1 mmol) and catalyst (0.01 mmol) were added in turn to a 4 mL glass vial with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times. Next, solvent (0.5 mL) was added by 1 mL syringe to dissolve the solid, followed by fluoride source (0.3 mmol) added in one portion under N 2 at room temperature. The reaction was heated to 30 °C and stirred at this temperature for 24 h. Then the reaction mixture was filtered through a pad of silica gel (a pipette with about 5 cm silica gel) and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in CDCl 3 and CH 2 Br 2 (0.1 mmol) was added as internal standard for 1 H NMR analysis.  a CuOTf•1/2C 6 H 6 (10 mol%), rac-BINAP (20 mol%) or (R)-(i-Pr)-Pybox (20 mol%) were premixed in THF at 60 °C for 1 h. b The reaction was completed within 5 h. c The reaction was completed within 2 h.     CuCl (244 mg,0.5 mmol) and AgOTs (139 mg, 0.5 mmol) were added in turn to a 4 mL glass vial with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times. Next, THF (2 mL) was added to the vial by syringe under N 2 . The mixture was allowed to stir at room temperature for 3 hours. Then the resulting white solids were filtered off a pad of Celite (a pipette with about 5 cm Celite) and washed with dry CH 2 Cl 2 . The filtrate was concentrated under reduced pressure to afford the tittle compound as an off-white solid (300 mg, 96%), which was used without further purification.

Cu OTs N N i-Pr i-Pr i-Pr i-Pr
A round-bottom flask with a stir bar was dried in the oven and cooled under N 2 . Ethynylmagnesium bromide in THF (0.5 M in THF, 1.2 eq.) was transferred to the flask via syringe. Then the reaction was cooled to 0 °C. Aldehyde (1.0 eq.) was dissolved in THF (0.5 M) and added dropwise via syringe to the above solution at 0 °C. After 30 min, the cooling bath was removed to reach room temperature. The mixture was stirred for a further 2 hours. Saturated aqueous ammonium chloride was then added and the mixture was extracted with Et 2 O three times. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The residue was purified by silica gel chromatography (Hexane/ethyl acetate as eluent) to give the corresponding propargylic alcohol. Yields have not been optimized.
Next, freshly fine powdered KOH (7.4 eq) was added portion wise by spatula while keeping temperature below -10 °C. The mixture was stirred at -5 °C for 1 h before poured into ice water (the same volume of Et 2 O). After vigorous shaking, the layers were separated and the aqueous layer was extracted twice with Et 2 O. The combined organic layers were washed with brine and dried over MgSO 4 . After the solvent was removed on a rotary evaporator, the residue was purified by silica gel chromatography (Hexane/ethyl acetate as eluent) to give the corresponding propargylic tosylate.

8-
propargylic alchol (2.6 g, 10.0 mmol) were added in turn to a round-bottom flask with a 2.0 cm stir bar. Et 2 O (50 mL) was added to dissolve the solid and then the reaction mixture was cooled at -10 °C. Next, freshly fine powdered KOH (4.1 g, 74.0 mmol) was added portionwise by spatula while keeping temperature below -10 °C.
The mixture was stirred at -5 °C for 1 h before poured into ice water (50 mL

8-Oxooct-1-yn-3-yl 4-methylbenzenesulfonate (1n-OTs).
A 100 mL round-bottom flask with a 1.5 cm stir bar was evacuated and refilled with N 2 three times. (COCl) 2 (0.2 mL, 2.2 mmol) and CH 2 Cl 2 (5 mL ) was added via syringe. The flask was cooled to -70 °C. A solution of DMSO (0.3 mL, 4.4 mmol) in CH 2 Cl 2 (5 mL) was added to the flask by syringe at -70 °C. After addition, the mixture was stirred at this temperature for 10 min before a solution of alcohol (592 mg, 2.0 mmol) in CH 2 Cl 2 (5 mL) was added dropwise. The mixture was stirred at -70 °C for further 0.5 h. Then Et 3 N (1.5 mL, 10.6 mmol) was added once. After that, the cooling bath was removed and the mixture was allowed to reach room temperature. H 2 O (20 mL) was added and the aqueous phase was extracted twice with CH 2 Cl 2 (60 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and then concentrated under reduced pressure. The crude oil was purified by silica gel chromatography (hexane/EtOAc = 3:1) to afford the product as a colorless oil (500 mg, 85% yield).

23
NaH 24 (1.0 eq, a 60% dispersion in oil, which had been previously washed twice with hexane) was added to a flask with a stir bar. The flask was evacuated and refilled with N 2 three times. Then THF (2.0 M) was added to the flask, followed by a solution of tertiary propargylic alcohol (1.0 eq) in THF (1.0 M) at room temperature.
After the mixture was stirred for 30 min at room temperature, the yellow alkoxide solution was added dropwise to a solution of freshly distilled trichloroacetonitrile (2.0 eq) in THF (2.0 M) at 0 °C. The resulting brown solution was stirred at 0 °C for 1 h and then concentrated to afford a dark oil. Pentane (the same volume of THF, containing 1% methanol) was added, and a small amount of dark, insoluble material was removed by filtration through Celite. The filtrate was concentrated under reduced pressure and the crude oil was purified by silica gel chromatography (Hexane/ethyl acetate + 1% Et 3 N) to give the corresponding tertiary propargylic trichloroacetimidate. Yields have not been optimized.

BocN O Cl 3 C NH
Propargylic tosylate (0.5 mmol) and (IPr)CuCl (0.05 mmol) were added in turn to a 4 mL vial with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times.
Then THF (2.5 mL) was added via 5 mL syringe to dissolve the solid, followed by Et 3 N•3HF (0.25 mL, 1.5 mmol) added in one portion via 1 mL syringe at room temperature. The reaction mixture was then stirred at 30 °C. After 24 h, the mixture was transferred to a 25 mL round-bottom flask via pipette and solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to afford the corresponding propargylic fluoride. Gram Scale: 5-Phenylpent-1-yn-3-yl 4-methylbenzenesulfonate (3.14 g, 10 mmol) and (IPr)CuCl (487 mg, 1 mmol) were added in turn to a 100 mL round-bottom flask with a 2 cm stir bar. The flask was evacuated and refilled with N 2 three times. Then THF (50 mL) was added via syringe to dissolve the solid, followed by Et 3 N•3HF
The crude material was purified by silica gel chromatography (hexanes/ethyl acetate = 20:1) to afford the title compound as a colorless oil.
6-Fluorooct-7-yn-1-ol (2m). Prepared according to general procedure E. The crude material was purified by silica gel chromatography (hexanes/ethyl acetate = 3:1) to afford the title compound as a colorless oil. Propargylic trichloroacetimidate (0.5 mmol) and (IPr)CuOTf (0.05 mmol) were added in turn to a 4 mL vial with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times. Then THF (2.5 mL) was added via 5 mL syringe to dissolve the solid, followed by Et 3 N•3HF (0.25 mL, 1.5 mmol) added in one portion via 1 mL syringe at room temperature. The reaction mixture was then stirred at 30 °C. After 2 h, the mixture was transferred to a 25 mL round-bottom flask via pipette and solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to afford the corresponding tertiary propargylic fluoride.
(3-Fluoro-3-methylpent-4-yn-1-yl)benzene (5a). Prepared according to general procedure F. The crude material was purified by silica gel chromatography (hexanes) to afford the title compound as a colorless oil.    (R)-5-Phenyl-1-pentyn-3-ol was prepared by analogy to the literature protocol for enzymatic kinetic resolution of propargylic alcohols. 26 A 250 mL round-bottomed flask was charged with 5-phenyl-1-pentyn-3-ol (2.48 g, 15.5 mmol) and a stir bar, and toluene (100 mL) was added. Candida antarctica lipase (Novozyme 435; 100 mg) was added, followed by vinyl acetate (1.43 g, 15.5 mmol). The reaction mixture was stirred for 16 h at room temperature, filtered through a plug of Celite, rinsing with CH 2 Cl 2 (50 mL), and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (gradient elution: 5% 7% 10% EtOAc in Hexanes) to give the product as a colourless oil (974 mg, 39%). All spectral data were in agreement with the racemic material described previously. mL round-bottomed flask equipped with a stir bar was dried under vacuum using a heat gun and cooled to room temperature. The flask was charged with (R)-5-Phenyl-1-pentyn-3-ol (320 mg, 2.0 mmol), a septum was fitted and the flask was evacuated and back-filled with nitrogen three times. CH 2 Cl 2 (8 mL) was added using a syringe and the solution was stirred at -50 °C using a cryo-cool to maintain reaction temperature. Meanwhile, an ovendired 4 mL vial fitted with a stir bar was charged with diethylaminosulfur trifluoride (DAST; 262 µL, 2.0 mmol), dissolved in CH 2 Cl 2 (2 mL), and stirred for 5 mins. The DAST solution was withdrawn into a 3 mL syringe and added over a period of 5 minutes to the solution of the alcohol. Dropwise addition was crucial and the solution was added down the side of the round-bottomed flask to prohibit significant heat fluctuations. After 1.5 h, the septum was removed and a saturated aqueous solution of Na 2 CO 3 (10 mL) was added and the mixture was allowed to warm to room temperature. The organic solution was separated and the aqueous phase was extracted using CH 2 Cl 2 (3 x 30 mL), dried (Na 2 SO 4 ) and concentration under reduced pressure. residue was purified by silica gel chromatography (hexanes) to afford the product as a colourless oil (135 mg, 42%). All spectral data were in agreement with the racemic material described previously. were added in turn to a 10 mL schlenk flask with a 1 cm stir bar. The flask was capped with a rubber septum and then it was evacuated and refilled with N 2 three times. 1,4-Dioxane (2.0 mL) was added to the flask by a syringe at room temperature followed by (c-Hex) 2 NH (0.18 mL, 0.9 mmol) and propargylic fluoride (81.0 mg, 0.5 mmol). The resulting mixture was then placed in a pre-heated oil bath at 110 °C and stirred for 24 h. After cooling to room temperature, the crude reaction mixture was concentrated, filtered through a short pad of silica gel (a pipette with about 5 cm silica gel) and washed with EtOAc (15 mL (3-Fluoropent-4-en-1-yl)benzene (9). Propargylic fluoride (81 mg, 0.5 mmol) and EtOAc (3 mL) were added to a 25 mL flask with a 1.5 cm stir bar. Next, Lindlar catalyst (25 mg) and quinoline (60 L, 0.5 mmol) were added to the above solution at room temperature under air. While the mixture was stirred, the flask was evacuated and refilled with H 2 from a balloon. After being stirred under H 2 atmosphere at room temperature for 24 h, the mixture was filtered through a pad of silica gel (a pipette with about 5 cm silica gel). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (hexane) to afford the product (78 mg, 95%) as a colorless oil.

S-36
3-Fluoro-5-phenylpentan-2-one (10). Propargylic fluoride (81 mg, 0.5 mmol) was added to a 4 mL vial with a 1 cm stir bar. In air, MeOH (0.75 mL) was added to the vial, followed by water (75 μL) and AgSbF 6 (17.2 mg, 0.05 mmol) at room temperature. The vial was capped with a PTFE-lined cap and stirred at 75 °C for 24 hours. Then the mixture was concentrated and Et 2 O (50 mL) was added. The organic phase was washed with aqueous ammonia (10 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc = 15:1) to afford the desired product (52 mg, 58% yield) as pale yellow oil.  and CuSO 4 ·5H 2 O (12.5 mg, 0.05 mmol) were added to a 4 mL via with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times. A mixture of t-BuOH/H 2 O (V/V = 1:1, 3.0 mL) was added to the vial and then progargylic fluoride (81 mg, 0.5 mmol), azidobenzene (1.1 mL, 0.5 M in 2-Me-THF, 0.55 mmol) were added sequentially at room temperature. The above mixture was stirred at ambient temperature for 18 h, upon which the mixture was diluted with NH 4 Cl (10 mL), extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and then concentrated. The crude oil was purified by silica gel chromatography (hexane/EtOAc = 10:1) to afford the desired product (102 mg, 82% yield) as a pale yellow oil.