Defluorosilylation of fluoroarenes and fluoroalkanes

Direct activation of carbon–fluorine bonds (C–F) to introduce the silyl or boryl groups and generate valuable carbon–silicon (C–Si) or carbon–boron (C–B) bonds is important in the development of synthetically useful reactions, owing to the unique opportunities for further derivatization to achieve more complex molecules. Despite considerable progress of C–F bond activation to construct carbon–carbon (C–C) and carbon–heteroatom (C–X) bond formation, the defluorosilylation via C–F cleavage has been rarely demonstrated. Here, we report an ipso-silylation of aryl fluorides via cleavage of unactivated C–F bonds by a Ni catalyst under mild conditions and without the addition of any external ligand. Alkyl fluorides are also directly converted into the corresponding alkyl silanes under similar conditions, even in the absence of the Ni catalyst. Applications of this protocol in late-stage defluorosilylation of potentially bioactive pharmaceuticals and in further derivatizations are also carried out.


General Procedure A
To the solution of alcohol (1 equiv) in the DCM (0.4 M) was added DAST (1.1 equiv) dropwise at -20 o C. Then the mixture was moved to room temperature and stirred for 6 h. After that, the reaction mixture was poured into cooled water, neutralized with aq. NaHCO3, and extracted with DCM. The combined organic phase was dried over MgSO4, filtered and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel (hexane) to give fluorides.

General procedure B
To a flame-dried screw-capped test tube were sequentially added a fluoroarene 1 (0.20 mmol, 1 equiv), silylborane 2 (0.30 mmol, 1.5 equiv), Ni(COD)2 (5.5 mg, 0.02 mmol, 10 mol%), KOtBu (56.1 mg, 0.5 mmol, 2.5 equiv) and c-hexane/THF (1/2, v/v, 0.8 ml) in a glovebox filled with argon gas. The tube with the mixture was sealed and removed from the glovebox, and stirred at room temperature for 2-12 h. The reaction progress was monitored by TLC. Then, the mixture was added saturated aqueous ammonium chloride (3 ml) and extracted with EtOAc (3 × 3 ml). The combined organic extract was dried over MgSO4 and filtrated. The filtrate was concentrated under reduced pressure. The residue was purified to give the silanes.

General procedure C
To a flame-dried screw-capped test tube were sequentially added a fluoroalkanes 1 (0.20 mmol, 1 equiv), silylborane 2 (0.30 mmol, 1.5 equiv), KOtBu (56.1 mg, 0.5 mmol, 2.5 equiv) and chexane/THF (1/2, v/v, 0.8 ml) in a glovebox filled with argon gas. The tube with the mixture was sealed and removed from the glovebox, and stirred at room temperature for 2-12 h. The reaction progress was monitored by TLC. The mixture was then added saturated aqueous ammonium chloride (3 ml) and extracted with EtOAc (3 × 3 ml). The combined organic extract was dried over MgSO4 and filtrated. The filtrate was concentrated under reduced pressure. The residue was purified to give the silanes. The chemical shifts were consistent with those reported in the literature 20 .
To the solution of S11 in THF (20 ml) was added NaH (0.115 g, 2.88 mmol, 60% in mineral oil) at 0 o C. After 15 min, MeI (0.35 ml, 5.52 mmol) was added. The mixture was stirred at room temperature overnight. To the mixture was added water (20 ml) and extracted by EtOAc (3 × 8 ml). The organic phases was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 40/1) to give 6 as white solid (0.296 g, 86%). 1

Synthesis of Pitavastatin Derivative (8)
Synthetic intermediates S1 and S2 were prepared according to procedures
To a solution of KHMDS ( 0.57 g, 2.86 mmol) in THF (5 ml) was added a solution of S5 (1.25 g, 2.6 mmol) in THF (5 ml) at −78 o C and stirred for 5 min. A solution of crude aldyhyde S6 in THF (10 ml) was added at −78 o C. Then the mixture was stirred for 12 h at 0 o C. To the mixture was added saturated aqueous ammonium chloride (5 ml) and extracted with EtOAc (5 ml × 3 ml). The organic phase was dried over MgSO4 and filtrated. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography silica gel (hexane/EtOAc = 10/1) to give S7 as colorless oil (0.76 g, 57%). 1

General procedure D for halogeneration of 3a
To the solution of 3a (56.5 mg, 0.2 mmol) in dried MeCN (1ml) was added NXS (0.5 mmol, 5 equiv) under N2 protected. The mixture was stirred at room temperature for 12 h. Then, the mixture was concentrated and purified by column chromatography silica gel (hexane) to give the aryl halide.
Following the general procedure B, using aryl halide (0.2 mmol) and 2a (72.6 mg, 0.3 mmol) for 12 h; and the mixture tube was added Et2O (20 ml), saturated aqueous ammonium chloride (1 ml), followed by n-decane (10 μl, 0.05 mmol) as an internal standard. After stirring the mixture vigorously, GC and GCMS analysis were conducted using a portion of the resulting organic phase.

Equation 2.
Following the general procedure C, using alkyl halide (0.2 mmol) and 2a (72.6 mg, 0.3 mmol) for 12 h. The mixture was analyzed by GCMS to determine the ratio of silylation and borylation products. Then, to the mixture was added saturated aqueous ammonium chloride (1 ml) and extracted by Et2O (3 × 5 ml). The organic phase was concentrated under reduced pressure. The residue was purified by PLC (hexane) to give corresponding silylated or borylated product.

Preliminary mechanistic investigations Radical clock experiments with 20
To the solution of 1-(bromomethyl)-2-fluorobenzene (0.61 ml, 5.0 mmol) in THF (7 ml) was dropwise added allymagnesium bromide (10.7 ml, 7.5 mmol, 0.7 M) at 0 o C. The reaction mixture was stirred for 30 min after warming to room temperature. To this was added saturated aqueous ammonium chloride at 0 o C. The mixture was extracted with Et2O (3 × 5 ml), washed with brine (5 ml) and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane) to give 20 as colorless liquid (0.63 g, 84%). 1  Following the general procedure B, using 12 (30.0 mg, 0.2 mmol) and 2a (72.6 mg, 0.3 mmol) for 12 h. The mixture was analyzed by GCMS to determine the products. Then, the mixture was added saturated aqueous ammonium chloride (1 ml) and extracted with Et2O (3 × 5 ml). The combined organic phase was dried over MgSO4 and filtrated. The filtration was concentrated under reduced pressure. The residue was purified by PLC (hexane) to give 21 as colorless liquid (25.0 mg, 51%). 1

Reaction with silicon radical scavengers 19 F and 11 B spectroscopic studies
To a NMR tube was sequentially added a silylborane 2a (36.3 mg, 0.15 mmol), KOtBu (28.0 mg, 0.25 mmol) and c-hexane/THF-d8 (1/2, v/v, 0.6 ml) in a glovebox filled with argon gas. The NMR tube with the mixture was sealed and removed from the glovebox, and stirred at room temperature. After 30 min, the 11 B NMR analysis of the crude mixture revealed that the adduct A was present in the reaction mixture as shown in the following chart 31 .

Experimental procedure for monitoring the catalytic reaction:
To a NMR tube was sequentially added a 1 (17.2 mg, 0.10 mmol), silylborane 2a (36.3 mg, 0.1.5 mmol), Ni(COD)2 (2.7 mg, 0.01 mmol), KOtBu (28.0 mg, 0.25 mmol) and c-hexane/THF-d8 (1/2, v/v, 0.6 ml) in a glovebox filled with argon gas. The NMR tube with the mixture was sealed and removed from the glovebox, and stirred at room temperature. The reaction progress was monitored by 19 F NMR and 11 B NMR as shown in the following chart. Figure 7. Monitoring of the reaction of 1l with Et3SiBpin in c-hexane/THF-d8 by means of 19 F NMR and 11 B NMR.

Supplementary
The reaction of π-extended 1l with Et3SiBpin is similar as 1a and yields K[(tBuO)2Bpin] and KF detected in the 11 B NMR and 19 F NMR, respectively.

Map of the conventional cross-coupling mechanism
Supplementary Figure 9. Proposed a conventional cross-coupling mechanism in defluorosilylation reaction.
Mechanism investigation for the reaction of 4k.
Supplementary Figure 10. Studies of defluorosilylation in the reaction of 4k.

Equation 1
To a flame-dried screw-capped test tube were sequentially added 4k (30.0 mg, 0.20 mmol), silylborane 2a (72.6 mg, 0.30 mmol), KOtBu (56.1 mg, 0.5 mmol) and c-hexane/THF (1/2, v/v, 0.8 ml) in a glovebox filled with argon gas. The tube with the mixture was sealed and removed from the glovebox, and stirred at room temperature for 30 min. The reaction progress was monitored by GCMS. After 30 min, 4k was completely consumed, the elimination products 4k ' was detected by GCMS, no silylated products. It was the same results at the absence of 2a.