Nickel-catalyzed alkyl-arylation of 3,3,3-trifluoropropene

Owing to the versatile synthetic utility of its carbon-carbon double bond, low-cost industrial chemical 3,3,3-trifluoropropene (TFP) represents one of the most straightforward and cost-efficient precursors to prepare trifluoromethylated compounds. However, only limited methods for the efficient transformations of TFP have been reported so far. Here, we report a nickel-catalyzed dicarbofunctionalization of TFP. The reaction uses inexpensive NiCl2·6H2O as the catalyst and 4,4’-biMeO-bpy and PCy2Ph as the ligands, allowing the alkyl-arylation of TFP with a variety of tertiary alkyl iodides and arylzinc reagents in high efficiency. This nickel-catalyzed process overcomes the previous challenges by suppressing β-H and β-F eliminations from TFP, rendering this strategy effective for the transformations of TFP into medicinal interest trifluoromethylated compounds.


Method A
The synthesis of arylzinc reagents was according to the literature. 9 To a dry 100 mL Schlenk flask were added magnesium turnings (3 g, 125 mmol, 2.5 equiv) and LiCl (2.7 g, 62.5 mmol, 1.25 equiv).

S7
The flask was evacuated and heated with a heatgun. The flask was evacuated again and backfilled with argon for 3 times. Upon cooling, tetrahydrofuran (anhydrous, 50 mL) was added, and the mixture was stirred vigorously for 5 min. DIBAL-H (1.0 M in hexane, 0.5 mL, 0.01 equiv) was added via syringe, and the mixture was stirred vigorously for 5 min. The flask was then cooled to 0 ℃ with an ice/water bath, and aryl bromide (50 mmol, 1.0 equiv) was added via a syringe. After 10 minutes, the ice/water bath was removed, and the mixture was stirred at room temperature for 3-5 h until all aryl bromide was consumed (the reaction was monitored by GC). After the reaction was completed, the resulting solution of Grignard reagent ArMgBr•LiCl was titrated with I2 according to Knochel's method 10

Method B
The procedure was a modification to the literature. 11

Optimization of Ni-Catalyzed Akylarylation of 3,3,3-Trifluoropropene 1 with Tertiary Alkyl Iodide 2a and Arylzinc Reagent 3a
To a 25 mL of Schlenck tube were added 4,4'-diMeO-2,2'-bpy (6 mol%), NiCl2•6H2O (5 mol%) and the monodentate phosphine ligand (PCy2Ph or tBu2MeP•HBF4, 5 mol%). The tube was evacuated and backfilled with argon for 3 times, then tertiary alkyl iodide 2a (0.4 mmol, 1.0 equiv) and TFP solution (1 M in DMA, 0.8 mmol, 2.0 equiv) were added under Ar. The resulting mixture was stirred for 20 min at room temperature, and the corresponding arylzinc reagent 3a (0.6 mmol, 1.5 equiv) was added slowly within a period of 5 min, and the tube was sealed with a Teflon cap. After stirring for 12 h at room temperature, the reaction mixture was quenched with aqueous NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a pad of Celite, and the filtrate was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated.
The residue was purified with silica gel chromatography to give the corresponding products 4a.
Isolated yields are based on the average of two runs under identical conditions. (1.5 equiv), and DMA (2 mL). b Determined by 19 F NMR using fluorobenzene as an internal standard. (1.5 equiv), and DMA+DME (2 mL). b Determined by 19 F NMR using fluorobenzene as an internal standard. S15 Supplementary Table 10. Effects of the phosphine ligands on the nickel-catalyzed alkylarylation of TFP 1 with alkyl iodide 2a and electron-deficient arylzinc reagent 3d a Entry P Ligand (1.5 equiv), and DMA (2 mL). b Determined by 19 F NMR using fluorobenzene as an internal standard. S16 Supplementary Table 11. Effects of DME on the nickel-catalyzed alkylarylation of TFP 1 with alkyl iodide 2a and electron-deficient arylzinc reagent 3d a (1.5 equiv), and DMA+DME (2 mL). b Determined by 19 F NMR using fluorobenzene as an internal standard.

General Procedure for the Ni-Catalyzed Alkylarylation of 3,3,3-Trifluoropropene 1 with Tertiary Alkyl Iodides 2 and Arylzinc Reagents 3
To a 25 mL of Schlenck tube were added 4,4'-diMeO-2,2'-bpy (6 mol%), NiCl2•6H2O (5 mol%) and the monodentate phosphine ligand (PCy2Ph or P t Bu2Me•HBF4, 5 mol%). The tube was evacuated and backfilled with argon for 3 times, then tertiary alkyl iodide 2 (0.4 mmol, 1.0 equiv) and TFP solution (1 M in DMA, 0.8 mmol, 2.0 equiv) were added under Ar. The resulting mixture was stirred for 20 min at room temperature, and the corresponding arylzinc reagent 3 (0.6 mmol, 1.5 equiv) was added slowly within a period of 5 min, and the tube was sealed with a Teflon cap. After stirring for 12 h at room temperature, the reaction mixture was quenched with aqueous NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a pad of Celite, and the filtrate was extracted with S17 EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated.
The residue was purified with silica gel chromatography to give the corresponding products 4 or 5.
Isolated yields are based on the average of two runs under identical conditions.

Gram-scale synthesis of compound 4a
To a 100 mL of Schlenck tube were added 4,4'-diMeO-2,2'-bpy (3 mol%), NiCl2•6H2O (2.5 mol%) and the monodentate phosphine ligand PCy2Ph (2.5 mol%). The tube was evacuated and backfilled with argon for 3 times, then tertiary alkyl iodide 2a (6 mmol, 1.0 equiv) and TFP solution (1 M in DMA, 25 mL) were added under Ar. The resulting mixture was stirred for 20 min at room temperature, and the corresponding arylzinc reagent 3a (9 mmol, 1.5 equiv) was added slowly within a period of 5 min, and the tube was sealed with a Teflon cap. After stirring for 12 h at room temperature, the reaction mixture was quenched with aqueous NH4Cl solution and diluted with EtOAc. The reaction mixture was filtered through a pad of Celite, and the filtrate was extracted with EtOAc and washed with brine.
The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified with S18 silica gel chromatography (Hexane/Ethyl Acetate = 15/1) to give compound 4a as a yellow solid (1.4 g, 50% yield).

Complex B1 Catalyzed Reaction under Standard Reaction Conditions
Procedure: To a 25 mL of Schlenck tube were added complex B1 (x mol%) and the monodentate phosphine ligand (PCy2Ph (P1) or P t Bu2Me•HBF4 (P2), x mol%). The tube was evacuated and backfilled with argon for 3 times, then tertiary alkyl iodide 2a (0.4 mmol, 1.0 equiv) and TFP solution (1 M in DMA, 1.6 mmol, 4.0 equiv, 2 mL) were added under Ar. The resulting mixture was stirred for 20 min at room temperature, and the corresponding arylzinc reagent 3a (0.6 mmol, 1.5 equiv) was added slowly within a period of 10 min, and the tube was sealed with Teflon cap. After stirring for 12 h at room temperature, the reaction mixture was quenched with aqueous NH4Cl solution and diluted with EtOAc. The yield was determined by 19 F-NMR using benzotrifluoride as the internal standard.
For using P1 as the co-ligand, 4a was provided in 57% yield (x = 5) and 4c was formed in 3% yield (x