Aryl acrylonitriles synthesis enabled by palladium-catalyzed α-alkenylation of arylacetonitriles with vinyl halides/triflates

Aryl acrylonitriles are an important subclass of acrylonitriles in the medicinal chemistry and pharmaceutical industry. Herein, an efficient synthesis of aryl acrylonitrile derivatives using a Palladium/NIXANTPHOS-based catalyst system was developed. This approach furnishes a variety of substituted and functionalized aryl acrylonitriles (up to 95% yield). The scalability of the transformation and the synthetic versatility of aryl acrylonitrile were demonstrated.


Procedure and characterization for the aryl acrylonitriles of arylacetonitriles with vinyl halides/triflates. General Procedure:
An oven-dried 8 mL reaction vial equipped with a stir bar was charged with Pd(OAc)2 (6.8 mg, 10 mol%) or (3.4 mg, 5 mol%), NIXANTPHOS (33.0 mg, 20 mol%) or (16.5 mg, 10 mol%), NaO t Bu (86.5 mg, 0.9 mmol), arylacetonitriles 1 (0.3 mmol) and vinyl halides/triflates 2 (0.9 mmol) under a nitrogen atmosphere in a glove box. Then a solvent of 3 mL dry DME was added to the reaction vial. The vial was sealed with a cap, removed from the glove box, and stirred for 1 -7 h at 80 -100 °C. The reaction mixture was cooled to room temperature and then opened to air, quenched with three drops of H2O, diluted with 3 mL of ethyl acetate, and filtered over a 2 cm pad of silica. The pad was rinsed with ethyl acetate (3 X 3 mL), and the combined organic solutions were concentrated in vacuo. The crude product was chromatographed on silica gel to give the product 3. a Reactions conducted on a 0.1 mmol scale using 1 equiv of 1a, and 1.5 equiv of 2a.

Optimization of the reaction conditions:
b Assay yield determined using CH2Br2 as the internal standard.
c Reactions conducted on a 0.1 mmol scale using 1 equiv of 1a, and 2 equiv of 2a.
d Reactions conducted on a 0.1 mmol scale using 1 equiv of 1a, and 3 equiv of 2a.
The crude product was chromatographed on silica gel to give the product 3aa (
Then a solvent of 94 mL dry DME was added to the reaction vial. The vial was sealed with a cap, removed from the glove box, and stirred for 1 h at 80 °C. The reaction mixture was cooled to room temperature and then opened to air, quenched with 5 mL of H2O, diluted with 15 mL of ethyl acetate, and filtered over a 3 cm pad of silica. The pad was rinsed with ethyl acetate (3 X 15 mL), and the combined organic solutions were concentrated in vacuo. The crude product was chromatographed on silica gel (petroleum ether:ethyl acetate = 20:1) to give the product 3aa (1.03 g, 70% yield) as a colorless oil.

Derivatization studies of product 3aa a. Reduction of carbon-carbon double bond
Pd/C (10%, 21 mg) was added to a solution of 3aa (62.9 mg, 0.4 mmol) in EtOAc (15 mL) at room temperature in a nonreactant borosilicate glass vessel under the shaker hydrogenation apparatus.
Hydrogen gas was installed to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 3 h. Then the reaction mixture was diluted with 3 mL of ethyl acetate, and filtered over a 2 cm pad of silica. The pad was rinsed with ethyl acetate (3 X 3 mL), and the combined organic solutions were concentrated in vacuo. The crude product was chromatographed on silica gel (petroleum ether:ethyl acetate = 20:1) to give the product 4aa (60.5 mg, 95% yield) as a colorless oil.

d. Epoxidation of carbon-carbon double bond and hydrolysis of nitrile group
To a solution of 3aa (78.6 mg, 0.5 mmol) in DMSO (5 mL) at room temperature was added K2CO3 (14.0 mg, 0.1 mmol) and H2O2 (30%, 140 µL, 1.10 mmol). The reaction mixture was then stirred at room temperature for 12 h. A saturated aqueous solution of ammonium chloride (10 mL) was added. The aqueous phase was extracted with dichloromethane (3 X 15 mL) and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the solvents were removed under reduced pressure and the residue was chromatographed on silica gel (petroleum ether:ethyl acetate = 5:1) to give the product 4ad (54.5 mg, 57%) as a white solid.