1,2-dibromo-4,5-dimethoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 106 g (0.36 mols) of 1.2-dibromo-4.5-dimethoxy-benzene, 98 g (1.06 mols) of copper cyanide and 300 ml of dimethylformamide is brought to reflux for five hours, then the mixture is cooled and is poured into 500 ml of 30% ammonia. The residue is again mixed for 10 minutes, then is filtered and washed with water and dried. The product is extracted by ether for 24 hours by using a Soxhlet device and the solvent is evaporated. Thus, 40 g of 1.2-dicyano-4.5 dimethoxybenzene is obtained in the form of white flakes, which corresponds to a yield of 58%. to reflux for five hours the mixture is cooled The residue is again mixed for 10 minutes is filtered washed with water dried The product is extracted by ether for 24 hours the solvent is evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.55 g of 1,2-dibromo-4,5-dimethoxybenzene (8.62 mmol; 2 eq) and 500 mg of 1,1-diethoxyethene (4.31 mmol; 1 eq) in 25 mL of toluene are stirred at 0° C. under argon. 3.5 mL of n-butyllithium (2.5M in hexane, 8.62 mmol; 2 eq) are added dropwise at 0° C. When the addition is complete, the reaction mixture is stirred for 22 hours at ambient temperature. The reaction mixture is then hydrolysed and extracted 3 times with ethyl acetate. The organic phases are dried and evaporated, and the crude product is purified by column chromatography over silica gel (eluant: heptane/ethyl acetate 90/10). There are obtained 333 mg of a yellow oil which crystallises at ambient temperature. When the addition hydrolysed and extracted 3 times with ethyl acetate The organic phases are dried evaporated the crude product is purified by column chromatography over silica gel (eluant: heptane/ethyl acetate 90/10)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.55 g of 1,2-dibromo-4,5-dimethoxybenzene (8.62 mmol; 2 eq) and 500 mg of 1,1-diethoxyethene (4.31 mmol; 1 eq) in 25 mL of toluene are stirred at 0° C. under argon. 3.5 mL of n-butyllithium (2.5M in hexane, 8.62 mmol; 2 eq) are added dropwise at 0° C. When the addition is complete, the reaction mixture is stirred for 22 hours at ambient temperature. The reaction mixture is then hydrolysed and extracted 3 times with ethyl acetate. The organic phases are dried and evaporated, and the crude product is purified by column chromatography over silica gel (eluant: heptane/ethyl acetate 90/10). There are obtained 333 mg of a yellow oil which crystallises at ambient temperature. When the addition hydrolysed and extracted 3 times with ethyl acetate The organic phases are dried evaporated the crude product is purified by column chromatography over silica gel (eluant: heptane/ethyl acetate 90/10)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv. CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystalization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystalization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292)2,4,6-triisopropylphenyiboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3 ×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco Combiflash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3 ×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco Combiflash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 106 g (0.36 mols) of 1.2-dibromo-4.5-dimethoxy-benzene, 98 g (1.06 mols) of copper cyanide and 300 ml of dimethylformamide is brought to reflux for five hours, then the mixture is cooled and is poured into 500 ml of 30% ammonia. The residue is again mixed for 10 minutes, then is filtered and washed with water and dried. The product is extracted by ether for 24 hours by using a Soxhlet device and the solvent is evaporated. Thus, 40 g of 1.2-dicyano-4.5 dimethoxybenzene is obtained in the form of white flakes, which corresponds to a yield of 58%. to reflux for five hours the mixture is cooled The residue is again mixed for 10 minutes is filtered washed with water dried The product is extracted by ether for 24 hours the solvent is evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9. To a 100-mL round bottom flask equipped with a magnetic stir bar The flask was purged with nitrogen for 30 minutes anhydrous, degassed tetrahydrofuran (20 mL) was added The reaction was stirred at reflux for 21 hours The reaction mixture was cooled to room temperature The phases were separated the aqueous layer was washed with ethyl acetate (3×20 mL) The combined organics were washed with brine (50 mL) dried over sodium sulfate filtered concentrated on a rotary evaporator The unreacted dibromoarene was removed by recrystallization from hot methanol The product was further purified by column chromatography on an Isco CombiFlash system (120-g column