5-bromo-3,3,7-trimethyl-2H-1-benzofuran

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 50 mL round bottom flask were added 5-bromo-3,3,7-trimethyl-2,3-dihydro-1-benzofuran (0.11 g, 0.46 mmol) and THF (3 mL). A solution of n-BuLi (0.20 mL, 2.5 M solution in hexanes) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then DMF (0.053 mL, 0.68 mmol) was added. The reaction mixture was allowed to warm to room temperature. EtOAc (20 mL) and wet silica gel (5 g silica gel/0.5 mL of water) were added. The resulting mixture was stirred at room temperature for 10 minutes and then filtered. The resulting solid was rinsed with EtOAc. The filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (40 mg) as colorless solid. To a nitrogen flushed 50 mL round bottom flask to warm to room temperature The resulting mixture was stirred at room temperature for 10 minutes filtered The resulting solid was rinsed with EtOAc The filtrate was concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 100 mL round bottom flask were added 2,4-dibromo-6-methylphenyl 2-methylprop-2-en-1-yl ether (710 mg, 2.22 mmol), Pd(dppf)Cl2 (36 mg, 0.044 mmol), Et4NCl (490 mg, 2.66 mmol), KOAc (544 mg, 5.55 mmol), HCO2Na (181 mg, 2.66 mmol), DMF (20 mL) and water (1 mL). The reaction mixture was heated at 75° C. overnight. After cooling to room temperature, it was diluted with water and extracted with EtOAc/hexanes (1:3). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (110 mg, 70% purity) as light yellow liquid. To a nitrogen flushed 100 mL round bottom flask After cooling to room temperature extracted with EtOAc/hexanes (1:3) The organic layer was dried over sodium sulfate filtered concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 50 mL round bottom flask were added 5-bromo-3,3,7-trimethyl-2,3-dihydro-1-benzofuran (0.11 g, 0.46 mmol) and THF (3 mL). A solution of n-BuLi (0.20 mL, 2.5 M solution in hexanes) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then DMF (0.053 mL, 0.68 mmol) was added. The reaction mixture was allowed to warm to room temperature. EtOAc (20 mL) and wet silica gel (5 g silica gel/0.5 mL of water) were added. The resulting mixture was stirred at room temperature for 10 minutes and then filtered. The resulting solid was rinsed with EtOAc. The filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (40 mg) as colorless solid. To a nitrogen flushed 50 mL round bottom flask to warm to room temperature The resulting mixture was stirred at room temperature for 10 minutes filtered The resulting solid was rinsed with EtOAc The filtrate was concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 100 mL round bottom flask were added 2,4-dibromo-6-methylphenyl 2-methylprop-2-en-1-yl ether (710 mg, 2.22 mmol), Pd(dppf)Cl2 (36 mg, 0.044 mmol), Et4NCl (490 mg, 2.66 mmol), KOAc (544 mg, 5.55 mmol), HCO2Na (181 mg, 2.66 mmol), DMF (20 mL) and water (1 mL). The reaction mixture was heated at 75° C. overnight. After cooling to room temperature, it was diluted with water and extracted with EtOAc/hexanes (1:3). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (110 mg, 70% purity) as light yellow liquid. To a nitrogen flushed 100 mL round bottom flask After cooling to room temperature extracted with EtOAc/hexanes (1:3) The organic layer was dried over sodium sulfate filtered concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 100 mL round bottom flask were added 2,4-dibromo-6-methylphenyl 2-methylprop-2-en-1-yl ether (710 mg, 2.22 mmol), Pd(dppf)Cl2 (36 mg, 0.044 mmol), Et4NCl (490 mg, 2.66 mmol), KOAc (544 mg, 5.55 mmol), HCO2Na (181 mg, 2.66 mmol), DMF (20 mL) and water (1 mL). The reaction mixture was heated at 75° C. overnight. After cooling to room temperature, it was diluted with water and extracted with EtOAc/hexanes (1:3). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (110 mg, 70% purity) as light yellow liquid. To a nitrogen flushed 100 mL round bottom flask After cooling to room temperature extracted with EtOAc/hexanes (1:3) The organic layer was dried over sodium sulfate filtered concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran (Compound 7, 0.6 g, 2.5 mmol), benzophenone imine (0.54 g, 3 mmol), sodium-tert-butoxide (0.34 g, 3.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.01 5 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.029 g, 0.047 mmol) in 10mL of anhydrous toluene was sparged with argon and heated at 80° C. for overnight. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in 7 mL of tetrahydrofiran and treated with 1 mL of 2M hydrochloric acid, and stirred at ambient temperature for 0.5 hour. The volatiles were removed by distillation in vacuo and the residue was dissolved in 0.5M hydrochloric acid and washed with 1:1 hexanes: ethyl acetate. The aqueous phase was neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound as a dark brown oil (0.16 g, 36%). 1H-NMR (300 MHz, CDCl3): δ 6.33 (s, 2H), 4.18(s, 2H), 2.16(s, 3H), 1.30(s, 3H). The reaction mixture was cooled to ambient temperature filtered The filtrate was evaporated in vacuo the residue was dissolved in 7 mL of tetrahydrofiran treated with 1 mL of 2M hydrochloric acid The volatiles were removed by distillation in vacuo the residue was dissolved in 0.5M hydrochloric acid washed with 1:1 hexanes extracted with dichloromethane The combined organic extracts were dried over anhydrous sodium sulfate filtered evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran (Compound 7, 0.6 g, 2.5 mmol), benzophenone imine (0.54 g, 3 mmol), sodium-tert-butoxide (0.34 g, 3.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.01 5 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.029 g, 0.047 mmol) in 10mL of anhydrous toluene was sparged with argon and heated at 80° C. for overnight. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in 7 mL of tetrahydrofiran and treated with 1 mL of 2M hydrochloric acid, and stirred at ambient temperature for 0.5 hour. The volatiles were removed by distillation in vacuo and the residue was dissolved in 0.5M hydrochloric acid and washed with 1:1 hexanes: ethyl acetate. The aqueous phase was neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound as a dark brown oil (0.16 g, 36%). 1H-NMR (300 MHz, CDCl3): δ 6.33 (s, 2H), 4.18(s, 2H), 2.16(s, 3H), 1.30(s, 3H). The reaction mixture was cooled to ambient temperature filtered The filtrate was evaporated in vacuo the residue was dissolved in 7 mL of tetrahydrofiran treated with 1 mL of 2M hydrochloric acid The volatiles were removed by distillation in vacuo the residue was dissolved in 0.5M hydrochloric acid washed with 1:1 hexanes extracted with dichloromethane The combined organic extracts were dried over anhydrous sodium sulfate filtered evaporated

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

Procedure: Following General Procedure A and using 5-bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran (1.2 g, 5 mmol), 12 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (6.17 mL, 10.5 mmol) and trimethyl borate (1.2 mL, 10.5 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran can be prepared as described in U.S. Pat. No. 6,093,838, incorporated herein by reference.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 50 mL round bottom flask were added 5-bromo-3,3,7-trimethyl-2,3-dihydro-1-benzofuran (0.11 g, 0.46 mmol) and THF (3 mL). A solution of n-BuLi (0.20 mL, 2.5 M solution in hexanes) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then DMF (0.053 mL, 0.68 mmol) was added. The reaction mixture was allowed to warm to room temperature. EtOAc (20 mL) and wet silica gel (5 g silica gel/0.5 mL of water) were added. The resulting mixture was stirred at room temperature for 10 minutes and then filtered. The resulting solid was rinsed with EtOAc. The filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (40 mg) as colorless solid. To a nitrogen flushed 50 mL round bottom flask to warm to room temperature The resulting mixture was stirred at room temperature for 10 minutes filtered The resulting solid was rinsed with EtOAc The filtrate was concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a nitrogen flushed 100 mL round bottom flask were added 2,4-dibromo-6-methylphenyl 2-methylprop-2-en-1-yl ether (710 mg, 2.22 mmol), Pd(dppf)Cl2 (36 mg, 0.044 mmol), Et4NCl (490 mg, 2.66 mmol), KOAc (544 mg, 5.55 mmol), HCO2Na (181 mg, 2.66 mmol), DMF (20 mL) and water (1 mL). The reaction mixture was heated at 75° C. overnight. After cooling to room temperature, it was diluted with water and extracted with EtOAc/hexanes (1:3). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (110 mg, 70% purity) as light yellow liquid. To a nitrogen flushed 100 mL round bottom flask After cooling to room temperature extracted with EtOAc/hexanes (1:3) The organic layer was dried over sodium sulfate filtered concentrated The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes