2,2-dimethyl-3H-1-benzofuran-7-carbaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-phenoxy-phenylamine (350 mg, 1.89 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg, 2.83 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (216 mg, 5.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min) to afford 560 mg (86%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine as a colourless oil. The reaction was cooled to 0° C. the mixture stirred for 15 min The solvents were removed in vacuo the residue quenched with saturated aqueous NaHCO3 (50 mL) extracted with DCM (2×30 mL) dried over MgSO4 filtered solvents removed in vacuo The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-phenoxy-phenylamine (350 mg, 1.89 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg, 2.83 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (216 mg, 5.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min) to afford 560 mg (86%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine as a colourless oil. The reaction was cooled to 0° C. the mixture stirred for 15 min The solvents were removed in vacuo the residue quenched with saturated aqueous NaHCO3 (50 mL) extracted with DCM (2×30 mL) dried over MgSO4 filtered solvents removed in vacuo The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carbaldehyde (281 mg, 1.59 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.63 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (61.5 mg, 1.63 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (303 mg, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.02 (m, 2H), 6.76-6.71 (m, 1H), 3.52 (s, 2H), 2.97 (s, 2H), 2.24 (s, 3H), 1.39 (s, 6H). The solution was concentrated to a yellow oil dissolved in anhydrous methanol (7 ml) the mixture was stirred overnight at room temperature the solution was concentrated Sodium hydroxide (20 ml, 1N) was added the aqueous layer was extracted with ethyl acetate (3×40 ml) Combined organic layers were dried over MgSO4 filtered concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-phenoxy-phenylamine (350 mg, 1.89 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg, 2.83 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (216 mg, 5.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min) to afford 560 mg (86%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine as a colourless oil. The reaction was cooled to 0° C. the mixture stirred for 15 min The solvents were removed in vacuo the residue quenched with saturated aqueous NaHCO3 (50 mL) extracted with DCM (2×30 mL) dried over MgSO4 filtered solvents removed in vacuo The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min)

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

Procedure: 5 g of 3-amino-2-chloropyridine was dissolved in 80 ml of acetic acid, and 7.1 g of 2,2-dimethyl-7-formyl-2,3-dihydrobenzofuran was added. Then, the mixture was stirred at room temperature for about 30 minutes, and 16.5 g of triacetoxy sodium borohydride was added gradually under ice-cooling. After stirring the obtained reaction mixture at room temperature for about four hours, the solvent was concentrated. After adding ice-water to the residue and alkalizing it with an aqueous sodium hydroxide solution, it was extracted twice with ethyl acetate. After washing the organic layer with water and drying, it was concentrated and purified with a short column (dichloromethane/methanol=10:1) using silica gel to obtain 12.2 g of oily 3-[(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-chloropyridine. cooling After stirring the obtained reaction mixture at room temperature for about four hours the solvent was concentrated After adding ice-water to the residue was extracted twice with ethyl acetate After washing the organic layer with water drying it was concentrated purified with a short column (dichloromethane/methanol=10:1)

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

Procedure: 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carbaldehyde (281 mg, 1.59 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.63 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (61.5 mg, 1.63 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (303 mg, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.02 (m, 2H), 6.76-6.71 (m, 1H), 3.52 (s, 2H), 2.97 (s, 2H), 2.24 (s, 3H), 1.39 (s, 6H). The solution was concentrated to a yellow oil dissolved in anhydrous methanol (7 ml) the mixture was stirred overnight at room temperature the solution was concentrated Sodium hydroxide (20 ml, 1N) was added the aqueous layer was extracted with ethyl acetate (3×40 ml) Combined organic layers were dried over MgSO4 filtered concentrated

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

Procedure: Sodium borohydride (1.08 grams, 0.0285 mole) was added carefully in small portions to a stirred solution of 2,3-dihydro-2,2-dimethylbenzofuran-7-carboxaldehyde (10.0 grams, 0.057 mole) in ethanol (150 ml) at 5°-10° C. during a ten minute period. The reaction mixture was stirred for thirty minutes and was then quenched by the dropwise addition of water (25 ml) followed by 10% hydrochloric acid (25 ml). The reaction mixture was concentrated under reduced pressure leaving a residue. This residue was partitioned between diethyl ether (75 ml) and 10% hydrochloric acid (30 ml). The layers were separated, and the organic layer was washed with water (40 ml) and a saturated aqueous solution of sodium chloride (40 ml). The dried (sodium sulfate) organic solution was concentrated under reduced pressure, yielding 2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethanol as a solid. The NMR spectrum was consistent with the proposed structure. was then quenched by the dropwise addition of water (25 ml) The reaction mixture was concentrated under reduced pressure leaving a residue This residue was partitioned between diethyl ether (75 ml) and 10% hydrochloric acid (30 ml) The layers were separated the organic layer was washed with water (40 ml) The dried (sodium sulfate) organic solution was concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyl lithium, 2.7M, (25.04 ml, 0.0676 mole) was added to a stirred solution of 2,3-dihydro-2,2-dimethylbenzofuran (10.0 grams, 0.0676 mole) in tetrahydrofuran (75 ml) at -78° C. The reaction mixture was then stirred at 0° C. for two hours after which it was added to a cooled (-78° C.) solution of dimethylformamide (5.42 ml, 0.07 mole) in tetrahydrofuran (25 ml). Upon completion of addition, the reaction mixture was stirred at -78° C. for ten minutes and then warmed to ambient temperature. The reaction mixture was quenched with aqueous ammonium chloride (1M, 150 ml) and stirred for three hours at ambient temperature. The reaction mixture was extracted with diethyl ether (2×150 ml), and the combined extract was washed with a saturated aqueous solution of sodium chloride. The dried (magnesium sulfate) extract was concentrated under reduced pressure leaving a residue. This residue was distilled, yielding 3.72 grams of 2,3-dihydro-2,2-dimethylbenzofuran-7 -carboxaldehyde, b.p. 80°-83° C./0.2 mmHg. The NMR spectrum was consistent with the proposed structure. was added to Upon completion of addition the reaction mixture was stirred at -78° C. for ten minutes warmed to ambient temperature The reaction mixture was quenched with aqueous ammonium chloride (1M, 150 ml) stirred for three hours at ambient temperature The reaction mixture was extracted with diethyl ether (2×150 ml) the combined extract was washed with a saturated aqueous solution of sodium chloride The dried (magnesium sulfate) extract was concentrated under reduced pressure leaving a residue This residue was distilled

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-phenoxy-phenylamine (350 mg, 1.89 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg, 2.83 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (216 mg, 5.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min) to afford 560 mg (86%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine as a colourless oil. The reaction was cooled to 0° C. the mixture stirred for 15 min The solvents were removed in vacuo the residue quenched with saturated aqueous NaHCO3 (50 mL) extracted with DCM (2×30 mL) dried over MgSO4 filtered solvents removed in vacuo The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min)