5-BROMO-2-HYDROXY-4-METHOXY-BENZALDEHYDE

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

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

Procedure: Ex-62B: A stream of N2 was bubbled through a solution of 5-bromo-2-hydroxy-4-methoxybenzaldehyde (1 g, 4.3 mmol) from Ex-62A in 30 mL of ethylene glycol dimethyl ether for 15 min. Tetrakis-triphenylphosphine palladium (0) (0.5 g, 0.4 mmol) was added along with thiophene-2-boronic acid (1.2 g, 6.5 mmol) and 10 mL of Na2CO3 (2M aqueous solution). The resulting mixture was stirred under reflux overnight. The solvent was removed by rotary evaporation and the residue was treated with saturated NaHCO3 and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, and filtered to remove drying agent. Solvent was removed by rotary evaporation. Purification of the crude material by silica gel chromatography (hexanes/EtOAc, 2:1) gave 1.04 g of the desired 5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde. under reflux overnight The solvent was removed by rotary evaporation the residue was treated with saturated NaHCO3 extracted with dichloromethane The organic phase was washed with brine dried over MgSO4 filtered to remove drying agent Solvent was removed by rotary evaporation Purification of the crude material by silica gel chromatography (hexanes/EtOAc, 2:1)

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

Procedure: Ex-62A: A solution of 2-hydroxy-4-methoxybenzaldehyde (3.03 g, 20 mmol) in 25 mL of dichloromethane was cooled to 0° C. and treated dropwise with a solution of bromine (3.41 g, 21 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 1.5 hours. The solvent was removed by rotary evaporation to give a residue. The residue was taken up in EtOAc and washed with 3 portions of water. The organic layer was dried over MgSO4. The drying agent was removed by filtration, and solvent was removed by rotary evaporation to give 3.9 g of the desired 5-bromo-2-hydroxy-4-methoxybenzaldehyde as a solid, m.p. 111-115° C. The solvent was removed by rotary evaporation to give a residue washed with 3 portions of water The organic layer was dried over MgSO4 The drying agent was removed by filtration, and solvent was removed by rotary evaporation

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ex-13C: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde (Ex-13B, 1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde as a yellow solid, mp 118–119° C. 1H-NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (d, 1H, J=3.6 Hz), 7.31 (dd, 1H, J=5.1, 1.5 Hz), 7.08 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z 235 ([M+H]+, 100%). Anal. Calcd. for C8H7O3S: C, 61.52; H, 4.30; S, 13.69; Found: C, 61.12; H, 4.34; S, 13.56. Nitrogen was bubbled into the solution for 10 min extracted with ethyl acetate (3×30 mL) The combined organic extracts were dried over sodium sulfate concentrated to a brown solid

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

Procedure: Ex-13B: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. using an ice-water bath. Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise to the cooled solution and stirred for 2 h at 0° C. The mixture was warmed to room temperature and stirred for an additional 1 h and the resulting yellow precipitate was collected. Recrystallization (ethyl acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, mp 63–64° C. 1H-NMR (300 MHz, CDCl3) δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H), 3.95 (s, 3H). Anal. Calcd. for C8H7BrO3: C, 41.59; H, 3.05; Found: C, 41.86; H, 3.05. The mixture was warmed to room temperature stirred for an additional 1 h the resulting yellow precipitate was collected Recrystallization (ethyl acetate/hexanes)

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

Procedure: A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water (4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). The reaction mixture was heated under reflux for 15 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane, to give 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde as a white solid (2.2 g, 73%). was degassed with argon for 15 minutes The reaction mixture was heated under reflux for 15 hours extracted with ethyl acetate (2×100 mL) The organic extracts were successively washed with water (100 mL) a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 filtered Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography eluting with 5% ethyl acetate/95% hexane

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

Procedure: A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%). The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL) a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 filtered Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography eluting with 5% ethyl acetate/95% hexane

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

Procedure: A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%). The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL) a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 filtered Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography eluting with 5% ethyl acetate/95% hexane

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

Procedure: A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water (4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). The reaction mixture was heated under reflux for 15 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane, to give 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde as a white solid (2.2 g, 73%). was degassed with argon for 15 minutes The reaction mixture was heated under reflux for 15 hours extracted with ethyl acetate (2×100 mL) The organic extracts were successively washed with water (100 mL) a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 filtered Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography eluting with 5% ethyl acetate/95% hexane

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

Procedure: A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%). The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL) a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 filtered Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography eluting with 5% ethyl acetate/95% hexane

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

Procedure: A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%). The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL) a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 filtered Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography eluting with 5% ethyl acetate/95% hexane

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

Procedure: Ex-62B: A stream of N2 was bubbled through a solution of 5-bromo-2-hydroxy-4-methoxybenzaldehyde (1 g, 4.3 mmol) from Ex-62A in 30 mL of ethylene glycol dimethyl ether for 15 min. Tetrakis-triphenylphosphine palladium (0) (0.5 g, 0.4 mmol) was added along with thiophene-2-boronic acid (1.2 g, 6.5 mmol) and 10 mL of Na2CO3 (2M aqueous solution). The resulting mixture was stirred under reflux overnight. The solvent was removed by rotary evaporation and the residue was treated with saturated NaHCO3 and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, and filtered to remove drying agent. Solvent was removed by rotary evaporation. Purification of the crude material by silica gel chromatography (hexanes/EtOAc, 2:1) gave 1.04 g of the desired 5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde. under reflux overnight The solvent was removed by rotary evaporation the residue was treated with saturated NaHCO3 extracted with dichloromethane The organic phase was washed with brine dried over MgSO4 filtered to remove drying agent Solvent was removed by rotary evaporation Purification of the crude material by silica gel chromatography (hexanes/EtOAc, 2:1)