4-bromo-2-chloro-1-methoxybenzene

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

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

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

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

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

Procedure: A mixture of magnesium turnings (0.31 g, 13.1 mmol), 2-chloro-4-bromoanisole (3.00 g, 13.5 mmol), 4-tert-butyldimethysilyloxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-en-1-one (2.58 g, 6.84 mmol) and dry tetrahydrofuran (35 ml) under nitrogen was stirred at room temperature for 4 h. Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure and the residual reaction mixture was extracted with ethyl acetate (3×35 ml), washed with water (2×20 ml) and dried over sodium sulfate. Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether) afforded the alcohol of the formula (4A) Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure the residual reaction mixture was extracted with ethyl acetate (3×35 ml) washed with water (2×20 ml) dried over sodium sulfate Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0° C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil) in THF (30 ml). After 15 min the solution was cooled to −40° C. and n-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one (1.5 g, 5.6 mmol, compound was prepared analogously to Step 1 of Example A(82), where 4-bromo-2-chloro-1-methoxybenzene was substituted in place of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification. After stirring for 1 h at −40° C. the reaction mixture was quenched with saturated NH4Cl extracted with EtOAc The organic layers were washed with brine dried with Na2SO4 concentrated to an orange oil that was used without further purification

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

Procedure: A solution of 4-bromo-2-chloroanisole (3 g, 13.55 mmol) and (S)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (3.79 g, 14.22 mmol) in THF (33.9 mL) was cooled to −20° C. with dry ice/acetone. To this solution was added isopropylmagnesium chloride lithium chloride complex (22.9 mL, 29.8 mmol) at −20° C. dropwise under N2. After addition, the reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was cooled to −40° C. and slowly poured into a stirred mixture of crushed ice and 30 mL of 1N HCl. The resulting mixture was diluted with 30 mL of brine, extracted with EtOAc (3×50 mL). The organic layer was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 0-100% EtOAc in hexane to give (S)-benzyl (1-(3-chloro-4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.82 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.05 (s, 1H), 7.92 (d, 1H), 6.98 (d, 1H), 5.93 (d, 1H), 5.29 (m, 1H), 5.16 (s, 2H), 3.99 (s, 3H), 1.43 (d, 3H). After addition The reaction mixture was cooled to −40° C. extracted with EtOAc (3×50 mL) The organic layer was dried with Na2SO4 concentrated The residue was purified by silica gel chromatography eluted with 0-100% EtOAc in hexane

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

Procedure: A solution of 4-bromo-2-chloroanisole (3 g, 13.55 mmol) and (S)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (3.79 g, 14.22 mmol) in THF (33.9 mL) was cooled to −20° C. with dry ice/acetone. To this solution was added isopropylmagnesium chloride lithium chloride complex (22.9 mL, 29.8 mmol) at −20° C. dropwise under N2. After addition, the reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was cooled to −40° C. and slowly poured into a stirred mixture of crushed ice and 30 mL of 1N HCl. The resulting mixture was diluted with 30 mL of brine, extracted with EtOAc (3×50 mL). The organic layer was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 0-100% EtOAc in hexane to give (S)-benzyl (1-(3-chloro-4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.82 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.05 (s, 1H), 7.92 (d, 1H), 6.98 (d, 1H), 5.93 (d, 1H), 5.29 (m, 1H), 5.16 (s, 2H), 3.99 (s, 3H), 1.43 (d, 3H). After addition The reaction mixture was cooled to −40° C. extracted with EtOAc (3×50 mL) The organic layer was dried with Na2SO4 concentrated The residue was purified by silica gel chromatography eluted with 0-100% EtOAc in hexane

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

Procedure: A solution of 4-bromo-2-chloroanisole (3 g, 13.55 mmol) and (S)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (3.79 g, 14.22 mmol) in THF (33.9 mL) was cooled to −20° C. with dry ice/acetone. To this solution was added isopropylmagnesium chloride lithium chloride complex (22.9 mL, 29.8 mmol) at −20° C. dropwise under N2. After addition, the reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was cooled to −40° C. and slowly poured into a stirred mixture of crushed ice and 30 mL of 1N HCl. The resulting mixture was diluted with 30 mL of brine, extracted with EtOAc (3×50 mL). The organic layer was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 0-100% EtOAc in hexane to give (S)-benzyl (1-(3-chloro-4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.82 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.05 (s, 1H), 7.92 (d, 1H), 6.98 (d, 1H), 5.93 (d, 1H), 5.29 (m, 1H), 5.16 (s, 2H), 3.99 (s, 3H), 1.43 (d, 3H). After addition The reaction mixture was cooled to −40° C. extracted with EtOAc (3×50 mL) The organic layer was dried with Na2SO4 concentrated The residue was purified by silica gel chromatography eluted with 0-100% EtOAc in hexane

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

Procedure: To a THF solution of 4-bromo-2-chloroanisole was added an n-butyllithium/n-hexane solution at −78° C., followed by 30 minutes of stirring. Then, trimethyl borate was added and the whole was warmed to room temperature, followed by 30 minutes of stirring. Using the residue obtained by evaporation of the solvent instead of 3,4-dimethoxyphenylboric acid, an objective compound was obtained in a similar manner to Reference Example 1. followed by 30 minutes of stirring

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

Procedure: A mixture of magnesium turnings (0.31 g, 13.1 mmol), 2-chloro-4-bromoanisole (3.00 g, 13.5 mmol), 4-tert-butyldimethysilyloxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-en-1-one (2.58 g, 6.84 mmol) and dry tetrahydrofuran (35 ml) under nitrogen was stirred at room temperature for 4 h. Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure and the residual reaction mixture was extracted with ethyl acetate (3×35 ml), washed with water (2×20 ml) and dried over sodium sulfate. Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether) afforded the alcohol of the formula (4A) Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure the residual reaction mixture was extracted with ethyl acetate (3×35 ml) washed with water (2×20 ml) dried over sodium sulfate Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether)

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

Procedure: A mixture of magnesium turnings (0.31 g, 13.1 mmol), 2-chloro-4-bromoanisole (3.00 g, 13.5 mmol), 4-tert-butyldimethysilyloxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-en-1-one (2.58 g, 6.84 mmol) and dry tetrahydrofuran (35 ml) under nitrogen was stirred at room temperature for 4 h. Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure and the residual reaction mixture was extracted with ethyl acetate (3×35 ml), washed with water (2×20 ml) and dried over sodium sulfate. Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether) afforded the alcohol of the formula (4A) Reaction was then quenched with dil hydrochloric acid (30 ml), tetrahydrofuran was removed under reduced pressure the residual reaction mixture was extracted with ethyl acetate (3×35 ml) washed with water (2×20 ml) dried over sodium sulfate Concentration and purification by column chromatography over silica gel (eluent-6% acetone in pet ether)