methyl 5-bromo-4-fluoro-2-methoxybenzoate

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame-dried flask, under a nitrogen atmosphere, oven-dried cesium carbonate (4.33 g, 13.3 mmol) was combined with palladium acetate (85.3 mg, 0.380 mmol) and R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.355 g, 0.570 mmol). While under a constant nitrogen flow, the mixture was dissolved in toluene (0.76 mL) and treated with 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.50 g, 9.50 mmol) and morpholine (0.995 mL, 11.4 mmol). After being heated to 100° C. for 24 h, the reaction was cooled to room temperature, diluted with ether, filtered and concentrated. Purification by MPLC (ethyl acetate in heptane) provided 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 47%): 1H NMR (DMSO-d6 300 MHz) δ 7.33 (d, J=9.9 Hz, 1 H), 7.08 (d, J=14.4 Hz, 1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.70 (t, J=4.7 Hz, 4 H), 2.90 (t, J=4.5 Hz, 4 H). the reaction was cooled to room temperature filtered concentrated Purification by MPLC (ethyl acetate in heptane)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirring solution of 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (5.0 g, 10.0 mmol) in DMF (38 mL, 0.5 M) was treated with CuCN (3.92 g, 43.7 mmol). Equipped with a reflux condenser, the mixture was heated at 150° C. for 24 hours. After cooling, the reaction was poured into a 2 L erlenmeyer flask. Ethyl acetate (400 mL), saturated aq LiCl (100 mL), 1N HCl (100 mL), 11 g of iron (III) chloride hexahydrate, and 15 mL of concd HCl was added to the solution. This green mixture was heated at 70° C. for 2 h (or until emulsion dissapated). After cooling to room temperature, the mixture was poured into a seperatory funnel and extracted with ethyl acetate (600 mL total). The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL) and saturated aq NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 5-cyano-4-fluoro-2-methoxy-benzoic acid methyl ester (2.98 g, 0.75%) as a white crystalline solid: 1H NMR (CDCl3, 300 MHz) δ 8.15 (d, J=7.5 Hz, 1 H), 6.80 (d, J=11.1 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H). Equipped with a reflux condenser After cooling the reaction was poured into a 2 L erlenmeyer flask This green mixture was heated at 70° C. for 2 h (or until emulsion dissapated) After cooling to room temperature the mixture was poured into a seperatory funnel extracted with ethyl acetate (600 mL total) The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL) and saturated aq NaCl (100 mL) The organic layer was dried over Na2SO4 filtered concentrated under reduced pressure Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) was added 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.0 g, 7.6 mmol), anhydrous K2CO3 (2.1 g, 15.2 mmol), phenylboronic acid (3.7 g, 30.4 mmol), and Pd(PPh3)4 (0.88 g, 0.76 mmol). Using a reflux condenser, the stirring mixture was heated to 110° C. for 3.5 h. The mixture was then cooled to room temperature, placed in an ice bath and H2O2 (30%, 10 mL) was slowly added. The ice bath was removed and the reaction was allowed to stir at room temperature for one hour. The mixture was then diluted with ether and washed successively with 2 N HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to afford a brown oil. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid methyl ester (1.8 g, 91%) as a pale yellow solid: Rf 0.5 (40% ethyl acetate in heptane); To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) The mixture was then cooled to room temperature placed in an ice bath The ice bath was removed The mixture was then diluted with ether washed successively with 2 N HCl and saturated aq NaCl The organic layer was dried over Na2SO4 filtered concentrated to afford a brown oil Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) was added 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.0 g, 7.6 mmol), anhydrous K2CO3 (2.1 g, 15.2 mmol), phenylboronic acid (3.7 g, 30.4 mmol), and Pd(PPh3)4 (0.88 g, 0.76 mmol). Using a reflux condenser, the stirring mixture was heated to 110° C. for 3.5 h. The mixture was then cooled to room temperature, placed in an ice bath and H2O2 (30%, 10 mL) was slowly added. The ice bath was removed and the reaction was allowed to stir at room temperature for one hour. The mixture was then diluted with ether and washed successively with 2 N HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to afford a brown oil. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid methyl ester (1.8 g, 91%) as a pale yellow solid: Rf 0.5 (40% ethyl acetate in heptane); To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) The mixture was then cooled to room temperature placed in an ice bath The ice bath was removed The mixture was then diluted with ether washed successively with 2 N HCl and saturated aq NaCl The organic layer was dried over Na2SO4 filtered concentrated to afford a brown oil Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min)

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame-dried flask, under a nitrogen atmosphere, oven-dried cesium carbonate (4.33 g, 13.3 mmol) was combined with palladium acetate (85.3 mg, 0.380 mmol) and R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.355 g, 0.570 mmol). While under a constant nitrogen flow, the mixture was dissolved in toluene (0.76 mL) and treated with 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.50 g, 9.50 mmol) and morpholine (0.995 mL, 11.4 mmol). After being heated to 100° C. for 24 h, the reaction was cooled to room temperature, diluted with ether, filtered and concentrated. Purification by MPLC (ethyl acetate in heptane) provided 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 47%): 1H NMR (DMSO-d6 300 MHz) δ 7.33 (d, J=9.9 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.70 (t, J=4.7 Hz, 4H), 2.90 (t, J=4.5 Hz, 4H). the reaction was cooled to room temperature filtered concentrated Purification by MPLC (ethyl acetate in heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame-dried flask, under a nitrogen atmosphere, oven-dried cesium carbonate (4.33 g, 13.3 mmol) was combined with palladium acetate (85.3 mg, 0.380 mmol) and R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.355 g, 0.570 mmol). While under a constant nitrogen flow, the mixture was dissolved in toluene (0.76 mL) and treated with 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.50 g, 9.50 mmol) and morpholine (0.995 mL, 11.4 mmol). After being heated to 100° C. for 24 h, the reaction was cooled to room temperature, diluted with ether, filtered and concentrated. Purification by MPLC (ethyl acetate in heptane) provided 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 47%): 1H NMR (DMSO-d6 300 MHz) δ 7.33 (d, J=9.9 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.70 (t, J=4.7 Hz, 4H), 2.90 (t, J=4.5 Hz, 4H). the reaction was cooled to room temperature filtered concentrated Purification by MPLC (ethyl acetate in heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flame-dried flask, under a nitrogen atmosphere, oven-dried cesium carbonate (4.33 g, 13.3 mmol) was combined with palladium acetate (85.3 mg, 0.380 mmol) and R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.355 g, 0.570 mmol). While under a constant nitrogen flow, the mixture was dissolved in toluene (0.76 mL) and treated with 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.50 g, 9.50 mmol) and morpholine (0.995 mL, 11.4 mmol). After being heated to 100° C. for 24 h, the reaction was cooled to room temperature, diluted with ether, filtered and concentrated. Purification by MPLC (ethyl acetate in heptane) provided 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 47%): 1H NMR (DMSO-d6 300 MHz) δ 7.33 (d, J=9.9 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.70 (t, J=4.7 Hz, 4H), 2.90 (t, J=4.5 Hz, 4H). the reaction was cooled to room temperature filtered concentrated Purification by MPLC (ethyl acetate in heptane)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirring solution of 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (5.0 g, 10.0 mmol) in DMF (38 mL, 0.5 M) was treated with CuCN (3.92 g, 43.7 mmol). Equipped with a reflux condenser, the mixture was heated at 150° C. for 24 hours. After cooling, the reaction was poured into a 2 L erlenmeyer flask. Ethyl acetate (400 mL), saturated aq LiCl (100 mL), 1N HCl (100 mL)), 11 g of iron (III) chloride hexahydrate, and 15 mL of concd HCl was added to the solution. This green mixture was heated at 70° C. for 2 h (or until emulsion dissapated). After cooling to room temperature, the mixture was poured into a seperatory funnel and extracted with ethyl acetate (600 mL total). The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL) and saturated aq NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 5-cyano-4-fluoro-2-methoxy-benzoic acid methyl ester (2.98 g, 75%) as a white crystalline solid: 1H NMR (CDCl3, 300 MHz)δ 8.15 (d, J=7.5 Hz, 1H), 6.80 (d, J=11.1 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H). Equipped with a reflux condenser After cooling the reaction was poured into a 2 L erlenmeyer flask This green mixture was heated at 70° C. for 2 h (or until emulsion dissapated) After cooling to room temperature the mixture was poured into a seperatory funnel extracted with ethyl acetate (600 mL total) The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL) and saturated aq NaCl (100 mL) The organic layer was dried over Na2SO4 filtered concentrated under reduced pressure Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) was added 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.0 g, 7.6 mmol), anhydrous K2CO3 (2.1 g, 15.2 mmol), phenylboronic acid (3.7 g, 30.4 mmol), and Pd(PPh3)4 (0.88 g, 0.76 mmol). Using a reflux condenser, the stirring mixture was heated to 110° C. for 3.5 h. The mixture was then cooled to room temperature, placed in an ice bath and H2O2 (30%, 10 mL) was slowly added. The ice bath was removed and the reaction was allowed to stir at room temperature for one hour. The mixture was then diluted with ether and washed successively with 2 N HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to afford a brown oil. Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 6-fluoro-4-methoxy-biphenyl-3-carboxylic acid methyl ester (1.8 g, 91%) as a pale yellow solid: Rf 0.5 (40% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=9.0 Hz, 1H), 7.53-7.33 (m, 5H), 6.79 (d, J=12.6 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H). To a flame dried flask containing degassed toluene (15.2 mL, 0.5 M) The mixture was then cooled to room temperature placed in an ice bath The ice bath was removed The mixture was then diluted with ether washed successively with 2 N HCl and saturated aq NaCl The organic layer was dried over Na2SO4 filtered concentrated to afford a brown oil Purification by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min)