chloro(fluoro)methane

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

Procedure: A 500 mL nitrogen purged round bottom flask fitted with a dry-ice condenser was cooled to −78° C. and 50 mL (ca. 40 g by cylinder difference) of chlorofluoromethane was condensed. DMF (200 mL), 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (40 g, 0.155 mol), powdered potassium carbonate (22 g, 0.159 mol, 1.03 equiv) and sodium bromide (22 g, 0.21 mol) were carefully added. An additional 100 mL of DMF was added and the dry-ice bath was removed. The pale yellow suspension was warmed first to room temperature, then to 70-75° C. (oil bath). Gentle reflux was noted. After 3 h, an additional 30 g of NaBr was added. The condenser was kept cold for ca. 10 h and allowed to warm to room temperature overnight. The white suspension which resulted was diluted with 2 L of water and extracted with ether (1×1 L, 2×500 mL). The combined extracts were washed with water (4×250 mL) and brine (500 mL), dried with magnesium sulfate, filtered and the filtrate concentrated. During concentration the product began to crystallize. The filtrare was concentrated to a small volume and the mixture flushed with hexanes. The resulting slurry was cooled to 0° C., aged 1 hr, filtered, and the cake washed with hexanes. The yield upon drying was 42.2 g (93.8%) of white crystalline 2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde: 1H NMR (CDCI3) δ 5.91 (d, JH-F=30.5 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 7.72 (dd, J=9, 2.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 10.49 (s, 1H). MS (EI) m/z 290. Anal. Calcd for C10H6F4N4O2: C, 41.39; H, 2.08; F, 26.19; N, 19.31. Found: C, 41.39; H, 1.98; F, 25.79; N, 19.53. A 500 mL nitrogen purged round bottom flask fitted with a dry-ice condenser condensed the dry-ice bath was removed The pale yellow suspension was warmed first to room temperature to 70-75° C. Gentle reflux an additional 30 g of NaBr was added The condenser was kept cold for ca. 10 h to warm to room temperature overnight The white suspension which resulted extracted with ether (1×1 L, 2×500 mL) The combined extracts were washed with water (4×250 mL) and brine (500 mL) dried with magnesium sulfate filtered the filtrate concentrated During concentration the product to crystallize The filtrare was concentrated to a small volume the mixture flushed with hexanes The resulting slurry was cooled to 0° C., aged 1 hr filtered the cake washed with hexanes The yield upon drying

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

Procedure: To a cooled (−78° C.) mixture of methyl 4-hydroxy-3-(trifluoromethyl)benzoate (2.45 g, 11.13 mmol) and cesium carbonate (5.44 g, 16.7 mmol) in DMF in a pressure vessel was bubbled chlorofluoromethane (7.00 g, 102 mmol). The vessel was sealed and the reaction was stirred at room temperature for 120 h. The reaction was filtered through Celite®. The filtrate was diluted with EtOAc, washed with water (4 times), dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a solid (2.44 g). LCMS m/z=253.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 5.98-6.20 (d, J=52.5 Hz, 2H), 7.59 (d, J=8.84 Hz, 1H), 8.18 (d, J=2.02 Hz, 1H), 8.28 (dd, J=8.84, 2.15 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ ppm −153.52 (s, 1F), −61.08 (s, 3F). To a cooled The vessel was sealed The reaction was filtered through Celite® The filtrate was diluted with EtOAc washed with water (4 times) dried over MgSO4 filtered concentrated under vacuum

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

Procedure: To a cooled (−78° C.) mixture of methyl 4-hydroxy-3-(trifluoromethyl)benzoate (2.45 g, 11.13 mmol) and cesium carbonate (5.44 g, 16.7 mmol) in DMF in a pressure vessel was bubbled chlorofluoromethane (7.00 g, 102 mmol). The vessel was sealed and the reaction was stirred at room temperature for 120 h. The reaction was filtered through Celite®. The filtrate was diluted with EtOAc, washed with water (4 times), dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a solid (2.44 g). LCMS m/z=253.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 5.98-6.20 (d, J=52.5 Hz, 2H), 7.59 (d, J=8.84 Hz, 1H), 8.18 (d, J=2.02 Hz, 1H), 8.28 (dd, J=8.84, 2.15 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ ppm −153.52 (s, 1F), −61.08 (s, 3F). To a cooled The vessel was sealed The reaction was filtered through Celite® The filtrate was diluted with EtOAc washed with water (4 times) dried over MgSO4 filtered concentrated under vacuum

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

Procedure: To a tared, sealed 350 mL round-bottomed pressure flask containing a suspension of 3,5-dibromophenol (10.0 g, 39.7 mmol; see step (ii) above) and Cs2CO3 (20.7 g, 63.5 mmol) in DMF (150 mL) at −78° C. was added chlorofluoromethane via bubbling for 5 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 9.0 g (131 mmol) of chlorofluoromethane. The solution was heated in an oil bath set at 70° C. overnight. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with water (100 mL). The aqueous layer was extracted with Et2O (3× 200 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (7.9 g, 71%) as a white solid. sealed 350 mL round-bottomed pressure flask containing via bubbling for 5 min through the septum the flask was then sealed The solution was heated in an oil bath The flask was cooled to room temperature The aqueous layer was extracted with Et2O (3× 200 mL) the combined organics were dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: To a cooled (−78° C.) mixture of methyl 4-hydroxy-3-(trifluoromethyl)benzoate (2.45 g, 11.13 mmol) and cesium carbonate (5.44 g, 16.7 mmol) in DMF in a pressure vessel was bubbled chlorofluoromethane (7.00 g, 102 mmol). The vessel was sealed and the reaction was stirred at room temperature for 120 h. The reaction was filtered through Celite®. The filtrate was diluted with EtOAc, washed with water (4 times), dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a solid (2.44 g). LCMS m/z=253.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 5.98-6.20 (d, J=52.5 Hz, 2H), 7.59 (d, J=8.84 Hz, 1H), 8.18 (d, J=2.02 Hz, 1H), 8.28 (dd, J=8.84, 2.15 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ ppm −153.52 (s, 1F), −61.08 (s, 3F). To a cooled The vessel was sealed The reaction was filtered through Celite® The filtrate was diluted with EtOAc washed with water (4 times) dried over MgSO4 filtered concentrated under vacuum

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (1.4 g, 57.1 mmol) was suspended in THF (50 mL) in a pressure flask under a nitrogen atmosphere and cooled to −10° C. with stirring. Ethyl (1,1-diethoxyethyl)phosphinate (10.0 g, 47.6 mmol) in THF (20 mL) was added dropwise to the mixture over 10 minutes; the internal temperature was maintained below 0° C. during the addition. On completion of addition, the reaction mixture was allowed to stir at this temperature for 90 minutes. The flask was cooled to −78° C. and chlorofluoromethane gas (9.7 g, 142.8 mmol) was condensed into the reaction mixture. The septum was removed and the flask was sealed with a screw thread stopper. The flask was then allowed to warm to room temperature and then heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C. and cautiously quenched with water (25 mL). Methylene chloride (50 mL) was added to the reaction mixture and the emulsion was filtered through a pad of Celite ® (20 g). The aqueous phase was extracted with methylene chloride (2×100 mL), dried over anhydrous magnesium sulfate, and the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g). The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes. This procedure afforded ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate as a clear, colorless oil (4.4 g, 42%). 1H NMR (300 MHz, CDCl3) δ 4.94–4.54 (m, 2H), 4.32–4.20 (m, 2H), 3.82–3.54 (m, 4H), 1.60–1.44 (m, 3H), 1.40–1.28 (m, 3H), 1.26–1.08 (m, 6H). the internal temperature was maintained below 0° C. during the addition On completion of addition to stir at this temperature for 90 minutes The flask was cooled to −78° C. condensed into the reaction mixture The septum was removed the flask was sealed with a screw thread stopper to warm to room temperature heated at 50° C. for 24 h The reaction mixture was cooled to 0° C. cautiously quenched with water (25 mL) Methylene chloride (50 mL) was added to the reaction mixture the emulsion was filtered through a pad of Celite ® (20 g) The aqueous phase was extracted with methylene chloride (2×100 mL) dried over anhydrous magnesium sulfate the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g) The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (1.4 g, 57.1 mmol) was suspended in THF (50 mL) in a pressure flask under a nitrogen atmosphere and cooled to −10° C. with stirring. Ethyl (1,1-diethoxyethyl)phosphinate (10.0 g, 47.6 mmol) in THF (20 mL) was added dropwise to the mixture over 10 minutes; the internal temperature was maintained below 0° C. during the addition. On completion of addition, the reaction mixture was allowed to stir at this temperature for 90 minutes. The flask was cooled to −78° C. and chlorofluoromethane gas (9.7 g, 142.8 mmol) was condensed into the reaction mixture. The septum was removed and the flask was sealed with a screw thread stopper. The flask was then allowed to warm to room temperature and then heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C. and cautiously quenched with water (25 mL). Methylene chloride (50 mL) was added to the reaction mixture and the emulsion was filtered through a pad of Celite® (20 g). The aqueous phase was extracted with methylene chloride (2×100 mL), dried over anhydrous magnesium sulfate, and the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g). The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes. This procedure afforded ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate as a clear, colorless oil (4.4 g, 42%). 1H NMR (300 MHz, CDCl3) δ 4.94-4.54 (m, 2H), 4.32-4.20 (m, 2H), 3.82-3.54 (m, 4H), 1.60-1.44 (m, 3H), 1.40-1.28 (m, 3H), 1.26-1.08 (m, 6H). the internal temperature was maintained below 0° C. during the addition On completion of addition to stir at this temperature for 90 minutes The flask was cooled to −78° C. condensed into the reaction mixture The septum was removed the flask was sealed with a screw thread stopper to warm to room temperature heated at 50° C. for 24 h The reaction mixture was cooled to 0° C. cautiously quenched with water (25 mL) Methylene chloride (50 mL) was added to the reaction mixture the emulsion was filtered through a pad of Celite® (20 g) The aqueous phase was extracted with methylene chloride (2×100 mL) dried over anhydrous magnesium sulfate the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g) The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes

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

Procedure: To a tared, sealed 350 mL round-bottomed pressure flask containing a suspension of 3,5-dibromophenol (10.0 g, 39.7 mmol; see step (ii) above) and Cs2CO3 (20.7 g, 63.5 mmol) in DMF (150 mL) at −78° C. was added chlorofluoromethane via bubbling for 5 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 9.0 g (131 mmol) of chlorofluoromethane. The solution was heated in an oil bath set at 70° C. overnight. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with water (100 mL). The aqueous layer was extracted with Et2O (3×200 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (7.9 g, 71%) as a white solid. sealed 350 mL round-bottomed pressure flask containing via bubbling for 5 min through the septum the flask was then sealed The solution was heated in an oil bath The flask was cooled to room temperature The aqueous layer was extracted with Et2O (3×200 mL) the combined organics were dried (Na2SO4) filtered concentrated in vacuo

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (1.4 g, 57.1 mmol) was suspended in THF (50 mL) in a pressure flask under a nitrogen atmosphere and cooled to −10° C. with stirring. Ethyl (1,1-diethoxyethyl)phosphinate (10.0 g, 47.6 mmol) in THF (20 mL) was added dropwise to the mixture over 10 minutes; the internal temperature was maintained below 0° C. during the addition. On completion of addition, the reaction mixture was allowed to stir at this temperature for 90 minutes. The flask was cooled to −78° C. and chlorofluoromethane gas (9.7 g, 142.8 mmol) was condensed into the reaction mixture. The septum was removed and the flask was sealed with a screw thread stopper. The flask was then allowed to warm to room temperature and then heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C. and cautiously quenched with water (25 mL). Methylene chloride (50 mL) was added to the reaction mixture and the emulsion was filtered through a pad of Celite® (20 g). The aqueous phase was extracted with methylene chloride (2×100 mL), dried over anhydrous magnesium sulfate, and the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g). The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes. This procedure afforded ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate as a clear, colorless oil (4.4 g, 42%). 1H NMR (300 MHz, CDCl3) δ4.94-4.54 (m, 2H), 4.32-4.20 (m, 2H), 3.82-3.54 (m, 4H), 1.60-1.44 (m, 3H), 1.40-1.28 (m, 3H), 1.26-1.08 (m, 6H). the internal temperature was maintained below 0° C. during the addition On completion of addition to stir at this temperature for 90 minutes The flask was cooled to −78° C. condensed into the reaction mixture The septum was removed the flask was sealed with a screw thread stopper to warm to room temperature heated at 50° C. for 24 h The reaction mixture was cooled to 0° C. cautiously quenched with water (25 mL) Methylene chloride (50 mL) was added to the reaction mixture the emulsion was filtered through a pad of Celite® (20 g) The aqueous phase was extracted with methylene chloride (2×100 mL) dried over anhydrous magnesium sulfate the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g) The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes

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

Procedure: To a tared, sealed 350 mL round-bottomed pressure flask containing a suspension of 3,5-dibromophenol (10.0 g, 39.7 mmol; see step (ii) above) and Cs2CO3 (20.7 g, 63.5 mmol) in DMF (150 mL) at −78° C. was added chlorofluoromethane via bubbling for 5 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 9.0 g (131 mmol) of chlorofluoromethane. The solution was heated in an oil bath set at 70° C. overnight. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with water (100 mL). The aqueous layer was extracted with Et2O (3×200 mL) then, the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound. (7.9 g, 71%) as a white solid. sealed 350 mL round-bottomed pressure flask containing via bubbling for 5 min through the septum the flask was then sealed The solution was heated in an oil bath The flask was cooled to room temperature The aqueous layer was extracted with Et2O (3×200 mL) the combined organics were dried (Na2SO4) filtered concentrated in vacuo

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (1.4 g, 57.1 mmol) was suspended in THF (50 mL) in a pressure flask under a nitrogen atmosphere and cooled to −10° C. with stirring. Ethyl (1,1-diethoxyethyl)phosphinate (10.0 g, 47.6 mmol) in THF (20 mL) was added dropwise to the mixture over 10 minutes; the internal temperature was maintained below 0° C. during the addition. On completion of addition, the reaction mixture was allowed to stir at this temperature for 90 minutes. The flask was cooled to −78° C. and chlorofluoromethane gas (9.7 g, 142.8 mmol) was condensed into the reaction mixture. The septum was removed and the flask was sealed with a screw thread stopper. The flask was then allowed to warm to room temperature and then heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C. and cautiously quenched with water (25 mL). Methylene chloride (50 mL) was added to the reaction mixture and the emulsion was filtered through a pad of Celite® (20 g). The aqueous phase was extracted with methylene chloride (2×100 mL), dried over anhydrous magnesium sulfate and the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g). The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes. This procedure afforded ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate as a clear, colorless oil (4.4 g, 42%). 1H NMR (300 MHz, CDCl3) δ 4.94-4.54 (m, 2H), 4.32-4.20 (m, 2H), 3.82-3.54 (m, 4H), 1.60-1.44 (m, 3H), 1.40-1.28 (m, 3H), 1.26-1.08 (m, 6H). the internal temperature was maintained below 0° C. during the addition On completion of addition to stir at this temperature for 90 minutes The flask was cooled to −78° C. condensed into the reaction mixture The septum was removed the flask was sealed with a screw thread stopper to warm to room temperature heated at 50° C. for 24 h The reaction mixture was cooled to 0° C. cautiously quenched with water (25 mL) Methylene chloride (50 mL) was added to the reaction mixture the emulsion was filtered through a pad of Celite® (20 g) The aqueous phase was extracted with methylene chloride (2×100 mL) dried over anhydrous magnesium sulfate the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g) The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes

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

Procedure: A 500 mL nitrogen purged round bottom flask fitted with a dry-ice condenser was cooled to −78° C. and 50 mL (ca. 40 g by cylinder difference) of chlorofluoromethane was condensed. DMF (200 mL), 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (40 g, 0.155 mol), powdered potassium carbonate (22 g, 0.159 mol, 1.03 equiv) and sodium bromide (22 g, 0.21 mol) were carefully added. An additional 100 mL of DMF was added and the dry-ice bath was removed. The pale yellow suspension was warmed first to room temperature, then to 70-75° C. (oil bath). Gentle reflux was noted. After 3 h, an additional 30 g of NaBr was added. The condenser was kept cold for ca. 10 h and allowed to warm to room temperature overnight. The white suspension which resulted was diluted with 2 L of water and extracted with ether (1×1 L, 2×500 mL). The combined extracts were washed with water (4×250 mL) and brine (500 mL), dried with magnesium sulfate, filtered and the filtrate concentrated. During concentration the product began to crystallize. The filtrare was concentrated to a small volume and the mixture flushed with hexanes. The resulting slurry was cooled to 0° C., aged 1 hr, filtered, and the cake washed with hexanes. The yield upon drying was 42.2 g (93.8%) of white crystalline 2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde: 1H NMR (CDCI3) δ 5.91 (d, JH-F=30.5 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 7.72 (dd, J=9, 2.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 10.49 (s, 1H). MS (EI) m/z 290. Anal. Calcd for C10H6F4N4O2: C, 41.39; H, 2.08; F, 26.19; N, 19.31. Found: C, 41.39; H, 1.98; F, 25.79; N, 19.53. A 500 mL nitrogen purged round bottom flask fitted with a dry-ice condenser condensed the dry-ice bath was removed The pale yellow suspension was warmed first to room temperature to 70-75° C. Gentle reflux an additional 30 g of NaBr was added The condenser was kept cold for ca. 10 h to warm to room temperature overnight The white suspension which resulted extracted with ether (1×1 L, 2×500 mL) The combined extracts were washed with water (4×250 mL) and brine (500 mL) dried with magnesium sulfate filtered the filtrate concentrated During concentration the product to crystallize The filtrare was concentrated to a small volume the mixture flushed with hexanes The resulting slurry was cooled to 0° C., aged 1 hr filtered the cake washed with hexanes The yield upon drying