N-(2-bromophenyl)-2,2,2-trifluoroacetamide

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

Procedure: 3.0 g N-(2-Bromo-phenyl)-2,2,2-trifluoro-acetamide was added in three portions to 3.74 mL (5.0 equiv.) chlorosulfonic acid under cooling in an ice-bath. The ice-bath was removed, the mixture was warmed to room temperature, and subsequently stirred for 1 hour at 80° C. After cooling, the clear brown reaction mixture was poured into ice and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give 3.36 g (80%) of an oil that solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=9.0, 2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.71 (br.s., 1H). under cooling in an ice-bath The ice-bath was removed After cooling the clear brown reaction mixture was poured into ice extracted with DCM The organic phase was dried over Na2SO4 filtered evaporated to dryness

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system

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

Procedure: 3.0 g N-(2-Bromo-phenyl)-2,2,2-trifluoro-acetamide was added in three portions to 3.74 mL (5.0 equiv.) chlorosulfonic acid under cooling in an ice-bath. The ice-bath was removed, the mixture was warmed to room temperature, and subsequently stirred for 1 hour at 80° C. After cooling, the clear brown reaction mixture was poured into ice and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give 3.36 g (80%) of an oil that solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=9.0, 2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.71 (br.s., 1H). under cooling in an ice-bath The ice-bath was removed After cooling the clear brown reaction mixture was poured into ice extracted with DCM The organic phase was dried over Na2SO4 filtered evaporated to dryness

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

Procedure: 3.0 g N-(2-Bromo-phenyl)-2,2,2-trifluoro-acetamide was added in three portions to 3.74 mL (5.0 equiv.) chlorosulfonic acid under cooling in an ice-bath. The ice-bath was removed, the mixture was warmed to room temperature, and subsequently stirred for 1 hour at 80° C. After cooling, the clear brown reaction mixture was poured into ice and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give 3.36 g (80%) of an oil that solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=9.0, 2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.71 (br.s., 1H). under cooling in an ice-bath The ice-bath was removed After cooling the clear brown reaction mixture was poured into ice extracted with DCM The organic phase was dried over Na2SO4 filtered evaporated to dryness

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

Procedure: 3.0 g N-(2-Bromo-phenyl)-2,2,2-trifluoro-acetamide was added in three portions to 3.74 mL (5.0 equiv.) chlorosulfonic acid under cooling in an ice-bath. The ice-bath was removed, the mixture was warmed to room temperature, and subsequently stirred for 1 hour at 80° C. After cooling, the clear brown reaction mixture was poured into ice and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to give 3.36 g (80%) of an oil that solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=9.0, 2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.69 (d, J=9.0 Hz, 1H), 8.71 (br.s., 1H). under cooling in an ice-bath The ice-bath was removed After cooling the clear brown reaction mixture was poured into ice extracted with DCM The organic phase was dried over Na2SO4 filtered evaporated to dryness

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCI (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system t afford the corresponding 2-bromo-N-trifluoroacetylaniline. The resulting reaction mixture The reaction mixture is then evaporated under reduced pressure This aqueous mixture is extracted with ethyl acetate (3×15 mL) dried (MgSO4) evaporated under reduced pressure chromatographed silica gel (approximately 50 g) and elution with an appropriate solvent system t

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

Procedure: A solution of o-bromotrifluoroacetanilide (325 mg, 1.2 mM) in tetrahydrofuran (THF)(20 cm3) was cooled to -78° C. and to this was added methyl lithium (1 molar equivalent of a 1.4 M solution in diethyl ether). This addition was followed 10 minutes later by the introduction of tert-butyllithium (2 molar equivalent of a 1.7 M solution in pentane). The reaction mixture was stirred for 1 hour at -78° C., and then a solution of the chloroindanone (272 mg. 1.2 mM) in THF (3 cm3) added dropwise via a cannula. The solution was allowed to warm slowly to room temperature, and stirred for one hour, then a 10% solution potassium hydroxide in methanol (3 cm3) was introduced. After stirring for 30 minutes, the reaction mixture was poured into 2 M HCl, and extracted with dichloromethane (3 ×10 cm3). The combined organic extracts were dried (Na2SO4 ) and evaporated in vacuo to afford a solid residue which was chromatographed on silica, eluting with 10% ethyl acetate/petroleum ether (60°-80° C.) to yield trifluoroacetanilide (RF 0.4)(50 mg), and the 2-chloro-1-hydroxy-5-methoxy-4,6-dimethyl-1-(2'-trifluoroacetamidophenyl)indane (RF 0.3) (220 mg, 44%). The latter compound is a colourless solid. M.p. 182° C. 1H NMR (CDCl3)δ: 10.7 (1H, br), 8.25 (1H, dd), 7.36 (1H, ddd), 7.06 (1H, s), 6.98 (1H, ddd), 6.39 (1H, dd), 4.76 (1H, dd, J=4.8, 2.7Hz), 3.78 (3H, s), 3.63 (1H, s, exchanges with D2O), 3.11 (2H, 2 ×2nd order multiplets), 2.33 (3H, s), 2.23 (3H, s). This addition to warm slowly to room temperature stirred for one hour After stirring for 30 minutes extracted with dichloromethane (3 ×10 cm3) The combined organic extracts were dried (Na2SO4 ) evaporated in vacuo to afford a solid residue which was chromatographed on silica eluting with 10% ethyl acetate/petroleum ether (60°-80° C.)