methyl 4-amino-2-(trifluoromethyl)benzoate

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

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

Procedure: Methyl 4-amino-2-(trifluoromethyl)benzoate (˜22 mmol), was dissolved in THF (100 mL) and the mixture was sparged with nitrogen for 15 minutes. Copper (I) iodide (4.14 g, 21.8 mmol) and diiodomethane (8.8 mL, 109 mmol) were added followed by isoamyl nitrite (8.8 mL, 66.2 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution: 1 M sodium thiosulfate (2×) and brine, dried over sodium sulfate, then filtered and concentrated to provide a brown oil which was purified by column chromatography (silica gel, 2-40% dichloromethane in hexanes) to afford methyl 4-iodo-2-(trifluoromethyl)benzoate (5.42 g, 16.4 mmol, ˜75% yield over 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.97 (dd, 1H), 7.52 (d, 1H), 3.93 (s, 3H); GCMS for C9H6F3IO2: 330 (M+). the mixture was sparged with nitrogen for 15 minutes at reflux for 4 h was partitioned between ethyl acetate and 1N hydrochloric acid The aqueous portion was extracted with ethyl acetate (2×) The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution 1 M sodium thiosulfate (2×) and brine, dried over sodium sulfate filtered concentrated to provide a brown oil which was purified by column chromatography (silica gel, 2-40% dichloromethane in hexanes)

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

Procedure: 4-Amino-2-(trifluoromethyl)benzoic acid (10 g, 48.8 mmol) was suspended in THF (100 mL) and methanol (30 mL) and was cooled in an ice bath. (Trimethylsilyl)diazomethane (2 M solution in hexanes; 32 mL) was added drop-wise. The mixture was stirred for 5 minutes and then concentrated to afford methyl 4-amino-2-(trifluoromethyl)benzoate (quantitative yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.99 (d, 1H), 6.77 (d, 1H), 4.18 (br s, 2H), 3.88 (s, 3H); GCMS for C9H8F3NO2: 219 (M+). concentrated

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

Procedure: 4-Amino-2-(trifluoromethyl)benzoic acid (10 g, 48.8 mmol) was suspended in THF (100 mL) and methanol (30 mL) and was cooled in an ice bath. (Trimethylsilyl)diazomethane (2 M solution in hexanes; 32 mL) was added drop-wise. The mixture was stirred for 5 minutes and then concentrated to afford methyl 4-amino-2-(trifluoromethyl)benzoate (quantitative yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.99 (d, 1H), 6.77 (d, 1H), 4.18 (br s, 2H), 3.88 (s, 3H); GCMS for C9H8F3NO2: 219 (M+). concentrated

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

Procedure: SOCl2 (1.1 mL, 14.62 mmol, 1 equiv.) was added to a solution of 4-amino-2-trifluoromethylbenzoic acid (3 g, 14.62 mmol, 1 equiv.) in 40 mL of MeOH and the reaction mixture was refluxed overnight. Solvent was removed in vacuo and the residue was taken into EtOAc and washed with sat. NaHCO3 (×2), brine and dried over MgSO4, and concentrated to give 2.06 g (Yield=64%) of product as a clear oil. the reaction mixture was refluxed overnight Solvent was removed in vacuo washed with sat. NaHCO3 (×2), brine dried over MgSO4 concentrated

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

Procedure: SOCl2 (1.1 mL, 14.62 mmol, 1 equiv.) was added to a solution of 4-amino-2-trifluoromethylbenzoic acid (3 g, 14.62 mmol, 1 equiv.) in 40 mL of MeOH and the reaction mixture was refluxed overnight. Solvent was removed in vacuo and the residue was taken into EtOAc and washed with sat. NaHCO3 (×2), brine and dried over MgSO4, and concentrated to give 2.06 g (Yield=64%) of product as a clear oil. the reaction mixture was refluxed overnight Solvent was removed in vacuo washed with sat. NaHCO3 (×2), brine dried over MgSO4 concentrated

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

Procedure: Methyl 4-nitro-2-(trifluoromethyl)benzoate (5.20 g, 20.9 mmol) was dissolved in EtOAc (100 mL) and tin chloride dihydrate (9.41 g, 41.7 mmol) was added to the reaction mixture. The reaction was heated at reflux for 2 h. The crude reaction mixture was purified by column chromatography (SiO2, EtOAc/hexanes) to give the title compound. LCMS: (FA) ES− 218.4 (M−1). The reaction was heated at reflux for 2 h The crude reaction mixture was purified by column chromatography (SiO2, EtOAc/hexanes)

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

Procedure: A solution of 4-nitro-2-trifluoromethyl benzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was treated with 10% Pd/C (50 mg) and hydrogenated at 1 atmosphere for 3 hrs. The mixture was filtered and concentrated to give a light yellow solid which was directly used for the next step. The mixture was filtered concentrated to give a light yellow solid which

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

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

Procedure: Methyl 4-amino-2-(trifluoromethyl)benzoate (˜22 mmol), was dissolved in THF (100 mL) and the mixture was sparged with nitrogen for 15 minutes. Copper (I) iodide (4.14 g, 21.8 mmol) and diiodomethane (8.8 mL, 109 mmol) were added followed by isoamyl nitrite (8.8 mL, 66.2 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution: 1 M sodium thiosulfate (2×) and brine, dried over sodium sulfate, then filtered and concentrated to provide a brown oil which was purified by column chromatography (silica gel, 2-40% dichloromethane in hexanes) to afford methyl 4-iodo-2-(trifluoromethyl)benzoate (5.42 g, 16.4 mmol, ˜75% yield over 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.97 (dd, 1H), 7.52 (d, 1H), 3.93 (s, 3H); GCMS for C9H6F3IO2: 330 (M+). the mixture was sparged with nitrogen for 15 minutes at reflux for 4 h was partitioned between ethyl acetate and 1N hydrochloric acid The aqueous portion was extracted with ethyl acetate (2×) The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution 1 M sodium thiosulfate (2×) and brine, dried over sodium sulfate filtered concentrated to provide a brown oil which was purified by column chromatography (silica gel, 2-40% dichloromethane in hexanes)

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

Procedure: 4-Amino-2-(trifluoromethyl)benzoic acid (10 g, 48.8 mmol) was suspended in THF (100 mL) and methanol (30 mL) and was cooled in an ice bath. (Trimethylsilyl)diazomethane (2 M solution in hexanes; 32 mL) was added drop-wise. The mixture was stirred for 5 minutes and then concentrated to afford methyl 4-amino-2-(trifluoromethyl)benzoate (quantitative yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.99 (d, 1H), 6.77 (d, 1H), 4.18 (br s, 2H), 3.88 (s, 3H); GCMS for C9H8F3NO2: 219 (M+). concentrated

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

Procedure: SOCl2 (1.1 mL, 14.62 mmol, 1 equiv.) was added to a solution of 4-amino-2-trifluoromethylbenzoic acid (3 g, 14.62 mmol, 1 equiv.) in 40 mL of MeOH and the reaction mixture was refluxed overnight. Solvent was removed in vacuo and the residue was taken into EtOAc and washed with sat. NaHCO3 (×2), brine and dried over MgSO4, and concentrated to give 2.06 g (Yield=64%) of product as a clear oil. the reaction mixture was refluxed overnight Solvent was removed in vacuo washed with sat. NaHCO3 (×2), brine dried over MgSO4 concentrated