4-bromo-2-fluoro-1-isothiocyanatobenzene

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

Procedure: 2-Amino-4-(trifluoromethyl)phenol (580 mg, 3.25 mmol) and 4-bromo-2-fluoro-1-isothiocyanatobenzene (750 mg, 3.25 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The crude material was suspended in ether, sonicated, and the resulting solid was collected by filtration to provide the title compound (214 mg, 18%). LC-MS m/z 375.1 (MH+), retention time 3.70 minutes. before being heated at reflux overnight The reaction was concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 2 N aqueous hydrochloric acid solution and water dried (Na2SO4) concentrated in vacuo sonicated the resulting solid was collected by filtration

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.41 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was heated in a 45° C. oil bath overnight cooled concentrated at reduced pressure The dark residue was diluted with ethyl acetate the organic layer was washed with water The organic layer was dried (MgSO4) concentrated in vacuo The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate The title compound was collected as a light pink solid (0.60 g, 57%)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.41 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was heated in a 45° C. oil bath overnight cooled concentrated at reduced pressure The dark residue was diluted with ethyl acetate the organic layer was washed with water The organic layer was dried (MgSO4) concentrated in vacuo The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate The title compound was collected as a light pink solid (0.60 g, 57%)

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

Procedure: An ambient solution of 2-amino-4,6-dimethylphenol (0.85 g, 6.2 mmol) and 2-fluoro-4-bromophenyl isothiocyanate (1.44 g, 6.20 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 335[M+H]+. was added The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL) The layers were separated the aqueous was extracted with additional ethyl acetate (2×75 mL) dried with anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by chromatography on SiO2 gel eluting with 25% ethyl acetate in hexane

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

Procedure: 2-Amino-4-(trifluoromethyl)phenol (580 mg, 3.25 mmol) and 4-bromo-2-fluoro-1-isothio-cyanatobenzene (750 mg, 3.25 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The crude material was suspended in ether, sonicated, and the resulting solid was collected by filtration to provide the title compound (214 mg, 18%). LC-MS m/z 375.1 (MH+), retention time 3.70 minutes. before being heated at reflux overnight was concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 2 N aqueous hydrochloric acid solution and water dried (Na2SO4) concentrated in vacuo sonicated the resulting solid was collected by filtration

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.41 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was heated in a 45° C. oil bath overnight cooled concentrated at reduced pressure The dark residue was diluted with ethyl acetate the organic layer was washed with water The organic layer was dried (MgSO4) concentrated in vacuo The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate The title compound was collected as a light pink solid (0.60 g, 57%)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55–7.41 (m, 3H), 7.35–7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was heated in a 45° C. oil bath overnight cooled concentrated at reduced pressure The dark residue was diluted with ethyl acetate the organic layer was washed with water The organic layer was dried (MgSO4) concentrated in vacuo The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate The title compound was collected as a light pink solid (0.60 g, 57%)

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

Procedure: 2-Amino-4-(trifluoromethyl)phenol (580 mg, 3.25 mmol) and 4-bromo-2-fluoro-1-isothio-cyanatobenzene (750 mg, 3.25 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The crude material was suspended in ether, sonicated, and the resulting solid was collected by filtration to provide the title compound (214 mg, 18%). LC-MS m/z 375.1 (MH+), retention time 3.70 minutes. before being heated at reflux overnight was concentrated under reduced pressure The residue was dissolved in ethyl acetate washed with 2 N aqueous hydrochloric acid solution and water dried (Na2SO4) concentrated in vacuo sonicated the resulting solid was collected by filtration

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.41 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was heated in a 45° C. oil bath overnight cooled concentrated at reduced pressure The dark residue was diluted with ethyl acetate the organic layer was washed with water The organic layer was dried (MgSO4) concentrated in vacuo The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate The title compound was collected as a light pink solid (0.60 g, 57%)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55–7.41 (m, 3H), 7.35–7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes. The reaction was heated in a 45° C. oil bath overnight cooled concentrated at reduced pressure The dark residue was diluted with ethyl acetate the organic layer was washed with water The organic layer was dried (MgSO4) concentrated in vacuo The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate The title compound was collected as a light pink solid (0.60 g, 57%)

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

Procedure: Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (500 mg, 2.5 mmol) and 4-bromo-2-fluorophenyl isothiocyanate (580 mg, 2.5 mmol) by the method of Example 1. Title compound obtained as an off-white solid (390 mg, 40%). δH (DMSO-d6) 10.37 (1H, br s), 8.25 (1H, dd, J 1.4, 8.1 Hz), 8.19 (1H, d, J 4.8 Hz), 7.69 (1H, dd, J 1.8, 10.2 Hz), 7.56-7.45 (2H, m), 7.32 (1H, dd, J 4.5, 8.1 Hz), 4.35 (2H, q, J 7.1 Hz), 1.37 (3H, t, J 7.1 Hz). LCMS (ES+) RT 4.66 minutes, 395 (M(79Br)+H)+.

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

Procedure: Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (500 mg, 2.5 mmol) and 4-bromo-2-fluorophenyl isothiocyanate (580 mg, 2.5 mmol) by the method of Example 1. Title compound obtained as an off-white solid (390 mg, 40%). δH (DMSO-d6) 10.37 (1H, br s), 8.25 (1H, dd, J 1.4, 8.1 Hz), 8.19 (1H, d, J 4.8 Hz), 7.69 (1H, dd, J 1.8, 10.2 Hz), 7.56-7.45 (2H, m), 7.32 (1H, dd, J 4.5, 8.1 Hz), 4.35 (2H, q, J 7.1 Hz), 1.37 (3H, t, J 7.1 Hz). LCMS (ES+) RT 4.66 minutes, 395 (M(79Br)+H)+.