5-bromo-2-fluoroaniline

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

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

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

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

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of sodium nitrate (0.49 g, 0.007 mM) in water (1.5 ml) was added drop wise to a vigorously stirred heterogeneous solution of 5-bromo-2fluoroaniline (1.4 g) in concentrated HC(aq)(3.5 ml) over a 30 minutes period at 0° C. Tin (II) chloride dihydrate (4.5 g, 0.02 mM) in concentrated HCl(aq) (3.5 ml) was added drop wise to the above solution over a period of 30 minutes. After the addition, the solution was allowed to stir at 0° C. for one hour. The reaction solution was basified (pH>7) by slowly adding a solution of 50% aqueous NaOH to the reaction mixture. The water layer was washed with diethyl ether (3×). The organic layers were combined, dried (MgSO4), and concentrated. The resultant solid was thoroughly washed with hexanes. The undissolved solid was captured on filter and further washed with hexanes to afford 0.81 g (54% yield) of the desired product as an off-white solid. NMR (CHCl3) δ 5.45 (bs, 1H); 6.80-6.86(m, 2H); 7.25-7.28 (m, 1H). After the addition The water layer was washed with diethyl ether (3×) dried (MgSO4) concentrated The resultant solid was thoroughly washed with hexanes on filter further washed with hexanes

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

Procedure: Iron powder (9.3 g, 0.166 mM) and ammonium chloride (1.7 g, 0.032 mM) were stirred in water (42 ml) at 100° C. for 30 minutes. Commercially available 2-nitro 4-bromo fluorobenzene (9.2 g, 0.42 mM) was added drop wise to the above solution over a period of 45 minutes. The reaction was stirred at 100° C. for an additional five hours. Water was removed in vacuo. The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes and the organic solution was decanted off. This wash was repeated two more times. The organic layers were combined, dried (MgSO4), passed through a plug of SiO2, and concentrated to afford 4.2 g (53% yield) of the desired product as a red oil. The product was used without further purification. NMR (CHCl3) δ 3.78 (bs, 2H); 6.65-7.07(m, 3H). Water was removed in vacuo The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes the organic solution was decanted off dried (MgSO4) concentrated

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

Procedure: Iron powder (9.3 g, 0.166 mM) and ammonium chloride (1.7 g, 0.032 mM) were stirred in water (42 ml) at 100° C. for 30 minutes. Commercially available 2-nitro 4-bromo fluorobenzene (9.2 g, 0.42 mM) was added drop wise to the above solution over a period of 45 minutes. The reaction was stirred at 100° C. for an additional five hours. Water was removed in vacuo. The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes and the organic solution was decanted off. This wash was repeated two more times. The organic layers were combined, dried (MgSO4), passed through a plug of SiO2, and concentrated to afford 4.2 g (53% yield) of the desired product as a red oil. The product was used without further purification. NMR (CHCl3) δ 3.78 (bs, 2H); 6.65-7.07(m, 3H). Water was removed in vacuo The resultant crude solution was stirred in ethyl acetate (100 mL) for 20 minutes the organic solution was decanted off dried (MgSO4) concentrated

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

Procedure: Add 4-bromo-1-fluoro-2-nitrobenzene (19.4 g, 88.2 mmol) and 10 g of fine mesh iron to a solution of acetic acid (75 mL) and water (5 mL) and heat to 105° C. for 4 h or until the 4-bromo-1-fluoro-2-nitrobenzene is completely consumed. Concentrate to remove most of the acetic acid, pour into water and extract with ethyl acetate. Wash the ethyl acetate layers with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with hexanes:ethyl acetate, to give the title compound as an amber oil (11.3 g, 67%). is completely consumed Concentrate to remove most of the acetic acid pour into water extract with ethyl acetate Wash the ethyl acetate layers with water an aqueous saturated solution of sodium chloride, dry (potassium carbonate) filter concentrate Purify the residue by silica gel chromatography eluting with hexanes

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

Procedure: To a mixture of 5-bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.63 g) and N,N-diisopropylethylamine (5.64 g) in 1,4-dioxane (80 mL) was added tris (dibenzylidene -acetone) dipalladium(0) (0.3 g), and the mixture was heated for reflux under an argon atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1−5/1−2/1) to give 2-fluoro-5-(2-methoxy -carbonylethylthio)aniline (4.62 g). This material was dissolved in tetrahydrofuran (120 mL). To the solution was added potassium tert-butoxide (1 mol/L tetrahydrofuran solution, 80.6 mL) at −78° C., and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (81 mL), and the mixture was warmed to room temperature and stirred for 5 minutes. The mixture was poured into ethyl acetate, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.85 g). the mixture was heated for reflux under an argon atmosphere overnight The insoluble material was removed by filtration the filtrate was concentrated under reduced pressure The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1−5/1−2/1)

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

Procedure: To a mixture of 1-bromo-4-fluoro-3-nitrobenzene (1.56 g), nickel(II) bromide (78 mg), methanol (28 mL) and tetrahydrofuran (28 mL) was added sodium borohydride (805 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-bromo-2-fluoroaniline (1.3 g). This material was dissolved in tetrahydrofuran (30 mL). To the solution were added 4-dimethylaminopyridine(0.26 g)and di(tert-butyl)dicarbonate (3.1 g), and the mixture was heated for reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue were added methanol (21 mL) and potassium carbonate (2.94 g), and the mixture was heated for reflux for 2 hours. To the reaction mixture was added water, and the mixture was poured into brine. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (1.72 g). cooling The mixture was stirred at room temperature for 30 minutes The resulting mixture was extracted with ethyl acetate The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure