3,5-difluoro-2,4-dimethoxyaniline

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

Procedure: A 0.3M solution of Compound 2 (0.566 g, 2.99 mmol) in 4M HCl is chilled in an ice bath, and treated with a cold solution of sodium nitrite (1.05 equivalents) in water. The resulting diazonium salt solution is stirred for 15 minutes, and then hypophosphorous acid (50% aqueous solution, Aldrich, 20 equivalents) is added over 5 minutes. The resulting mixture is stirred at room temperature for two hours, then diluted with water. The resulting mixture is neutralized with aqueous sodium carbonate or sodium hydroxide, and extracted twice with ether. The organic extract is washed once with water, once with brine, and dried over anhydrous sodium sulfate. The solution is concentrated in vacuo and the resulting residue is purified by flash chromatography to give 0.38 g (73%) of Compound 3 as a clear, colorless liquid: 1H NMR (CDCl3) 6.80 (td, 1H), 6.58 (m, 1H), 4.00 (s, 3H), 3.87 (s, 3H); 19F NMR (CDCl3) 138.8 (d, 1F), 150.1 (d, 1F). Anal. calc. for C8H8O2F2 : C, 55.19; H, 4.63. Found: C, 54.76; H, 4.63. extracted twice with ether The organic extract is washed once with water, once with brine dried over anhydrous sodium sulfate The solution is concentrated in vacuo the resulting residue is purified by flash chromatography

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

Procedure: The nitro group of 3,5-difluoro-2,4-dimethoxynitrobenzene (10.9 g, 49.7 mmol) is reduced by catalytic hydrogenation at 40 psi in ethanol/ethyl acetate over 10% Pd/carbon. Progress is monitored by TLC. When the reaction is complete, the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration. The filtrate is concentrated in vacuo, giving pure 1-amino-3,5-difluoro2,4-dimethoxybenzene (2) as 9.40 g (99.8%) of a clear, pale brown oil: 1H NMR (CDCl3) 6.25 (dd, 1H), 3.89 (two s, 6H), 3.7 (br s, 2H); 19F NMR (CDCl3) 135.5 (d, 1F), 146.9 (s, 1F). Anal. calc. for C8H9NO2F2 : C, 50.80; H, 4.80; N, 7.40. Found: C, 50.61; H, 4.81; N, 7.26. The hydrochloride salt is obtained by treating a dioxane solution of 5 with 4M HCl in dioxane, collecting the precipitate on a Buchner funnel, rinsing with dioxane, and drying in vacuo to give the hydrochloride salt of Compound 2 as a bone-white powder: m.p. 213°-218° C. (dec.); 1H NMR (D2O) 7.1 (br d, 1H), 4.05 (br s, 6H); 19F (D2O) 131.1 (dd, 1F), 141.6 (s, 1F). Anal. calc. for C8 H10NO2F2Cl: C, 42.59; H, 4.47; N, 6.21. Found: C, 42.75; H, 4.47; N, 6.14. the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration The filtrate is concentrated in vacuo

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

Procedure: A 0.3M solution of Compound 2 (0.566 g, 2.99 mmol) in 4M HCl is chilled in an ice bath, and treated with a cold solution of sodium nitrite (1.05 equivalents) in water. The resulting diazonium salt solution is stirred for 15 minutes, and then hypophosphorous acid (50% aqueous solution, Aldrich, 20 equivalents) is added over 5 minutes. The resulting mixture is stirred at room temperature for two hours, then diluted with water. The resulting mixture is neutralized with aqueous sodium carbonate or sodium hydroxide, and extracted twice with ether. The organic extract is washed once with water, once with brine, and dried over anhydrous sodium sulfate. The solution is concentrated in vacuo and the resulting residue is purified by flash chromatography to give 0.38 g (73%) of Compound 3 as a clear, colorless liquid: 1H NMR (CDCl3) 6.80 (td, 1H), 6.58 (m, 1H), 4.00 (s, 3H), 3.87 (s, 3H); 19F NMR (CDCl3) 138.8 (d, 1F), 150.1 (d, 1F). Anal. calc. for C8H8O2F2 : C, 55.19; H, 4.63. Found: C, 54.76; H, 4.63. extracted twice with ether The organic extract is washed once with water, once with brine dried over anhydrous sodium sulfate The solution is concentrated in vacuo the resulting residue is purified by flash chromatography

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

Procedure: The nitro group of 3,5-difluoro-2,4-dimethoxynitrobenzene (10.9 g, 49.7 mmol) is reduced by catalytic hydrogenation at 40 psi in ethanol/ethyl acetate over 10% Pd/carbon. Progress is monitored by TLC. When the reaction is complete, the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration. The filtrate is concentrated in vacuo, giving pure 1-amino-3,5-difluoro2,4-dimethoxybenzene (2) as 9.40 g (99.8%) of a clear, pale brown oil: 1H NMR (CDCl3) 6.25 (dd, 1H), 3.89 (two s, 6H), 3.7 (br s, 2H); 19F NMR (CDCl3) 135.5 (d, 1F), 146.9 (s, 1F). Anal. calc. for C8H9NO2F2 : C, 50.80; H, 4.80; N, 7.40. Found: C, 50.61; H, 4.81; N, 7.26. The hydrochloride salt is obtained by treating a dioxane solution of 5 with 4M HCl in dioxane, collecting the precipitate on a Buchner funnel, rinsing with dioxane, and drying in vacuo to give the hydrochloride salt of Compound 2 as a bone-white powder: m.p. 213°-218° C. (dec.); 1H NMR (D2O) 7.1 (br d, 1H), 4.05 (br s, 6H); 19F (D2O) 131.1 (dd, 1F), 141.6 (s, 1F). Anal. calc. for C8 H10NO2F2Cl: C, 42.59; H, 4.47; N, 6.21. Found: C, 42.75; H, 4.47; N, 6.14. the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration The filtrate is concentrated in vacuo

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

Procedure: A 0.3M solution of Compound 2 (0.566 g, 2.99 mmol) in 4M HCl is chilled in an ice bath, and treated with a cold solution of sodium nitrite (1.05 equivalents) in water. The resulting diazonium salt solution is stirred for 15 minutes, and then hypophosphorous acid (50% aqueous solution, Aldrich, 20 equivalents) is added over 5 minutes. The resulting mixture is stirred at room temperature for two hours, then diluted with water. The resulting mixture is neutralized with aqueous sodium carbonate or sodium hydroxide, and extracted twice with ether. The organic extract is washed once with water, once with brine, and dried over anhydrous sodium sulfate. The solution is concentrated in vacuo and the resulting residue is purified by flash chromatography to give 0.38 g (73%) of Compound 3 as a clear, colorless liquid: 1H NMR (CDCl3) 6.80 (td, 1H), 6.58 (m, 1H), 4.00 (s, 3H), 3.87 (s, 3H); 19F NMR (CDCl3) 138.8 (d, 1F), 150.1 (d, 1F). Anal. calc. for C8H8O2F2 : C, 55.19; H, 4.63. Found: C, 54.76; H, 4.63. extracted twice with ether The organic extract is washed once with water, once with brine dried over anhydrous sodium sulfate The solution is concentrated in vacuo the resulting residue is purified by flash chromatography

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

Procedure: The nitro group of 3,5-difluoro-2,4-dimethoxynitrobenzene (10.9 g, 49.7 mmol) is reduced by catalytic hydrogenation at 40 psi in ethanol/ethyl acetate over 10% Pd/carbon. Progress is monitored by TLC. When the reaction is complete, the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration. The filtrate is concentrated in vacuo, giving pure 1-amino-3,5-difluoro2,4-dimethoxybenzene (2) as 9.40 g (99.8%) of a clear, pale brown oil: 1H NMR (CDCl3) 6.25 (dd, 1H), 3.89 (two s, 6H), 3.7 (br s, 2H); 19F NMR (CDCl3) 135.5 (d, 1F), 146.9 (s, 1F). Anal. calc. for C8H9NO2F2 : C, 50.80; H, 4.80; N, 7.40. Found: C, 50.61; H, 4.81; N, 7.26. The hydrochloride salt is obtained by treating a dioxane solution of 5 with 4M HCl in dioxane, collecting the precipitate on a Buchner funnel, rinsing with dioxane, and drying in vacuo to give the hydrochloride salt of Compound 2 as a bone-white powder: m.p. 213°-218° C. (dec.); 1H NMR (D2O) 7.1 (br d, 1H), 4.05 (br s, 6H); 19F (D2O) 131.1 (dd, 1F), 141.6 (s, 1F). Anal. calc. for C8 H10NO2F2Cl: C, 42.59; H, 4.47; N, 6.21. Found: C, 42.75; H, 4.47; N, 6.14. the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration The filtrate is concentrated in vacuo