4,5-difluorobenzene-1,2-diamine

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:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 50.7 g (0.35 mol) 1,2-diamino-4,5-difluorobenzene, 55.1 g (0.35 mol) 4-chlorobenzoic acid and 507 g polyphosphoric acid was heated to 160° C. and stirred at this temperature for 90 min. After cooling to 55° C., 1000 mL water and 500 mL ethyl acetate were added. Under ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9). The suspension was filtered over dicalite and the filter cake was washed with 1.5 L ethyl acetate. The phases were separated and the aqueous phase was washed with 0.5 L ethyl acetate. The organic phases were washed with 1M aqueous sodium hydroxide solution and brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (4:1 to 1:1, v/v) as eluant. The fractions containing the product in pure form were pooled and evaporated. The remaining fractions were dissolved in ethyl acetate, washed twice with 1M aqueous sodium hydroxide solution and brine, the combined aqueous layers extracted once with ethyl acetate and the combined organic layers dried over magnesium sulfate and filtered. Chromatography over silica gel afforded a second batch of compound. Total yield: 75 g (80%) light yellow solid. MS (Turbo Spray): m/z=264.9 [M+H]. After cooling to 55° C. Under ice cooling ca 1000 mL 32% aqueous sodium hydroxide solution was added (pH ca 9) The suspension was filtered over dicalite the filter cake was washed with 1.5 L ethyl acetate The phases were separated the aqueous phase was washed with 0.5 L ethyl acetate The organic phases were washed with 1M aqueous sodium hydroxide solution and brine dried over magnesium sulfate filtered To the solution, silica gel was added the solvent evaporated was purified by column chromatography over silica gel using a gradient of n-heptane:ethyl acetate (4:1 to 1:1 The fractions containing the product in pure form evaporated The remaining fractions were dissolved in ethyl acetate washed twice with 1M aqueous sodium hydroxide solution and brine the combined aqueous layers extracted once with ethyl acetate the combined organic layers dried over magnesium sulfate filtered Chromatography over silica gel afforded a second batch of compound

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

Procedure: 4,5-Difluorobenzene-1,2-diamine (0.651 g, 0.562 mmol, commercially available from Matrix Scientific) in acetonitrile (10 mL) and water (2 ml) at 0° C. was treated with cyanogen bromide (0.063 g, 0.6 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 14 hours. The reaction mixture was then treated with saturated aqueous sodium hydrogen carbonate solution (50 ml) and shaken. The resulting solid was filtered off, washed with water and dried under reduced pressure to give 0.39 g of 5,6-difluoro-1H-benzo[d]imidazol-2-amine (yield, 40%). MS (EI): 186 (MH+). shaken The resulting solid was filtered off washed with water dried under reduced pressure

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

Procedure: A suspension of diethyl ketomalonate (1.11 mL, 7.3 mmol) and 1,2-diamino-4,5-difluorobenzene (1.0 g, 6.9 mmol) in anhydrous ethanol (20 mL) was heated at reflux under nitrogen for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/methylene chloride (1:2), to provide ethyl 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylate as a light yellow solid: was heated at reflux under nitrogen for 3 h The solvent was removed under reduced pressure the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/methylene chloride (1:2)

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

Procedure: To a solution of 4,5-difluorobenzene-1,2-diamine (2.0 g, 0.014 mol) and triethylamine (7.8 mL, 0.056 mol) in dichloromethane (80 mL) was added SOCl2 (4.04 mL, 0.055 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a white solid as the crude compound. The crude product was purified by flash column chromatography (silica gel, hexanes) to afford 5,6-difluorobenzo[1,2,5]thiadiazole as a white crystalline solid (1.4 g, 58% yield). 1H NMR (CDCl3 500 MHz): δ: 7.76 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 154.94, 154.78, 152.86, 152.70, 150.89, 150.85, 150.81, 106.26, 106.21, 106.14, 106.09. Anal. calcd. for (C6H2F2N2S): C, 41.86; H, 1.17; N, 16.27. Found: C, 41.41; H, 1.22; H, 15.87. m.p: 64-65° C. The resulting reaction mixture was heated to reflux overnight quenched with water carefully The resulting mixture was extracted with dichloromethane dried over Na2SO4 concentrated on a rotary evaporator to give a white solid as the crude compound The crude product was purified by flash column chromatography (silica gel, hexanes)

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

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

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

Procedure: To a stirred solution of 4.9 mL of 5M BrCN/MeCN in 50 mL of H2O, was added dropwise a solution of 3.515 g (24.389 mmole) of 10 in 50 mL of MeOH over 20 min. After the addition, stirring was continued at room temperature for 2 h. The reaction mixture was concentrated to ~50 mL and was extracted with EtOAc (50 mL×3). The combined EtOAc solution was back washed with 100 mL of H2O and then discarded. The combined H2O phase was basified with sat. NaHCO3 solution (precipitation occurred) and was extracted again with EtOAc (70 mL×3). The EtOAc solution was dried (Na2SO4) and evaporated to dryness. The residue was suspended in 50 mL of CHCl3 and filtered. The yellowish solid was washed with portions of CHCl3 to give 3.40 g of 11. The filtrate and washings were evaporated to dryness and the procedure was repeated to give an additional 0.355 g of 11. The total yield of 11 was 3.755 g (91%). 1H NMR (DMSO-d6) d 10.79 (br. s, 1, 1-NH), 7.06 (dd, 2, 4-H and 7-H, 3JF-H =11.0 Hz, 4JF-H =7.5 Hz), 6.30 (br. s, 2, 2-NH2). After the addition The reaction mixture was concentrated to ~50 mL was extracted with EtOAc (50 mL×3) The combined EtOAc solution was back washed with 100 mL of H2O was extracted again with EtOAc (70 mL×3) The EtOAc solution was dried (Na2SO4) evaporated to dryness filtered The yellowish solid was washed with portions of CHCl3