4,5-dichloro-2-methylaniline

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 solution of 4,5-dichloro-2-methylaniline (1.69 g, 9.6 mmol) in CHCl3 (25 ml) at 0° C. was slowly added acetic anhydride (2.09 ml, 22.1 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. A thick white precipitate had gradually formed. Potassium acetate (283 mg, 2.88 mmol) was added followed by slow addition of isoamyl nitrite (2.78 ml, 20.6 mmol). The reaction mixture was heated at reflux overnight. The homogeneous deep orange reaction mixture was cooled to room temperature and concentrated. Water (10 mL) was added and the mixture was reconcentrated to an orange solid. This solid was suspended in conc. HCl (15 mL) and heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH. Extracted with EtOAc, dried over MgSO4 and concentrated to an orange solid. This solid was dissolved in THF/MeOH (1:1, 25 mL) and 10% NaOH (3 mL) was added. The deep maroon reaction mixture was stirred at room temperature for 5 min then neutralized with 1.0 M HCl and diluted with water. The mixture was extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was absorbed onto silica gel and purified by chromatography with 30% to 50% EtOAc/hexanes to afford 1.50 g (84%) of 5,6-dichloro-1H-indazole as a light orange solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H). at 0° C. A thick white precipitate had gradually formed The reaction mixture was heated at reflux overnight The homogeneous deep orange reaction mixture was cooled to room temperature concentrated Water (10 mL) was added heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH Extracted with EtOAc dried over MgSO4 concentrated to an orange solid This solid was dissolved in THF/MeOH (1:1, 25 mL) 10% NaOH (3 mL) was added The deep maroon reaction mixture was stirred at room temperature for 5 min The mixture was extracted with EtOAc (2×) then dried over MgSO4 concentrated The residue was absorbed onto silica gel purified by chromatography with 30% to 50% EtOAc/hexanes

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

Procedure: To a solution of 4,5-dichloro-2-methylaniline (1.69 g, 9.6 mmol) in CHCl3 (25 ml) at 0° C. was slowly added acetic anhydride (2.09 ml, 22.1 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. A thick white precipitate had gradually formed. Potassium acetate (283 mg, 2.88 mmol) was added followed by slow addition of isoamyl nitrite (2.78 ml, 20.6 mmol). The reaction mixture was heated at reflux overnight. The homogeneous deep orange reaction mixture was cooled to room temperature and concentrated. Water (10 mL) was added and the mixture was reconcentrated to an orange solid. This solid was suspended in conc. HCl (15 mL) and heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH. Extracted with EtOAc, dried over MgSO4 and concentrated to an orange solid. This solid was dissolved in THF/MeOH (1:1, 25 mL) and 10% NaOH (3 mL) was added. The deep maroon reaction mixture was stirred at room temperature for 5 min then neutralized with 1.0 M HCl and diluted with water. The mixture was extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was absorbed onto silica gel and purified by chromatography with 30% to 50% EtOAc/hexanes to afford 1.50 g (84%) of 5,6-dichloro-1H-indazole as a light orange solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H). at 0° C. A thick white precipitate had gradually formed The reaction mixture was heated at reflux overnight The homogeneous deep orange reaction mixture was cooled to room temperature concentrated Water (10 mL) was added heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH Extracted with EtOAc dried over MgSO4 concentrated to an orange solid This solid was dissolved in THF/MeOH (1:1, 25 mL) 10% NaOH (3 mL) was added The deep maroon reaction mixture was stirred at room temperature for 5 min The mixture was extracted with EtOAc (2×) then dried over MgSO4 concentrated The residue was absorbed onto silica gel purified by chromatography with 30% to 50% EtOAc/hexanes

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

Procedure: To a partial suspension of 1,2-dichloro-4-methyl-5-nitrobenzene (2.0 g, 9.71 mmol) in MeOH (25 ml), water (25 ml), and THF (10 ml) was added NH4Cl (5.19 g, 97.1 mmol) followed by iron powder (2.71 g, 48.5 mmol). The heterogeneous reaction mixture was heated at 100° C. for 3 h then cooled to room temperature and filtered over a Buchner funnel, rinsing with MeOH. The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 1.69 g (99%) of 4,5-dichloro-2-methylaniline as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.10 (s, 1H), 6.75 (s, 1H), 3.74 (br. s., 2H), 2.12 (s, 3H). then cooled to room temperature filtered over a Buchner funnel rinsing with MeOH The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×) The combined organics were dried over MgSO4 concentrated

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

Procedure: To a partial suspension of 1,2-dichloro-4-methyl-5-nitrobenzene (2.0 g, 9.71 mmol) in MeOH (25 ml), water (25 ml), and THF (10 ml) was added NH4Cl (5.19 g, 97.1 mmol) followed by iron powder (2.71 g, 48.5 mmol). The heterogeneous reaction mixture was heated at 100° C. for 3 h then cooled to room temperature and filtered over a Buchner funnel, rinsing with MeOH. The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 1.69 g (99%) of 4,5-dichloro-2-methylaniline as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.10 (s, 1H), 6.75 (s, 1H), 3.74 (br. s., 2H), 2.12 (s, 3H). then cooled to room temperature filtered over a Buchner funnel rinsing with MeOH The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×) The combined organics were dried over MgSO4 concentrated

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

Procedure: Into a nitrogen-purged round bottom flask was charged 5.53 grams (0.03 mole) of 2-methyl-4,5-dichloroaniline, 3.18 grams (0.03 mole) of triethylamine and 190 milliliters of tetrahydrofuran solvent. With vigorous stirring, a 5.55 gram (0.03 mole) portion of ethyl 1-chlorocarbonylcyclopropanecarboxylate prepared in Example XVIII was added in one portion, after which the mixture was stirred at ambient temperature for a six-hour period. A precipitate of triethylamine hydrochloride was then filtered off and the filtrate vacuum stripped to give a light yellow solid. The solid was taken up in ether and the solution water-washed, dried over magnesium sulfate, and solvent evaporated to give a yellow powder. Recrystallization from ethyl acetate-hexane gave 4.51 grams (0.01 mole) of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 105° C.-107° C. Into a nitrogen-purged round bottom flask A precipitate of triethylamine hydrochloride was then filtered off to give a light yellow solid the solution water-washed dried over magnesium sulfate, and solvent evaporated to give a yellow powder Recrystallization from ethyl acetate-hexane

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

Procedure: 4,5-Dichloro-2-methyl-nitrobenzene 5 (5.0 g, 24.3 mmol) was heated at 100° C. in titanium trichloride (30% in aqueous hdyrochloric acid, 25 mL) for 2 hrs., cooled to RT, the reaction solution was basified to pH 8 with 50% aqueous sodium hydroxide, then extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using 10% ethyl acetate in hexanes to give 2.4 g (56%) of the title product. 1H NMR (400 MHz, CDCl3) δ7.09 (s, 1 H, Ar), 6.74 (s , 1 H, Ar), 3.63 (s, 2 H, NH2), 2.10 (s, 3H, CH3). extracted with ethyl acetate The ethyl acetate layer was washed with water, brine dried over sodium sulfate filtered concentrated The residue was purified by silica gel chromatography

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

Procedure: Into a nitrogen-purged round bottom flask was charged 5.53 grams (0.03 mole) of 2-methyl-4,5-dichloroaniline, 3.18 grams (0.03 mole) of triethylamine and 190 milliliters of tetrahydrofuran solvent. With vigorous stirring, a 5.55 gram (0.03 mole) portion of ethyl 1-chlorocarbonylcyclopropanecarboxylate prepared in Example XVIII was added in one portion, after which the mixture was stirred at ambient temperature for a six-hour period. A precipitate of triethylamine hydrochloride was then filtered off and the filtrate vacuum stripped to give a light yellow solid. The solid was taken up in ether and the solution water-washed, dried over magnesium sulfate, and solvent evaporated to give a yellow powder. Recrystallization from ethyl acetate-hexane gave 4.51 grams (0.01 mole) of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 105° C.-107° C. Elemental analysis of the product indicated the following: Into a nitrogen-purged round bottom flask A precipitate of triethylamine hydrochloride was then filtered off to give a light yellow solid the solution water-washed dried over magnesium sulfate, and solvent evaporated to give a yellow powder Recrystallization from ethyl acetate-hexane

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

Procedure: Into a nitrogen-purged round bottom flask was charged 5.53 grams (0.03 mole) of 2-methyl-4,5-dichloroaniline, 3.18 grams (0.03 mole) of triethylamine and 190 milliliters of tetrahydrofuran solvent. With vigorous stirring, a 5.55 gram (0.03 mole) portion of ethyl 1-chlorocarbonylcyclopropanecarboxylate prepared in Example XVIII was added in one portion, after which the mixture was stirred at ambient temperature for a six-hour period. A precipitate of triethylamine hydrochloride was then filtered off and the filtrate vacuum stripped to give a light yellow solid. The solid was taken up in ether and the solution water-washed, dried over magnesium sulfate, and solvent evaporated to give a yellow powder. Recrystallization from ethyl acetate-hexane gave 4.51 grams (0.01 mole) of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 105° C.-107° C. Elemental analysis of the product indicated the following: Into a nitrogen-purged round bottom flask A precipitate of triethylamine hydrochloride was then filtered off to give a light yellow solid the solution water-washed dried over magnesium sulfate, and solvent evaporated to give a yellow powder Recrystallization from ethyl acetate-hexane

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

Procedure: To a solution of 4,5-dichloro-2-methylaniline (1.69 g, 9.6 mmol) in CHCl3 (25 ml) at 0° C. was slowly added acetic anhydride (2.09 ml, 22.1 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. A thick white precipitate had gradually formed. Potassium acetate (283 mg, 2.88 mmol) was added followed by slow addition of isoamyl nitrite (2.78 ml, 20.6 mmol). The reaction mixture was heated at reflux overnight. The homogeneous deep orange reaction mixture was cooled to room temperature and concentrated. Water (10 mL) was added and the mixture was reconcentrated to an orange solid. This solid was suspended in conc. HCl (15 mL) and heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH. Extracted with EtOAc, dried over MgSO4 and concentrated to an orange solid. This solid was dissolved in THF/MeOH (1:1, 25 mL) and 10% NaOH (3 mL) was added. The deep maroon reaction mixture was stirred at room temperature for 5 min then neutralized with 1.0 M HCl and diluted with water. The mixture was extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was absorbed onto silica gel and purified by chromatography with 30% to 50% EtOAc/hexanes to afford 1.50 g (84%) of 5,6-dichloro-1H-indazole as a light orange solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H). at 0° C. A thick white precipitate had gradually formed The reaction mixture was heated at reflux overnight The homogeneous deep orange reaction mixture was cooled to room temperature concentrated Water (10 mL) was added heated at 60° C. for 2 h then cooled to 0° C. and neutralized with 50% NaOH Extracted with EtOAc dried over MgSO4 concentrated to an orange solid This solid was dissolved in THF/MeOH (1:1, 25 mL) 10% NaOH (3 mL) was added The deep maroon reaction mixture was stirred at room temperature for 5 min The mixture was extracted with EtOAc (2×) then dried over MgSO4 concentrated The residue was absorbed onto silica gel purified by chromatography with 30% to 50% EtOAc/hexanes

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

Procedure: To a partial suspension of 1,2-dichloro-4-methyl-5-nitrobenzene (2.0 g, 9.71 mmol) in MeOH (25 ml), water (25 ml), and THF (10 ml) was added NH4Cl (5.19 g, 97.1 mmol) followed by iron powder (2.71 g, 48.5 mmol). The heterogeneous reaction mixture was heated at 100° C. for 3 h then cooled to room temperature and filtered over a Buchner funnel, rinsing with MeOH. The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 1.69 g (99%) of 4,5-dichloro-2-methylaniline as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.10 (s, 1H), 6.75 (s, 1H), 3.74 (br. s., 2H), 2.12 (s, 3H). then cooled to room temperature filtered over a Buchner funnel rinsing with MeOH The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×) The combined organics were dried over MgSO4 concentrated