1,3-dichloro-2-methoxybenzene

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

Procedure: A reaction mixture of 1,3-dichloro-2-methoxybenzene (885 mg, 5 mmol), potassium hydroxide (280 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.125 mmol) and tert-butyl X-Phos (159 mg, 0.375 mmol) in dioxane/water (1:1, 5 mL) was stirred at 100° C. for 2 hours. The reaction mixture was mixed with aqueous hydrochloride solution (1 N). The organic components were extracted with EtOAc. The combined EtOAc layers were washed with brine, and then concentrated. The residue was purified by chromatography. Elution with 10% EtOAc in hexane gave 3-chloro-2-methoxyphenol (22-1, 489 mg, 62% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.98-6.84 (m, 3H), 5.73 (br s, 1H), 3.93 (s, 3H). The organic components were extracted with EtOAc The combined EtOAc layers were washed with brine concentrated The residue was purified by chromatography Elution with 10% EtOAc in hexane

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

Procedure: A reaction mixture of 1,3-dichloro-2-methoxybenzene (885 mg, 5 mmol), potassium hydroxide (280 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.125 mmol) and tert-butyl X-Phos (159 mg, 0.375 mmol) in dioxane/water (1:1, 5 mL) was stirred at 100° C. for 2 hours. The reaction mixture was mixed with aqueous hydrochloride solution (1 N). The organic components were extracted with EtOAc. The combined EtOAc layers were washed with brine, and then concentrated. The residue was purified by chromatography. Elution with 10% EtOAc in hexane gave 3-chloro-2-methoxyphenol (22-1, 489 mg, 62% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.98-6.84 (m, 3H), 5.73 (br s, 1H), 3.93 (s, 3H). The organic components were extracted with EtOAc The combined EtOAc layers were washed with brine concentrated The residue was purified by chromatography Elution with 10% EtOAc in hexane

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

Procedure: A reaction mixture of 1,3-dichloro-2-methoxybenzene (885 mg, 5 mmol), potassium hydroxide (280 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.125 mmol) and tert-butyl X-Phos (159 mg, 0.375 mmol) in dioxane/water (1:1, 5 mL) was stirred at 100° C. for 2 hours. The reaction mixture was mixed with aqueous hydrochloride solution (1 N). The organic components were extracted with EtOAc. The combined EtOAc layers were washed with brine, and then concentrated. The residue was purified by chromatography. Elution with 10% EtOAc in hexane gave 3-chloro-2-methoxyphenol (22-1, 489 mg, 62% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.98-6.84 (m, 3H), 5.73 (br s, 1H), 3.93 (s, 3H). The organic components were extracted with EtOAc The combined EtOAc layers were washed with brine concentrated The residue was purified by chromatography Elution with 10% EtOAc in hexane

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

Procedure: An intermediate compound 1-(3-Chloro-2-methoxy-phenyl)-piperazine, was produced as follows. A solution of 2,6-dichloroanisole (1.55 mL, 11.30 mmol) in dry toluene (40 mL) was degassed for 10 min by blowing nitrogen into the solution. This solution was then added via cannula to a flask containing Boc-piperazine 3.16 g, 16.90 mmol), Cs2CO3 (5.15 g, 15.80 mmol), Pd2(dba)3 (414 mg, 0.452 mmol, 4 mol %) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (356 mg, 0.904 mmol, 8 mol %) under nitrogen. The reaction mixture was heated at 100° C. overnight (16 h). MS showed a small product peak and a large Boc-piperazine peak. TLC (10% EtOAc/Hex) showed a product spot. The reaction was allowed to cool to room temperature and Et2O was added. The mixture was filtered through Celite washing with Et2O. The filtrate was washed 3 times with 0.5 M citric acid (to remove excess Boc-piperazine) and once with brine, dried over MgSO4 and concentrated to give a brown oil. Purification by SiO2 chromatography (10% EtOAC/Hexanes) gave 4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid (278 mg, 8%). This solution was then added via cannula to a flask to cool to room temperature The mixture was filtered through Celite washing with Et2O The filtrate was washed 3 times with 0.5 M citric acid (to remove excess Boc-piperazine) once with brine, dried over MgSO4 concentrated to give a brown oil Purification by SiO2 chromatography (10% EtOAC/Hexanes)