1-[4-(Trifluoromethyl)phenyl]piperazine

colorless to light yellow crystals

Chlorobenzotrifluoride (18.5 g, 100 mmol) and piperazine (12.9 g, 150 mmol) were dissolved in 200 ml of tri-n-butylamine, and degassed at room temperature by passing nitrogen through for 15 min. Dry sodium tert-butoxide (13.5 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, [2-(2, 6-dimethoxyphenyl)phenyl]dicyclohexylphosphine (41 mg, 0.1 mmol) and (dibenzylideneacetone)palladium (20 mg, 0.025 mmol) were stirred under nitrogen in 5 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 110° C. After 8 h, the reaction was allowed to cool to 50° C. and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and extracted with dilute hydrochloric acid at pH 3. The aqueous phase was removed and adjusted to pH 10 with the aid of sodium hydroxide solution. The precipitated white solid was filtered off and dried under reduced pressure. 22.1 g (96 mmol, 96percent of theory) of N-(4-trifluoromethylphenyl)piperazine were obtained. The product content of the solid was determined to be >99percent by quantitative proton NMR.4-chloro-benzotrifluoride in the reaction vessel (18.5g 100mmol) and piperazine (12.9g 150mmol) at room temperature, a nitrogen atmosphere 200ml tri-N-butylamine and the mixture was stirred for 15 minutes. And further stirred for 10 minutes after adding sodium tert-butoxide (13.5g 140mmol).[2-(2, 6-dimethoxyphenyl)phenyl]dicyclohexylphosphine (41mg 0.1mmol) and (dibenzylideneacetone)palladium (20mg 0.025mmol)using a syringe slowly dropping thereby under a nitrogen atmosphere tetrahydrofuran 5ml for 30 minutes and then stirred temperature at 110°C for 8 hours to give a solid content of N- (trifluoromethylphenyl) piperazine (22.1g 96mmol) in white. Yield: 96percent.Chlorobenzotrifluoride (18.5 g, 100 mmol) and piperazine (12.9 g, 150 mmol) were dissolved in a mixture of 120 ml of toluene and 80 ml of tetrahydrofuran, and degassed at room temperature by passing nitrogen through for 15 min. Dry sodium tert-butoxide (13.5 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, [2-(2, 6-dimethoxyphenyl)phenyl]dicyclohexylphosphine (164 mg, 0.4 mmol) and palladium acetate (45 mg, 0.2 mmol) were stirred under nitrogen in 10 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 90° C. After 8 h, the reaction was allowed to cool to 50° C. and the precipitated solid was filtered off. The filtrate was extracted with dilute hydrochloric acid at pH 3. The aqueous phase was removed and adjusted to pH 10 with the aid of sodium hydroxide solution. The precipitated white solid was filtered off and dried under reduced pressure. 21.8 g (95 mmol, 95percent of theory) of N-(4-trifluoromethylphenyl)piperazine were obtained. The product content of the solid was determined to be >99percent by quantitative proton NMR.Example 3 Chlorobenzotrifluoride (18.5 g, 100 mmol) and piperazine (12.9 g, 150 mmol) were dissolved in a mixture of 120 ml of toluene and 80 ml of methanol, and degassed at room temperature by passing nitrogen through for 15 min. Sodium hydroxide (5.6 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, [2-(2, 4, 6-triisopropylphenyl)phenyl]dicyclohexylphosphine (95 mg, 0.2 mmol) and (dibenzylideneacetone)palladium (40 mg, 0.05 mmol) were stirred under nitrogen in 10 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 78° C. After 8 h, the reaction was allowed to cool to 50° C. and the precipitated solid was filtered off. The filtrate was extracted with dilute hydrochloric acid at pH 3. The aqueous phase was removed and adjusted to pH 10 with the aid of sodium hydroxide solution. The precipitated white solid was filtered off and dried under reduced pressure. 21.8 g (95 mmol, 95percent of theory) of N-(4-trifluoromethylphenyl)piperazine were obtained. The product content of the solid was determined to be >99percent by quantitative proton NMR.Chlorobenzotrifluoride (18.5 g, 100 mmol) and piperazine (12.9 g, 150 mmol) were dissolved in a mixture of 120 ml of toluene and 80 ml of tetrahydrofuran, and degassed at room temperature by passing nitrogen through for 15 min. Dry sodium tert-butoxide (13.5 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, [2-(2, 6-dimethoxyphenyl)phenyl]dicyclohexylphosphine (41 mg, 0.1 mmol) and (dibenzylideneacetone)palladium (20 mg, 0.025 mmol) were stirred under nitrogen in 10 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 90° C. After 8 h, the reaction was allowed to cool to 50° C. and the precipitated solid was filtered off. The filtrate was extracted with dilute hydrochloric acid at pH 3. The aqueous phase was removed and adjusted to pH 10 with the aid of sodium hydroxide solution. The precipitated white solid was filtered off and dried under reduced pressure. 21.4 g (93 mmol, 93percent of theory) of N-(4-trifluoromethylphenyl)piperazine were obtained. The product content of the solid was determined to be >99percent by quantitative proton NMR.Comparative Experiment Chlorobenzotrifluoride (18.5 g, 100 mmol) and piperazine (12.9 g) were initially charged in 400 ml of xylene and the mixture was degassed at room temperature by passing nitrogen through for 15 min. Dry sodium tert-butoxide (13.5 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, tris-tert-butylphosphine (81 mg, 0.4 mmol) with careful exclusion of air and (dibenzylideneacetone)palladium (41 mg, 0.05 mmol) were stirred under nitrogen in 10 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 120° C. After 8 h, the reaction mixture was allowed to cool to 50° C. and the precipitated solid was filtered off. The solvent was removed under reduced pressure and the crude product isolated by chromatographic purification on silica gel. 12.4 g (54 mmol, 54percent of theory) of N-(4-trifluoromethylphenyl)piperazine were obtained.Example 5 Bromobenzotrifluoride (22.5 g, 100 mmol) and piperazine (12.9 g, 150 mmol) were dissolved in 200 ml of toluene, and degassed at room temperature by passing nitrogen through for 15 min. Dry sodium tert-butoxide (13.5 g, 140 mmol) was added and the mixture was degassed for a further 10 min. In a separate vessel, [2-(2, 4, 6-triisopropylphenyl)phenyl]dicyclohexylphosphine (95 mg, 0.2 mmol) and palladium acetate (23 mg, 0.1 mmol) were stirred under nitrogen in 10 ml of degassed tetrahydrofuran. After 30 min, this catalyst solution was introduced dropwise at room temperature into the larger flask with the aid of a transfer needle. On completion of addition, the reaction was heated to internal temperature 110° C. After 8 h, the reaction was allowed to cool to 50° C. and the precipitated solid was filtered off. The filtrate was extracted with dilute hydrochloric acid at pH 3. The aqueous phase was removed and adjusted to pH 10 with the aid of sodium hydroxide solution. The precipitated white solid was filtered off and dried under reduced pressure. 22.1 g (96 mmol, 96percent of theory) of N-(4-trifluoromethylphenyl)piperazine were obtained. The product content of the solid was determined to be >99percent by quantitative proton NMR.[0705] The mixture of 1-bromo-4-(trifluoromethyl)benzene (15 g, 67 mmol), piperazine (28.8 g, 334.4 mmol, 5 eq.), Pd

Molecular Weight:230.23
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:230.10308291
Monoisotopic Mass:230.10308291
Topological Polar Surface Area:15.3
Heavy Atom Count:16
Complexity:216
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes