Safrole → N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide

2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide (7) To a solution of compound 5 (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound 6 (0.38 g, 2.14 mmol) in 10 mL EtOH. The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo, and the residue was purified by using Prep. TLC (10:1 dichloromethane:methanol) to afford compound 7:Mass spectrum (MH+1)=426.34. N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide (9). Compound 9 was prepared in the manner of compound 7 substituting 4-phenyl-butene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 9: Mass spectrum (MH+1)=396.32. N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3(2-methoxyphenyl)-propyl]piperazinyl}acetamide (10) Compound 10 was prepared in the manner of compound 7 substituting 3-(2-methoxyphenyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 10:Mass spectrum (MH+1)=412.35. N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide (11). Compound 11 was prepared in the manner of compound 7 substituting 3-(4-methoxyphenyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 11: Mass spectrum (MH+1)=412.35. N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl]piperazinyl}acetamide (12) Compound 12 was prepared in the manner of compound 7 substituting 3-phenyl-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 12:Mass spectrum (MH+1)=382. N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-naphthylpropyl)piperazinyl]acetamide (13). Compound 13 was prepared in the manner of compound 7 substituting 3-(1-naphthyl)-1-propene for 3-(3,4-methylendioxyphenyl)-1-propene in part C to afford compound 13:Mass spectrum (MH+1)=432.55. Part A Intermediate (14): To a solution of 4-methoxybenzyl chloride (2-mmol) in anhydrous ether (10 mL), was added allylmagnesium bromide (4 mL, 1M solution in THF) and the reaction mixture was allowed to stir for 16 h at room temperature. Sat. ammonium chloride solution 91 mL) was added and the ether layer was separated, washed with water and dried. Evaporation of ether under reduced pressure afforded olefin 14 as an oil. It was used in the next reaction without purification. Part B Intermediate (15): To an ice cold solution of 15 (2 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (4 mmol) in 20 mL dichloromethane over a period of 1 h. The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200 ml), and it was washed with saturated sodium bicarbonate (3×100 ml). The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified using Prep. TLC (2:1 hexane: ethyl acetate) to yield 15. Part C Synthesis of N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide(16) To a solution of compound 5 (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound 15 (2.14 mmol) in 10 mL EtOH. The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo, and the residue was purified by using Prep. TLC (10:1 dichloromethane: methanol) to afford compound 16. (M+1)=426.3 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide(17) Compound 17 was prepared in a manner similar to that of compound 16 substituting 2,6-difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=432.2 N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide(18) Compound 18 was prepared in a manner similar to that of compound 16 substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=430.2 2-(4- {4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide(19) Compound 19 was prepared in a manner similar to that of compound 16 substituting 4-t-butylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=452.3 N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide(20) Compound 20 was prepared in a manner similar to that of compound 16 substituting 2-fluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=414.2 N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide(21) Compound 21 was prepared in a manner similar to that of compound 16 substituting 4-trifluoromethylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=464.2 2-[4-(3-Benzo[1,3]dioxol-5-yl-2-hydroxy-propyl)-piperazin-1-yl]-N-(2,6-dimethyl-phenyl-isobutyramide (22) This compound was prepared in a manner similar to that of 7, substituting 2-chloro-2-methylpropionyl chloride for chloroacetyl chloride in part A. (M+1)=454.54 N-(2,6-Dimethyl-phenyl)-2-[4-(2-hydroxy-3-phenyl-propyl)-piperazin-1-yl]-isobutyramide (23) This compound was prepared in a manner similar to that of 7, substituting 2-chloro-2-methylpropionyl chloride for chloroacetyl chloride in part A and allylbenzene for 8. (M+1)=410.34. N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)prophyl]piperazinyl}acetamide (24) This compound was prepared in a manner similar to that of 7, substituting 2-chloro-2-methylpropionyl chloride for chloroacetyl chloride in part A and 3,4,5-trimethoxy allybenzene for 8. (M+1)=472.54 N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide (25) This compound was prepared in a manner similar to that of 16, substituting phenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1)=410.4. N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide(26) This compound was prepared in a manner similar to that of 16, substituting 2-fluorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1)=428.1. N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide(27) This compound was prepared in a manner similar to that of 16, substituting 2-chlorophenethyl chloride for 4-methoxybenzyl chloride in part A. (M+1)=444.3