(-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine → 4-[(S)-[(2S,5R)-2,5-Dimethyl-4-(2-propenyl)-1-piperazinyl]phenylmethyl]-N,N-diethylbenzamide

Participants

Reaction Steps

A solution of 4-formyl-N,N-diethylbenzamide (4.105 g, 20 mmol), benzotriazole (2.38 g, 20 mmol) and (2R,5S)-1-allyl-2,5-dimethylpiperazine (3.085 g, 20 mmol) in toluene (200 mL) was heated under reflux with azeotropic removal of water for 2.5 h. The volume of the reaction mixture was reduced to approximately 75 mL by distillation. Anhydrous tetrahydrofuran (50 mL) was added to the solution under nitrogen, and the reaction was stirred during the addition of phenylmagnesium bromide (1.0 M in tetrahydrofuran, 40 mL, 40 mmol). The reddish brown suspension was stirred at ambient temperature for 1 h and quenched with saturated aqueous ammonium chloride solution (10 mL). The yellow suspension was stirred for 15 min, and anhydrous magnesium sulfate (10 g) added. The suspension was stirred for a further 15 min and filtered. The filter cake was washed with tetrahydrofuran, and the combined filtrate and washings were evaporated to a thick oil. The residue was partitioned between ethyl acetate (400 mL) and aqueous sodium hydroxide solution (1.0 M, 100 mL). The organic layer was separated and washed successively with 1M-NaOH (3×100 mL), water (100 mL) and saturated aqueous sodium chloride solution (100 mL). The ethyl acetate solution was extracted with 1.0 M HCl (2×25 mL), and the combined acid extracts were basified to pH 10 with 10 M aqueous NaOH. The oily aqueous suspension was extracted with methylene chloride (2×25 mL) and the organic layer dried over anhydrous magnesium sulfate. The methylene chloride solution was evaporated to dryness, and the semi-crystalline residue crystallized from ethyl acetate to yield the title compound (1.84 g, 21.9%). Calc. for C27H37N3O 0.15 H2OC, 76.79; H, 8.90; N, 9.95. Found C, 76.79; H, 8.85; N, 9.87% 1H NMR ((CD3)2SO, 500 MHz); δ 0.94 (d, J=6.2 Hz, 3H); 1.09 (d, J=6.2 Hz, 3H, partially obscured by br m, 6H); 1.80 (m, 1H); 2.09 (dd, J=11, 7 Hz, 1H); 2.50 (br m, 1H, partially obscured by DMSO); 2.72 (dd, J=11, 2.8 Hz, 1H); 2.84 (dd, J=14, 7 Hz, 1H); 3.16 (dd, J=14, 5.2 Hz, 1H); 3.28 (br m, 3H); 5.10 (s, 1H), overlapped by 5.09 (d, J=10.6 Hz, 1H); 5.16 (dd, J=17, 1.4 Hz, 1H); 5.79 (m, 1H); 7.28 (m, 5H); 7.38 (m, 2H); 7.42 (d, J=8 Hz, 2H).

Provenance & Evidence