Preparation of 1-phenylpyrrolidine_Kain Industrial Additive

Background and overview^[1]

The Chinese alias of 1-phenylpyrrolidine is N-phenylpyrrolidine. N-substituted five-membered nitrogen heterocyclic compounds including 1-phenylpyrrolidine are an important basic structural unit in organic compounds and often appear in biologically active natural products and drug molecules. The synthesis of N-substituted five-membered nitrogen heterocyclic compounds has therefore received widespread attention. At present, there are two common ways to synthesize such compounds: 1. Under the catalysis of iron, copper, palladium and other metal compounds, it is synthesized from halogenated aromatic hydrocarbons and five-membered nitrogen heterocyclic compounds, for example, from N heterocyclic carbene palladium complex Synthesis of N-aryl tetrahydropyrrole catalyzed by (s)-proline and CuI -Synthesis of N-aryl tetrahydropyrrole catalyzed by Al alloy; 2. Synthesis of N-substituted tetrahydropyrrole compounds from aromatic amines and 1,4-dihalobutane under alkaline conditions, such as in potassium carbonate aqueous solution N-substituted tetrahydropyrrole compounds were synthesized from 1,4-dibromobutane and aromatic amines. In addition, N-substituted tetrahydropyrrole may also be synthesized from aromatic amines and 1,4-butanediol or tetrahydrofuran, but the reaction generally requires that the reaction be carried out under high temperature and pressure.

Preparation ^[1]

The synthesis of 1-phenylpyrrolidine (1) is as follows: under argon protection, add 0.15mL (1.2mmol, 170.3mg) boron trifluoride ether solution and 0.1mL (1mmol, 93mg) aniline at room temperature. 4 mL of freshly steamed toluene was stirred at room temperature for 60 min, then 1.0 mL (10 mmol) of tetrahydrofuran was added, the temperature was slowly raised to 110°C, and refluxed for 24 h. The reaction system was lowered to room temperature, 10 mL of saturated sodium bicarbonate solution was added, stirred thoroughly, and extracted with dichloromethane (3 × 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and 87 mg of the product was obtained as a light yellow oil through silica gel column chromatography using petroleum ether (60-90°C): dichloromethane = 1:4 (volume ratio) as the developing solvent. The yield was 59%. The nuclear magnetic data are as follows: ¹H NMR (solvent: CDCl ₃ , chemical shift): δ1.96-1.99 (m, 4H), 3.25-3.28 (m, 4H) ), 6.56 (d, J=7.9Hz, 2H), 6.64 (t, J=7.3Hz, 1H), 7.21 (td, J=6.8, 0.9Hz, 2H); ¹³C NMR (Solvent: CDCl ₃ , chemical shift): δ25.7, 47.8, 111.9, 115.6, 129.3, 148.2;

Main reference materials

[1] CN107935965 A new synthesis method of N-substituted tetrahydropyrrole derivatives