1,4-Dibromobutane → 1-(2,4-Dimethoxyphenyl)pyrrolidine

Temperature

150 °C

Ex-38A: Method A: A mixture of 2,4-dimethoxyaniline (1.0 g, 6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was heated at 150° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. After the mixture was partitioned, the aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography. Elution with ethyl acetate and hexane (1:2, v/v) gave 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (0.85 g, 63%). 1H-NMR (300 MHz, CDCl3) δ 6.76 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.41 (dd, J=2.7, 8.9 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.18–3.14 (m, 4H), 1.95–1.90 (m, 4H). Method B: Sodium tert-butoxide was charged to a mixture of 1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75 mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.26 g, 0.28 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.35 g, 0.56 mmol) in degassed toluene (60 mL). The reaction mixture was heated at 100° C. under N2 for 17 h. After cooling to room temperature, the reaction mixture was diluted with water (60 mL) and partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate and toluene was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography with ethyl acetate and hexane (1:2, v/v) to give 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (1.82 g, 63%).

1. concentrationThe reaction mixture was concentrated under reduced pressure
2. additionThe residue was taken up in a mixture of water and ethyl acetate
3. customAfter the mixture was partitioned
4. extractionthe aqueous solution was extracted with ethyl acetate
5. washThe combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated
8. customThe residue was purified by flash chromatography
9. washElution with ethyl acetate and hexane (1:2

ORD record

ord-a28f5774f3b2471b8f01c0bf5e3921dc

Source dataset

uspto-grants-2007_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07173129B2