反应详情

To a 250 mL round-bottomed flask charged with magnesium (1.646 g, 67.7 mmol) and ethyl ether (47.0 ml) was added two drops of dibromoethane and the mixture was heated to reflux for 15 minutes. p-Bromoanisole (6.35 ml, 50.8 mmol) in diethyl ether (47.0 ml) was slowly added through an addition funnel while a refluxing temperature was maintained. The resulting mixture was heated for 3 hrs, and then cooled to room temperature. A solution of 2-aminobenzonitrile (2 g, 16.93 mmol) in diethyl ether (47.0 ml) was added dropwise over 15 min. After the addition, the mixture was refluxed for 16 hrs. The volume was then reduced by half under reduced pressure and the resulting mixture was quenched slowly with ice (100 g). Next, 6N HCl (10 mL) was then added and the mixture was stirred at room temperature for 16 hrs. The pH was adjusted to pH 8 with 5N NaOH and diluted with saturated NaHCO3 (50 ml). The phases were separated and the aqueous layer was back extracted with ethyl acetate (2×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 70% solvent A/B=heptane/EtOAc, REDISEP® SiO2 120 g). Concentration of the appropriate fractions provided Intermediate 6A (3.13 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 7.62-7.55 (m, 2H), 7.34-7.22 (m, 2H), 7.09-7.01 (m, 2H), 6.87-6.78 (m, 3H), 6.53 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 3.85 (s, 3H).

1. temperaturethe mixture was heated
2. temperatureto reflux for 15 minutes
3. temperaturewas maintained
4. temperatureThe resulting mixture was heated for 3 hrs
5. additionAfter the addition
6. temperaturethe mixture was refluxed for 16 hrs
7. customthe resulting mixture was quenched slowly with ice (100 g)
8. additionNext, 6N HCl (10 mL) was then added
9. additiondiluted with saturated NaHCO3 (50 ml)
10. customThe phases were separated
11. extractionthe aqueous layer was back extracted with ethyl acetate (2×200 mL)
12. dry with materialThe combined organic layers were dried (MgSO4)
13. filtrationfiltered
14. concentrationconcentrated
15. customThe crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 70% solvent A/B=heptane/EtOAc, REDISEP® SiO2 120 g)