反应详情

温度

70 °C

Zinc (4.60 g, 70.3 mmol) and oven dried Celite (870 mg) was added to a flask and the flask was heated with a heat gun while under high-vac for 5 min and then back-filled with nitrogen. N,N-Dimethylacetamide (57 mL) was added, followed by 1,2-dibromoethane (430 μL, 5.0 mmol) and the mixture was heated at 70° C. for 10 min and then cooled to room temperature. The reaction mixture was treated with chlorotrimethylsilane (630 μL, 5.0 mmol) dropwise and stirred at room temperature for 1 h. The reaction mixture was treated with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (18 g, 62 mmol) in N,N-dimethylacetamide (28 mL) dropwise (internal temperature was kept below 40° C. with a water bath) and heated at 40° C. for 2 h. The zinc-iodo reagent (transferred via canula) was filtered through a plastic filter (that was appropriately sealed to avoid atmospheric exposure) directly into a clean, dry flask that was flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (720 mg, 0.79 mmol) and tri-(2-furyl)phosphine (370 mg, 1.6 mmol) and degassed with nitrogen for a few minutes. The reaction mixture was treated with a solution of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (14 g, 41 mmol) in N,N-dimethylacetamide (130 mL) (degassed with nitrogen) quickly and heated at 70° C. for 2 h. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5%-45%) to give the desired product (14 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 4.42-4.20 (m, 5H), 3.80 (q, J=7.0 Hz, 2H), 2.59 (s, 3H), 1.44 (s, 9H), 1.37 (t, J=7.0 Hz, 3H). LCMS for C15H16ClN2O4 ([M-(t-Bu)+H]+H)+: m/z=323.1; Found: 323.0.

1. additionwas added to a flask
2. temperaturethe flask was heated with a heat gun while under high-vac for 5 min
3. additionback-filled with nitrogen
4. temperaturecooled to room temperature
5. temperatureheated at 40° C. for 2 h
6. filtrationThe zinc-iodo reagent (transferred via canula) was filtered through a plastic
7. filtrationfilter (that
8. customwas appropriately sealed
9. customdry flask that
10. customwas flushed with nitrogen
11. customdegassed with nitrogen for a few minutes
12. temperatureheated at 70° C. for 2 h
13. extractionextracted with ethyl acetate (3×300 mL)
14. washThe combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL)
15. dry with materialdried with magnesium sulfate
16. filtrationfiltered
17. concentrationconcentrated to a crude dark oil
18. customThe crude material was purified by flash column chromatography