反应详情

温度

-20 °C

A 22-L, 3-neck, round bottom flask was equipped with a J-KEM temperature controller, a mechanical stirrer, a nitrogen inlet, and an addition funnel. The flask was flushed with nitrogen then charged with anhydrous THF (5 L) and diisopropylamine (731 mL, 5.219 mol). The solution was cooled to −20° C. using a dry ice/acetone bath. The stirring mixture was slowly treated with 1.6 M n-butyllithium in hexanes (3.02 L, 4.833 mol) via cannula over 1 h maintaining the temperature between −20° C. and −27° C. The reaction mixture was cooled to −40° C. and hexamethylphosphoramide (2.7 L, 16.317 mol) was slowly added via addition funnel over 40 min. The reaction mixture was cooled to −73° C. and dimethyl cyclopentane-1,3-dicarboxylate (360 g, 1.933 mol) dissolved in anhydrous THF (2 L) was slowly added via addition funnel over 2 h. The reaction mixture was warmed to −10° C. and stirred at that temperature for 30 min, then cooled to 70° C. and treated with 1-bromo-2-chloroethane (267 mL, 3.209 mol) via addition funnel over 4 h. The reaction mixture was allowed to slowly warm to room temperature over 12 h and then was quenched with saturated aqueous ammonium chloride (2 L) over 90 min. The reaction mixture was diluted with hexane (2 L), the layers were separated, and the aqueous layer was further extracted with hexane (3×2 L). The combined organic layers were washed with brine (2×1 L), dried over sodium sulfate, filtered, and concentrated to a brown oil. The crude product was purified by silica gel purification (0-10% ethyl acetate/hexane). The product containing fractions were concentrated to near dryness and diluted with hexanes. The resulting crystalline solids were filtered and washed with hexane (200 mL) providing pure product as a clear crystalline solid. Additional batches of product were obtained from the filtrate in a similar manner. All product batches were combined to provide 208 g (51%) of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate as a clear crystalline solid. 1H NMR (500 Hz, CDCl3) δ ppm 3.68 (s, 6H), 2.03 (d, J=6.4 Hz, 4H), 1.90 (s, 2H), 1.67 (d, J=7.0, 4H).

1. customThe flask was flushed with nitrogen
2. temperaturemaintaining the temperature between −20° C. and −27° C
3. temperatureThe reaction mixture was cooled to −40° C.
4. temperatureThe reaction mixture was cooled to −73° C.
5. additionwas slowly added via addition funnel over 2 h
6. temperatureThe reaction mixture was warmed to −10° C.
7. temperaturecooled to 70° C.
8. temperatureto slowly warm to room temperature over 12 h
9. customwas quenched with saturated aqueous ammonium chloride (2 L) over 90 min
10. additionThe reaction mixture was diluted with hexane (2 L)
11. customthe layers were separated
12. extractionthe aqueous layer was further extracted with hexane (3×2 L)
13. washThe combined organic layers were washed with brine (2×1 L)
14. dry with materialdried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated to a brown oil
17. customThe crude product was purified by silica gel purification (0-10% ethyl acetate/hexane)
18. additionThe product containing fractions
19. concentrationwere concentrated
20. additiondiluted with hexanes
21. filtrationThe resulting crystalline solids were filtered
22. washwashed with hexane (200 mL)
23. customproviding pure product as a clear crystalline solid
24. customAdditional batches of product were obtained from the filtrate in a similar manner