反应详情

温度

75 °C

A nitrogen-purged, 2-L, 3-neck flask containing 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (114.14 g, 0.4715 mol) was sequentially charged (while stirring) with LiCl (39.62 g, 0.9347 mol), LiOAc (15.41 g, 0.2334 mol), DMAc (283 mL), and H2O (28.3 mL). The solution was then purged (subsurface) with N2 for 1 h. The flask was then charged with 1-cyclopentyl-prop-2-en-1-ol (73.70 g, 0.5808 mol), Et3N (6.5 mL, 0.0466 mol, 10% of the total to be added), and Pd(OAc)2 (5.2487 g, 0.0234 mol) followed by a careful purge of the headspace. The reaction was heated towards 75° C. Once the internal temperature reached 60° C. the reaction may exotherm. It took a total of 20 minutes to heat the reaction to 75° C. Fifteen minutes after the internal temp had reached 60° C., an aliquot was removed and analyzed by HPLC, showing a 3:1 ratio of starting material to product. At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction. Each addition of TEA causes additional exotherms. Twenty minutes after the second NEt3 addition, an aliquot was removed and analyzed by HPLC, showing a 2:1 ratio of starting material to product. Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction. Thirty-five minutes after the final NEt3 addition, an aliquot was removed and analyzed by HPLC, showing >70:1 ratio of product to starting material. The reaction was heated for 30 min more, then cooled to <30° C. over 15 min. The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g). The solution stirred well for 2 hours then filtered over a cake of celite (28.5 g packed in a 4″ buchner funnel). This filtration of the bilayer through celite was slow, and the vacuum caused a significant portion of the organic solvent to boil away. The cake was washed with MTBE (250 mL followed by 125 mL). The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL), the phases mixed well, and the lower aqueous layer removed. The organic phase was extracted with H2O (200 mL) and the phases mixed well. The lower aqueous layer was removed. The organic layer was extracted with a 5% NaCl/H2O solution (200 mL). The phases were separated and the organic layer was added to a 1 L, 3-neck flask. The solution was concentrated by atmospheric distillation until the internal volume was ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.35% H2O. An additional portion of MTBE (150 mL) was added and distillation continued until the internal volume was again ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K—F titration, showing 0.14% H2O. The solution was cooled under nitrogen and held overnight at rt. The solution was used directly in the next reaction without further processing. 1H NMR (300 MHz, CDCl3): 1.52–1.72 (m, 9), 1.77 (s, 6), 2.73–2.92 (m, 4), 6.90–7.00 (m, 1), 7.33–7.39 (m, 1)

1. customA nitrogen-purged
2. additionwas sequentially charged
3. customThe solution was then purged (subsurface) with N2 for 1 h
4. customa careful purge of the headspace
5. customreached 60° C.
6. customthe reaction
7. customa total of 20 minutes
8. temperatureto heat
9. customthe reaction to 75° C
10. customFifteen minutes
11. customhad reached 60° C.
12. customan aliquot was removed
13. additionAt this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total
14. additionto be added)
15. additionwas added to the reaction
16. additionEach addition of TEA
17. additionTwenty minutes after the second NEt3 addition
18. customan aliquot was removed
19. additionTen minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added)
20. additionwas added to the reaction
21. additionThirty-five minutes after the final NEt3 addition
22. customan aliquot was removed
23. temperatureThe reaction was heated for 30 min more
24. temperaturecooled to <30° C. over 15 min
25. additionThe flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g)
26. filtrationthen filtered over a cake of celite (28.5 g
27. filtrationThis filtration of the bilayer through celite
28. washThe cake was washed with MTBE (250 mL followed by 125 mL)
29. additionThe filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL)
30. additionthe phases mixed well
31. customthe lower aqueous layer removed
32. extractionThe organic phase was extracted with H2O (200 mL)
33. additionthe phases mixed well
34. customThe lower aqueous layer was removed
35. extractionThe organic layer was extracted with a 5% NaCl/H2O solution (200 mL)
36. customThe phases were separated
37. additionthe organic layer was added to a 1 L, 3-neck flask
38. concentrationThe solution was concentrated by atmospheric distillation until the internal volume
39. temperatureAfter cooling
40. temperaturebelow reflux
41. customan aliquot was removed
42. additionAn additional portion of MTBE (150 mL) was added
43. distillationdistillation
44. temperatureAfter cooling
45. temperaturebelow reflux
46. customan aliquot was removed
47. temperatureThe solution was cooled under nitrogen
48. waitheld overnight at rt
49. customThe solution was used directly in the next reaction without further processing