反応 #76304

反応方程式

para ethyl (4-chloro-1-oxobutyl)benzene acetic acid

ethyl benzeneacetic acid

para ethyl (4-chloro-1-oxobutyl)benzene acetic acid

LiOH

4-chlorobutyryl chloride

AlCl3

→

(cyclopropylcarbonyl)benzeneacetic acid

収率 11.0%

溶媒

Methylene chloride

water

ethanol

methylene chloride

反応条件

後処理

1. 1
   温度while maintaining the pot temperature below 10° C
2. 2
   温度maintaining the pot temperature below 100° C
3. 3
   温度heated to 40° C
4. 4
   workup.WAITAfter 4 hours
5. 5
   温度the solution is cooled to room temperature
6. 6
   workup.ADDITIONpoured
7. 7
   その他The organic phase is separated
8. 8
   抽出The aqueous phase is extracted with two 1 L portions of methylene chloride
9. 9
   乾燥The combined organics are dried (MgSO4)
10. 10
    濃縮concentrated
11. 11
    workup.ADDITIONToluene (1 L) is added
12. 12
    濃縮the solution is concentrated to ca. 500 mL
13. 13
    workup.ADDITIONEthanol (500 mL) is added
14. 14
    温度The solution is heated to 70° C.
15. 15
    その他HCl (g) is bubbled through for 20 minutes
16. 16
    その他The solution is sparged with N2
17. 17
    濃縮concentrated
18. 18
    その他gives
19. 19
    温度is cooled with an ice bath
20. 20
    workup.WAITAfter 1 hour
21. 21
    温度to warm to room temperature
22. 22
    workup.WAITAfter 18 hours
23. 23
    濃縮the mixture is concentrated
24. 24
    workup.ADDITIONWater (400 mL) and conc. HCl are added (until pH 4)
25. 25
    workup.ADDITIONEthyl acetate (600 mL) is added
26. 26
    その他The organic phase is separated
27. 27
    洗浄washed with brine
28. 28
    乾燥dried (MgSO4)
29. 29
    温度The solution is heated on a steam bath
30. 30
    workup.ADDITIONcharcoal (ca. 3 g) is added
31. 31
    ろ過The mixture is filtered through Celite
32. 32
    濃縮concentrated
33. 33
    workup.DISSOLUTIONThe residue is dissolved in ethyl acetate (300 mL)
34. 34
    温度heptane (600 mL) with heating
35. 35
    workup.ADDITIONSeed crystals are added
36. 36
    温度After cooling an organic oil
37. 37
    workup.ADDITIONHeptane (500 mL) is added
38. 38
    温度the mixture is heated
39. 39
    温度to reflux
40. 40
    workup.ADDITIONtreated with charcoal (ca. 5 g)
41. 41
    ろ過filtered
42. 42
    その他A solid forms and is collected
43. 43
    workup.ADDITION4:1 mixture of para
44. 44
    その他Recrystallization from ethyl acetate/heptane

実験手順

To a slurry of AlCl3 (210 g, 1.6 mol) in methylene chloride (200 mL) cooled in an ice bath is added 4-chlorobutyryl chloride (121 g) dropwise while maintaining the pot temperature below 10° C. After 10 minutes, ethyl benzeneacetic acid (118 g, 0.72 mol) is added dropwise maintaining the pot temperature below 100° C. The mixture is stirred at room temperature for 1 hour, then heated to 40° C. After 4 hours, the solution is cooled to room temperature and poured onto crushed ice (2 L). Methylene chloride (1 L) is added. The organic phase is separated. The aqueous phase is extracted with two 1 L portions of methylene chloride. The combined organics are dried (MgSO4) and concentrated. Toluene (1 L) is added and the solution is concentrated to ca. 500 mL. Ethanol (500 mL) is added. The solution is heated to 70° C. and HCl (g) is bubbled through for 20 minutes. The solution is sparged with N2 and concentrated. Chromatography through silica gel (2.5 L) using an ethyl acetate/heptane gradient gives a 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (119 g). To a slurry of LiOH (23.5 g, 0.56 mol) in water (100 mL) and ethanol (100 mL) is added the 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (50 g, 0.19 mol). The reaction becomes exothermic and is cooled with an ice bath. After 1 hour, the solution is allowed to warm to room temperature. After 18 hours, the mixture is concentrated. Water (400 mL) and conc. HCl are added (until pH 4). Ethyl acetate (600 mL) is added. The organic phase is separated, washed with brine and dried (MgSO4). The solution is heated on a steam bath and charcoal (ca. 3 g) is added. The mixture is filtered through Celite and concentrated. The residue is dissolved in ethyl acetate (300 mL) and heptane (600 mL) with heating. Seed crystals are added. After cooling an organic oil appears. Heptane (500 mL) is added and the mixture is heated to reflux, treated with charcoal (ca. 5 g), filtered and seeded. A solid forms and is collected. 1H NMR shows ca. 4:1 mixture of para:meta isomers. Recrystallization from ethyl acetate/heptane gives 4 (cyclopropylcarbonyl)benzeneacetic acid (4.3 g, 11%).

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