Benzaldehyde → HCID 86748150, compound

Temperature

-78 °C

4-Bromomethylphenylacetic acid (20 g, 8.7 mmol) was suspended in toluene (300 ml). Triphenylphosphine (45 g, 170 mmol) was added and the mixture heated at reflux for 16 hours giving a thick white precipitate. This solid was collected by filtration, washing with ether×3, and dried under high vacuum to give 4-triphenylphosphinemethylphenylacetic acid bromide (42 g, 86 mmol); δH (250 MHz, DMSO-d6) 3.52 (2H, s, CH2COOH), 5.12 (2H, d, J 15 Hz, CH2P), 6.92 (2H, dd, J 8 and 2 Hz, PCH2CCH), 7.12 (2H, d, J 8 Hz, HOOCCH2CCH), 7.61-7.79 (12H, m, Ph-H), 7.90 (3H, dt, J 7 and 2 Hz, PPh(4)H). The phosphonium salt (40 g, 81.5 mmol) was suspended in anhydrous THF (300 ml) and diisopropylamine (35.4 ml, 187 mmol) added. The mixture was cooled to -78° C. and n-butyl lithium (70 ml of a 2.5M solution in hexanes, 175 mmol) was slowly added maintaining the temperature of the mixture at <-60° C. A colour change to brown through yellow and orange was observed. The reaction vessel was warmed to 0° C. and stirred for 30 mins. After recooling to -78° C., freshly distilled benzaldehyde (10.4 g, 97.8 mmol) was added whereupon the colour faded to orange. The reaction was stirred for 30 mins before being allowed to warm to room temperature for a further 30 mins and changing colour to yellow. The mixture was evaporated in vacuo to 100 ml then diluted with ethyl acetate and washed with water and brine, dried (Na2SO4) and evaporated to give a white solid. The solid was extracted with hot toluene and hot ether. Combined organic extracts were evaporated in vacuo. The residue (20.5 g) was dissolved in methanol (250 ml) and cooled to 0° C. Hydrogen chloride gas was bubbled through the solution for 5 mins then the mixture was stirred at room temperature under nitrogen for 16h. The solid formed was removed by filtration. The filtrate was evaporated, swilled with ether, refiltered and reduced in vacuo. The residue was separated by dry flash chromatography eluting with 0%-8% ethyl acetate in hexane to give a mixture of cis and trans methyl 4-stilbene acetates (3.9 g). This mixture was separated by flash chromatography eluting with 6% ethyl acetate/hexane to give stereoisomer A (1.45 g) and stereoisomer B (1.25 g). Isomer A (1.0 g, 4.0 mmol)was dissolved in THF (15 ml) and water (10 ml). Lithium hydroxide (9.52 ml of a 0.5M solution, 4.8 mmol) was added and the mixture stirred at room temperature for 45 mins. The THF was removed in vacuo and the aqueous residue partitioned between ether and sodium hydroxide solution. The aqueous fraction was retained and acidified to pH 1 (hydrochloric acid) giving a white precipitate which was extracted into ethyl acetate×2. The combined organic fractions were washed with water and brine before drying (Na2SO4) and evaporating in vacuo to give cis 4-stilbene acetic acid as a clear colourless oil (0.95 g, 4.0 mmol). δH (360 MHz, DMSO-d6) 3.52 (2H, s, CH2), 6.59 (1H, d, J 12.4 Hz, ArCH:CHAr), 6.64 (1H, d,J 12.4 Hz, ArCH:CHAr), 7.11-7.30 (9H, m, Ar--H); m/z (EI+) 238 (M+). [Isomer B was treated with lithium hydroxide as described for isomer A to give trans 4-stilbene acetic acid. δH (250 MHz, DMSO-d6) 7.14(1H, d, J 15.5 Hz, ArCH:CHAr)]. Isomer A was taken through to give the title compound as a buff coloured amorphous solid; m.p. 284°-286° C. (from dimethylformamide/acetone/water) (Found: C, 73.80;H, 3.97;N, 3.69. C23H16ClNO2 requires C, 73.90;H, 4.31;N, 3.75%); δH (360 MHz, DMSO-d6) 6.64 (2H, s, ArCH:CHAr), 7.20-7.35 (11H, m, Ar--H, 6-H and 8-H), 7.93(1H, d, J 8.7 Hz, 5-H), 10.1-10.5(1H, v br s, OH), 11.53(1H, br s, NH); m/z (EI+) 273 (M+).

1. temperaturemaintaining the temperature of the mixture at <-60° C
2. temperatureThe reaction vessel was warmed to 0° C.
3. customAfter recooling to -78° C.
4. stirringThe reaction was stirred for 30 mins
5. temperatureto warm to room temperature for a further 30 mins
6. customThe mixture was evaporated in vacuo to 100 ml
7. additionthen diluted with ethyl acetate
8. washwashed with water and brine
9. dry with materialdried (Na2SO4)
10. customevaporated
11. customto give a white solid
12. extractionThe solid was extracted with hot toluene and hot ether
13. customCombined organic extracts were evaporated in vacuo
14. dissolutionThe residue (20.5 g) was dissolved in methanol (250 ml)
15. temperaturecooled to 0° C
16. customHydrogen chloride gas was bubbled through the solution for 5 mins
17. stirringthe mixture was stirred at room temperature under nitrogen for 16h
18. customThe solid formed
19. customwas removed by filtration
20. customThe filtrate was evaporated
21. customThe residue was separated
22. customby dry flash chromatography
23. washeluting with 0%-8% ethyl acetate in hexane
24. customto give
25. customThis mixture was separated by flash chromatography
26. washeluting with 6% ethyl acetate/hexane
27. customto give stereoisomer A (1.45 g) and stereoisomer B (1.25 g)
28. stirringthe mixture stirred at room temperature for 45 mins
29. customThe THF was removed in vacuo
30. customthe aqueous residue partitioned between ether and sodium hydroxide solution
31. customgiving a white precipitate which
32. extractionwas extracted into ethyl acetate×2
33. washThe combined organic fractions were washed with water and brine
34. dry with materialbefore drying (Na2SO4)
35. customevaporating in vacuo

ORD record

ord-74a9ef6d13884e4884854ee7cd69a162

Source dataset

uspto-grants-1996_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05559125