Oxazole → 4-Hydroxy-4-[4-(1,3-oxazol-2-yl)phenyl]cyclohexanone

Temperature

0 °C

To a solution of oxazole (240 mg, 3.5 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1.6 M, 2.6 mL). After the mixture was stirred for 1 hour, a solution of zinc chloride in THF (0.5 M, 8.2 mL) was added in and the resulting mixture was allowed to warm to 0° C. over 1 hour. To the mixture was added 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (1.35 g, 3.5 mmol) and the resulting mixture was degassed with N2 for 3 times. To a suspension of PdCl2(PPh3)2 (122 mg, 5%) in THF (2 mL) was added nBuLi (1.6 M, 0.26 mL) and the mixture was added into the above mixture. The resulting mixture was heated to reflux under N2 for 4 hours. The resulting mixture was diluted with ethyl acetate (50 mL). The organic layer was filtered through Celite and the filtrate was washed with saline solution (2×10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in THF (2.5 mL) and was treated with 5% HCl (22.5 mL) at rt for 24 h. The mixture was neutralized with 1 N NaOH to pH 7, concentrated on rotvap, and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The resulting residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (100/0 to 100/0), to provide the desired compound (0.56 g, 62% for the two steps). LCMS: 258.2 (M+H+, 100%). 1H NMR: (CDCl3) δ 8.06 (d, 2H), 7.73 (s, 1H), 7.63 (d, 2H), 2.99-2.91 (m, 2H), 2.42-2.30 (m 4H), 2.22-2.05 (m, 2H).

1. customthe resulting mixture was degassed with N2 for 3 times
2. additionTo a suspension of PdCl2(PPh3)2 (122 mg, 5%) in THF (2 mL)
3. additionwas added nBuLi (1.6 M, 0.26 mL)
4. additionthe mixture was added into the above mixture
5. temperatureThe resulting mixture was heated
6. temperatureto reflux under N2 for 4 hours
7. additionThe resulting mixture was diluted with ethyl acetate (50 mL)
8. filtrationThe organic layer was filtered through Celite
9. washthe filtrate was washed with saline solution (2×10 mL)
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated in vacuo
12. dissolutionThe residue was dissolved in THF (2.5 mL)
13. additionwas treated with 5% HCl (22.5 mL) at rt for 24 h
14. concentrationconcentrated on rotvap
15. extractionextracted with EtOAc (2×50 mL)
16. washwashed with saline solution (2×50 mL)
17. dry with materialdried over sodium sulfate
18. concentrationconcentrated in vacuo
19. customThe resulting residue was chromatographed on silica gel
20. washeluting with hexane/ethyl acetate (100/0 to 100/0)

ORD record

ord-e50dda7a89274b3d87977ede98ebf392

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08362003B2