Water → HCID 68654526, compound

To a three-neck round-bottomed flask equipped with two nitrogen inlets, reflux condenser, rubber septum, and magnetic stir bar were added zinc powder (0.53 g, 8.1 mmol) and THF (15 mL). To the stirred suspension was slowly added TiCl4 via syringe at room temperature under a nitrogen atmosphere (Note: significant fuming occurred upon addition of TiCl4). The reaction mixture was heated at reflux for 2 h. To the refluxing reaction mixture was added a solution of 4,4-dimethylcyclohexanone (20) (0.447 g, 3.54 mmol) and (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.314 g, 1.13 mmol) in THF (15 mL). The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature. To the stirred reaction mixture was added water (8 mL) followed by 10% aqueous K2CO3 (8 mL). The mixture was filtered through a pad of Celite. The pad washed with EtOAc. The filtrate was transferred to a separatory funnel and washed with water. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give a pale tan solid. The intermediate aryl bromide was partially purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 3:1) to give 0.381 g of impure 4-[(4-bromophenyl)(4,4-dimethylcyclohexylidene)methyl]phenol as an oil. To the impure intermediate aryl bromide (0.37 g) were added tert-butyl acrylate (0.60 mL, 0.525 g, 4.1 mmol), Pd(OAc)2 (0.067 g, 0.30 mmol), Et3N (0.84 mL, 0.61 g, 6.03 mmol), P(o-tolyl)3 (0.134 g, 0.44 mmol) and CH3CN (15 mL). The stirred reaction mixture was heated overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel. The reaction mixture was partitioned between EtOAc and H2O. The layers were separated and the organic phase was dried (MgSO4) and filtered. Silica gel was added to the filtrate and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 1:1) as eluant to give 0.24 g (51% from (4-bromophenyl)(4-hydroxyphenyl)methanone) of compound 21 as an oil. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6 H), 1.31 (m, 4 H), 1.45 (s, 9 H), 2.16 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.05 (d, J=8.2 Hz, 2 H), 7.48 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.32 (s, 1H). LRMS (ESI) m/z 417 (M−H)−.

1. customTo a three-neck round-bottomed flask equipped with two nitrogen inlets
2. temperaturereflux condenser
3. customat room temperature
4. temperatureThe reaction mixture was heated
5. temperatureat reflux for 2 h
6. customTo the refluxing reaction mixture
7. temperatureThe reaction mixture was heated
8. temperatureat reflux
9. customTo the stirred reaction mixture
10. filtrationThe mixture was filtered through a pad of Celite
11. washThe pad washed with EtOAc
12. customThe filtrate was transferred to a separatory funnel
13. washwashed with water
14. customThe organic phase was separated
15. washwashed with brine
16. dry with materialdried over MgSO4
17. filtrationfiltered
18. concentrationthe filtrate was concentrated
19. customto give a pale tan solid
20. customThe intermediate aryl bromide was partially purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 3:1)

ORD record

ord-39c072c39579444296642cbe5397de51

Source dataset

uspto-grants-2009_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07569601B2