61% |
With N-Bromosuccinimide; In acetonitrile; for 24h; |
Example 30 3-F 4- [3- ()- (4-ETHYL-2-THIOPHEN-2-YL-PHENOXY)-BUTOXY]-2-METHYL-PHENYL}-PROPIONIC ACID Step A 2-BROMO-4-ETHYL-PHENOL; N-bromosuccinimide (1. 58 g, 8.92 mmol) is added to a solution of 4-ethyl phenol (1.0 g, 8.19 mmol) in ACN (35 mL), and the mixture is stirred under N2 at ambient temperature. After 24 h, the mixture is concentrated under reduced pressure and diluted with water. The mixture is extracted with EtOAc, and organic phases are washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) yields title compound (1.01 g, 4.9 mmol, 61%): RF 0.34 hexanes: EtOAc (90: 10), 1H NMR (400 MHz, CDC13) 7.28 (d, 1H, J= 2. 4 Hz), 7.03 (dd, 1H, JL= 2.4 Hz, J2= 8.4 Hz), 6. 92 (d, 1H, J= 8. 4 Hz), 5.34 (s, 1H), 2.56 (q, 2H, J = 7.6 Hz), 1.20 (t, 3H, J= 7. 6 Hz). |
52% |
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h; |
To a solution of 4-ethylphenol (1.0 g, 8.2 mmol, 1.0 eq) in dry acetonitrile (40 mL) was added NBS (1.46 g, 8.2 mmol, 1.0 eq). The mixture was allowed to stir at RT for 2 h followed by removal of acetonitrile. The residue was redissolved in Et20 and washed with H20. The organic extracts were dried over Na2S04, filtered, and concentrated. The crude material was purified by flash chromatography (Biotage FLASH 40S KP-Sil silica, 5% Et20/hexanes) to yield 1.0 g (52%) of 16 as a clear oil. ¹H NMR (CD2Cl2, 300 MHz) : 7.33 (s, 1H), 7.07 (d, J= 8.1 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 2.58 (m, J= 7.5 Hz, 2H), 1.20 (t, J= 7.5 Hz, 3H). |
|
With bromine; In methanol; chloroform; |
114.1 8.41 ml of bromine in 100 ml of CHCl3 were added dropwise within 2 hrs. to a solution, cooled to 0 C., of 20 g of 4-ethylphenol in 200 ml of CHCl3 and 100 ml of MeOH. The reaction mixture was left to warm to room temperature and was concentrated. The product was isolated by extraction. There were obtained 33.14 g of 2-bromo-4-ethyl-phenol as a light brown oil. |
|
With bromine; sodium hydrogencarbonate; In chloroform; water; |
Reference example 1 A solution was prepared by dissolving 105 g of 4-ethylphenol into 500 ml of chloroform. The solution was cooled by ice water bath, followed by dropwise addition of 45 ml of bromine while stirring. The addition was took 1 hour. Then, the reaction mixture was cooled by an ice water bath while stirring for 4 hours, moved into a separatory funnel to wash with water, an aqueous solution saturated with NaCl, 10% water solution of sodium hydrogencarbonate and an aqueous solution saturated with NaCl in turn, and dried with magnesium sulfate anhydride. The solvent in the reactant was distilled off under reduced pressure to yield 173 g of light brown and oily 2-bromo-4-ethylphenol. NMR (CDCl3) delta: 1.20 (3H, t, J=7.5 Hz); 2.56 (2H, q, J=7.5 Hz), 5.33 (1H, s), 6.92 (1H, d, J=8.0 Hz), 7.04 (1H, dd, J=8.0 Hz, 2.5 Hz), 7.28 (1H, d, J=2.5 Hz). |
|
With bromine; In dichloromethane; at 0℃; for 0.0833333h; |
To a cooled 0 C. solution of of 4-ethylphenol (12.94 g, 106 mmol) in dichloromethane (212 mL) was added dibromine (5.70 mL, 111 mmol) slowly. After the addition was complete, the reaction mixture was stirred for 5 minutes and quenched with 1N aqueous NaOH. The reaction mixture was diluted with water and the organic layer was separated, concentrated and purified on a 220 g silica gel cartridge eluting with a gradient 0-20% methyl tert-butyl ether/heptanes to provide the title compound. 1H NMR (400 MHz, chloroform-d) delta ppm 7.28 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.3, 2.1 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 5.34 (s, 1H), 2.56 (q, J=7.6 Hz, 2H), 1.32-1.15 (t, 3H)+ |
|
With bromine; acetic acid; at 0℃; for 0.5h; |
The synthesis of compound 1a was examplified. A solution of phenol (1.00 g, 10.63 mmol) and Br2 (0.49 mL, 9.56 mmol) in AcOH (7 mL) was stirred for 30 min at 0 C, the reaction mixture was poured into a separatory funnel with ice water (10 mL) and the aqueous phase was extracted with DCM (3 × 15 mL). The combined organic extracts were washed with saturated NaCl (aq) and dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in THF (15 mL) and added to HMDS (2.44 mL, 11.69 mmol) for reflux at 70 C for 2 h. The solvent was evaporated under reduced pressure and the crude product was dissolved in THF (15 mL). Finally, the solution was cooled to -78 C and n-BuLi (5.53 mL, 2.5 M, 13.82 mmol) was added dropwise and stirred for 1 h. Tf2O (1.97 mL, 11.69 mmol) was added dropwise and was stirred for 1.5 h. Cold saturated aqueous NaHCO3 (20 mL) was added after separation, and the aqueous layer was extracted with Et2O. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 1a. The remaining compounds 1b-1m (structures showed in Figure 1) were obtained by the same synthetic route. |