4-(4-BROMO-PHENOXY)-BUTYRIC ACID

Step 2: 4-(4-Bromophenoxy)butanoic acid Step 2: 4-(4-Bromophenoxy)butanoic acid To a solution of the crude product from Step 1 in methanol (100 mL) was added aqueous sodium hydroxide solution (3N, 200 mL). The mixture was heated to 70 C for 1 hr then poured into ice followed by addition of aqueous HC1 solution (37%, 50 mL). The mixturewas extracted with ethyl acetate and the combined organic phases were washed with water, dried over Na2S04and evaporated. The crude product was triturated with diethyl ether to provide the title compound (41 g, 79% for two steps) as a white solid. 1H NMR (500 MHz, CDC13) delta ppm 2.12-2.16 (m, 2H), 2.61 (t, J=7.0 Hz, 2H), 4.02 (t, J=6.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H)General procedure: A volumeof 20 mL of ethanol was added to 4- (4-fluorophenoxy) ethylbutyrate (1.08 g, 4.80 mmol) in a 100 mL three-neck flask, and thesolutionwas agitated until dissolution. A total of 3 mL of water wasadded to sodium hydroxide (0.75 g, 18.8 mmol) at room temperature, and the solution refluxed for 2 h. The reaction was monitoredby thin layer chromatography(TLC). The solutionwas then cooled to25 C, dried using a rotary evaporator, and the residue was dilutedwith 30 mL of water. The solutionwas adjusted to pH = 5 using 1MHCl to form a solid white precipitate, which was filtered and rinsedwith a small amount ofwater. The precipitatewas dried via vacuumfiltration, which yielded a crude product (White solid 0.71 g, yield78.7%) that was immediately used for the next step without furtherpurification.Step 3: 7-Bromo-3 , 4-dihydrobenzo [b] oxepin-5 (2H)-one To pre-heated PPA (200 g) at 120 C was added General procedure: Following the addition of 4-(4-fluorophenoxy) butyric acid (0.71 g, 3.6 mmol) to 20 mL ofdichloromethane in a 50 mL three-necked round-bottom flask, thesolution was agitated until dissolution. Subsequently, EDCI (0.85 g, 4.44 mmol) HOBt (0.6 g, 4.44 mmol) and triethylamine (0.84 g, 9.25 mmol) were added in turn at 0 C. Stirring in an ice bath for 1 h, 3-amino-2-oxazolidinone (0.37 g, 3.6 mmol) was added again. Thesolutionwas brought to 25 C and stirred overnight. Following TLC, the product was filtered by vacuum and dried under rotary evaporation.The product was a white solid weighing 0.51 g with a yieldof 50.2%.Compound b1 (2 g, 7.7 mmol, 1.0 eq), bis(pinacolato)diboron (2.2 g, 9.0 mmol, 1.1 eq), KOAc (4.5 g, 46.3 mmol, 6.0 eq), 48 mL DMSO are mixed in a flask. The reaction was degassed under Ar for 20 min and then Pd(dppf)Cl2.CH2Cl2 (0.085 g, 0.1 mmol, 0.03 eq) was added under high argon flow. The reaction was heated at 80 C. for 8 hours. After cooling to room temperature, the reaction was extracted with EtOAc and washed with brine several times. The organic layer was then dried with MgSO4, and the solvent was removed with a rotary evaporator. The resulting crude product was purified by silica gel column chromatography and EtOAc:hexane=1:1 as the eluent. A pale yellow solid was obtained after removal of the solvents (1.7 g, 73% yield). 1H NMR (400 MHz, CDCl3): deltaH=7.58 (d, 2H, J=9.0 Hz), 6.93 (d, 2H, J=9.0 Hz), 3.99 (t, 2H), 2.37 (m, 2H), 1.93 (m, 2H), 1.27 (s, 12H) ppm. 13C NMR (500 MHz, CDCl3): deltaC=178.97, 161.46, 136.65, 113.95, 105.13, 83.70, 66.42, 30.58, 25.15, 24.98 ppm. HRMS (+ESI/APCI) (mass m/z): 307.1706 [M+H]+Compound 1a (3.0 g, 12.4 mmol, 1.0 eq) was dissolved in 62 mL DMF (0.2 M), and 1.6 mL OsO4 (0.01 eq, 2.5% in tBuOH) was added and stirred for 5 min. Oxone (15 g, 49.6 mmol, 4.0 eq) was added in one portion and the reaction was stirred at RT for 8 h. Na2SO3 (100 mg, 6.0 eq w/w) was added, to reduce the remaining Os(VIII), and stirred for an additional hour. The final solution would became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (3×) and brine, dried over MgSO4, and the solvent was removed under reduced pressure to obtain the crude product. Products were purified by silica gel column chromatography to give 2.3 g of a white solid (70%). 1H NMR (400 MHz, CDCl3): delta=7.38 (d, 2H, J=9.0 Hz), 6.78 (d, 2H, J=9.0 Hz), 3.99 (t, 2H), 2.58 (m, 2H), 2.12 (m, 2H) ppm. 13C NMR (500 MHz, CDCl3): delta=178.97, 157.96, 132.38, 116.39, 113.09, 66.87, 30.53, 24.39 ppm. HRMS (-ESI/APCI) (mass m/z): 256.9829 [M-H]-.

Molecular Weight:259.10
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:257.98916
Monoisotopic Mass:257.98916
Topological Polar Surface Area:46.5
Heavy Atom Count:14
Complexity:176
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes