4-Bromo-3-fluorobenzotrifluoride

liquid

General procedure: Benzimidazole (5 mmol), 1-bromo-2-fluorobenzene derivatives (15 mmol, 2 equiv) and tripottasium phosphate (5.31g, 25 mmol, 5 equiv) were dissolved in DMF (30 mL). The mixture was stirred at 150 C. The reaction time was determined by monitoring with TLC. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL). The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organic layerswere washed with water (3 × 50 mL), dried with MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/AcOEt).To a stirred solution of oxetan-3-ol (4.5 g, 61.7 mmol) in THF (50 ml) was added 60 % NaH (2.5 g, 61.7 mmol) at 0 C for 20 min and then 1 -bromo-2-fluoro-4- (trifluoromethyl)benzene (7.5 g, 30.9 mmol) was added. The resultant mixture was stirred at 50 C for 12 h. Reaction mixture was then poured into cold water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by column chromatography to obtain a white solid (Yield = 6.7g, 73%). NMR (500 MHz, DMSO-ifc) delta 7.88 (d, J= 8.2 Hz, 1H), 7.30 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 5.53 (ddd, J= 10.7, 6.0, 4.7 Hz, 1H), 4.98 (ddd, J = 7.2, 5.9, 1.0 Hz, 2H), 4.59 (ddd, J= 7.4, 4.7, 1.0 Hz, 2H). GCMS: m/z 296.02 & 298.10 (M +).To a solution of l-bromo-2-fluoro-4-(trifluoromethyl)benzene (200 mg; 0.82 mmol)[CAS 40161-54-4] in tetrahydrofuran (15 mL) cooled to -70 C was added dropwise a solution of 1.6M n-butyllithium in n- hexane (0.7 mL; 1.1 mmol). After agitation at -70 C for 1 hour, the reaction mixture was treated dropwise with a solution of teri-butyl 4-[methoxy(methyl)carbamoyl]piperidine-l-carboxylate (247 mg; 0.91 mmol) [CAS 139290-70-3] in tetrahydrofuran (5 niL). The reaction mixture was stirred for 0.5 hours at -70 C and then for 2 hours at room temperature. The reaction mixture was deactivated with a saturated aqueous ammonium chloride solution (20 mL), then ethyl acetate (30 mL) was added. The organic layer was separated, dried over Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; petroleum ethenethyl acetate; 30:1 ; v/v) to afford teri-butyl 4-[2- fluoro-4-(trifluoromethyl)benzoyl]piperidine-l-carboxylate (180mg) as a white solid. MS m/z (+ESI): 320.1 [M-iBu+H]+.(Step 3) Synthesis of 2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-5-(4-(trifluoromethypplicnyl)-1H-imidazole 3-oxide (Compound 1-5) 1.0 g (4.1 mmol, 1.1 eq) of 1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazole 3-oxide, 0.043 g (0.19 mmol, 5 mol %) of palladium acetate, 0.18 g (0.57 mol, 15 mol %) of tri(p-fluorophenyl)phosphine, 0.11 g (1.1 mmol, 30 mol %) of pivalic acid, and 1.0 g (7.4 mmol, 2.0 eq) of carbonic acid potassium were added to a reactor, followed by replacing the air with argon gas. 14 mol of anhydrous acetonitrile solution of 0.90 g (3.7 mmol, 1.0 eq) of 4-bromo-3-fluorobenzene trifluoride was added to the resulting mixture, followed by stirring over night at 70 C. The resulting reaction liquid was filtered over celite and concentrated under reduced pressure. The obtained crude crystal was washed with diethylether to obtain 1.1 g of the objective compound (yield: 73%). 1H-NMR of the obtained compound is shown below: 1H-NMR (400 MHz, CDCl3): delta 8.21(m, 1H), 7.80(m, 2H), 7.64(m, 111), 7.59(m, 2H), 7.57(m, 1H), 7.47(s, 1H), 3.57(d, 3H).The compound 5 (1 mmol), The compound 4-bromo-3-fluorotrifluorotoluene (1 mmol)Dissolved in NMP (10 mL)CuI (20 mmol%) was added, Pd (PPh3) 2Cl2 (5 mmol%), DIEA (5 mmol).Under nitrogen protection, 60 reaction 12h.TCL monitoring reaction is complete, Extracted three times with ethyl acetate, Combine organic phase, Washed twice with saturated NaCl, Anhydrous Na2SO4 dry.Spin dry, Column chromatography gave compound 7c.tert-Butyllithium (21.8 mL, 1.7M in pentane, 37.0 mmol) was added dropwise to 3.6-Dihydro-2H-pyran-4-boronic acid pinacol ester (5.62 g, 26.75 mmol),

Molecular Weight:243.00
XLogP3:3.6
Hydrogen Bond Acceptor Count:4
Exact Mass:241.93543
Monoisotopic Mass:241.93543
Heavy Atom Count:12
Complexity:156
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes