1-Bromo-4-chloro-2,5-difluorobenzene

Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and t-butyl nitrite (1.56 g, 15.1 mmol) were combined in anhydrous acetonitrile (25 mL). 2. Under nitrogen, (12 g, 52.8 mmol), (2-methoxyphenyl)boronic acid (8.42 g, 55.4 mmol), and potassium carbonate (14.58 g, 106 mmol) were dissolved in a toluene (100 ml)/ water (20 ml) mixture under nitrogen to give a colorless suspension. Tetrakis(triphenylphosphine)palladium(0) (0.544 g, 0.528 mmol) was added to the reaction mixture in one portion. The reaction mixture was degassed and heated to reflux under nitrogen for 16 h. Based on the results of gas chromatography-mass spectroscopy (GCMS) analysis the reaction was not complete. Thus, 7 g more boronic acid, 1 g of K2CO3, and 0.6 g of Pd(PPh3)4 as catalyst was added, and the resulting mixture was degassed and refluxed under nitrogen for 14 h. The reaction mixture was then cooled down and the organic phase was separated, evaporated, and purified by column chromatography on silica gel, eluted with heptanes to yield 4-chloro-2, 5-difluoro-2?-methoxy-1, 1?-biphenyl (11.0 g, 82% yield) as yellow oil.1-Bromo-4-chloro-2, 5-difluoro-benzene (1.0 g, 4.4 mmol, 1.0 eq.) is dissolved in MeOH (10mL) and a solution of sodium methoxide in MeOH (25percent wt, 1.90 mL, 8.8 mmol, 2.0 eq.) is added. The reaction mixture is submitted to microwave irradiation for 50 min at 120°C. The reaction mixture is diluted with water and extracted with DCM. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crystallization upon standing and filtration afford the expected productA mixture of 1 -bromo-4-chloro-2, 5-difluorobenzene (9.00 g, 39.6 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi-1 , 3, 2-dioxaborolane (15.1 g, 59.5 mmol), and potassium acetate (7.8 g, 80 mmol) in 1 , 4-dioxane (80 mL) was degassed via sparging with nitrogen for 2 minutes. [1 , 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(l l) (1 .5 g, 2.0 mmol) was then added, and the reaction mixture was stirred at 100 °C for 18 hours. It was then filtered; the filtrate was concentrated in vacuo and subjected to silica gel chromatography (Gradient: 0percent to 10percent ethyl acetate in petroleum ether), affording the product as a yellow solid. Yield: 6.1 g, 2.2 mmol, 56percent. 1H NMR (400 MHz, CDCI3) delta 7.48 (dd, J=8.8, 4.9 Hz, 1 H), 7.12 (dd, J=8.0, 5.6 Hz, 1 H), 1 .36 (s, 12H).

Molecular Weight:227.43
XLogP3:3.4
Hydrogen Bond Acceptor Count:2
Exact Mass:225.89965
Monoisotopic Mass:225.89965
Heavy Atom Count:10
Complexity:122
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes