4-(Bromomethyl)-1-chloro-2-fluorobenzene

White solid

Step 1: 1.86 g (10 mmol) of fe/7-Butyl piperazine- 1-carboxylate, 2.23 g (10 mmol) of 4- chloro-3-fluorobenzylbromide and 2.78 g (20 mmol) of K2CO3 was solved in 30 mb of ethanol, and heated to reflux for 12 hours. The slurry was concentrated in vacuo, 20 mL of water was added, and it was extracted three times with 20 mL of CH2CI2. The combined organic layers were dried over Na2S04 and concentrated in vacuo to yield 3.28 g (99 %) of fer/-butyl 4-[(3-chloro-4-fluorophenyl) methyl] piperazine-l-carboxyJate.Compound 2-d (552 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at room temperature, zinc powder (390 mg, 6.0 mmol) and To a stirred solution of methyl 3-(phenylsulfonamido)bicyclo[1.1.1]pentane-1-carboxylate (11 , 9.07 g) and General procedure: To a cooled solution of compound 6 (361.0 mg, 1 mmol) in DMF (10 mL) was added NaH (60% in oil, 48.0 mg, 1.2 mmol) carefully. The mixture was stirred at 0 C for 1h. A solution of R1X (X=Cl, Br; 1.2 mmol) in DMF (5 mL) was then added dropwise in the mixture. The mixture was heated to 40 C and stirred for 8-16 h. The reaction mixture was cooled and quenched at 0 C with a saturated NH4Cl aqueous solution. Then mixture was concentrated under vacuum to remove most of the DMF and re-dissolved with CH2Cl2. After filtering, the filtrate was washed with saturated NaCl aqueous solution, dried with MgSO4 and concentrated under vacuum. The crude material was purified by column chromatography (PE/EA) on silica gel to afford compound 6a-6r.To a solution of 4-(bromomethyl)-1 -chloro-2-fluorobenzene (0.500 g, 2.25 mmol), 6-aminopyridin-3-ylboronic acid (0.31 1 g, 2.25 mmol), potassium carbonate (0.621 g, 4.51 mmol) in tetrahydrofuran (8 ml_) and water (2 ml_) was added tetrakis(triphenylphosphine)palladium(0) (0.260 g, 0.225 mmol) under nitrogen. The mixture was heated to 90 C and stirred for 2 h. The volatiles were removed under reduced pressure. Aqueous layer was acidified to pH = 1 -3 with 1 N hydrogen chloride and extracted with ethyl acetate (50 ml_). The aqueous layer was then adjusted to pH = 8-10 with aqueous sodium bicarbonate and extracted with dichloromethane (50 ml_ x 2). The combined dichloromethane layers were dried over sodium sulfate, filtered and concentrated to give 5-(3-chloro-4-fluorobenzyl)pyridin-2-amine as a yellow oil (0.300 g, crude); LCMS (ESI) m/z: 237.1 [M+H]+. Used in the next step without additional purification.

Molecular Weight:223.47
XLogP3:3.2
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:221.92472
Monoisotopic Mass:221.92472
Heavy Atom Count:10
Complexity:110
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes