4-(Morpholinomethyl)phenylboronic acid

A) (4-(morpholino methyl)phenyl)boronic acid [0843] To a mixture of (4-(bromomethyl)phenyl)boronic acid (500 mg) and potassium carbonate (643 mg) in acetonitrile (10 mL) was added morpholine (0.304 mL), and the mixture was stirred at room temperature for 60 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether and ethyl acetate to give the title compound (449 mg). MS(ESI+): [M+H]A) (4-(morpholino methyl)phenyl)boronic acid [0843] To a mixture of (4-(bromomethyl)phenyl)boronic acid (500 mg) and potassium carbonate (643 mg) in acetonitrile (10 mL) was added morpholine (0.304 mL), and the mixture was stirred at room temperature for 60 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether and ethyl acetate to give the title compound (449 mg). MS(ESI+): [M+H]+ 222.1. MS(ESI+), found: 222.2.To a solution of (4-(bromomethyl)phenyl)boronic acid (1 g, 465 mmol), in 2-methyltetrahydrofuran (15 mL) was added morpholine (0.405 g, 4.65 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was filtered on celite, washed with EtOAc (50 mL) and the filtrate was evaported to afford crude (4-(morpholinomethyl)phenyl)boronic acid (1.5g).A mixture of BPBA (2.33mmol, 500mg), morpholine (4.65mmol, 405mg) and K2CO3 (9.31mmol, 1.29g) in 10mL CH3CN was stirred at room temperature for 24h. After completion of the reaction, the solid K2CO3 was filtered out and filtrate was concentrated. The residue was dissolved in DCM (10mL), washed with brine (3×10mL) until neutrality, and then the orange extracts was dried over anhydrous Na2SO4 and concentrated in vacuo to give white solid. Because of the intrinsic tendency to exist as mixtures of oligomeric anhydrides, it was directly used for next step without purification.1 g (4.65 mmol) of 4-(bromomethyl)phenylboronic acid and 490 mg (5.6 mmol) of morpholine was dissolved in dichloromethane (30 mL).940 mg (9.3 mmol) of triethylamine was added dropwise at normal temperature. The reaction was repeated overnight at room temperature. After completion of the reaction, the product was concentrated under reduced pressure to give 4-(morpholin-4-ylmethyl)phenylboronic acid. Go directly to the next step.General procedure: To a 5 mL microwave vial were added the iodotriazole (13a-b, 14a-b, 15a-b, or 16: 0.15 mmol), arylboronic acid (0.45 mmol), Cs2CO3 (0.45 mmol), Pd(dppf)Cl2CH2Cl2 (0.02 mmol), and suspended in DMF (1.4 mL) and H2O (0.1 mL). After purging with N2, the vial was placed into the cavity of the microwave and stirred for 30 min at 100 C. The reaction mixture was then diluted with ethyl acetate and washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was filtered through a silica gel pad to give the crude intermediate. To a solution of the intermediate (0.1 mmol) in dichloromethane (5 mL) was BBr3 (0.3 mL, 1 M in CH2Cl2) was added and stirred at 40 C for 2 h. The reaction was quenched by water and the organic materials were extracted with DCM:MeOH = 4:1. The organic layer was dried over MgSO4, filtered and evaporated under vacuum. The residue was purified by prep HPLC to give the target products.Mix 5-bromo-7-iodobenzo [d] isoxazol-3-amine (500 mg, 1.5 mmol), 4-(morpholinomethyl) phenylboronic acid (326 mg, 1.5 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol) and K2CO3 (622 mg, 4.5 mmol) in a microwave tube, and dioxane (10 mL) and water (5 drops) were added. The reaction mixture was reacted at 80 C for 40 min using a microwave synthesizer.After the reaction solution was extracted with ethyl acetate and water, the organic layer was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain a pure product of compound Z-6-1 (220 mg, yield 38.4%).General procedure: A mixture of compound 67 4 (2mmol), boric acids or borates (2.4mmol), 68 [1, 1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5mol %), and 69 sodium carbonate (6mmol) in 11 1, 4-dioxane (8mL) and 56 water (4mL) was heated under nitrogen conditions (90C, 6h). After cooling to ambient temperature, the reaction mixture was filtered and concentrated. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane three additional times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to provide compounds 5a-q.

Molecular Weight:221.06
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:221.1223235
Monoisotopic Mass:221.1223235
Topological Polar Surface Area:52.9
Heavy Atom Count:16
Complexity:201
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes