4-HYDROXY-8-BROMOQUINOLINE

Off-white powder

A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2, 2-dimethyl-1, 3-dioxane-4, 6-dione (22.6 g) in 2-propanol (240 ml) was heated to reflux for 1 hour. The reaction solution was cooled to 0° C., and the deposit was then filtrated to obtain a pale yellow solid (35.0 g). A suspension of the obtained pale yellow solid (10.0 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). Phosphorus oxychloride (5.9 ml) was added to 8-bromoquinolin-4(1H)-one (9 g), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-bromo-4-chloroquinoline (8.3 g) as a white solid. [0309] Pd(PPhGeneral procedure: To a stirred solution of 8-iodoquinolin-4(1H)-one (5c) (50.0 mg, 0.184 mmol) in dioxane/H2O (3:1) (0.7 mL) at ca. 20 C was added in sequence powdered K2CO3 (50.8 mg, 0.360 mmol), phenylboronic acid (39.5 mg, 0.276 mmol), and then Pd(dppf)Cl2xCH2Cl2 (1.87 mg, 1.25 mol%). The reaction mixture was then immersed into a preheated oil bath and heated at ca. 89 C (reflux) for 5 min until the iodoquinolinone 5c was consumed (by TLC). The reaction mixture was then allowed to cool to ca. 20 C, diluted (CH2Cl2, 15 mL), dried (Na2SO4), filtered and adsorbed onto silica gel. Dry flash chromatography (THF/EtOAc, 50:50) gave the title compound 6a (37.1 mg, 96%) as colorles scubes, mp (hot-stage) 202.1-203.6 C (PhCl) (lit., 5 203.5-204.5 C); Rf 0.52 (THF/EtOAc, 50:50); lambdamax(CH2Cl2)/nm 239 inf (log epsilon 4.35), 248 inf (4.24), 280 (3.75), 290 (3.86), 314 inf (4, 05), 326 (4.24), 336 (4.25); numax/cm-1 3192brw (N-H), 1620s (C=O), 1557s, 1518s, 1445m, 1344m, 1312w, 1240w, 1200m, 1180s, 1074w, 1049w, 1024w, 916w, 901w, 839w, 799m, 752s, 698s; deltaH (500 MHz, CDCl3) 9.26 (1H, br s, NH), 8.34 (1H, dd, J = 8.0, 1.5 Hz, Ar H), 7.71 (1H, d, J = 7.5 Hz, Ar H), 7.55 (1Eta, dd, J = 7.5, 1.5 Hz, Ar H) 7.53-7.50 (2H, m, Ar H), 7.46-7.44 (3H, m, Ar H), 7.41 (1H, d, J = 8.5 Hz, Ar H), 6.33 (1H, d, J = 7.0 Hz, Ar H); deltaC (125 MHz, CDCl3) 178.3 (s), 138.6 (d), 137.0 (s), 136.2 (s), 132.9 (d), 131.2 (s), 129.5 (d), 129.4 (d), 128.7 (d), 126.1 (s), 125.5 (d), 123.8 (d), 109.5 (d); m/z (MALDI-TOF) 222 (MH+, 100%).General procedure: To a stirred solution of 8-iodoquinolin-4(1H)-one (5c) (50.0 mg, 0.184 mmol) in dioxane/H2O (3:1) (0.7 mL) at ca. 20 C was added in sequence powdered K2CO3 (50.8 mg, 0.360 mmol), phenylboronic acid (39.5 mg, 0.276 mmol), and then Pd(dppf)Cl2xCH2Cl2 (1.87 mg, 1.25 mol%). The reaction mixture was then immersed into a preheated oil bath and heated at ca. 89 C (reflux) for 5 min until the iodoquinolinone 5c was consumed (by TLC). The reaction mixture was then allowed to cool to ca. 20 C, diluted (CH2Cl2, 15 mL), dried (Na2SO4), filtered and adsorbed onto silica gel. Dry flash chromatography (THF/EtOAc, 50:50) gave the title compound 6a (37.1 mg, 96%) as colorles scubes.Step 3: Compound 88-5 (20 g, 89 mmol), compound 88-6 (14.4 g, 98 mmol), Pd(dppf)Cl2 (6.5 g, 8.9 mmol)and Na2CO3 (18.8 g, 178 mmol) were dissolved in DMF (200 mL), and 40 mL H2O was added into the solution. Thereaction system reacted at 90C overnight. After the reaction was complete as monitored by LC-MS, the reaction systemwas poured into 500 mL H2O, filtrated to deliver brown solid (19 g, 87%). MS ESI calcd for C16H10N2O [M+H]+ 247, found 247.

Molecular Weight:224.05
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:222.96328
Monoisotopic Mass:222.96328
Topological Polar Surface Area:29.1
Heavy Atom Count:12
Complexity:227
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes