4-Fluoronaphthalen-1-ol

Pale Brown Solid

Fluoro-naphthaldehyde 8 (3.1 g, 17.8 mmol) and dichloromethane (80 mL) were added to a 250 mL flask. At 0To this clear solution was added MCPBA (6.7 g, 19.5 mmol, 1.1 equiv). The white was cloudy at 0 & lt; 0 & gt; C under nitrogenThe reaction mixture was stirred and allowed to equilibrate to room temperature overnight. After about 18 hours, the light yellow reaction mixture was added20percent sodium thiosulfate (40 ml) was added and stirred at room temperature for 45 minutes. An additional 20percent sodium thiosulfate (30 mL) was added, And the mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 50 mL)Line extraction. The combined organic layers were washed sequentially with 20percent sodium thiosulfate (2 x 40 mL) and saturated sodium chloride (80 mL)Polyester. This organic layer was concentrated under reduced pressure. The off-white residue was taken up in methanol (50 mL) and tetrahydrofuran (50 mL)And cooled to 0 & lt; 0 & gt; C. To the mixture was added 30 mL of a 3.0 molar solution of potassium hydroxide in methanol. The pale yellow solutionThe liquid turned dark brown while maintaining the temperature below 5 ° C during the addition. The mixture was stirred at 0 ° C for about 30 minutesminute. The pH of the solution was adjusted to 1 with concentrated hydrochloric acid (8.0 mL). The solution turned yellow and was stirred for about 1 hour, thenDiluted with water (50 ml). The mixture was transferred to a separatory funnel. The aqueous solution was extracted with dichloromethane (3 x 80 mL)take. The combined organic layers were washed with water and saturated sodium chloride (180 mL each). The organic layer was dried over sodium sulfateDried, filtered, and concentrated under reduced pressure to give a beige solid. This material was carried out by Biotage chromatographyPurification (gradient elution: 5percent to 50percent dichloromethane / hexane) to give 1.51 g (54percent) of 9 as a tan solidbody.In a 500 mL single-necked flask, 4-fluoronaphthalene-1-boronic acid (21.1 g, 0.111 mol), 20percent aqueous potassium hydroxide (13.1 g, 0.233 mol) and 30percent hydrogen peroxide solution (containing 18.9 g of H2O2, 0.555 mol) were added and reacted at room temperature for 8 h. After completion of the reaction, the mixture was extracted with ether and the aqueous phase was adjusted to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate (150.0 mL x 2). The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 13.3 g of 4-fluoronaphthalen-1-ol solid in a yield of 74.0percent.General procedure: A mixture of phenol (20 mg), F‐TEDA‐BF4 (1.1 equivalents), IL(0‐15 equivalents) and the organic solvent (5 mL) was stirred for 5 h at various temperatures under an argo atmosphere (Tables 1‐5). The mixture was evaporated at a reduced pressure and analysed by 1H, 19F NMR assolution in CDCl3 or CDCl3‐DMSO‐d6. Cl2CHCHCl2 and PhCF3 were used as internal standards for peakintegration.General procedure: A mixture of phenol (20 mg), F‐TEDA‐BF4 (1.1 equivalents), IL(0‐15 equivalents) and the organic solvent (5 mL) was stirred for 5 h at various temperatures under an argo atmosphere (Tables 1‐5). The mixture was evaporated at a reduced pressure and analysed by 1H, 19F NMR assolution in CDCl3 or CDCl3‐DMSO‐d6. Cl2CHCHCl2 and PhCF3 were used as internal standards for peakintegration.General procedure: A mixture of phenol (20 mg), F‐TEDA‐BF4 (1.1 equivalents), IL(0‐15 equivalents) and the organic solvent (5 mL) was stirred for 5 h at various temperatures under an argo atmosphere (Tables 1‐5). The mixture was evaporated at a reduced pressure and analysed by 1H, 19F NMR assolution in CDCl3 or CDCl3‐DMSO‐d6. Cl2CHCHCl2 and PhCF3 were used as internal standards for peakintegration.To a stirred solution of 2.71 g of 1-acetoxy-4-fluoro-naphthalene in 142 ml of degassed methanol was added a solution of 9.2 g of potassium carbonate in 95 ml of degassed water. The mixture was stirred at room temperature for 5 h. The mixture was cooled with ice, acidified to pH1-2 with conc. HCL, extracted with dichloromethane, dried (magnesium sulphate), filtered and concentrated to an orange solid. The material was purified by chromatography on silica gel eluting with DCM/heptanes/toluene to provide 1.98g of 4-fluoro-1-hydroxynaphthalene as a white solid. C10H7FO (162.05), LC/MS (ESI-): 161.01 (M-H)To a stirred solution of (rac)-ethyl 1 -(3-bromopropyl)-12-ethyl-13-fluoro-10-methyl-4, 5, 6, 7, 9, 10- hexahydropyrazolo[4', 3':9, 10][1]oxa[6]azacycloundecino[8, 7, 6-/7/]indole-2-carboxylate (see Intermediate 58, 156 mg, 0.30 mmol, 1.00 eq.) in anhydrous tetrahydrofuran (3.00 ml_, 0.10 M) was added cesium carbonate (583 mg, 1.79 mmol, 6.00 eq.) and 4-fluoronaphthalen-1 -ol (97.2 mg, 0.60 mmol, 2.00 eq.). The resulting suspension was heated at 55 for 20 hours and cooled to room temperature. Celite was added to the resulting suspension, volatiles were removed under reduced pressure, and the residue was loaded onto a silica gel cartridge which was subjected to reverse phase column chromatography (10-100% acetonitrile/water with 0.1 % formic acid gradient) to give the title compound as an orange solid (146 mg). LC-MS (Method 4): R, = 5.60 min; MS (ESIpos): m/z = 602 [M+H]+. 1H-NMR (300 MHz, CHLOROFORM-d) d [ppm]: 8.33 (m, 1H), 8.06 (m, 1H), 7.60 (m, 3H), 7.01 (dd, 1H), 6.87 (t, 1H), 6.63 (dd, 1H), 4.59 (m, 2H), 4.35 (m, 3H), 4.16 (m, 3H), 3.96 (s, 3H), 3.41 (m, 3H), 2.93 (ddd, 1H), 2.33 (m, 4H), 1.34 (m, 7H), 1.01 (t, 3H).To a stirred solution of (rac)-ethyl 1 -(3-bromopropyl)-13-fluoro-10, 12-dimethyl-4, 5, 6, 7, 9, 10- hexahydropyrazolo[4', 3':9, 10][1]oxa[6]azacycloundecino[8, 7, 6-/7/]indole-2-carboxylate (see Intermediate 49, 101 mg, 0.20 mmol, 1.00 eq.) in anhydrous tetrahydrofuran (2.00 ml_, 0.10 M) was added cesium carbonate (390 mg, 1.20 mmol, 6.00 eq.) and 4-fluoronaphthalen-1 -ol (64.8 mg, 0.40 mmol, 2.00 eq.). The resulting suspension was heated at 55 for 20 hours and cooled to room temperature. Celite was added to the resulting suspension, volatiles were removed under reduced pressure, and the residue was loaded onto a silica gel cartridge which was subjected to reverse phase column chromatography (10-100% acetonitrile/water with 0.1 % formic acid gradient) to give the title compound as a tan solid (105 mg). LC-MS (Method 4): R, = 5.40 min; MS (ESIpos): m/z = 588 [M+H]+. 1H-NMR (300 MHz, CHLOROFORM-d) d [ppm]: 8.33 (m, 1H), 8.05 (m, 1H), 7.60 (m, 3H), 7.01 (dd, 1H), 6.88 (t, 1H), 6.63 (dd, 1H), 4.61 (m, 2H), 4.34 (m, 3H), 4.15 (m, 3H), 3.95 (s, 3H), 3.41 (m, 3H), 2.91 (ddd, 1H), 2.32 (m, 2H), 1.99 (d, 4H), 1.34 (m, 7H).To a stirred solution of (rac)-ethyl 1 -(3-bromopropyl)-12-ethyl-13-fluoro-11 -methyl-4, 5, 6, 7, 9, 1 1 - hexahydropyrazolo[4', 3':9, 10][1]oxa[6]azacycloundecino[8, 7, 6-hi]indole-2-carboxylate (see Intermediate 40, 167 mg, 0.32 mmol, 1.00 eq.) in anhydrous tetrahydrofuran (3.20 ml_, 0.10 M) was added cesium carbonate (625 mg, 1.92 mmol, 6.00 eq.) and 4-fluoronaphthalen-1 -ol (104 mg, 0.64 mmol, 2.00 eq.). The resulting suspension was heated at 55 for 2 days and cooled to room temperature. Celite was added to the resulting suspension, volatiles were removed under reduced pressure, and the residue was loaded onto a silica gel cartridge which was subjected Toreverse phase column chromatography (10-100% acetonitrile/water with 0.1 % formic acid gradient) to give the title compound as a brown solid (187 mg). LC-MS (Method 3): Rt = 2.05 min; MS (ESIpos): m/z = 602 [M+H]+. 1H-NMR (300 MHz, CHLOROFORM-d) d [ppm]: 8.34 (m, 1H), 8.06 (m, 1H), 7.58 (m, 3H), 7.01 (dd, 1H), 6.87 (t, 1H), 6.62 (dd, 1H), 4.65 (d, 1H), 4.33 (m, 3H), 4.15 (t, 2H), 4.01 (m, 1H), 3.90 (s, 3H), 3.35 (m, 4H), 2.28 (m, 3H), 1.37 (m, 5H), 1.21 (m, 2H), 0.93 (m, 3H).To a stirred solution of (rac)-ethyl 1 -(3-bromopropyl)-13-fluoro-1 1, 12-dimethyl-4, 5, 6, 7, 9, 1 1 - hexahydropyrazolo[4', 3':9, 10][1]oxa[6]azacycloundecino[8, 7, 6-hi]indole-2-carboxylate (see Intermediate 31, 101 mg, 0.20 mmol, 1.00 eq.) in anhydrous tetrahydrofuran (2.00 ml_, 0.10 M) was added cesium carbonate (390 mg, 1.20 mmol, 6.00 eq.) and 4-fluoronaphthalen-1 -ol (64.8 mg, 0.40 mmol, 2.00 eq.). The resulting suspension was heated at 55 for 19 hours and cooled to room temperature. Celite was added to the resulting suspension, volatiles were removed under reduced pressure, and the residue was loaded onto a silica gel cartridge which was subjected to reverse phase column chromatography (10-100% acetonitrile/water with 0.1 % formic acid gradient) to give the title compound as a tan solid (1 10 mg). LC-MS (Method 4): R, = 5.33 min; MS (ESIpos): m/z = 588 [M+H]+. 1H-NMR (300 MHz, CHLOROFORM-d) d [ppm]: 8.33 (m, 1H), 8.05 (m, 1H), 7.58 (m, 3H), 7.01 (dd, 1H), 6.88 (m, 1H), 6.62 (dd, 1H), 4.66 (d, 1H), 4.34 (m, 4H), 4.15 (t, 2H), 3.99 (ddd, 1H), 3.87 (s, 3H), 3.35 (m, 4H), 2.30 (m, 2H), 1.91 (s, 3H), 1.37 (m, 5H), 1.22 (dd, 2H)

Molecular Weight:162.16
XLogP3:3.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:162.048093005
Monoisotopic Mass:162.048093005
Topological Polar Surface Area:20.2
Heavy Atom Count:12
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes