2,6-DIMETHYL-4-FLUOROBENZOIC ACID

4-Amino-2, 6-dimethyl benzoic acid (200 mg, 1.1 mmol) and NOBF4 (196 mg, 1.7 mmol) were heated in 1, 2-dichlorobenzene at 100 °C for 30 min. The solution was cooled and diluted with MeOH and water. A few pellets (2-3) of KOH were added, and the solution was heated at reflux for 16 h. The solution was concentrated. The residue was partitioned between Et2O and 1 N NaOH. The aqueous layer was extracted with Et2O. The aqueous layer was cooled to 0 °C and acidified with conc. HCl (pH = 1-2). The aqueous layer was extracted with CH2Cl2. The organic layers were dried (Na2SO4). Filtration and concentration gave 58 mg (31 percent) of the acid as a tan solid.0.6 mmol of potassium acetate, 0.3 mmol of 4-fluoro-2-methylbenzoic acid, Palladium acetate 0.03 mmol, peroxydi-tert-butyl ether 0.6 mmol, 0.8 mL of hexafluoroisopropanol was added to a 15 mL reaction tubeThe mixture was placed in an oil bath at 80 C, and reacted in an air atmosphere at a pressure of 1 atm for 24 hours;After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with water.The organic phase was dried over anhydrous Na2SO4, filtered and concentrated.Purification by thin layer chromatography gave 37.8 mg of the desired product as a white solid.The yield was 75%.4-fluoro-2, 6-dimethylbenzoic acid (S6) was prepared using a modified version of a publishedprocedure.5 To an oven-dried 25 mL round bottom flask under argon atmosphere were added 2-bromo-5-fluoro-1, 3-dimethylbenzene (3.07 g, 15.1 mmol, 1 equiv) and dry Et2O (18.0 mL). Theresulting solution was cooled to 0 C and n-butyllithium (1.6 M solution in hexanes, 10.4 mL, 16.6mmol, 1.1 equiv) was added dropwise. The solution was stirred at 0 C for 1 h. The ice bath wasremoved and the reaction vessel was fitted with a balloon of CO2 (equipped with a calcium sulfatedrying tube) and a vent needle. Dry CO2 was then bubbled through the reaction for 1 h. Thereaction was quenched with 2 M HCl. The biphasic mixture was diluted with water and extractedwith 3 x 50 mL portions of Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by trituration with hexanes to give 4-fluoro-2, 6-dimethylbenzoic acid (437 mg, 2.60 mmol, 17% yield) as a white solid. The product was usedin the next step without any further purification.General procedure: To a 250 mL round bottom flask equipped with a stir barwere added 2, 4, 6-trimethylbenzoic acid (6.57 g, 40.0 mmol, 1 equiv), potassium carbonate (8.29g, 60.0 mmol, 1.5 equiv) and DMF (50 mL). Iodomethane (3.00 mL, 48.0 mmol, 1.2 equiv) wasslowly added to the reaction vessel and the resulting suspension was stirred vigorously at roomtemperature for 24 h. The reaction was poured onto 300 mL of H2O and extracted with 3 x 300mL portions of Et2O. The combined organic extracts were washed with 3 x 150 mL portions ofH2O and 2 x 150 mL portions of brine. The organic layer was dried over MgSO4, filtered, andconcentrated to dryness. The residue was purified by passing through a pad of silica eluting with1:1 EtOAc/hexanes to give methyl ester S4 (6.28 g, 35.2 mmol, 88% yield) as a pale yellow oil.Spectral data are in agreement with those previously published.4General procedure: To a flame-dried 250 mL round-bottom flask under argon wereadded 4 (8.02 g, 28.4 mmol, 1 equiv), TMEDA (8.71 mL, 58.2mmol, 2.05 equiv), and anhydrous n-hexane (28 mL). Theresulting solution was cooled in an ice bath and sec-butyllithium(1.4 M solution in cyclohexane, 42.0 mL, 58.2 mmol, 2.05equiv) was added dropwise. The ice bath was removed and thereaction mixture was stirred at room temperature for 4 h. Thereaction was cooled to -78 C and a solution of methyl 2, 4, 6-trimethylbenzoate (5.11 g, 28.7 mmol, 1.01 equiv) in anhydrousn-hexane (28 mL) was added slowly via cannula. After the addition, the mixture was allowed to slowly warm to room temperatureand stirred for 12 h. The reaction was quenched with water(25 mL) and the biphasic mixture was stirred vigorously for 30min. The mixture was diluted with Et2O (100 mL) and the layerswere separated. The organic layer was washed with water(2 × 150 mL) and brine (1 × 150 mL). The organic layer wastransferred to a 250 mL round-bottom flask equipped with astir bar. To the vigorously stirred solution was added conc. HCl(12 mL), resulting in a bright-yellow precipitate. The suspensionwas stirred vigorously for 30 min then diluted with water (150mL). The layers were separated and the organic layer wasextracted with water (3 × 150 mL or until the washings becomecolorless). To the combined aqueous layers was added solidNaBF4 (9.35 g, 85.2 mmol, 3 equiv), resulting in a bright-yellowprecipitate. The resulting suspension was extracted withdichloromethane (3 × 150 mL or until the washings become colorless).To the combined organic layers was added HBF4·Et2Ocomplex (3.46 mL, 28.4 mmol, 1 equiv). The solution wasswirled to achieve homogeneity then washed with water(1 × 100 mL) and aq. NaBF4 (1 M, 1 × 100 mL). The organic layerwas dried over solid NaBF4, filtered, and concentrated to dryness.The residue was purified by trituration with hexanes andfiltered. The solid was rinsed with n-pentane and dried in vacuoto give xanthylium 3 (10.6 g, 21.3 mmol, 75% yield) as a yelloworangesolid.To a so[ution of 169 mg (1.00 mmo[) 4-f[uoro-2, 6-dimethy[benzoic acid and 112 j.iL (1.30 mmo[) oxa[y[ch[oride in 5 mL dry dich[oromethane, a few drops of DMF were added under an argon atmosphere. After stirring for 2 hours at room temperature the reaction mixture was concentrated in vacuo to give 187 mg of the tit[ecompound which was used without further purification.General procedure: A solution of 8-aminoquinoline (0.3950 g, 2.74 mmol) and Et3N (0.42 mL, 3 mmol) in CH2Cl2 (5 mL) was cooled to 0 C, then an acyl chloride (2.74 mmol) was added (the acyl chloride was prepared by reaction of the appropriate carboxylic acid with SOCl2). After addition, the reaction mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was washed with water (1 mL), brine (1.5 mL × 3), and dried over Na2SO4. The solvent was removed and theproduct was obtained by recrystallisation or flash chromatography.

Molecular Weight:168.16
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:168.05865769
Monoisotopic Mass:168.05865769
Topological Polar Surface Area:37.3
Heavy Atom Count:12
Complexity:169
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes