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Step 2: Preparation of 4-bromo-2-ethylphenylboronic acidTo a solution of <strong>[175278-30-5]4-bromo-2-ethyl-1-iodobenzene</strong> (80 g, 0.25 mol) in tetrahydrofuran (800 ml) at - 75 0C is added n-butyl lithium (1.6 M in hexanes, 188 ml, 0.3 mol) dropwise maintaining the temperature of the reaction mixture below -70 °C. When the addition is complete the mixture is stirred at -75 0C for an additional 30 minutes and then trimethyl borate (153.7 g, 1.48 mol) is added dropwise. After the addition is complete the reaction is stirred at -75 0C for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3 x 500 ml) and the organic fractions are combined, washed with brine, then dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2- ethylphenylboronic acid (26 g) as a white solid.
Step 2: Preparation of 4-bromo-2,6-diethylphenylboronic acidTo a solution of 4-bromo-2,6-diethyl-1-iodobenzene (1O g, 0.029 mol) in tetrahydrofuran (100 ml) at -75 °C is added n-butyl lithium (1.6 M in hexanes, 22.2 ml, 0.035 mol) dropwise maintaining the temperature of the reaction mixture below -70 0C. When the addition is complete the mixture is stirred at -75 °C for an additional 30 minutes and then trimethyl borate (17.98 g, 0.17 mol) is added dropwise. After the addition is complete the reaction is stirred at -75 0C for 1 hour, then allowed to come to room temperature and stirred for 2 hours, followed by cooling in an ice bath and acidification with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3 x 300 ml) and the organic fractions are combined, washed with brine, dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2,6- diethylphenylboronic acid ( 5 g) as a white solid.
With isopropylmagnesium chloride; In tetrahydrofuran; at -15 - 25℃; for 3h;Inert atmosphere;
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Example R: Preparation of 4-bromo-2-ethylbenzaldehydeTo a solution of <strong>[175278-30-5]4-bromo-2-ethyl-1-iodobenzene</strong> (75 g, 0.24 mol) in tetrahydrofuran (375 ml) at - 75 0C is added n-butyl lithium (1.6 M in hexanes, 196 ml, 0.31 mol) dropwise, maintaining the temperature of the reaction mixture below -70 °C. When the addition is complete the mixture is stirred at -75 0C for an additional 30 minutes and then lambda/,lambda/-dimethylformamide (70.7 g, 0.97 mol) is added dropwise. After the addition is complete the reaction is stirred at -75 °C for 2 hours, then allowed to warm to room temperature for 2 hours. The mixture is cooled in an ice bath and acidified with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3 x 500 ml) and the organic fractions are combined, washed with brine, and dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2- ethylbenzaldehyde (48 g) as an oil.
Step 1: Preparation of 4-bromo-2-ethyl-1-iodobenzene <n="166"/>To a stirred mixture of 4-bromo-2-ethylaniline (80 g, 0.4 mol) in distilled water (400 ml) is added concentrated sulphuric acid (80 ml), followed by brief heating to 60 0C for 1 hour until dissolution is complete. The mixture is allowed to cool to room temperature then further cooled to approximately 0 0C in an ice/salt bath. To this slurry is added an aqueous solution of sodium nitrite (28 g, 0.4 mol) in distilled water (140 ml) dropwise over 15 minutes, maintaining the temperature below 5 0C, followed by additional stirring for 30 minutes. The reaction mixture is allowed to come to room temperature and then a solution of aqueous potassium iodide (199 g, 1.2 mol) in distilled water (200 ml) is added dropwise at room temperature. After the addition is complete the solution is briefly heated to 80 0C then allowed to cool to room temperature again. The reaction mixture is extracted with ethyl acetate (1000 ml x 3) and the organic phase is washed with 1M aqueous hydrochloric acid (500 ml) and aqueous sodium thiosulfate (2 x 250 ml). The organic phase is dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethyl-1-iodobenzene (84.6 g) as an orange liquid.
Example 6 : Preparation of 2-r4-(4-chlorophenoxy)-2-ethylphenyl1cvclopentane-1 ,3-dioneStep 1 : Preparation of (4-bromo-2-ethylphenyl)furan-2-yl methanolMagnesium turnings (1.16g, 0.048mol) are stirred under a nitrogen atmopsphere for 30 minutes, followed by dropwise addition of <strong>[175278-30-5]4-bromo-2-ethyl-1-iodobenzene</strong> (15.Og, 0.048mol) as a solution in anhydrous tetrahydrofuran (40ml), until the magnesium is just covered. A crystal of iodine is added and the reaction heated to reflux. After initiation begins external heating is stopped and the remaining aryl halide solution is added at such a rate as to maintain a controlled reflux. Once addition is complete the reaction is heated at reflux for 1 hour and the mixture is then cooled to room temperature. A solution of furan-2-carbaldehyde (4.0ml, 0.048mol) in anhydrous tetrahydrofuran (10ml) is then added dropwise, and the suspension is then stirred at room temperature for 20 hours. The reaction is quenched with saturated ammonium chloride (200ml) and extracted with ethyl acetate (200ml). The organic phase is separated, dried over anhydrous magnesium sulfate then evaporated under reduced pressure. The crude product is purified by flash column chromatography (1 :4 ethyl acetate/hexane eluant) to afford (4-bromo-2-ethyl- phenyl)furan-2-yl methanol as a brown oil.
4-Bromo-2-iodoethyl benzene (50.0 g, 160.8 mmol) is dissolved in anhydrous tetrahydrofuran (250 ml) and cooled to -7O0C under an atmosphere of nitrogen, lsopropylmagnesium chloride (2M solution in THF, 100 ml, 200 mmol) is added dropwise with vigorous stirring over 40 minutes, maintaining the internal temp below -6O0C by external cooling. When the addition is complete, the reaction is stirred at -7O0C for 20 minutes then allowed to warm to room temperature over 1 h 20 minutes. The reaction mixture is then cooled to -7O0C and a solution of 2-furaldehyde (16 ml, 18.6 g, 190 mmol) in tetrahydrofuran (50 ml) is added dropwise over 40 minutes. On completion of the addition, the reaction is allowed to warm to room temperature and stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (-500 ml) is added and the mixture is extracted into ethyl acetate. The organic solutions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is further purified by column chromatography on silica gel to give (5-bromo-2- ethylphenyl)furan-2-ylmethanol (40.7 g).
With copper(l) iodide; tetrabutylammomium bromide; sodium t-butanolate; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Sealed tube; Microwave irradiation;
General procedure: In a conical-bottomed microwave vial, the mixture of 8 mercaptoadenine (0.1 mmol), respective aryl iodide (0.1 mmol), Cul (0.02 mmol), NaO?-Bu (0.3 mmol) and ?-butyl ammonium bromide (0.02 mmol) in DMF (2 mL) was charged. The sealed vial was irradiated in the microwave for 1.5 h at 150 °C. After cooling, the reaction mixture was condensed under reduced pressure and purified by flash chromatography (CH2Cl2:MeOH:AcOH, 20: 1 :0.5). [0216] 8-((4-Bromo-2-ethylphenyl)thio)-9H-purin-6-amine (2a). Obtained by method B as a light yellow solid in 49 percent yield. MS (ESI): m/z 351.8 [M + H]+.
Method 1 : To a solution of <strong>[175278-30-5]4-bromo-2-ethyliodobenzene</strong> (1 .61 mmol, 0.5 g) dissolved in anhydride THF (6 mL) at -785C was added 2.5 M n-butyllithium solution in hexane (1 .9 mmol, 0.77 mL) dropwise. The mixture was stirred 30 min at -78 5C before /V-formylmorpholine (3.69 mmol, 0.37 mL) was added and the reaction stirred at this temperature for 1 h. The reaction was quenched with aqueous 1 N HCI and extracted with EtAcO. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the crude material by flash chromatography on silica gel using an elution of 3percent ethylacetate in hexanes afforded the title compound (21 1 mg, 62percent). 1 H (400 MHz, CDCI3) delta 10.24 (1 H, s), 7.69 (1 H, d, J = 8.4 Hz), 7.51 (1 H, dd, J = 8.4 & 2 Hz), 7.48 (1 H, d, J = 2 Hz), 3.05 (2H, q, J = 7.6 Hz), 1 .28 (3H, t, J = 7.6 Hz). LC-MS: tR = 3.67 [M+H]+= 213/215 (method 3)
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