2,5-Dimethylbromobenzene (CAS: 553-94-6) is a halide compound that serves as a versatile and effective tool for modifying alcohols.
Application In Synthesis of [ 553-94-6 ]
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Tetrahedron, 1980, vol. 36, p. 3535 - 3542
2
[ 553-94-6 ]
[ 7697-27-0 ]
Reference：
[1] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
3
[ 593-53-3 ]
[ 95-46-5 ]
[ 576-22-7 ]
[ 553-94-6 ]
[ 583-70-0 ]
[ 576-23-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 4, p. 775 - 780
4
[ 553-94-6 ]
[ 15540-81-5 ]
Yield
Reaction Conditions
Operation in experiment
36.1%
at 8 - 10℃; for 1.75 h;
Example 4; 4-(2-Fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1- carboxamide; l-Bromo-2,5-dimethyl-4-nitrobenzene; To a slurry of 2-bromo-1,4-dimethylbenzene (10.13 g, 54.7 mmol) in acetic acid (44 mL) at 8 °C (inner temperature) was added a solution of nitric acid (6 mL, 134 mmol) in sulfuric acid (22 mL, 413 mmol) over 45 min; temperature rose to 10 °C. After 1 hr, the reaction mixture was poured into ice and stirred, filtered and washed with water to give a light yellow solid. This was triturated with EtOH (10 mL) to give the desired product (4.550 g, 19.78 mmol, 36.1percent yield) as an off-white solid.
Reference：
[1] Tetrahedron, 1980, vol. 36, p. 3535 - 3542
[2] Patent: WO2011/159857, 2011, A1, . Location in patent: Page/Page column 68
[3] Journal of the Indian Chemical Society, 1935, vol. 12, p. 540
5
[ 75366-05-1 ]
[ 553-94-6 ]
[ 583-70-0 ]
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 23, p. 7076 - 7079
6
[ 593-53-3 ]
[ 95-46-5 ]
[ 576-22-7 ]
[ 553-94-6 ]
[ 583-70-0 ]
[ 576-23-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 4, p. 775 - 780
7
[ 106-42-3 ]
[ 553-94-6 ]
[ 1074-24-4 ]
Reference：
[1] RSC Advances, 2014, vol. 4, # 92, p. 51016 - 51021
[2] Synthetic Communications, 1992, vol. 22, # 8, p. 1095 - 1099
[3] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 23, p. 4397 - 4399
[2] Journal of Organic Chemistry, 1983, vol. 48, # 23, p. 4397 - 4399
14
[ 106-42-3 ]
[ 7553-56-2 ]
[ 553-94-6 ]
[ 1074-24-4 ]
[ 23488-38-2 ]
Reference：
[1] Chemische Berichte, 1885, vol. 18, p. 357
15
[ 553-94-6 ]
[ 1483-47-2 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 52, p. 6872 - 6874
16
[ 553-94-6 ]
[ 586-35-6 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With acetic acid In water at 150℃; for 2 h; Stage #2: With oxygen In water at 180℃; for 4 h;
Example 6; This example illustrates the production of 2- bromoterephthalic acid from 2-bromo-l , 4-dimethylbenzene . In a stirred autoclave with internal cooling coil and reflux condenser, 2-bromo-l, 4-dimethylbenzene (541 mmol) was combined with a solution containing Co (OAc) 2 -4H2O (0.625 mmol), Mn (OAc) 2.bul. 4H2O (0.625 mmol), Zr(OAc)4 (0.15 mmol), and NaBr (0.525 mmol) in 500 g of 97percent acetic acid. The mixture was stirred at a constant rate using a gas dispersing stirrer for better gas mixing and the mixture was heated to 150°C for 2 h followed by increasing the temperature to 180°C for 4 h. While the reaction was heating, air was continuously blown through the system with 400 psig (2.76 MPa) back pressure. After reaction completion, the pressure was released and the reactor was allowed to cool to 50°C. The product was discharged, rinsing the reactor twice with 50 g acetic acid to collect further product. The white solid was <n="18"/>collected via suction filtration, washed with water, and dried under vacuum to yield 113 g (85percent) of the product 2- bromoterephthalic acid as a white solid with a purity of 99percent, as determined by 1H NMR.
51%
With potassium permanganate In water at 70℃; for 12 h;
To a solution of 2-bromo-1 ,4-dimethyl-benzene (20 g, 108.1 mmol) in water (400 ml) was added potassium permanganate (69 g, 432.3 mmol) in portions at ambient temperature. The reaction mass was heated at 70°C for 12 h. The dark coloured reaction mass was cooled to room temperature and acidified to pH 2 using 2N HCI. Aqueous solution extracted with ethyl acetate (3X100 ml). Combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography over silicagel with cyclohexane/ethyl acetate 85:15 to 50:50 as eluent to obtain 2-bromoterephthalic acid (13.5 g, 51 percent of theoretical yield) as a white solid. H NMR (400 MHz, DMSO-c/6) δ ppm 7.80 - 7.84 (m, 2 H) 7.98 (dd, J=7.91 , 1.63 Hz, 2 H) 8.14 (d, J=1 .51 Hz, 2 H) 13.62 (br. s., 2 H) MS [M-H] " : 244.9 (rt 0.87-0.92 min)
47%
Stage #1: With potassium permanganate In water for 6 h; Reflux Stage #2: With hydrogenchloride In water at 0 - 5℃;
Preparation ID) dimethyl 2-amino-5-fluoro-l,4-benzenedicarboxylate; Step 1:; A mixture of 2-bromo-p-xylene (18.5 g, 100 mmole) and KMnO4 (15.8 g; 100 mmole) in water (225 ml) was refluxed for 2 h under stirring. After the disappearance of KMnO4- color, TLC showed the presence of starting material. Additional KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, another lot Of KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, however, the reaction was worked up. The mixture was cooled to RT and filtered. The filtrate was extracted with ethyl acetate (2 X 25 ml). The ethyl acetate layer was dried and evaporated to recover 6.15 g (33percent) of the starting material. The aqueous filtrate was concentrated to half volume on a rotavap. The concentrated aqueous mixture was cooled to 0-50C and acidified to pH 2 with cone. HCl. The precipitated solid was filtered and washed with water and dried to yield 11.39 g (47percent) of 2-bromo terephthalic acid as a colorless solid. 1H NMR in CD3OD-(I4 δ ppm : 7.86 (IH, d, J = 7.8 Hz, Ar-H), 8.05 (IH, dd, J = 8.4 Hz 1.6 Hz, Ar-H), 8.28 (IH, d, J = 1.6 Hz, Ar-H).
Reference：
[1] Patent: WO2008/82501, 2008, A1, . Location in patent: Page/Page column 16-17
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3553 - 3557
[3] Journal of Coordination Chemistry, 2012, vol. 65, # 18, p. 3205 - 3215
[4] CrystEngComm, 2016, vol. 18, # 36, p. 6914 - 6925
[5] Patent: WO2015/97276, 2015, A1, . Location in patent: Page/Page column 46; 47
[6] Patent: WO2010/59549, 2010, A1, . Location in patent: Page/Page column 23-24
[7] Chlorine Alkali News, 1953, # 11, p. 44,48[8] Chem.Abstr., 1955, p. 7523
[9] Journal of Organic Chemistry USSR (English Translation), 1968, vol. 4, p. 1547 - 1550[10] Zhurnal Organicheskoi Khimii, 1968, vol. 4, p. 1609 - 1613
[11] Patent: US1867766, 1928, ,
[12] Tetrahedron, 2009, vol. 65, # 42, p. 8738 - 8744
[13] Polymer, 2016, vol. 87, p. 260 - 267
[14] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5797 - 5801
17
[ 121-43-7 ]
[ 553-94-6 ]
[ 7732-18-5 ]
[ 85199-06-0 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78℃; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
1L round bottom flask, 1-bromo-2,5-dimethylbenzene (25.0g, 0.135mol), into 200mlof tetrahydrofuran was cooled to -78 ° C under a nitrogen atmosphere.To the cooled solution was added dropwise a 1.6M n-butyllithium (101ml, 0.162mol).After 2 hours stirring at the same temperature was added dropwise trimethyl borate(18.2g, 0.176mol).Put the 1 normal hydrochloric acid and then stirred for 1 hour at room temperature thesolution was acidified.The mixture was concentrated under reduced pressure, and recrystallized with nhexaneto give the [intermediate 1-b].(12.5g, 62percent)
Reference：
[1] Patent: KR2015/52989, 2015, A, . Location in patent: Paragraph 0326-0331
18
[ 553-94-6 ]
[ 11113-50-1 ]
[ 85199-06-0 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 16, p. 5343 - 5346
[2] Chemistry - A European Journal, 2018, vol. 24, # 53, p. 14084 - 14087
With N-Bromosuccinimide; In 1,2-dichloro-ethane; at 25℃; for 30h;Sealed tube;
General procedure: NBS (1.0 mmol) and catalyst 1 (0.1 or 1 mol % Au based on the substrate) were weighted into a 10 mL sealed vessel, and then DCE (2 mL) and the substrate (1.0 mmol) were added. The reaction was stirred at the required temperature for the specified time. After reaction, the catalyst was removed with a magnet, and the solution was concentrated under reduced pressure and purified by column chromatography.
With sulfuric acid; nitric acid; acetic acid; at 8 - 10℃; for 1.75h;
Example 4; 4-(2-Fluorophenyl)-7-methyl-6-(pyrimidin-5-yloxy)-9H-pyrido[3,4-b]indole-1- carboxamide; l-Bromo-2,5-dimethyl-4-nitrobenzene; To a slurry of 2-bromo-1,4-dimethylbenzene (10.13 g, 54.7 mmol) in acetic acid (44 mL) at 8 C (inner temperature) was added a solution of nitric acid (6 mL, 134 mmol) in sulfuric acid (22 mL, 413 mmol) over 45 min; temperature rose to 10 C. After 1 hr, the reaction mixture was poured into ice and stirred, filtered and washed with water to give a light yellow solid. This was triturated with EtOH (10 mL) to give the desired product (4.550 g, 19.78 mmol, 36.1% yield) as an off-white solid.
With 2,2'-azobis(isobutyronitrile); oxygen; cobalt(II) diacetate tetrahydrate; acetic acid; sodium bromide; at 130℃; under 9000.9 Torr; for 1.5h;Green chemistry;
2,5-Dimethylbromobenzene 25 g (135.1 mmol, 1.0 eq), AIBN 521 mg (3.2 mmol, 0.024 eq),Co(OAc) 2·4H2O 1.6 g (6.6 mmol, 0.049 eq), NaBr 459 mg (4.5 mmol, 0.033 eq), dissolved in HOAc 250 mL (10V).Stir the whole solution, increase the temperature of the outer bath of the reaction coil to 130 C, adjust the coil pressure to 1.2 MPa with oxygen, and start the materialing. The system residence time is 1.5 h and the oxygen is 3 to 5 eq.The system was directly pumped into 375 mL of purified water, and the pH of the system was adjusted to 12-14 with NaOH solids.The aqueous phase was extracted twice with 125 mL MTBE, and the aqueous phase was adjusted to pH 1 with concentrated HCl.A large amount of solid was precipitated, and 29.8 g of the target product was obtained by filtration, yield 90%.
85%
Example 6; This example illustrates the production of 2- bromoterephthalic acid from 2-bromo-l , 4-dimethylbenzene . In a stirred autoclave with internal cooling coil and reflux condenser, 2-bromo-l, 4-dimethylbenzene (541 mmol) was combined with a solution containing Co (OAc) 2 -4H2O (0.625 mmol), Mn (OAc) 2 ? 4H2O (0.625 mmol), Zr(OAc)4 (0.15 mmol), and NaBr (0.525 mmol) in 500 g of 97% acetic acid. The mixture was stirred at a constant rate using a gas dispersing stirrer for better gas mixing and the mixture was heated to 150C for 2 h followed by increasing the temperature to 180C for 4 h. While the reaction was heating, air was continuously blown through the system with 400 psig (2.76 MPa) back pressure. After reaction completion, the pressure was released and the reactor was allowed to cool to 50C. The product was discharged, rinsing the reactor twice with 50 g acetic acid to collect further product. The white solid was <n="18"/>collected via suction filtration, washed with water, and dried under vacuum to yield 113 g (85%) of the product 2- bromoterephthalic acid as a white solid with a purity of 99%, as determined by 1H NMR.
51%
With potassium permanganate; In water; at 70℃; for 12h;
To a solution of 2-bromo-1 ,4-dimethyl-benzene (20 g, 108.1 mmol) in water (400 ml) was added potassium permanganate (69 g, 432.3 mmol) in portions at ambient temperature. The reaction mass was heated at 70C for 12 h. The dark coloured reaction mass was cooled to room temperature and acidified to pH 2 using 2N HCI. Aqueous solution extracted with ethyl acetate (3X100 ml). Combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography over silicagel with cyclohexane/ethyl acetate 85:15 to 50:50 as eluent to obtain 2-bromoterephthalic acid (13.5 g, 51 % of theoretical yield) as a white solid. H NMR (400 MHz, DMSO-c/6) delta ppm 7.80 - 7.84 (m, 2 H) 7.98 (dd, J=7.91 , 1.63 Hz, 2 H) 8.14 (d, J=1 .51 Hz, 2 H) 13.62 (br. s., 2 H) MS [M-H] " : 244.9 (rt 0.87-0.92 min)
47%
Preparation ID) dimethyl 2-amino-5-fluoro-l,4-benzenedicarboxylate; Step 1:; A mixture of 2-bromo-p-xylene (18.5 g, 100 mmole) and KMnO4 (15.8 g; 100 mmole) in water (225 ml) was refluxed for 2 h under stirring. After the disappearance of KMnO4- color, TLC showed the presence of starting material. Additional KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, another lot Of KMnO4 (15.8 g; 100 mmole) was added and refluxing continued for 2 h. TLC showed the presence of starting material, however, the reaction was worked up. The mixture was cooled to RT and filtered. The filtrate was extracted with ethyl acetate (2 X 25 ml). The ethyl acetate layer was dried and evaporated to recover 6.15 g (33%) of the starting material. The aqueous filtrate was concentrated to half volume on a rotavap. The concentrated aqueous mixture was cooled to 0-50C and acidified to pH 2 with cone. HCl. The precipitated solid was filtered and washed with water and dried to yield 11.39 g (47%) of 2-bromo terephthalic acid as a colorless solid. 1H NMR in CD3OD-(I4 delta ppm : 7.86 (IH, d, J = 7.8 Hz, Ar-H), 8.05 (IH, dd, J = 8.4 Hz & 1.6 Hz, Ar-H), 8.28 (IH, d, J = 1.6 Hz, Ar-H).
41.7%
With potassium permanganate; In water;Reflux;
To a 2.5 L round-bottom flask were added 2-bromo-p-xylene (55.5 g, 0.3 mol), 1.2 L water, and KMnO4 (94.8 g, 0.6 mol). The mixture was refluxed slowly until the color faded. Then a second KMnO4 (47.4 g, 0.3 mol) was added. After the color faded, a third KMnO4 (47.4 g, 0.3 mol) was added. The reaction was stopped when the solution was colorless again. The mixture was filtered to remove the insoluble salt. The collected filtrates was acidified to pH 3 ~ 4 by HCl when large amount of white solid precipitated from the solution. The crude product was collected by filtration and washed with water, then dried under vacuum to yield 30.6g of 2-bromoterephthalic acid (yield 41.7%).1H NMR (400MHz, DMSO-d6, delta, ppm): 8.15 (d, J = 1.4 Hz, ArH ortho to Br,1H), 7.99 (dd, J = 8.0, 1.5 Hz, ArH meta to Br,1H), 7.84 (d, J = 8.0 Hz, ArH para to Br,1H).
Stage #1: 4-bromo-m-xylene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: With phosphorus trichloride In tetrahydrofuran at -78 - 23℃; for 18h;
In a 250mL dry four-neck flask, evacuate and replace the system three times with nitrogen, and then add 60mL of anhydrous ether, 3.77g of magnesium filings (molecular weight 24.3, 155.20mmol, 1.2eq) and a small iodine (15mg) under nitrogen protection. ), Raise the temperature to 60 C, and slowly add about one-fifth of a solution of 2,5-dimethylbromobenzyl ether [25.75g of 2,5-dimethylbromobenzyl (molecular weight 199.09, 129.33mmol) , 1eq) dissolved in 30mL of ether], the temperature did not increase significantly, stirred at this temperature for about 30 minutes, at this time observed the temperature rose significantly, reached a reflux state, at the same time the yellow in the solution faded and turned off-white. The remaining 2,5-dimethylbromobenzyl ether solution was slowly added dropwise, and the drop was completed in about 40 minutes. After dripping and holding for 1 hour, it was observed that the magnesium dust in the reaction solution had basically disappeared. The temperature of the reaction solution was lowered to 0 C, and 46.04 g of ethylene oxide (molecular weight 44.05, 1034.6 mmol, 8.0 eq) was slowly added. After the addition, the temperature was maintained at about 0 C and stirring was continued for 3 hours. 70 mL of saturated ammonium chloride solution was added to extract the reaction. After the tetrahydrofuran was distilled off under negative pressure, the aqueous phase was extracted three times with 40 mL of dichloromethane. The dichloromethane phases were combined and the dichloromethane was evaporated to dryness under negative pressure to obtain 18.87 g (molecular weight 150.22, theoretically obtained). 19.43 g) a white solid. The purity was 97.5%, which was 2,5-dimethylphenylethanol, and the mass yield was 94.69%.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;
The procedure of Katz33 was repeatedusing 7.37 g (39.8 mmol) of <strong>[553-94-6]2-bromo-p-xylene</strong>(3), 15.6 g (87.6 mmol,1.1 eq) of recrystallized34N-bromosuccinimide, and 25 mg of 2,2?-azobis(2-methylpropionitrile) in 100 mLof CCl4 to afford a yellow solid that was crystallized from 1:50 diethyl ether-hexane to afford 6.5 g (47%) of 1,4-bis(bromomethyl)-2-bromobenzenethat was sufficiently pure to be used directly in the next reaction. The procedure of Zhuang22 was repeated using 6.5 g (18.9 mmol) of 1,4-bis(bromomethyl)-2-bromobenzene and 6.6 mL (37.9 mmol, 1 eq) of triethylphosphite to afford 7.6 g (88%) of tetraethyl(2-bromo-1,4-phenylene)bis(methylene)diphosphonate that was sufficiently pure to be used directly in the next reaction.The procedure of Zhuang22 was repeated using 4.6 g (23.7mmol) of 3-carbomethoxy-4-methoxybenzaldehyde, 5.4 g (11.9 mmol, 1 eq) of tetraethyl (2-bromo-1,4-phenylene)bis(methylene)diphosphonate and 30 mL of 3.2 M sodium methoxide to afford 3.02 g (47%) of 4 as a yellow solid
With chlorosulfonic acid In chloroform at 0 - 20℃; for 4.5h;
With chlorosulfonic acid
With chlorosulfonic acid at 10℃; for 0.416667h;
2.A
To chlorosulfonic acid (4.2 mL, 63 mmol) cooled to 10 0C was added 2-bromo-/?- xylene (5.0 g, 27 mmol) dropwise over 15 min. The reaction mixture was stirred further for 10 min, and then poured with stirring onto 125 mL of crushed ice to precipitate a white solid. The solid was isolated by filtration and washed with water. The solid was dissolved in tetrahydrofuran (40 mL) and an aqueous 30% ammonium hydroxide solution (8.0 mL) was added. The reaction mixture was stirred for 10 min and concentrated under reduced pressure to precipitate a white solid. The solid was isolated by filtration and washed with water to afford 4.6 g of the title compound as a solid. 1H NMR (CDCl3) δ 7.87 (s, IH), 7.52 (s, IH), 4.75 (br s, 2H), 2.61 (s, 3H), 2.41 (s, 3H).
1.3 g
With chlorosulfonic acid In tetrahydrofuran; 1,4-dioxane at 0 - 80℃; for 3.41667h;
1-(4-bromo-2,5-dimethyl-phenyl)-ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With aluminum (III) chloride; In dichloromethane; at 20℃; for 16h;Cooling with ice;
Add 15 mL of solvent dichloromethane to a 100 mL round bottom flask and weigh 3.0 g (16.21 mmol)2,5-Dimethylbromobenzene was added to a round bottom flask containing dichloromethane to make them mutually soluble, put into a stir bar, and stirred under ice water bath; 10 mL of dichloromethane was added to a 100 mL beaker, and 3.240 g was quickly weighed. (24.32 mmol) anhydrous aluminum chloride powder was added to a beaker containing dichloromethane, 2.36 g (27.56 mmol) of acetyl chloride was weighed into a beaker, and stirred with a glass rod to completely dissolve anhydrous aluminum trichloride. After dissolving, it was transferred to a constant pressure funnel, and then slowly and continuously added dropwise to the above 2,5-dimethylbromobenzene solution, and the reaction was stirred under an ice water bath condition; after the dropwise addition, the ice water bath was stirred for 1 hour, and the ice water bath was removed. The reaction was stirred at room temperature for 15 h; after the reaction was over, the burgundy solution obtained by the reaction was slowly added to a beaker containing 300 mL of cold water, and continuously stirred with a glass rod until the solution turned from burgundy to yellowish, and after cooling, Dichloromethane extraction (extraction 2 times, once with 100 mL), the lower layer of methylene chloride was retained, poured into a 500 mL beaker, dried over anhydrous sodium sulfate for 5 h, dried and filtered, and then evaporated. The solvent is removed, and the crude product is added. 100mL round bottom flask was added n-hexaneRecrystallization. The crude product was crystallized to give 2.76 g of white crystals, yield 75%.
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; at 110℃; for 4h;Inert atmosphere;
1.84 g of 2,5-dimethylbromobenzene, 1.07 g of p-toluidine, 3. lg of sodium t-butoxide,Add to a 100ml three-necked flask and dissolve in 30ml of toluene solution.Then, under nitrogen, 0. lg pd2 (dba) 3, 0.67 g of 10% tri-tert-butylphosphine, heated at 110 C, stirred for 4 hours, the reaction was completed, and 25 ml of toluene, 25 ml of water were added.Dispensing, the organic phase column is added to the silica gel to spin dry,Column chromatography (solvent ethyl acetate / petroleum ether = 1:20), spin dry the column,1.4 g of white intermediate A3-1 was obtained in a yield of 67%.
AICI3 (9.0 g, 60 mmol) was added to a 250 ml Schlenk containing a stirring bar. Dried and degassed dichloromethane (80 ml) was added. A solution of 3-chloropropionyl chloride (7.3 ml, 76 mmol) in 10 ml of dichloromethane was added dropwise to the yellow slurry and stirred 15 min to obtain a dark brown solution. A solution of 2,5-dimethylbromobenzene (8.6 ml, 62 mmol) in 10 ml of dichloromethane was added dropwise to the brown solution and the mixture was stirred 20 h at room temperature, until no HCI overpressure was observed. The brown mixture was poured onto ice and extracted with dichloromethane (3 x 120 ml). The organic phase was washed with aqueous NaHCC>3 and brine and dried over Na2S04. Volatiles were pumped off to give 3-chloro-1 -(4-bromo-3,5-dimethyl)propanone as a white solid (17.3 g, 99%). This solid was used without further purification.1H NMR (300 MHz, Chloroform-d) o 7.49 (s, 1 H, 3'a), 7.44 (s, 1 H, 6'a), 3.88 (t, J = 6.6 Hz, 2H,2a, 2b), 3.34 (t, J = 6.6 Hz, 2H, 3a, 3b), 2.44 (s, 3H, 5'Me), 2.40 (s, 3H, 2'Me)
61%
With aluminum (III) chloride; In carbon disulfide; at 0℃; for 1h;Reflux;
AlCl3 (2.60 g, 19.5 mmol) was added to a magnetically stirred solution of 2-bromo-1,4-dimethylbenzene (1 mL, 7.2 mmol) and beta-chloro-propionyl chloride (0.92 mL, 9.6 mmol) in CS2 (7 mL) at 0 C over a period of 30 min. The reaction mixture was heated under reflux for a further 30 min. The resulting dark-brown solution was cooled at room temperature and carefully poured onto ice and was extracted with CH2Cl2 (20 mL), washed with water (2 × 10 mL), dried over anhydrous Na2SO4, and evaporated in vacuo. Yield: 1.22 g, 61%, mp: 82-83 C (mp lit.17 84-85 C). 1H NMR (CDCl3) delta ppm: 2.40 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.34 (t, J = 6.5 Hz, 2H, CH2), 3.87 (t, J = 6.5 Hz, 2H, CH2), 7.44 (s, 1H, H-Ar), 7.49 (s, 1H, H-Ar).
With [Pd2{(C,N)-C6H4CH2NH(Et)}2(mu-1,2-bis(diphenylphosphino)ethane)(Cl)2]; sodium carbonate; In methanol; at 85℃; for 2h;
General procedure: A round-bottom flask was charged with aryl halide (0.5 mmol), phenylboronic acid (0.75 mmol), base (1.5 mmol), catalyst (0.01 mmol), and solvent (7 mL). The mixture was heated for the time and at the temperature given in figures and tables in section 3.3, using the base and catalyst therein indicated. The products were characterized by GC.
91.1%
With C36H33N2O5PPd; sodium carbonate; In methanol; at 85℃; for 2h;
General procedure: A round bottom flask was charged with the aryl halide (0.5mmol), phenylboronic acid (0.75mmol), base (1.5 or 3mmol), catalyst (0.01mmol) and solvent (7mL), although the amount of the reagents and catalysts was diminished to half when catalysts 2-4 were utilized. The mixtures were heated for the times 2, 4, 8 and 24h and at the temperatures 85 and 100C given in the tables using the bases and catalysts there indicated. The products were characterized by GC.
90%
With potassium phosphate; tetraphosphine N,N,N?,N?-tetra(diphenylphosphinomethyl)-pyridine-2,6-diamine; palladium dichloride; In o-xylene; at 90℃; for 6h;Inert atmosphere; Schlenk technique;
K3PO4 (212 mg, 1 mmol),aryl halides (0.5mmol) and phenylboronicacid (0.75 mmol) were added successively into a dried Schlenk tubewith a magnetic bar under nitrogen. Then a N,N-dimethylacetamide (DMA 0.05 mL) solution of tetraphosphine TPPDA (0.0005 mmol) andPdCl2 (0.0005 mmol), which was reacted at 100 C for 1 h prior to use,was added into the mixture. Afterwards, o-xylene (3 ml) was addedwith syringe. After being stirred for the required time in the preset con-ditions, the reaction mixture was cooled to room temperature. The mix-ture solution was extracted with ethyl acetate (3 5 mL). Combinedorganic phase was washed with brine (3 5 mL) and dried over anhy-drous MgSO4. The dried solution was ltered and puried by silica gelchromatography (petroleum ether 60-90 C) to give a correspondingproduct. Reaction condition: aryl halides 0.5 mmol, phenylboronic acid 0.75 mmol, K3PO4 1.0mmol, o-xylene 3 mL, catalyst PdCl2/TPPDA = 1/1, 90 C, under nitrogen, GC yields.
88%
With C14H19NO3*C6H15N; potassium hydroxide; palladium dichloride; In ethanol; water; at 80℃; for 2h;Green chemistry;
General procedure: In the first step,reference solution (CPd=0.5×10-4mmol/mL,CLigand=1.0×10-4mmol/mL) was prepared. A single-neckedground tube (rinner=1.1 cm, L=17.5 cm) was equipped with a magnetic stirbar. 0.5 mmol of aryl halides, 0.75 mmol of phenyl boronic acid and 1 mmol basewere added into the tube under atmospheric condition. Then, appropriate amountof reference solution and solventwere added into the tube. The reaction mixture was stirredat the pre-arranged temperature for appropriate reaction time in oil bath. Afterthe reaction was completed, 3 mL water was added, and the mixture was extractedwith EtOAc(10 mL×4). Then the organic phase was dried with Na2SO4and concentrated under reduced pressure. The residue was then purified by columnchromatography on silica gel. The pure product was obtained and was analyzed by1H NMR spectroscopy.
80%
With Pd(memantine)2Cl2; sodium hydroxide; In ethanol; at 80℃; for 24h;
General procedure: In the reaction tube with a magnetic bar was added the solution of aryl bromides (0.5 mmol) and phenylboronic acid (91 mg, 0.75 mmol), NaOH (24 mg, 0.6 mmol), complex 1 (0.0001-0.02 mol%, dissolved in DMA) and ethanol (3 mL). After stirred for the required time in the preset conditions, the reaction mixture was cooled to room temperature, and then quenched by 1 mL brine and 3 mL water, and extracted with ethyl acetate (3×5 mL). The combined organic layer was dried over anhydrous MgSO4 and the filtrate was concentrated to dryness under reduced pressure. The crude products were purified by column chromatography (petroleum ether, ethyl acetate) on silica gel.
66%Chromat.
With [Pd(triphenylphosphine)(Cl){P(OPh)2(OC6H4)}]; potassium hydroxide; In tetrahydrofuran; water; at 20℃; for 1h;
General procedure: In this context complex 2a was used as a catalyst for the Suzuki cross-coupling reaction. A 25ml round-bottom flask was charged with the appropriate aryl halide (0.50mmol), phenylboronic acid (0.55mmol), base (1.00mmol), and THF/H2O (6ml of a 2:1v/v mixture). The catalyst (0.005mmol) was then added to the solution and the mixture was stirred at room temperature for 1h. Different aryl halides were employed in the Suzuki cross-coupling reaction with phenylboronic acid and the coupling products are listed in Table 4. Gas chromatographic (GC) analyses were performed using an Agilent Technologies 6890N chromatograph equipped with a flame ionization detector (FID) and an HB-50+ column (length=30m, inner diameter=320mum, and film thickness=0.25mum). The temperature program for the GC analysis was from 70 to 200C at 20C/min, held at 200C for 0min, heated from 200 to 280C at 10C/min and held at 280C for 1min. The inlet and detector temperatures were set at 260 and 280C, respectively. Products were identified by comparison with authentic samples.
With potassium hydroxide; In water; isopropyl alcohol; at 80℃; for 6h;Schlenk technique; Green chemistry;
General procedure: Suzuki-Miyaura reactions were performed in a Schlenk tube. Weighed amounts of the solid reactants: phenylboronic acids (1.1 mmol), base (2. mmol), catalyst (20.00 mg), aryl bromide (1 mmol), and 5 mL of the solvent (2-propanol/water mixture) were introduced to the Schlenk tube. Next, the Schlenk tube was sealed with a rubber septum and introduced into an oil bath pre-heated to 80C. The reaction mixture was magnetically stirred at a given temperature for 6 h and, after that time, left for several min-utes to cool down. Next, the organic products were separated by extraction with 10 mL of diethyl ether. The extracts (10 mL) were GC-FID analyzed with dodecane (0.050 mL) as an internal standard to determine the conversion of aryl bromide. The products of the reaction were determined by GC-MS.
With C28H44Cl2N4O2Pd; potassium hydroxide; In water; isopropyl alcohol; at 60℃; for 3h;Schlenk technique; Sealed tube;
General procedure: The Suzuki-Miyaura reactions were carried out in a Schlenk tube. Weighed amounts of the solid reactants: phenylboronic acid (135 mg; 1.1 mmol), KOH (112.0 mg; 2.0 mmol), catalyst (20.0 mg), 2-Br-toluene (0.118 mL; 1 mmol) and 5 mL of solvent (2-propanol/water mixture) were introduced to the Schlenk tube. Next, the Schlenk tube was sealed with a rubber septum and introduced into an oil bath preheated to 80 C. The reaction mixture was magnetically stirred at the given temperature for 6 h and after this time left for several minutes to cool down. Next, the organic products were separated by extraction with 10 mL of DEE. The extracts (10 mL) were GC-FID analyzed with dodecane (0.050 mL) as an internal standard to determine the conversion of aryl bromide.The products of the reaction were determined by GC-MS.
55%Chromat.
With C33H42Br3N2Pd(1-)*C33H43N2(1+); potassium carbonate; In water; isopropyl alcohol; at 20℃; for 12h;
General procedure: In a typical run, in the air atmosphere, a reaction tube was charged with aryl halide (1.0 mmol), phenylboronic acid (1.0 mmol), ionic Pd-NHC complex (0.001 mmol), and K2 CO3 (1 mmol). Solvent (2-propanol/H2 O, 1:2 v/v) (3 mL) was added to tube and the mixture was vigorously stirred at room temperature for a specific time. After the desired reaction time, 5 mL of diethyl ether was added to the reaction mixture, and the organic phase was extracted with the appropriate volume of water and dried over MgSO4 . Next, the organic phase (1 L ) was injected to GC. The reactions were monitored with a Shimadzu GC-2010 Plus (FID) (Kyoto, Japan). The results were the average of the 2 runs. The yields were determined by GC with use of undecane as the internal standard. All of the coupling products were previously reported. The turn over frequency (TOF) was calculated using the following equations: TOF = TON/time of reaction and TON = moles of desired product formed/moles of the catalyst.
Stage #1: 4-bromo-m-xylene With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 2h;
Stage #2: 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran; hexane at -78 - 20℃; for 24h;
74%
Stage #1: 4-bromo-m-xylene With n-butyllithium In tetrahydrofuran; hexane at -78 - -10℃;
Stage #2: 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran; hexane at -78 - 20℃; Further stages.;
Stage #1: 4-bromo-m-xylene With n-butyllithium In tetrahydrofuran
Stage #2: 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Stage #1: formaldehyd; 4-bromo-m-xylene With phosphoric acid; hydrogen bromide; acetic acid for 30h; Heating;
Stage #2: With 2-nitropropane; sodium ethanolate In ethanol for 70h; Further stages.;
Stage #1: 4-bromo-m-xylene; sodium cyanide With potassium iodide; N,N`-dimethylethylenediamine In toluene at 110℃; for 24h;
Stage #2: With ammonia In water; ethyl acetate; toluene at 25℃; for 0.166667h;
20 Example 20; [2, 5-DIMETHYLBENZONITRILE]; [FROM 2-BROMO-1, 4-DINZETHYLBENZENE]
An oven dried screw cap test tube was charged [WITH NACN] (93 mg, [1.] [898] mmol), dried KI (52 mg, 0.313 mmol, 20 mol%) and Cul (30 mg, 0.158 mmol, 10 mol%), evacuated and backfilled with argon three times. [2-BROMO-1,] 4-dimethylbenzene (215 [L,] 1.557 [RNMOL), N, N'-DIMETHYLETHYLENEDIAMINE (165, UL,] 1.549 mmol) and anhydrous toluene (1 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110 [°C] for 24 h. The resulting yellow suspension was cooled to room temperature, 2 [ML] of ethyl acetate, [1] mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at [25 °C] for 10 min, then the organic layer was washed with 1 [ML] of water and dried over [MGS04.] The GC analysis showed consumption of the majority of the starting material, and formation of the title compound (as confirmed by GC- MS).
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
EXAMPLE 36 Synthesis of 2,5-dimethylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), phenylboronic acid (183 mg. 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-bromo-p-xylene (0.138 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 149 mg (82percent) of the title compound.
149 mg (82%)
With potassium fluoride;palladium diacetate; In tetrahydrofuran;
Example 36 Synthesis of 2,5-dimethylbiphenyl An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol percent), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol percent), phenylboronic acid (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-bromo-p-xylene (0.138 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 149 mg (82percent) of the title compound.
With potassium carbonate;Pd(PPh3)4; In water; argon; toluene;
EXAMPLE V1 Synthesis of 2,5-Dimethyl-4'-hexyloxybiphenyl Bromo-p-xylene (8.3 g, 45 mmol) (cf. A1 a)), K2CO3 (12.4 g, 90 mmol), 70 ml of toluene and 70 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. <strong>[121219-08-7]4-hexyloxyphenylboronic acid</strong> (10 g, 45 mmol) and Pd(PPh3)4 (0.65 g, 0.56 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas for about 20 hours at an internal temperature of 85 C. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The crude product was purified by distillation under reduced pressure: the product was obtained as a yellow oil (boiling point: 117-125 C./0.08 mbar): 10.3 g (81%). Purity >95% (1H-NMR). 1H NMR (400 MHz; CDCl3): delta [ppm]=7.22, 6.92 (AA'BB'; 4 H; H-phenyl), 7.13 (d; 1 H; J=8.2 Hz; H-6), 7.04 (m; 2 H; H-3, H-5), 3.99 (t; 2 H; J=7.2 Hz; O-CH2), 2.33, 2.23 (each: s; 3 H; aryl-Me), 1.80 (quint; 2 H; J=7.0 Hz; O-CH2-CH2), 1.50-1.34 (m; 6 H; H-alkyl), 0.92 (m; 3 H; CH3).
General procedure: To a flask containing Mg turnings (0.28 g, 14 mmol) was added p-bromotoluene (1.38 g, 8.0 mmol) in THF (8 mL) at room temperature. After being stirred for 2 h, DMF (1.3 mL, 12 mmol) was added to the reaction mixture. The obtained mixture was stirred for 2 h at room temperature. Then, aq NH3 (7 mL, 28-30%) and I2 (4.06 g, 1.6 mmol) were added to the reaction mixture. After being stirred overnight, the reaction mixture was poured into aq sat. Na2SO3 solution and extracted with CHCl3 (3 × 30 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue was purified by short column chromatography on silica gel (eluent: hexane / ethyl acetate = 9:1, v/v) to provide pure p-tolunitrile (0.77 g) in 67% yield. Most aromatic nitriles mentioned in this work are commercially available and were identified by comparison with the authentic samples.
64%
General procedure: n-Butyllithium (1.67 M solution in hexane, 3.3 mL, 5.5 mmol) was added dropwise to a solution of p-bromotoluene (0.86 g, 5.0 mmol) in THF (5 mL) at -70 C. After 30 min, the resulting mixture was stirred for 5 min at 0 C and then DMF (4.25 mL, 5.5 mmol) was added and the obtained mixture was stirred at 0 C. After 1 h at the same temperature, aq NH3 (10 mL, 150 mmol) and DIH (1.14 g, 3.0 mmol) were added and the resulting mixture was stirred for 2 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (15 mL) and extracted with ether (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide 4-methylbenzonitrile in over 75% purity. The product was purified by a column chromatography on silica gel (Hexane/EtOAc=9:1) to give pure 4-methylbenzonitrile in 75% yield as a colorless solid.
With C15H11ClN4SZn; p-benzoquinone In <i>tert</i>-butyl alcohol for 8h;
2.5. Photo-oxidation of methyl arenes
25 mg of photo-catalyst was placed in 10 mmol of methyl arene in a10 mL cylindrical quartz glass reactor. Then 25 mg of superoxide orhydroxyl radical scavengers(benzoquinone (BQ) / t-butyl alcohol (TB))was added [22]. The photo-oxidation experiments were carried outunder visible light (300 Watts Tungsten lamp) for 8 h [13]. The reactionmixture was monitored with TLC. After completion of reaction, thephoto-catalyst was filtered and washed with distilled water andextracted by using ethyl acetate. The crude products were purified bysimple filter column to yield pure aldehydes (Scheme 2) with 70 to 85%yields.
80.1%
Stage #1: 4-bromo-m-xylene With chromium(VI) oxide; sulfuric acid; acetic anhydride; acetic acid at 6 - 12℃; for 1.5h;
Stage #2: With sulfuric acid In ethanol; water for 1.5h; Reflux;
2-Bromoterephthalaldehyde (1b).
A 200-mL three-necked flask equipped with a refluxed condenser,mechanical stirrer, and thermometer, was charged with3.7 g (0.02 mol) of 2-bromoxylene, 60 mL (0.95 mol)of glacial acetic acid, and 56.5 mL (0.1 mol) of aceticanhydride, and 8.5 mL (0.15 mol) of sulfuric acid wasadded in small portions with continuous stirring andcooling, maintaining the temperature at 6-12°C.Chromium(VI) oxide, 10 g (0.1 mol), was then addedin portions at 5-10°C, and the mixture was stirred for1.5 h at 6-12°C. The mixture was then poured into icewater and left to stand at room temperature for 24 h,and the precipitate was filtered off, dried in air, andrecrystallized from ethanol.A 250-mL round-bottom flask equipped with a refluxcondenser was charged with 6.26 g (0.015 mol) ofthe corresponding acetoxy derivative, 60 mL of ethanol, 60 mL of water, and 8 mL of concentratedsulfuric acid. The mixture was refluxed for 1.5 h,cooled to room temperature, and diluted with 200 mLof water. The light yellow solid was filtered off andpurified by recrystallization from chloroform-petroleumether.2-Bromoterephthalaldehyde (1b). Yield 2.56 g(80.1%). mp 75-78°C. IR spectrum, ν, cm-1: 1696 s(C=O), 1199 m, 817 m, 694 m. 1H NMR spectrum(CDCl3), δ, ppm: 7.72-7.81 m (2H), 8.15 d.d (1H, J =1.8, 0.4 Hz), 10.33 s (1H), 10.37 s (1H). 13C NMRspectrum (CDCl3), δC, ppm: 125.3, 126.1, 130.5, 131.7,135.4, 137.6, 189.5, 190.2 (S=O). Found, %: C 45.18;H 2.36. C8H5BrO2. Calculated, %: C 45.11; H 2.37.
38%
Stage #1: 4-bromo-m-xylene With chromium(VI) oxide; sulfuric acid In acetic anhydride; acetic acid at 5℃; for 5h;
Stage #2: With water Reflux;
With chromium(VI) oxide; sulfuric acid; acetic anhydride; acetic acid at 0 - 5℃; for 5h;
6.1 Step 1
After dissolving 2-bromo-1,4-dimethylbenzene (10 g, 54 mmol) in acetic acid (65 mL) and acetic anhydride (130 mL) at 0-5 ° C, sulfuric acid (48 mL) Chromium trioxide (17.29 g, 172 mmol) was added to the mixture while maintaining the temperature.After 5 hours' reaction, the green mixture was poured into ice water (1000 mL), extracted with chloroform, and the organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.Distilled water (70 mL), ethanol (70 mL) and sulfuric acid (7 mL) were then added to the mixture and heated for 5 hours.The mixture was cooled to room temperature, distilled water (500 mL) was added, the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and purified by silica gel chromatography (SiO2, n-hexane: ethyl acetate = 4: 1) The product was obtained.
Multi-step reaction with 2 steps
1: sulfuric acid; acetic anhydride; chromium(VI) oxide; acetic acid / 1.5 h / 6 - 12 °C
2: sulfuric acid; water / ethanol / 1.5 h / Reflux
2.1 g
With chromium(VI) oxide; sulfuric acid; acetic anhydride; acetic acid at 0℃; for 12h;
With dichloro[1-(2,4,6-trimethylbenzyl)-3-(4-adamantylbenzyl)-5,6-dimethylbenzimidazole-2-ylidene]triphenylphosphine palladium(II); potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 3h;Schlenk technique;
General procedure: Aryl bromide (1mmol), palladium catalyst (1mol%), t-KOBu (1mmol) and DMF (4ml) were added under air to a Schlenck tube containing a stirring bar, followed by (1.5mmol) of phenylacetylene. The reaction mixture was heated to 100C and stirred vigorously for the indicate time then cooled to room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate, dried with MgSO4, and filtered on short silica. Purity of compounds is checked by GC using an internal standard (undecane) and yields are based on aryl bromide
92%Chromat.
With dichloro[1-(methoxyethyl)-3-(4-methylbenzyl)benzimidazole-2-ylidene]triphenylphosphinepalladium(II); potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 3h;Schlenk technique;
General procedure: Aryl bromide (1mmol), 3a-h (0.5mol%), t-KOBu (1mmol) and DMF (2ml) were added under air to a Schlenk tube containing a stirring bar, followed by (1.5mmol) of phenylacetylene. The reaction mixture was heated to 80C and stirred vigorously for the indicate time then cooled to room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate, dried with MgSO4, and filtered on short silica. Purity of compounds was checked by GC using an internal standard (undecane) and yields were based on aryl bromide.
With dichloro[1-(3,5-dimethylbenzyl)-3-(2-methylbenzyl)-5,6-dimethylbenzimidazole-2-ylidene](triphenylphosphine)palladium(II); potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 6h;Inert atmosphere; Schlenk technique;
Under argon atmosphere, arylbromides (0.6 mmol), palladium catalyst (0.5 mol%), KOtBu(0.6 mmol) and DMF (5 mL) were added to a schlenck containing a magnetic stir bar, followedby (0.6 mmol) of phenylacetylene. The resulting mixture was placed in an oil bath preheatedto 100 C and stirred vigorously for the indicated time. Upon completion, the mixture wascooled to room temperature, was partitioned between 30 mL of water and 20 mL of diethyletheror ethyl acetate and the combined organic layer was further washed with 2 × 20 mLof diethylether or ethyl acetate and was dried over MgSO4. The extraction was done withDCM when 2,6-dibromopyridine was used as a substrate. The ltrate was sampled at intervalsfor GC analysis to check the purity and the conversions are based on arylbromides.
Stage #1: 4-bromo-m-xylene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere;
Stage #2: With zinc(II) chloride In tetrahydrofuran; hexane at -78 - 20℃; for 1h; Inert atmosphere;
Stage #3: tert-butyl 4-(4-iodophenyl)tetrahydro-1(2H)-pyrazinecarboxylate With methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); XPhos In tetrahydrofuran; hexane at 75℃; for 12h; Inert atmosphere;
General procedure: To a flask containing Mg turnings (0.29 g, 12 mmol) was added1-bromo-4-methylbenzene (1.37 g, 8.0 mmol) in THF (8 mL) at room temperature. After being stirred for 2 h, DMF (1.3 mL,12 mmol) was added to the reaction mixture. The obtained mixturewas stirred for 2 h at 0 C. Then, aq NH3 (7 mL, 28-30%) and I2 (4.06 g, 16 mmol) were added to the reaction mixture. After beingstirred for 2 h at room temperature, the reaction mixture waspoured into satd aq Na2SO3 solution and was extracted with CHCl3 (3*30 mL). The organic layer was dried over Na2SO4 and filtered.After removal of the solvent, the residue was purified by shortcolumn chromatography on silica gel (eluent: hexane/ethylacetate=9:1, v/v) to provide pure 4-methyl-1-benzonitrile (0.77 g) in 82% yield.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 72h; Inert atmosphere; Reflux;
2.1 2.2. Synthetic procedures
2.2.1. Preraration of 1,4-dimethyl-2-(4-fluoro-3-trifluoromethylbenzyl) benzene2-bromo-para-xylene (2 g, 10.8 mmol), 4-fluoro-3-trifluoromethylbenzylboronic acid (2.7 g, 12.97 mmol), K2CO3 (2.82 g,0.1 mol) were mixed into 2:1 of toluene and H2O, Pd (PPh3)4(0.14 g, 0.6 mol %) was added as catalyst. N2was bubbled for halfan hour to remove the dissolve oxygen. The reaction mixture wasrefluxed for three days under nitrogen atmosphere. After the completion of the reaction (monitored by TLC) organic layer was separated from the reaction mixture and passed through neutralalumina to remove the dissolved catalyst. The organic layer wasthen dried over anhydrous magnesium sulfate, concentrated underreduced pressure to get a off white solid material. Further purification by silica gel column chromatography (with n-hexane as aneluent) leads to 2.47 g (85%) of white solid material. Anal. Calcd.for C15H12F4(268.08 g/mol): C, 67.16 H, 4.51; Found: C, 66.76; H,4.68;1H NMR (CDCl3, 200 MHz, dppm): 2.20 (s, 3 H) 2.35 (s, 3H) 6.96-7.10 (m, 1 H) 7.10-7.20 (m, 2 H) 7.24 (d,J= 9.22 Hz, 1H) 7.42-7.58 (m, 2 H).13C NMR (CDCl3, 200 MHz, d ppm):157.30, 139.02, 137.55 133.43, 133.26, 130.64, 129.90, 128.39126.79, 126.66, 116.23, 115.82, 31.17, 29.73.
1L round bottom flask, 1-bromo-2,5-dimethylbenzene (25.0g, 0.135mol), into 200mlof tetrahydrofuran was cooled to -78 C under a nitrogen atmosphere.To the cooled solution was added dropwise a 1.6M n-butyllithium (101ml, 0.162mol).After 2 hours stirring at the same temperature was added dropwise trimethyl borate(18.2g, 0.176mol).Put the 1 normal hydrochloric acid and then stirred for 1 hour at room temperature thesolution was acidified.The mixture was concentrated under reduced pressure, and recrystallized with nhexaneto give the [intermediate 1-b].(12.5g, 62%)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,2-dimethoxyethane for 3h; Reflux; Inert atmosphere;
14.1 2-(2,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
2-bromo-1,4-dimethylbenzene 14a (1.02 g, 5.50 mmol), bis(pinacolato)diboron (1.95 g, 8.30 mmol),1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium (202 mg, 0.30 mmol) and potassium acetate (1.35 g, 13.88 mmol) was dissolved in 20 mL of ethylene glycol dimethyl ether and heated to reflux for 3 hours. Filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title product, 2-(2,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 14b (538 mg, yellow oil), yield: 42.1%.
methyl 3-(2,5-dimethylphenyl)prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With N-Methyldicyclohexylamine; 2C32H41O4P*Pd(2+)*2Cl(1-); In N,N-dimethyl acetamide; at 100℃; for 16h;Inert atmosphere;
General procedure: A dried and argonated Schlenk tube containing a magnetic stir bar was charged with aryl halide (1mmol), methyl acrylate (2mmol), 4mL of DMA, 400muL of Cy2NMe (3mmol), and catalyst (2mol%). The flask was evacuated, backfilled with argon and placed in to the oil bath (kept at 100C) on a magnetic stirrer for 16h. After that 20mL of water was added to the reaction mixture and product was extracted with Et2O (3×10mL), combined organic layer was dried over MgSO4, filtered, solvent was evaporated and the product was isolated by column chromatography. Yields: 68-99%.
With hydrogen bromide; dihydrogen peroxide In water for 25h; Irradiation; Green chemistry;
Typical reaction procedure for visible-lightinduced bromination with the H2O2-HBrsystem
General procedure: Analogous as described in [16], substituted p-xylene (1.0 mmol)was added to 2.0 mL solution (CCl4or water) of 2.0 mmol ofH2O2(0.23 g, 30% H2O2aqueous) and 1.1 mmol of HBr(0.22 g, 30% HBr aqueous). The mixture was stirred at 300 rpmat appropriate temperature under irradiation from a 40 W incandescent light bulb. At the end of the bromination reaction(6-20 h), the mixture was transferred into a separating funneland 4 mL of 0.005 M NaHSO3was added. The crude productwas extracted using 3 × 5 mLCH2Cl2and the combinedorganic phase was dried over MgSO4. Then the solvent wasevaporated under reduced pressure and the crude mixture wasanalyzed by 1H NMRspectroscopy. Lastly the products wereseparated by column chromatography (SiO2, hexane/EtOAc)and identified by comparison with literature data
General procedure: 1) Add 1 mol of <strong>[553-94-6]2-bromo-p-xylene</strong> or chloroacetyl chloride to the reaction kettle.The catalyst and DMSO were heated to 100 C under stirring for 5 h.Then a mixture of sodium sulfite and water was added dropwise to control the dropping time to 45 min.After the completion of the dropwise addition, the reaction temperature was raised to 135 C, and the reaction was continued for 7.5 h; The ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to chloroacetyl chloride is 1:1.14,The ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to catalyst is 1:0.07, and the ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to DMSO is 1g: 13ml.The ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to sodium sulfite was 1:1.18, and the ratio of sodium sulfite to water was 1:4.5. The preparation process of the catalyst is: Mix ruthenium oxide and 10% palladium carbon in a weight ratio of 1:20. Then soaked in 4% concentration of hydrochloric acid for 6 minutes,Then, a solid was obtained by filtration, and the solid was washed and then placed at 280 C for 2.5 h to obtain a catalyst. 2) cooling the system, filtering to remove insoluble matter to obtain a filtrate, and adding the filtrate to about 5 volumes of water.Then, the filtrate is added twice the volume of toluene, and the layer is allowed to stand, and the organic phase is washed with water.After drying with anhydrous sodium sulfate,Concentration gave the product in a molar yield of 98.1% and a HPLC purity of 97.5%.
1) Add 1 mol of <strong>[553-94-6]2-bromo-p-xylene</strong> or chloroacetyl chloride to the reaction kettle.The catalyst and DMSO were heated to 100 C under stirring for 5 h.Then a mixture of sodium sulfite and water was added dropwise to control the dropping time to 45 min.After the completion of the dropwise addition, the reaction temperature was raised to 135 C, and the reaction was continued for 7.5 h; The ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to chloroacetyl chloride is 1:1.14,The ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to catalyst is 1:0.07, and the ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to DMSO is 1g: 13ml.The ratio of <strong>[553-94-6]2-bromo-p-xylene</strong> to sodium sulfite was 1:1.18, and the ratio of sodium sulfite to water was 1:4.5. The preparation process of the catalyst is: Mix ruthenium oxide and 10% palladium carbon in a weight ratio of 1:20. Then soaked in 4% concentration of hydrochloric acid for 6 minutes,Then, a solid was obtained by filtration, and the solid was washed and then placed at 280 C for 2.5 h to obtain a catalyst. 2) cooling the system, filtering to remove insoluble matter to obtain a filtrate, and adding the filtrate to about 5 volumes of water.Then, the filtrate is added twice the volume of toluene, and the layer is allowed to stand, and the organic phase is washed with water.After drying with anhydrous sodium sulfate,Concentration gave the product in a molar yield of 98.1% and a HPLC purity of 97.5%.
General procedure: For the synthesized diaryl dichlorosilanes a lithiationreaction was preferred over the Grignard route due to comparativelylessby-products.Inatypicalreactionthearylbromidewaslithiatedat-78C in Et 2 O (diethyl ether) and subsequently transferred onto asolutionof0.5equivalentsSiCl 4 at0C(Fig.1,route2a).Afterstirringat room temperature, filtratio no fth eforme dsalt san devaporatio nofthe solvent, the products were purifie db ydistillatio norrecrystallization from THF, toluene or ethyl acetate. The compounds2,5-xylyl 2 SiCl 2 and 1-naphthyl 2 SiCl 2 could be obtained in satisfactoryyields of 65%. In the case of the mixed substituent compound 1-naphthyl(phenyl)SiCl 2 theprocedurewasoptimisedbytransferringthelithiated aryl species onto a solution of 2.0 equivalents phenylSiCl 3 at-20C (Fig. 1, route 2b). Thus, the formation of side-products wasminimised and the yield of the desiredproduct reached 62% whilethestandard procedure yields only approximately 40%.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; In toluene; at 85℃; for 15h;Inert atmosphere;
To a 75 ml three-necked flask, 30 ml of toluene, 2.0 g of 1-aminotetrahydronaphthalene, 1.70 g of 2,5-dimethylbromobenzene, 1.74 g of sodium t-butoxide, and 0.14 g of tris(dibenzylideneacetone)palladium were sequentially added. , 2-cyclohexylphosphine-2,6-methoxy-1,1-biphenyl 0.18g, after three times of nitrogen replacement, the system is heated to 85 degrees, the reaction is kept for 12 hours, the system is directly cooled down after cooling, column chromatography , dichloromethane (DCM): petroleum ether (PE) = 1:10,A yellow solid was obtained in 2.07 g. The yield was 90%.
With ethanolamine; In N,N-dimethyl-formamide; at 120℃; for 24h;Schlenk technique;
Accurately weigh <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.1237g, 0.3mmol), ethanolamine (92muL, 1.5mmol) into a 25mL Schlenk reaction bottle,Then 2,5-dimethylbromobenzene (47 muL, 0.3 mmol) was added and the solvent was N,N-dimethylformamide (2 mL).The reaction was carried out at 120 C for 24 h. After the reaction,Extracted with ethyl acetate/water,Dry the organic phase with anhydrous sodium sulfate,The solvent was removed under reduced pressure.Using petroleum ether/ethyl acetate as the eluent,The silica gel column was separated and the yield of the product was 64%.
Stage #1: 4-bromo-m-xylene With n-butyllithium In tetrahydrofuran; hexane at -50℃; for 0.5h; Inert atmosphere;
Stage #2: tert-butyl isocyanide In tetrahydrofuran; hexane at -50 - 20℃; for 0.5h; Inert atmosphere; Further stages;
4.2. Typical procedure (1): transformation of 4-bromobiphenyl 1a into 4-cyanobiphenyl 2a
General procedure: To a solution of 4-bromobiphenyl 1a (3.0 mmol, 699.3 mg) in THF (3.0 mL) was added n-BuLi (4.5 mmol, 1.55 M in hexane, 2.87 mL) at 50 °C. The obtained mixture was stirred for 30 min at 50 °C under an argon atmosphere. Pivalonitrile (6.0 mmol, 498.8 mg) in THF (2.0 mL) was added to the mixture at 50 °C and the obtained mixture was stirred for 30 min in the temperature range of 50 °C to room temperature. MeOH (2.0 mL) was added to the mixture. Then, I2 (12.0 mmol, 3045.6 mg) and K2CO3 (12.0 mmol, 1658.4 mg) were added to the mixture at room temperature, and the obtained mixture was stirred for 6 h at 70 °C. Sat. aq. Na2SO3 solution (20.0 mL) was added to the reaction mixture, and the product was extracted with AcOEt (10.0 mL x 3). The organic layer was dried over Na2SO4. After filtration and removal of the solvent, the residue was purified by silica-gel column chromatography (chloroform: n-hexane 1:1) to give 4-cyanobiphenyl 2a (451.6 mg, 84%).
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