* 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.
With tris-(dibenzylideneacetone)dipalladium(0); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃; for 16 h; Sealed tube; Inert atmosphere
To a 50 mL sealed tube were added R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.20 g, 0.31 mmol), tris(dibenzylideneacetone)dipalladium (0.095 g, 0.10 mmol), sodium tert-butoxide (0.49 g, 5.0 mmol), p-dibromobenzene (1.00 g, 4.15 mmol) and morpholine (0.37 mL, 4.2 mmol), then anhydrous toluene (8 mL) was added under nitrogen protection. The resulting mixture was stirred for 16 h at an oil bath temperature of 80°C. The reaction mixture was cooled to rt and to the mixture was added EtOAc (20 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE:EtOAc=15:1, V/V)to give a white solid (0.56 g, 56percent). MS(ESI, pos.ion)m/z:242.00(M+1)
47%
With tris-(dibenzylideneacetone)dipalladium(0); potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene for 16 h; Inert atmosphere; Reflux
A solution of tris(dibenzylideneacetone)dipalladium(0) (0.093 g, 0.1 mmol) and (±)-BINAP (0.13 g, 0.21 mmol) in toluene (7 mL) was degassed with argon for 10 min and then heated at 110 °C for 15 min. The reaction mixture was allowed to cool to room temperature before potassiumtert-butoxide (0.53 g, 4.73 mmol), 1,4-dibromobenzene (80) (0.6 g, 2.54 mmol) and morpholine (332 µL, 3.82 mmol) were added. The resulting mixture was heated at reflux for 16 h, cooled to room temperature and filtered through a pad of Celite®, the pad was further washed with toluene (30 mL) and the combined filtrates evaporated under reduced pressure to give the crude product. Purification by flash chromatography on silica eluting with hexane-ethyl acetate (6:1) gave the desired amine81(0.19 g, 47percent) as a colourless solid; mp 110–111 °C;νmax/cm-12965, 2857, 2831, 1589, 1495, 1259, 1236, 1120, 923, 818; δH(300 MHz, CDCl3) 7.35 (2 H, d,J9.0 Hz), 6.78 (2 H, d,J9.0 Hz), 3.84 (4 H, t,J6.0 Hz), 3.11 (4 H, t,J6.0 Hz);δC(75 MHz, CDCl3) 150.3, 132.0, 117.4, 112.3, 66.8, 49.3;m/z(APCI) 242/244 ([M + H]+, 68/100).
26.96%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; johnphos In 1,4-dioxane at 100℃; for 12 h; Sealed tube; Inert atmosphere
To a stirred solution of morpholine (2.0 g, 23.0 mmol), 1, 4-dibromo benzene (19.4 g,82.2 mmol) and 1,4-dioxane (10.0 mL) in sealed tube, 0s2003 (22.4 g, 68.7 mmol)was added and degasified with argon. To the above solution Pd2(dba)3 (0.2 g, 0.22mmol) and 2-(di-tert-butylphosphino)biphenyl (0.6 g, 2.0 mmol) was added andheated at 100 00 for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with water, brine solution and dried. Finally, concentrated under vacuo and purified by the column chromatography to yield the desired product (1 .5 g, 26.96percent) as a yellow solid. LCMS: (M+2) =244.0; 1HNMR: (ODd3, 300MHz) 6 7.34-7.37 (d, 2H), 6.76-6.79 (d, 2H), 3.84-3.87 (t, 4H),3.10-3.13 (t, 4H).
Reference：
[1] Tetrahedron, 2008, vol. 64, # 13, p. 2938 - 2950
[2] Patent: EP3342765, 2018, A1, . Location in patent: Paragraph 0306
[3] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
[4] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 132; 133
[5] Patent: WO2004/22526, 2004, A1, . Location in patent: Page 66-67
With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 15.1667 h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110∘C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
85%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h;
General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60–120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
81%
With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
Reference：
[1] Synlett, 2012, vol. 23, # 8, p. 1240 - 1244
[2] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[3] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[4] Applied Catalysis A: General, 2016, vol. 513, p. 53 - 66
[5] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[6] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[7] Tetrahedron, 2017, vol. 73, # 16, p. 2191 - 2195
[8] Synlett, 2008, # 19, p. 3068 - 3072
7
[ 106-37-6 ]
[ 10040-96-7 ]
Reference：
[1] Chemistry - A European Journal, 2006, vol. 12, # 13, p. 3636 - 3646
8
[ 106-37-6 ]
[ 23449-08-3 ]
Yield
Reaction Conditions
Operation in experiment
59.2%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 120℃; for 24 h; Inert atmosphere
3) In a 250ml three-vial bottle,Under nitrogen protection,Add 0.05 mol intermediate S3-1,0.06 mol of dibromobenzene,100ml toluene, stirring and mixing,Add 0.0025mol Pd(PPh3)4,0.06mol potassium carbonate,50 ml of a mixed solution of water and ethanol in a volume ratio of 1:1Stirred to 120°C and refluxed for 24 hours.Sampling point board showing no intermediate S3-1 remaining,The reaction is complete; it is naturally cooled to room temperature, filtered, and the filtrate is separated. The organic phase is taken and vacuum-steamed under reduced pressure to a fraction-free, neutral silica gel column.Intermediate B1 was obtained, HPLC purity 99.3percent, yield 59.2percent;
Reference：
[1] Patent: CN107880030, 2018, A, . Location in patent: Paragraph 0051; 0054-0056
9
[ 106-37-6 ]
[ 3842-55-5 ]
[ 23449-08-3 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 73, p. 10956 - 10959
10
[ 27329-70-0 ]
[ 106-37-6 ]
[ 20005-42-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 36, p. 7402 - 7417
11
[ 1066-35-9 ]
[ 106-37-6 ]
[ 2488-01-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
With magnesium In tetrahydrofuran at 50 - 85℃; for 16 h; Inert atmosphere
A three-neck round bottom flask is set up with a reaction device on which a feeding pipe and a return pipe are installed. 6.1 g (0.25 moles) of magnesium metal was weighed and placed in a three-necked flask reaction apparatus, and the inside thereof was dried to remove water and replaced with a nitrogen or argon atmosphere. The tetrahydrofuran (20 ml) was slowly added to the reaction apparatus and covered with magnesium metal sufficiently. After the reaction mixture was kept in a stable state, 27.9 ml (0.25 millimolar) of dimethylchlorosilane (Me2HSiCl) was slowly added dropwise to the reaction apparatus. This was the first solution. Separately, dibromobenzene, 24.7 g (0.11 mole) and tetrahydrofuran (60 ml), were placed in a feeding tube or a dose pump to be mixed into a dibromobenzene solution, which was the second solution. A small amount (approximately 0.5 ml) of the second solution is slowly added dropwise to the first solution in the reaction device to initiate the Grinnard reaction. The dripping rate was controlled and the feed was slowly fed into the reaction apparatus so that the reaction mixture was maintained in a non-boiling state at a reaction temperature of about 50 to 60°C. After the addition was completed, dibromobenzene in the feed tube was rinsed with a small amount of tetrahydrofuran (5 to 10 ml) into the reactor as a third solution, which was heated to reflux for 16 hours. If there is a device temperature sensor, the internal reaction temperature required for the reflux of tetrahydrofuran is 65 °C. If the temperature sensor is not installed, the temperature of the oil bath is about 75 °C ~ 85 °C, depending on the size of the reaction device. After the reaction was completed, distilled water (150 ml) was slowly added dropwise to the third solution in the reaction apparatus to quench the reaction. After continuous stirring for 5 to 10 minutes, two immiscible solutions were obtained, which was the fourth solution. The fourth solution was transferred to a separatory funnel, and the aqueous layer was extracted with ether (60 ml/time, 3 times) to collect the upper organic solvent layer. Separately wash with water (100 ml) and dry saturated brine (120 ml). After drying over anhydrous sodium sulfate followed by filtration, the filtrate was concentrated under reduced pressure to give 20.4 g of the dinonane product of formula (A-1) in 98percent yield.
98%
Stage #1: With magnesium In tetrahydrofuranInert atmosphere Stage #2: at 50 - 85℃;
Setup a reaction device, such as a feeding pipe and a reflux pipe, on a three-necked round bottom flask. Put 6.1 g (0.25 mol) of metallic magnesium in the three-necked round bottom flask. Dry the inside of the three-necked round bottom flask. Introduce nitrogen gas or argon gas into the three-necked round bottom flask. Introduce 20 mL of tetrahydrofuran into the reaction device slowly, cover it fully with metallic magnesium, and stir the reactants. Introduce 27.9 mL (0.25 mmol) of dimethylsilyl chloride (Me2HSiCl) into the reaction device slowly, thereby producing the first solution. Producing the second solution entails introducing 24.7 g (0.11 mol) of dibromobenzene and 60 mL of tetrahydrofuran into the feeding pipe or a dosage transmission pump to blend the dibromobenzene solution. Drip 0.5 mL of the second solution slowly to the first solution in the reaction device, so as to trigger the Grignard reaction. Then, feed the mixed first and second solutions to the reaction device slowly enough to prevent the reacting mixture from boiling; meanwhile, the reaction temperature ranges from 50° C. to 60° C. Afterward, residual dibromobenzene in the feeding pipe is washed into the reaction device by 510 mL of tetrahydrofuran to produce the third solution, and then the third solution is heated and refluxed for 16 hours. In the presence of a device temperature sensor, the reflux of tetrahydrofuran requires an internal reaction temperature of 65° C. In the absence of any device temperature sensor, the reflux of tetrahydrofuran requires an oil or sand bath tank temperature of 75° C.85° C., depending on the size of the reaction device. Upon completion of the reaction, 150 mL of distilled water is slowly introduced into the third solution in the reaction device to trigger a quenching reaction, and then the third solution is stirred continuously for 510 minutes to form two layers of immiscible solution known as the fourth solution. Transfer the fourth solution to a separatory funnel to extract the aqueous layer with 60 mL of ether thrice, and then collect the organic supernatant before rinsing it with 100 mL of water and 120 mL of saturated saline solution for the sake of drying. A drying process is performed with anhydrous sodium sulfate, and then filtration is performed so that the filtrate is depressurized and concentrated to obtain 20.4 g of disilane structural formula (A-1), with a yield of 98percent. Referring to FIG. 3, it shows the 1H-NMR spectrum for phenylene disilane according to an embodiment of the present invention.
84.7%
With magnesium In diethyl ether; toluene
[0028] A series of runs was made using a co-solvent comprising diethyl ether and toluene, using procedures similar to those utilized in Example 3, to prepare 1,4-bis(dimethylsilyl)benzene from the reaction of either 1,4-dibromobenzene or 1,4-dichlorobenzene and Me2HSiCl.
Reference：
[1] Patent: TWI606055, 2017, B, . Location in patent: Paragraph 0034
[2] Patent: US2018/201631, 2018, A1, . Location in patent: Paragraph 0041
[3] Journal of Organometallic Chemistry, 1992, vol. 435, # 1.2, p. 21 - 28
[4] Patent: US2003/233005, 2003, A1, . Location in patent: Page 3
[5] Dalton Transactions, 2017, vol. 46, # 14, p. 4530 - 4541
[6] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 11, p. 2265 - 2274
[7] Journal of Organic Chemistry, 1996, vol. 61, # 18, p. 6227 - 6232
[8] Patent: US6274754, 2001, B1,
12
[ 106-37-6 ]
[ 1692-25-7 ]
[ 129013-83-8 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 9, p. 4430 - 4442
[2] Patent: CN105601613, 2016, A, . Location in patent: Paragraph 0093; 0094; 0095
13
[ 106-37-6 ]
[ 3638-73-1 ]
Reference：
[1] Tetrahedron, 2004, vol. 60, # 1, p. 81 - 92
[2] Organic Letters, 2001, vol. 3, # 7, p. 993 - 995
[3] Journal of the American Chemical Society, 1993, vol. 115, # 11, p. 4935 - 4936
[4] European Journal of Organic Chemistry, 2012, # 36, p. 7066 - 7074
[5] Dyes and Pigments, 2013, vol. 96, # 3, p. 619 - 625
[6] Tetrahedron, 2015, vol. 71, # 11, p. 1700 - 1704
[7] Patent: CN103923102, 2017, B,
[8] Patent: CN108623473, 2018, A,
With aluminum (III) chloride In dichloromethane at -20℃; for 3 h;
1,4-dibromobenzene (20 mmol), CH2Cl2 (50 mL) and CH3COCl (1.5 eq., 30 mmol) were added to a 250 mL round-bottom flask. After cooled to -20 oC, AlCl3 (3 eq., 8.0 g) was added to the mixture slowly. The reaction was stirred vigorously for 3 h at -20 oC. 80 mL ice water was added to the flask and the mixture was extracted with CH2Cl2 (30 mL x 3), dried by anhydrous Na2SO4. Evaporation of the solvent followed by purification on silica gel provided 1-(2,4-dibromophenyl)ethanone, yield 68percent.
Reference：
[1] Chinese Chemical Letters, 2015, vol. 26, # 10, p. 1231 - 1235
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5327 - 5332
22
[ 75-77-4 ]
[ 106-37-6 ]
[ 13183-70-5 ]
Reference：
[1] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1307[2] Chem.Abstr., 1960, p. 5525
23
[ 106-37-6 ]
[ 67-64-1 ]
[ 2077-19-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: at -78 - 0℃; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane at 0℃;
Preparation of Intermediate 2-(4-bromophenyl)propan-2-ol (1AK-1); Dibromobenzene (2g, 8.478mmol) in tetrahydrofuran (25ml_) was cooled to -78°C and n -buthyllithium (2.5 /W in hexane; 3.8ml_, 9.33mmol) was added drop wise and stirred for1 hour. Acetone (591 mg, 10.2mmol) added drop wise and once addition was complete, the reaction was warmed up to 00C and stirred for 3 hours. Saturated ammonium chloride and water added and extracted with 75percent ethyl acetate in heptane. Organic washed with brine, dried over magnesium sulfate, filtered and concentrated to give (1AK-1 ) (1.74g, 95percent) as a colorless oil.1 H NMR (500 MHz, CHLOROFORM-d) d ppm 1.58 (s, 6 H) 1.79 - 1.82 (m, 1 H) 7.38 (d,2 H) 7.47 (d, 2 H)
63.8%
Stage #1: With n-butyllithium In tetrahydrofuran at -60℃; for 1 h; Stage #2: at -60 - 20℃; for 1 h;
[0166] To the mixture of 1,4-dibromobenzene (5.2 g, 22.0mmol) in THF (50 mL) was added dropwise n-BuLi (8.9 mL,22.0 mmol, 2.5 M) at -60° C. The resulting mixture wasstirred at -60° C. for 1 hr, then a mixture of acetone (3.8 g,65.5 mmol) in THF (10 mL) was added dropwise at -60° C.After addition, the mixture was allowed to 20° C. slowly.After 1 hr, TLC (PE) showed the starting material was consumedcompletely. The reaction was quenched by sat. NH4Cl(50 mL). The mixture was extracted with EtOAc (50 mL *3).The combined organic layers were dried over Na2S04 andfiltered. After concentration, the residue was purified byMPLC to give the title compound (3.0 g, yield: 63.8percent) as ayellow oil.
50%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 0℃; for 3 h;
n-Butyl lithium (2.5 M in hexanes, 6.8 mE, 17.0 mmol) was added dropwise to a stirred and cooled (-78 °C) solution of I ,4-dibromobenzene (4.0 g, 16.9 mmol) in THF (50 mL). Afier addition, stirring at -78 °C was continued for 1 h, and acetone (3,0 g, 51.7 mmol) was added dropwise. The resulting mixture was warmed to 0 °C and stirred for another 3 h before being quenched by addition of saturated aqueous ammonium chloride (40 mL). The mixture was extracted with 75percent ethyl acetate/petroleum ether (3 x 50 mL). The combined organic extractswere washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give title compound (1.8 g, 50percent) as a colorless oil. LCMS MJZ [M-OHj 197.
50%
With n-butyllithium In tetrahydrofuran at -78 - 78℃; for 4 h;
n-Butyl lithium (6.8 n L, 17.0 mmol) was added dropwise to a stirred and cooled (-78 °C) solution of 1 ,4-dibromobenzene (4.0 g, 16.9 mmol) in THF (50 mL). After addition, stirring at 78 °C was continued for 1 h, and acetone (3.0 g, 51.7 mmol) was added dropwise. The resultin mixture was warmed to 0 °C and stirred for another 3 h before being quenched by addition of saturated aqueous ammonium chloride (40 mL). The mixture was extracted with 75percent ethyl acetate/petroleum ether (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give title compound (1.8 g, 50percent yield) as a colorless oil. LCMS M/Z [M-OH+] 197.0
Reference：
[1] Patent: WO2010/86820, 2010, A1, . Location in patent: Page/Page column 56
[2] Patent: US2016/31892, 2016, A1, . Location in patent: Paragraph 0164-0166
[3] Patent: WO2016/77378, 2016, A1, . Location in patent: Page/Page column 126; 127
[4] Patent: WO2016/77380, 2016, A1, . Location in patent: Page/Page column 86; 87
[5] Journal of the American Chemical Society, 1980, vol. 102, p. 2869
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
[7] Patent: EP2196465, 2010, A1, . Location in patent: Page/Page column 38
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 192 - 202
26
[ 106-37-6 ]
[ 625-36-5 ]
[ 31736-73-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 2015, vol. 173, p. 63 - 68
27
[ 106-37-6 ]
[ 3460-18-2 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sulfuric acid; nitric acid In dichloromethane at 20℃; for 0.833333 h;
A mixture of nitric acid (90percent, 4.6 g, 70 mmol) and concentrated sulfuric acid (75 mL) was added to a solution of 1,4-dibromobenzene (11.8 g, 50 mmol) in CH2Cl2 (30 mL) and concentrated sulfuric acid (20 mL) using a dropping funnel, and was allowed to react for 20 min at room temperature. The reaction mixture was stirred for 30 min, quenched with a solution of 25percent aq. NaOH (3 mL), extracted with CH2Cl2 (30 mL), washed with water (10 mL), and dried over MgSO4. Evaporation in vacuo afforded compound 2 (13.7 g, 97percent yield) as light yellow crystals. mp 83–84 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.3 Hz, 1H), 7.55–7.63 (m, 2H).
68%
at 50℃; for 0.5 h;
A mixture of 68percent nitric acid/98percent sulfuric acid (32/64 mL) was added dropwis to a solution of 1,4-dibromobenzene (100 mmol) in 98percent sulfuric acid (40 mL) and the reaction mixture was heated at 50 °C for 30 min. The reaction mixture was allowed to cool to rt, was diluted with ice water (200 mL), and was extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (2 x 100 mL) and 10percent potassium hydroxide (3 x 100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by by Flash chromatography (petroleum ether) to provide 1 ,4-dibromo-2- nitrobenzene in 68percent yield as a light green-yellow solid.
68%
With sulfuric acid; nitric acid In water at 50℃;
Intermediate 26: Synthesis of 2,3-dihydrobenzofuran-6-sulfonyl chloride; 1. Synthesis of 1,4-dibromo-2-nitrobenzene; A mixture of 68percent nitric acid/98percent sulfuric acid (32/64 mL) was added dropwise to a solution of 1,4-dibromobenzene (100 mmol) in 98percent sulfuric acid (40 mL) and the reaction mixture was heated at 50° C. for 30 min. The reaction mixture was allowed to cool to rt, was diluted with ice water (200 mL), and was extracted with dichloromethane (3.x.200 mL). The combined organic layers were washed with water (2.x.100 mL) and 10percent potassium hydroxide (3.x.100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by Flash chromatography (petroleum ether) to provide 1,4-dibromo-2-nitrobenzene in 68percent yield as a light green-yellow solid.
68%
at 20 - 50℃;
Intermediate 38: Synthesis of 2,3-dihydrobenzofuran-6-suIfonyl chloride.MeCN, NaOH, H2O 1. Synthesis of 1 ,4-dibromo-2-nitrobenzene.A mixture of 68percent nitric acid/98percent sulfuric acid (32/64 mL) was added dropwise to a solution of 1 ,4-dibromobenzene (100 mmol) in 98percent sulfuric acid (40 mL) and the reaction mixture was heated at 50 0C for 30 min. The reaction mixture was allowed to cool to rt, was diluted with ice water (200 mL), and was extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (2 x 100 mL) and 10percent potassium hydroxide (3 x 100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by Flash chromatography (petroleum ether) to provide l,4-dibromo-2-nitrobenzene in 68percent yield as a light green- yellow solid.
68%
at 50℃; for 0.5 h;
A mixture of 68percent nitric acid/98percent sulfuric acid (32/64 mL) was added dropwise to a solution of 1,4-dibromobenzene (100 mmol) in 98percent sulfuric acid (40 mL) and the reaction mixture was heated at 50° C. for 30 min. The reaction mixture was allowed to cool to rt, was diluted with ice water (200 mL), and was extracted with dichloromethane (3.x.200 mL). The combined organic layers were washed with water (2.x.100 mL) and 10percent potassium hydroxide (3.x.100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by Flash chromatography (petroleum ether) to provide 1,4-dibromo-2-nitrobenzene in 68percent yield as a light green-yellow solid.
68%
With sulfuric acid; nitric acid In water at 50℃; for 0.5 h;
Intermediate 38: Synthesis of 2,3-dihydrobenzofuran-6-sulfonyl chloride.MeCN, NaOH, H2O 1. Synthesis of 1 ,4-dibromo-2-nitrobenzene.A mixture of 68percent nitric acid/98percent sulfuric acid (32/64 mL) was added dropwis to a solution of 1 ,4-dibromobenzene (100 mmol) in 98percent sulfuric acid (40 mL) and the reaction mixture was heated at 50 0C for 30 min. The reaction mixture was allowed to cool to rt, was diluted with ice water (200 mL), and was extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (2 x 100 mL) and 10percent potassium hydroxide (3 x 100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by by Flash chromatography (petroleum ether) to provide 1 ,4-dibromo-2-nitrobenzene in 68percent yield as a light green- yellow solid.
68%
at 50℃;
A mixture of 68percent nitric acid/98percent sulfuric acid (32/64 mL) was added dropwise to a solution of 1,4-dibromobenzene (100 mmol) in 98percent sulfuric acid (40 mL) and the reaction mixture was heated at 50° C. for 30 min. The reaction mixture was allowed to cool to rt, was diluted with ice water (200 mL), and was extracted with dichloromethane (3*200 mL). The combined organic layers were washed with water (2*100 mL) and 10percent potassium hydroxide (3*100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by Flash chromatography (petroleum ether) to provide 1,4-dibromo-2-nitrobenzene in 68percent yield as a light green-yellow solid.
Reference：
[1] Tetrahedron, 2004, vol. 60, # 1, p. 81 - 92
[2] European Journal of Organic Chemistry, 2012, # 36, p. 7066 - 7074
[3] Dyes and Pigments, 2013, vol. 96, # 3, p. 619 - 625
[4] Journal of Materials Chemistry C, 2016, vol. 4, # 23, p. 5448 - 5460
[5] Organic Letters, 2001, vol. 3, # 7, p. 993 - 995
[6] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 129
[7] Patent: US2010/16297, 2010, A1, . Location in patent: Page/Page column 33
[8] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 94
[9] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 62
[10] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 112
[11] Patent: US2010/22581, 2010, A1, . Location in patent: Page/Page column 44
[12] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[13] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
[14] Justus Liebigs Annalen der Chemie, 1865, vol. 133, p. 52
[15] Journal of the Indian Chemical Society, 1930, vol. 7, p. 629
[16] Journal of the American Chemical Society, 1993, vol. 115, # 11, p. 4935 - 4936
[17] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1989, vol. 28, # 6, p. 472 - 476
[18] Journal of the American Chemical Society, 1994, vol. 116, # 26, p. 11723 - 11736
[19] Chemical Communications, 1997, # 6, p. 613 - 614
[20] Patent: US6627651, 2003, B1,
[21] Patent: EP1182195, 2002, A1, . Location in patent: Example 66
[22] Tetrahedron, 2011, vol. 67, # 22, p. 4025 - 4030
[23] Tetrahedron, 2015, vol. 71, # 11, p. 1700 - 1704
[24] Patent: CN103923102, 2017, B, . Location in patent: Paragraph 0033; 0034; 0038; 0039; 0043; 0044
28
[ 106-37-6 ]
[ 3460-18-2 ]
[ 71173-22-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2006, # 17, p. 3809 - 3825
29
[ 106-37-6 ]
[ 615-54-3 ]
[ 3460-18-2 ]
[ 586-78-7 ]
Reference：
[1] Synthesis, 1994, # 8, p. 841 - 845
[2] Synthesis, 1994, # 8, p. 841 - 845
30
[ 106-37-6 ]
[ 7697-37-2 ]
[ 3460-18-2 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1864, vol. 59, p. 142[2] Justus Liebigs Annalen der Chemie, 1865, vol. 133, p. 52
31
[ 383-63-1 ]
[ 106-37-6 ]
[ 16184-89-7 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 36, p. 11606 - 11609
[2] European Journal of Organic Chemistry, 2007, # 23, p. 3870 - 3878
[3] Organic Letters, 2018, vol. 20, # 24, p. 8073 - 8076
32
[ 431-47-0 ]
[ 106-37-6 ]
[ 16184-89-7 ]
Reference：
[1] Patent: US5225607, 1993, A,
[2] Patent: US4891450, 1990, A,
[3] Patent: US4791139, 1988, A,
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6523 - 6532,10
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 21, p. 6523 - 6532
33
[ 106-37-6 ]
[ 104863-67-4 ]
[ 16184-89-7 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 14, p. 5364 - 5367
34
[ 340-07-8 ]
[ 106-37-6 ]
[ 16184-89-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 52, p. 14191 - 14195[2] Angew. Chem., 2013, vol. 125, # 52, p. 14441 - 14445,5
Reference：
[1] Journal of the Chemical Society, 1931, p. 2388,2406
37
[ 75-21-8 ]
[ 106-37-6 ]
[ 4654-39-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With n-butyllithium In diethyl ether; hexane at -40 - 20℃; for 3 h; Inert atmosphere Stage #2: at -40 - 20℃; for 1 h; Inert atmosphere
The solution of 1,4-dibromobenzene (40 g, 0.17 mol) in drydiethyl ether (200 mL) was cooled to 40 C and n-buthyllithium(105.6 mL, 1.6 M in hexanes, 0.17 mol) was added dropwise for1 h. The mixture was allowed to warm up to rt and stirred for2 h. The reaction was once again cooled to 40 C and a solutionof ethylene epoxide (8.46 mL, 0.17 mol) in 40 mL of diethyl etherwas added slowly to the mixture. The reaction mixture was slowlywarmed to room temperature and stirred for 1 h at room temperature.Then 40 mL of NH4Cl was added to quench the reaction. Theproduct was extracted with diethyl ether (3 100 mL). Theorganic layers were dried over MgSO4, filtered and concentrated.Distillation afforded 28.63 g (85percent) of a colourless liquid of 10.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 12, p. 3465 - 3472
[2] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3552 - 3562
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1977, p. 2357 - 2364
38
[ 111-25-1 ]
[ 106-37-6 ]
[ 23703-22-2 ]
Reference：
[1] Journal of Materials Chemistry, 2005, vol. 15, # 31, p. 3208 - 3213
39
[ 106-37-6 ]
[ 35656-89-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 35, p. 8114 - 8117
40
[ 106-37-6 ]
[ 15890-72-9 ]
[ 126930-72-1 ]
Reference：
[1] Macromolecules, 2003, vol. 36, # 2, p. 291 - 297
[2] Chemical Communications, 2006, # 17, p. 1862 - 1863
41
[ 106-37-6 ]
[ 214360-73-3 ]
[ 3365-85-3 ]
Yield
Reaction Conditions
Operation in experiment
52%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 24 h; Schlenk technique; Inert atmosphere; Heating
1,4-dibromobenzene (0.980 g, 4.15 rnmol), SI (2.0 g, 9.13 mmol), Pd(PPh3)4 (0.3 g, 0.415 mmol), K2C03 (8.6 g, 62.3 mmol), water (10 mL), toluene (10 mL) were loaded in a 50 mL Schlenk flask loaded with a magnetic stirrer. The mixture was flash frozen in liquid N2, evacuated to an internal pressure of 50 mtorr, and allowed to thaw under static vacuum. The freeze/pump/thaw procedure was repeated three more times, after which the flask was backfilled with N2(g) and under N2 flow a water cooled condenser was attached with a red septum, bubbler and a positive N2(g) flow at the top. The reaction mixture was heated to 120 °C for 24 h under N2(g), tracked by TLC. The reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with EtOAc (3 x 10 mL) and the combined organic extracts were rinsed with water (3 x 10 mL), brine (3 x 10 mL), dried over anhydrous Na2S04(i) and filtered through celite. Removal of the solvent at 40 °C under reduced pressure in a rotary evaporator followed by column chromatography (S1O2, 45percent EtOAc in hexanes) afforded a white solid. Yield: 0.560 g (52percent). NMR (400 MHz, DMSO-ifc) δ 7.53 (s, 1H), 7.39 - 7.35 (d, 1H), 6.66 - 6.62 (d, 1H), 5.20 (s, 1H). 13C NMR (100 MHz, DMSO) δ 148.18, 137.93, 127.11, 126.82, 125.55, 114.22, 99.51, 39.52. HRMS (ESI-TOF) m/z calculated for Ci8Hi6N2 [M+H]+: 261.1393, found 261.1355.
Reference：
[1] Patent: WO2018/13682, 2018, A1, . Location in patent: Page/Page column 27
[2] Chemical Communications, 2018, vol. 54, # 50, p. 6947 - 6950
42
[ 106-37-6 ]
[ 140-88-5 ]
[ 70364-29-3 ]
[ 40640-98-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 1, p. 105 - 111
43
[ 106-37-6 ]
[ 3032-92-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 18, p. 3056 - 3059
44
[ 106-37-6 ]
[ 3282-30-2 ]
[ 30314-45-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 3, p. 856 - 866
[2] Organic Letters, 2018, vol. 20, # 10, p. 2835 - 2838
45
[ 630-18-2 ]
[ 106-37-6 ]
[ 30314-45-5 ]
Reference：
[1] Journal of the American Chemical Society, 1962, vol. 84, p. 4259 - 4263
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 28, p. 7228 - 7232[2] Angew. Chem., 2013, vol. 125, # 28, p. 7369 - 7373,5
[3] Angewandte Chemie - International Edition, 2011, vol. 50, # 10, p. 2249 - 2252
[4] Organic and Biomolecular Chemistry, 2016, vol. 14, # 11, p. 3040 - 3046
[5] Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 10, p. 1349 - 1357
[6] Chemical Communications, 2013, vol. 49, # 31, p. 3242 - 3244
[7] Chemical Communications, 2013, vol. 49, # 32, p. 3300 - 3302
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 10, p. 2658 - 2661[9] Angew. Chem., 2014, vol. 126, # 10, p. 2696 - 2699,4
51
[ 106-37-6 ]
[ 122-39-4 ]
[ 36809-26-4 ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: With sodium t-butanolate In toluene at 25℃; for 0.25 h; Stage #2: for 0.25 h; Stage #3: at 90℃; for 15 h;
Example 28e Synthesis of 4-bromo-phenyl-diphenyl-amine (16). To a solution of tris(dibenzylideneacetone)dipalladium (0.41 g, 0.44 mmol), and bis-(diphenylphosphino)ferrocene (0.37 g, 0.67 mmol) in 50 mL dry toluene under inert atmosphere, was added sodium tert-butoxide (4.2 g, 0.04 mol) at 25° C. The mixture was stirred for 15 min followed by addition of 1,4-dibromobenzene (27.9 g, 0.12 mol), and stirred for another 15 min. Diphenylamine (5.0 g, 0.029 mmol) were added, and the reaction mixture was heated to 90° C. for 15 h. The reaction mixture was subsequently cooled to 25° C. and poured into water. The organic layer was separated, and the aqueous layer was extracted with toluene (3*100 mL). The extracts were combined with the original organic layer, and the solvent was removed under vacuum to give the resultant crude product. The crude product was purified by chromatography on silica gel using hexane: ethylene chloride (6:1) as the eluant. Compound 16 was obtained as a white solid (5.6 g) in 59percent yield. 1H NMR (CDCl3): δ 6.94(d, J=8 Hz, 2H), 7.01-7.08(m, 6H), 7.23-7.27(m, 4H), 7.32(d, J=8 Hz, 2H). MS (m/z): 323.2 [M,100].
48%
With tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; sodium t-butanolate In toluene for 12 h; Reflux
1, 4-to [...] multi function cap opening 250 ml 2 (1, 4-dibromobenzene) (24.9 ml, 206.83mmol), diphenylamine (diphenylamine) (10.0g, 59.09mmol), tris (d it cuts qualitative the acetone which is burnt) d palladium (0) (Pd 2 (dba) 3) (1.08g, 1.18mmol), tri-o- [...] (tri-o-tolyphosphine) phosphine (899 mg, 2.96mmol), sodium (sodium tert-butoxide) [...] - [...] (11.4g, 118.19mmol) doesn't have any error frames, toluene reflux time stirring signals senses a rotation velocity of the disk 12. Reaction after vacuum distilling a column (Hex 100percent)the solvent is removed by inserting the non-system and the solution of decompressing distilled methylene chloride and oil ether solvent 9.26g solid white the recrystallization (yield 48percent)is obtained.
Reference：
[1] Tetrahedron, 2009, vol. 65, # 24, p. 4726 - 4734
[2] Tetrahedron, 2009, vol. 65, # 46, p. 9626 - 9632
[3] Advanced Functional Materials, 2010, vol. 20, # 15, p. 2448 - 2458
[4] Journal of the American Chemical Society, 2003, vol. 125, # 48, p. 14704 - 14705
[5] Patent: US2005/234256, 2005, A1, . Location in patent: Page/Page column 16; sheet 17
[6] Patent: KR2015/65389, 2015, A, . Location in patent: Paragraph 0070; 0071; 0072
[7] Journal of Photochemistry and Photobiology A: Chemistry, 2011, vol. 222, # 1, p. 192 - 202
[8] Dyes and Pigments, 2013, vol. 96, # 3, p. 705 - 713
52
[ 106-37-6 ]
[ 1066-54-2 ]
[ 16116-78-2 ]
Reference：
[1] Organic Letters, 2005, vol. 7, # 3, p. 391 - 394
[2] Synthesis, 2011, # 22, p. 3604 - 3611
[3] RSC Advances, 2014, vol. 4, # 98, p. 55179 - 55186
[4] Organic Letters, 2014, vol. 16, # 24, p. 6302 - 6305
[5] European Journal of Organic Chemistry, 2016, vol. 2016, # 18, p. 3056 - 3059
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 21, p. 6090 - 6094[7] Angew. Chem., 2018, vol. 130, p. 6198 - 6202,5
53
[ 1719-58-0 ]
[ 106-37-6 ]
[ 4519-17-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: With magnesium In tetrahydrofuran at 40℃; Stage #2: at 20 - 40℃;
General procedure: Magnesium 1.28 g (52.5 mmol) was added to a dried flask. Then a solution of 6.59 g (25 mmol) 3,6-(dibromo)benzocyclobutene in 20 mL freshly distilled THF was added dropwise over a period of 2 h. The reaction mixture was heated to 40°C and stirred continuously for 2 h. After cooled to room temperature, a solution of 6.65 g (55 mmol) of (vinyldimethylchloro)silane in 15 mL freshly distilled THF was added into the reaction mixture over a period of 1 h at ambient temperature. The reaction mixture was then heated to 40°C, and stirred for 2 h. Then the mixture was allowed to stand overnight and was poured into distilled water. The aqueous phase was extracted with petroleum ether (30 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate. After removal of the solvents under reduced pressure, the residue was purified by chromatography (petroleum ether) to give 2 of 5.57 g (82percent yield).
Stage #1: With iodine; magnesium In tetrahydrofuran at 30℃; for 3 h; Inert atmosphere Stage #2: at -70℃; for 1 h;
under the protection of nitrogen, into 200 ml THF, 15 . 0g (0.62 µM) magnesium,1.0g(0.004mol)I2, slowly dropping containing 68.4g (0.29 µM) of the two 1, 4 - bromobenzene 300 ml THF solution, adds by drops in 30 °C reaction 3h, cooling to -70 °C, slowly dropping boric acid three methyl ester (78.5 ml, 0 . 72 µM) and 300 ml THF of a mixed solution of the, completion of the dropping, for -70 °C reaction 1h, Slowly to room temperature stirring 12h. Adding 2.5M HCl950ml fast stirring 15min, filtering, with 300 ml hexane washing three times, vacuum drying, the white solid obtained 40.7g, yield of 84.6percent.
Reference：
[1] Chemistry - An Asian Journal, 2013, vol. 8, # 7, p. 1368 - 1371
[2] Synthesis, 2002, # 6, p. 757 - 760
[3] Chemical Communications, 2000, # 8, p. 681 - 682
[4] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2002, vol. 377, p. 109 - 112
[5] Journal of the American Chemical Society, 2011, vol. 133, # 40, p. 16219 - 16234
[6] CrystEngComm, 2013, vol. 15, # 11, p. 2067 - 2075
56
[ 121-43-7 ]
[ 106-37-6 ]
[ 7732-18-5 ]
[ 4612-26-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 40, p. 16219 - 16234
57
[ 106-37-6 ]
[ 2199-32-8 ]
Reference：
[1] Tetrahedron, 2003, vol. 59, # 20, p. 3593 - 3601
[2] Journal of Porphyrins and Phthalocyanines, 2014, vol. 18, # 3, p. 209 - 220
58
[ 106-37-6 ]
[ 13315-17-8 ]
Reference：
[1] Patent: KR2015/47298, 2015, A,
59
[ 106-37-6 ]
[ 35480-52-5 ]
Reference：
[1] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2525 - 2537
60
[ 106-37-6 ]
[ 25462-61-7 ]
Reference：
[1] American Chemical Journal, 1902, vol. 28, p. 472
61
[ 1191-95-3 ]
[ 106-37-6 ]
[ 19936-14-2 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 0.25 h; Inert atmosphere Stage #2: at -70 - 0℃;
Step 1: (0135) (0136) 47.2 g (0.2 mol) p-dibromobenzene was dissolved in 280 ml tetrahydrofuran, and cooled to −70° C. under nitrogen atmosphere, during which the reaction solution became sticky. 84 ml (0.21 mol, 2.5M) n-butyl lithium was added dropwise for exchanging bromine with lithium, and stirred for an additional 15 min after addition. 14 g (0.2 mol) cyclobutanone was added at this temperature to perform the addition reaction with the lithium reagent, during which the reaction system gradually became thin and completely clear after addition. The reaction solution was heated to 0° C. and poured into 300 ml water. The organic layer is separated, extracted, washed with water, evaporated to completely remove the solvent, and recrystallized in ethanol, to obtain 25 g of a white crystal (1-a). Yield: 60percent.
54%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexanes
l-(4-Bromo-pheπyl)-cycIobutanol (3-1).; n-Butyllithium (1.2 mL 1.92 mmol, 1.6 M/hexanes) was added to a -78 °C solution of 1 ,4-dibromobenzene (489 mg, 2.07 mmol) in THF (4.2 mL). After 30 min., a solution of cyclobutanone EPO <DP n="40"/>(141 mg, 2.01 mmol) in 1 inL THF was added by cannula, rinsing with 0.5 mL THF. The reaction was allowed to warm to room temperature and after 2 h, saturated NH4Cl solution was added. The resulting mixture was extracted with ethyl acetate (3 x 30 mL) and the combined ethyl acetate solution was washed with brine. The solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (5percent -> 10percent ethyl acetate/hexanes) gave 3-1 (235 mg, 54percent).
34%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 0℃; for 3.25 h;
To a solution of 1,4-dibromobenzene (1.00 g, 4.24 mmol) at -78° C. in ether (20 ml) was added n-BuLi (2.65 ml, 1.6 M solution in hexane, 4.24 mmol) and the reaction mixture was stirred at -78° C. for 30 min. Cyclobutanone (348 μl, 4.66 mmol) was then added and the reaction mixture was stirred at -78° C. for 15 min. The reaction mixture was then slowly (over 2 h) warmed to 0° C. and stirred for a further 1 h. Water was added followed by sat. NH4Cl and the reaction mixture was extracted with ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:4 ether/pentane) to give 1-(4-bromophenyl)-cyclobutanol (330 mg, 34percent) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 2.57-2.48 (m, 2H), 2.41-2.31 (m, 2H), 2.02 (m, 1H), 1.69 (m, 1H).
Reference：
[1] Synlett, 2004, # 8, p. 1440 - 1442
[2] Organic Process Research and Development, 2018, vol. 22, # 6, p. 681 - 696
[3] Patent: US9481828, 2016, B2, . Location in patent: Page/Page column 34
[4] Patent: WO2006/63179, 2006, A1, . Location in patent: Page/Page column 37-38
[5] Patent: US2007/185058, 2007, A1, . Location in patent: Page/Page column 8
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
62
[ 106-37-6 ]
[ 112671-42-8 ]
Reference：
[1] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[2] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
63
[ 106-37-6 ]
[ 13922-41-3 ]
[ 204530-94-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate In tetrahydrofuran; water; toluene for 24 h; Reflux; Inert atmosphere
Step 1: Synthesis of Intermediate (C)15 g (63 mmol) of 1,4-dibromobenzene, 7.66 g (44 mmol) of 1-naphthaleneboron acid, 17.58 g (127 mmol) of potassium carbonate, and 1.83 g (50 mmol) of tetrakis-(triphenylphosphine) palladium were suspended in a mixed solvent including 200 ml of tetrahydrofuran, 200 ml of toluene, and 50 ml of purified water, and heated and refluxed under a nitrogen atmosphere for 24 hours.The reaction fluid was cooled to room temperature, and separated into two layers. Then, the solvent of an organic layer thereof was removed under a reduced pressure to provide a fluid. The fluid was separated by column chromatography (hexane) to remove the solvent and to provide 15 g of a gel intermediate (C) at a yield of 83percent.
64%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; waterReflux
The starting material, 1,4-dibromobenzene (30 g, 127 mmol) to THF (560 mL) after the dissolved, naphthalen-1-ylboronic acid (21.9 g, 127 mmol), Pd (PPh3) 4 (4.41 g, 3.82 mmol ), K2CO3 (52.7 g, 381 mmol), followed by the addition of water (280 mL), stirred and refluxed. When the reaction is complete, the ether was extracted with water, the organic layer was concentrated and then the next, the resulting product to the organic was dried with MgSO4 and concentrated to silicagel column and recrystallization. To obtain 23 g (Yield: 64percent)
Reference：
[1] Patent: US2012/280221, 2012, A1, . Location in patent: Page/Page column 23-24
[2] Patent: KR2016/5944, 2016, A, . Location in patent: Paragraph 0238-0241
64
[ 106-37-6 ]
[ 80-10-4 ]
[ 18733-91-0 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 14 h; Inert atmosphere
1,4-Dibromobenzene (10 g, 42.4 mmol) into a THF (100 ml) in a nitrogen stream -78°C From 2.5M n-BuLi (16.9 ml, 42.4 mmol) slowly into the stirring for 2 hours now and, at -78°C dichlorodiphenylsilane (4.9 g, 19.3 mmol) slowly into the stirring for 2 hours at room temperature after 12 hours stirring. EA and extracted with waterBack, and then dried over MgSO4, and concentrated to the resulting organic ilicagel column and recrystallization to give the desired compound 9.2 g (96percent).
85%
Stage #1: With n-butyllithium In diethyl ether at 0℃; for 3 h; Inert atmosphere Stage #2: at 20℃; for 48 h; Inert atmosphere
In a 250 mL round bottom flask, Dissolve 1,4-dibromobenzene (50 mmol, 11.69 g) in freshly distilled ether. Under a nitrogen atmosphere at 0 °C, n-butyl lithium (55 mmol, 2.4 M, 23 mL) was added dropwise with stirring. Stirring was continued for 3 hours at 0 °C. Diphenyldichlorosilane (50 mmol, 10.51 mL) was added dropwise to the reaction system, and the mixture was stirred at room temperature under nitrogen for two days. Pour into water to quench the reaction, extract with dichloromethane, and concentrate the extract by rotary evaporation. Recrystallization from ethanol gave a white solid (20.91 g, yield: 85percent).
82.9%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 2.5 h; Inert atmosphere Stage #2: at -78 - 20℃; Inert atmosphere
In lOOOmL three-neck flask, into 40.1gl, 4- dibromobenzene (0.17 mol) and anhydrous ether 600mlL, protection of nitrogen, cooled with stirring to _78 ° C, was added dropwise 78ml2 · 2mol / L n-BuLi (0 · 17mol), from about 0 •5 hour drop complete, incubated for 2 hours, the system was white turbid, after the end of the incubation 71/92 dichlorodiphenylsilane 20.99g (0.083mol), drop about 20 minutes to complete, after the addition was complete insulation 2 hours, slowly warmed to room temperature and stirred overnight. Dilute aqueous hydrochloric acid was added to terminate the reaction. The organic phase was separated, the aqueous phase was extracted with ethyl acetate, combined organic phases were twice washed with water until neutral, dried over anhydrous sodium sulfate, dry off the solvent under reduced pressure to give a white solid 38g. In toluene V: V = stone face 1:10 as eluent, silica gel column chromatography to give 33.9g white solid, a yield of 82.9percent billion
81%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 78℃; for 1 h; Stage #2: at 20 - 78℃;
a) Bis(4-bromophenyl)diphenylsilane 10.81 g (50 mmol) of 1,4-dibromobenzene are dissolved in 400 ml of dry THF and cooled to -78° C. 20 ml (50 mmol) of n-butyllithium are subsequently added dropwise at -78° C., and, when the addition is complete, the mixture is stirred at 78° C. for a further 1 h. 6.3 g (25 mmol) of dichlorodiphenylsilane, dissolved in 80 ml of dry THF, are then slowly added dropwise and allowed to come to room temperature overnight. The reaction mixture is evaporated to dryness in a rotary evaporator, and the solid is recrystallised from toluene and then from n-butanol. The yield is 10 g (0.21 mmol), corresponding to 81percent of theory.
74.2%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: for 1 h; Heating
Under the protection of argon, to the three port are sequentially added in the bottle 1,4-dibromobenzene 14.87g, tetrahydrofuran 210 ml, cooling to -78 °C, dropwise 26.25 ml n-BuLi, completion of the dropping, at -78 ° C stirring 1 hour, then slowly dripping 7.59g dichlorodiphenylsilane, insulation reaction completion of the dropping 1 hour later automatic heating, reaction sleepovers. Quenching reaction with water, evaporate the solvent, by adding methylene chloride and water-soluble residue, water washing, separating the organic layer, the organic water-washing two times with water to neutral, the organic layer is dried with anhydrous sodium sulfate, evaporation solvent dichloromethane, residue column chromatography separation, showering liquid is petroleum ether: chloroform = 35:1(V/V), evaporate the solvent, after drying, to obtain 11.0g white crystalline powder, the yield is 74.2percent.
74.2%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: Heating
Under argon, 14.87 g of 1,4-dibromobiphenyl and 210 mL of tetrahydrofuran were successively added to a three-necked flask, cooled to -78 ° C, 26.25 mL of n-butyllithium was added dropwise, and the mixture was stirred at -78 ° C 1 hour, and then slowly dropping 7.59 g of dichlorodiphenylsilane, dropping the insulation reaction after 1 hour automatically heat up, the reaction overnight. Add water to quench the reaction, steaming the solvent, adding methylene chloride and water to dissolve the residue, washing, separating the organic layer, the organic layer was washed with water twice to neutral, the organic layer was dried with anhydrous sodium sulfate, , The residue was separated by column chromatography, and the eluent was petroleum ether: chloroform = 35: 1 (v / v). The solvent was evaporated and dried to give 11.0 g of white crystalline powder in a yield of 74.2percent.
73%
Stage #1: With n-butyllithium In diethyl ether at 0℃; for 2 h; Inert atmosphere Stage #2: at 25℃; for 24 h; Inert atmosphere
A stir bar was placed in a 250 mL dry double neck bottle and followed by flushed and purged by nitrogen three times to be used later. A separatory funnel was installed. 1,4-dibromobenzene (11.7 mg, 50 mmol) was dissolved in anhydrous ether (100 mL) dried by sodium under an argon system and followed by cooling the temperature of the system to 0° C. To the solution was slowly added n-BuLi (1.6 M, 36 mL, 55 mmol) via the separatory funnel and react for 2 hours under the system temperature at 0° C. Ether (50 mL) and dichlorodiphenylsilane (5.27 mL, 25 mmol) were slowly added in the double neck bottle via the separatory funnel, and the solution is bright yellow at this time. Then, the solution was reacted 24 hours at room temperature to become white cloudy. After quenched with water, ether was removed in a rotary evaporator. Again, quenched with dichloromethane, and the organic layer was dried and condensed. Followed by recrystallized from dichloromethane/methylene, compound 7 ( bis(4-bromophenyl)diphenylsilane, 9.08 g, yield: 73percent) as a white solid was obtained. Spectral data as follow: 1H NMR (400 MHz, CDCl3) δ7.54-7.48 (m, 8H), 7.45 (t, J=7.32 Hz, 2H), 7.41-7.35 (m, 8H); 13C NMR (100 MHz, CDCl3) δ137.80, 136.20, 132.96, 132.62, 131.19, 129.99, 128.08, 124.95.
72.2%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: for 1 h;
Under the protection of argon, to the three port are sequentially added in the bottle 1,4-dibromo biphenyltetrazole 14.87g, tetrahydrofuran 210 ml, cooling to -78 °C, dropwise 26.25 ml n-BuLi, completion of the dropping, at -78 ° C stirring 1 hour, then slowly dripping 7.59g two chlorine diphenyl silane, insulation reaction completion of the dropping 1 hour later automatic heating, reaction sleepovers. Quenching reaction with water, evaporate the solvent, by adding methylene chloride and water-soluble residue, water washing, separating the organic layer, the organic water-washing two times with water to neutral, the organic layer is dried with anhydrous sodium sulfate, evaporation solvent dichloromethane, residue column chromatography separation, showering liquid is petroleum ether: chloroform = 35:1(V/V), evaporate the solvent, after drying, to obtain 11.0g white crystalline powder, the yield is 74.2percent.
64.3%
Stage #1: With n-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 20℃; Inert atmosphere
Compound 1 was prepared according to modified procedure from the literature [11]. 1,4-Dibromobenzene (4.20 g,17.8 mmol) was dissolved in 15 mL dry THF under nitrogen atmosphere. The solution was cooled to 78°C. 9.6 mL of n-BuLi (2.0 M in cyclohexane) was added dropwise and stirred for 1 h. Dichlorodiphenylsilane (1.68 mL, 8 mmol) was added slowly at –78°C. The mixture was stirred overnight while allowing the temperature to rise to room temperature. The reaction was then quenched with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After the solvent was evaporated, the crude product was purified by recrystallization from ethanol to afford white solid (2.54 g, 64.3percent). 1HNMR (CDCl3, 400 MHz): δ (ppm) = 7.57–7.52(m, 8H), 7.48–7.38 (m, 10H). 13C NMR (CDCl3,100 MHz): δ (ppm) = 137.93, 136.32, 134.98, 133.36,131.14, 129.88, 128.02, 124.82.
51%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 20℃;
1,4-dibromobenzene (12 mmol, 2.83 g) was weighed into a 250-mL, 2 necked flask and dissolved in THF (50 mL). The solution was cooled to -78 °C by using a dry ice/acetone mixture. N-butyllithium (n-BuLi, 2.5 M in hexane, 14.40 mmol, 5.76 mL) was added dropwise to the flask using a syringe and the solution was stirred at -78 °C for 1 h. After that, dichloro(diphenyl)silane (5 mmol, 1.05 mL) was added dropwise and the resultant solution was stirred at RT overnight. Water (50 mL) was added to the reaction mixture and the THF phase was extracted. The water phase was washed with CH2Cl2 (2 * 50 mL), and the organic phases were collected and dried over MgSO4. After the removal of the solvents, a white solid was obtained and purified by recrystallization from the DCM/EtOH mixture. Yield: 51percent. 1H NMR (CDCl3, 400 MHz): δH (ppm) 7.60-7.52 (8H, m, Ar), 7.47-7.35 (10H, m, Ar). 13C NMR (100 MHz, CDCl3): δC (ppm) 138.07, 136.47, 133.27, 132.93, 131.47, 130.25, 128.36, 125.23.
37%
With n-butyllithium In diethyl ether; hexane
Example 13 Synthesis of Compound 35 Into a solution of 1,4-dibromobenzene (34 g, 144 mmol) in diethyl ether (600 mL) was added 2.5M butyllithium solution in hexane (60.3 mL, 151 mmol) dropwise at -78° C. The solution was stirred at -78° C. for 3.5 hours before dichlorodiphenylsilane (13.49 mL, 65.5 mmol) dissolved in 20 ml of diethyl ether was added dropwise. The reaction mixture was allowed to warm up to room temperature overnight and was quenched with water. The organic phase was isolated, filtered to remove solids, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:toluene as eluent and precipitation from toluene to methanol to yield bis(4-bromophenyl)diphenylsilane (12 g, 37percent) as a white powder.
37%
With n-butyllithium In diethyl ether; hexane at -78℃; for 3.5 h;
Into a solution of 1 ,4-dibromobenzene (34 g, 144 mmol) in diethyl ether (600 mL) was added 2.5 butyllithium solution in hexane (60.3 mL, 151 mmol) dropwise at -78 °C. The solution was stirred at -78 °C for 3.5 hours before dichlorodiphenylsilane (13.49 mL, 65.5 mmol) dissolved in 20ml of diethyl ether was added dropwise. The reaction mixture was allowed to warm up to room temperature overnight and was quenched with water. The organic phase was isolated, filtered to remove solids, and dried over Na2S04. After evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane :toluene as eluent and precipitation from toluene to methanol to yield bis(4-bromophenyl)diphenylsilane (12 g, 37percent) as a white powder.
Reference：
[1] Patent: KR2016/69021, 2016, A, . Location in patent: Paragraph 0191-0193
[2] Patent: CN108129386, 2018, A, . Location in patent: Paragraph 0155; 0157; 0158
[3] Patent: CN103804409, 2016, B, . Location in patent: Paragraph 0026; 0056-0057
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[6] Chemistry - A European Journal, 2014, vol. 20, # 25, p. 7589 - 7592
[7] Patent: CN105418667, 2016, A, . Location in patent: Paragraph 0021
[8] Patent: CN105368445, 2017, B, . Location in patent: Paragraph 0028; 0029; 0030; 0031
[9] Patent: US2018/40836, 2018, A1, . Location in patent: Paragraph 0079
[10] Patent: CN105367595, 2016, A, . Location in patent: Paragraph 0023; 0031
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[18] Patent: WO2012/162325, 2012, A1, . Location in patent: Page/Page column 67-68
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[21] Turkish Journal of Chemistry, 2015, vol. 39, # 5, p. 917 - 929
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[ 775-12-2 ]
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69
[ 106-37-6 ]
[ 181219-01-2 ]
[ 113682-56-7 ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene for 48 h; Inert atmosphere; Reflux
Example 1 Synthesis of 4,4'-(1,4-phenylene)bis(1-hexylpyridin-1-ium) bis(tetrafluroborate) A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.34 g, 21.2 mmol), 1,4-dibromobenzene (2.00 g, 8.5 mmol), K2CO3 (2.92 g, 21.2 mmol) and Pd(PPh3)4 (0.49 g, 5 mol percent) in PhMe (30 mL) and EtOH (30 mL) under N2 was heated at reflux for 48 h. The resulting mixture was poured into water (50 mL), extracted with dichloromethane (2*100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using MeOH (0-5percent) in dichloromethane as eluent. The solvent was removed under reduced pressure and the residue crystallised from hot EtOAc/hexanes to give 1,4-di(4-pyridyl)benzene (1.52 g, 77percent) as a pale yellow powder.
71%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In N,N-dimethyl-formamide; toluene at 130℃; for 48 h; Inert atmosphere
Pyridylboronic pinacol ester (3.64 g, 17.8 mmol), 1,4-dibromobenzene (1.40 g, 5.92 mmol), and Cs2CO3 (11.6 g, 35.5 mmol) were added to a 1:1 mixture of dry PhMe/DMF (300 mL), which had been degassed with Ar for 15 min. Next, Pd(PPh3)4 (0.68 g, 0.59 mmol) was added to the reaction mixture and the solution heated to 130° C. under Ar for 48 h. Then, the reaction mixture was cooled to room temperature and the palladium catalyst filtered off using Celite. The organic phase was concentrated under vacuum and then dissolved in CH2Cl2 followed by extraction with H2O three times. The organic layer was made acidic (pH 2-3) by adding dropwise concentrated HCl, which caused the desired product to precipitate from solution. The precipitate was collected by filtration and then dissolved in H2O. Finally, aq. NaOH (10 M) was added dropwise to the water layer until the pH was 8-9, which resulted in precipitation of pure product ExBIPY (973 mg, 71percent) as a white solid. The yield of the product obtained in the reaction was 71percent. 1H NMR (500 MHz, CDCl3, ppm): δH 8.72 (AA′ of AA′XX′, J=4.6, 1.6 Hz, 4H), 7.80 (s, 4H), 7.59 (XX′ of AA′XX′, J=4.6, 1.6 Hz, 4H).
Reference：
[1] Patent: US2018/194995, 2018, A1, . Location in patent: Paragraph 0117
[2] Journal of the American Chemical Society, 2013, vol. 135, # 1, p. 183 - 192
[3] Patent: US2014/179017, 2014, A1, . Location in patent: Paragraph 0072
[4] Organic Letters, 2010, vol. 12, # 8, p. 1888 - 1891
[5] Chemistry - A European Journal, 2014, vol. 20, # 3, p. 649 - 652
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[ 106-37-6 ]
[ 1692-15-5 ]
[ 113682-56-7 ]
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[1] Chemistry - A European Journal, 2011, vol. 17, # 50, p. 14020 - 14030
[2] New Journal of Chemistry, 2018, vol. 42, # 4, p. 2526 - 2536
[3] Chemical Communications, 2015, vol. 51, # 43, p. 8998 - 9001
[4] Journal of the American Chemical Society, 2018, vol. 140, # 23, p. 7206 - 7212
[5] Chemical Communications, 2009, # 37, p. 5585 - 5587
[6] Inorganic Chemistry, 2013, vol. 52, # 8, p. 4205 - 4216
[7] Chemistry - A European Journal, 2015, vol. 21, # 45, p. 16083 - 16090
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[ 106-37-6 ]
[ 59020-06-3 ]
[ 113682-56-7 ]
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[1] Bulletin of the Chemical Society of Japan, 1992, vol. 65, # 7, p. 1855 - 1859
[2] Tetrahedron Letters, 1995, vol. 36, # 29, p. 5247 - 5250
[3] Journal of the Chemical Society, Chemical Communications, 1992, # 8, p. 620 - 622
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[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 22, p. 6696 - 6700[2] Angew. Chem., 2018, vol. 130, p. 6806 - 6810,5
75
[ 75-77-4 ]
[ 106-37-6 ]
[ 17865-11-1 ]
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[1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2816 - 2819
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[ 106-37-6 ]
[ 61676-62-8 ]
[ 68-12-2 ]
[ 128376-64-7 ]
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[1] Journal of Organic Chemistry, 2007, vol. 72, # 17, p. 6618 - 6620
77
[ 106-37-6 ]
[ 101-70-2 ]
[ 194416-45-0 ]
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[2] Journal of Photochemistry and Photobiology A: Chemistry, 2012, vol. 231, # 1, p. 51 - 59
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[ 106-37-6 ]
[ 104-94-9 ]
[ 100308-69-8 ]
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[1] Journal of the American Chemical Society, 2005, vol. 127, # 15, p. 5586 - 5595
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[ 106-37-6 ]
[ 13677-42-4 ]
[ 100308-69-8 ]
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[1] European Journal of Organic Chemistry, 2012, # 7, p. 1394 - 1403
[2] Chemistry - A European Journal, 2015, vol. 21, # 5, p. 2230 - 2240
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[ 106-37-6 ]
[ 104-94-9 ]
[ 13677-42-4 ]
[ 100308-69-8 ]
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[1] European Journal of Organic Chemistry, 2012, # 7, p. 1394 - 1403
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[ 106-37-6 ]
[ 100308-69-8 ]
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[1] European Journal of Organic Chemistry, 2012, # 7, p. 1394 - 1403
[2] European Journal of Organic Chemistry, 2012, # 7, p. 1394 - 1403
[3] Chemistry - A European Journal, 2015, vol. 21, # 5, p. 2230 - 2240
With tris-(dibenzylideneacetone)dipalladium(0); potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene for 16 h; Inert atmosphere; Reflux
A solution of tris(dibenzylideneacetone)dipalladium(0) (0.04 g, 0.084 mmol) and (±)-BINAP (0.10 g, 0.16 mmol) in toluene (10 mL) was degassed with argon for 10 min and then heated at 110 °C for 15 min. The reaction mixture was allowed to cool to room temperature before potassiumtert-butoxide (0.44 g, 3.94 mmol), 1.4-dibromobenzene (80) (0.5 g, 2.12 mmol) and 1-methylpiperazine (260 µL, 2.34 mmol) were added. The resulting mixture was heated at reflux for 16 h, cooled to room temperature and filtered through a pad of Celite®, the pad was further washed with toluene (30 mL) and the combined filtrates evaporated under reduced pressure to give the crude product. Purification by flash chromatography on silica eluting with hexane-ethyl acetate (3:1) gave the desired amine83(0.16 g, 50percent) as a colourless solid; mp 81–83 °C;νmax/cm-12940, 2814, 1568, 1456, 1245, 1220, 1107, 930; δH(500 MHz, CDCl3) 7.33 (2 H, d,J9.0 Hz), 6.79 (2 H, d,J9.0 Hz), 3.19 (4 H, t,J5.0 Hz), 2.57 (4 H, t,J5.0 Hz), 2.35 (3 H, s);δC(125 MHz, CDCl3) 150.4, 132.0, 117.8, 111.9, 55.1, 49.1, 46.3;m/z(ESI) 255/257 ([M + H]+, 70/100).
33.5%
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxaneHeating / reflux
To a solution of N-methylpiperazine (1.5g, 15mmol) in dioxane (2OmL) was added <n="44"/>13a (8.85g, 37.5mmol), Binap (563mg, 0.9mmol), Cs2CO3 (6.85g, 21mmol) and Pd2(dba)3 (275mg, 0.3mmol) subsequently under the protection of nitrogen. The mixture was heated under reflux overnight. After the reaction was complete, the mixture was cooled, diluted with EtOAc and washed with water and brine subsequently. The organic layer was concentrated under vacuo. The residue was chromatographed on silic gel (EA:PE =1 :10) and recrystallized from EtOAc to provide 13b (648 mg, 33.5percent).
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
[2] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 42-43
86
[ 106-37-6 ]
[ 201802-67-7 ]
[ 202831-65-0 ]
Yield
Reaction Conditions
Operation in experiment
64%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water; toluene for 24 h; Reflux; Inert atmosphere
General procedure: A mixture of compound 5 (0.307 g, 1 mmol), N,N-diphenyl-4-aminophenylboronic acid (0.289 g, 1 mmol), Pd(PPh3)4 (0.116 g, 0.1 mmol), and Na2CO3 (0.106 g, 1 mmol) was dissolved in toluene–THF–H2O (1 mL–1 mL–0.2 mL) and was heated under reflux for 24 h under nitrogen atmosphere. Water was added to quench the reaction after the reaction was completed. The mixture was then extracted with diethyl ether, dried over anhydrous MgSO4, and evaporated under vacuum. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) to afford two fractions. Fractions 1 product 7a (0.132 g, 28percent yield). mp 151–153 °C. IR (KBr): 3053, 3032, 1589, 1509, 1490, 1459, 1277, 1170, 909, 835, 816, 805, 755, 696, 656, 535, 509. 1H NMR (400 MHz, d6-DMSO) δ 7.76 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 7.8, 8.0 Hz, 4H), 7.10–7.05 (m, 8H), 2.83 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ 167.2, 150.0, 147.4, 139.1, 133.8, 131.8, 130.9, 130.1, 128.2, 127.7, 124.8, 123.8, 111.2, 20.6. HRMS (EI, m/z): calcd. for C26H19N2SBr, 470.0452 [M]+; found, 470.0446.(0012) Fraction 2 product 7b (24percent yield). mp 149–151 °C. IR (KBr): 3031, 2921, 1590, 1511, 1488, 1462, 1275, 1175, 921, 810, 751, 695, 643, 581, 539. 1H NMR (400 MHz, d6-DMSO) δ 7.80 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.41–7.34 (m, 5H), 7.14–7.06 (m, 8H), 2.83 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ 168.9, 151.6, 148.1, 147.2, 135.1, 135.0, 132.7, 130.3, 130.2, 128.9, 125.4, 125.1, 124.2, 122.7, 114.1, 20.2. HRMS (EI, m/z): calcd. for C26H19N2SBr, 470.0452 [M]+; found, 470.0457.
Reference：
[1] Dyes and Pigments, 2013, vol. 96, # 3, p. 619 - 625
87
[ 106-37-6 ]
[ 203314-28-7 ]
Reference：
[1] Patent: CN107759459, 2018, A,
88
[ 106-37-6 ]
[ 419536-33-7 ]
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[1] Patent: WO2011/14039, 2011, A1,
[2] Advanced Functional Materials, 2010, vol. 20, # 15, p. 2448 - 2458
[3] Patent: US8093399, 2012, B2,
[4] Inorganica Chimica Acta, 2012, vol. 391, p. 50 - 57
[5] Patent: US8288012, 2012, B2,
[6] Organic and Biomolecular Chemistry, 2012, vol. 10, # 47, p. 9481 - 9490
[7] Dyes and Pigments, 2013, vol. 96, # 3, p. 705 - 713
[8] Chemical Communications, 2013, vol. 49, # 34, p. 3597 - 3599
[9] Angewandte Chemie - International Edition, 2014, vol. 53, # 19, p. 4850 - 4855[10] Angew. Chem., 2014, vol. 126, # 19, p. 4950 - 4955,6
[11] Patent: EP2857395, 2015, A1,
[12] Journal of the Chilean Chemical Society, 2015, vol. 60, # 2, p. 2971 - 2974
[13] Journal of Materials Chemistry C, 2015, vol. 3, # 48, p. 12529 - 12538
[14] Patent: CN105585577, 2016, A,
89
[ 106-37-6 ]
[ 470478-90-1 ]
Reference：
[1] Patent: US2018/179183, 2018, A1,
90
[ 106-37-6 ]
[ 1009033-87-7 ]
Reference：
[1] Patent: WO2014/202528, 2014, A1,
91
[ 106-37-6 ]
[ 73183-34-3 ]
[ 1256781-64-2 ]
[ 1457983-17-3 ]
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[1] Journal of the American Chemical Society, 2015, vol. 137, # 25, p. 8058 - 8061
92
[ 106-37-6 ]
[ 1045332-30-6 ]
Reference：
[1] Patent: CN105601613, 2016, A,
93
[ 897671-69-1 ]
[ 106-37-6 ]
[ 1246562-40-2 ]
Yield
Reaction Conditions
Operation in experiment
79%
With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 95℃; for 4 h;
1,4-dibromobenzene (2.4 g, 0.010 mol) in N-(biphenyl-4-yl) -9,9-dimethyl-9H-fluoren-2-amine (3.6 g, 0.010 mol), Pd(dba)2 ( 0.5 g, 0.0005 mol), sodium-tert-butoxide (1.9 g, 0.020 mol) in 70 mL TOL into a 95°C, 4 hours reaction was stirred. After completion of the reaction H 2 0: after the delamination MC column purification (n-HEXANE: MC) to afford 4.1 g of Intermediate 1-1 (79percent). (M / z = 516)
70%
With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 95℃; for 4 h;
General procedure: Intermediates 1-1 (5.0 g, 0.018 mol), 4-bromo-N,N-dip-tolylaniline (12.5 g, 0.036 mol), Pd(dba)2 (0.8 g, 0.0009 mol), sodium-tert-butoxide (3.5 g, 0.052 mol) in TOL 200 ml was reacted at 95 °C for 4 hours. Reaction after column purification separation H20:MC (n-HEXANE: MC) 11.2 g (75percent yield) of compound 1 are obtained. 1,4-dibromobenzene (3.0 g, 0.013 mol) N-(biphenyl-4-yl)-9,9-dimethyl-9H-fluoren-2-amine (4.7 g, 0.013 mol) for inserting and removing manufacturing e.g. in the embodiment 1-(2) the same method used in the synthesis of <intermediate 5-2> 4.7 g (70percent yield) is obtained. (m/z=516)
57%
With tri-tert-butyl phosphine; palladium diacetate; caesium carbonate In toluene at 110℃; Inert atmosphere
A mixture of 1,4-dibromobenzene(0.2 g, 0.8 mmol), 2-(4-biphenylyl)amino-9,9-dimethylfluorene (0.36 g, 1 mmol), Pd(OAc)2 (0.046 g, 0.2 mmol),P(t-Bu)3 (0.04 g, 0.2 mmol), and Cs2CO3 (1.63 g, 5 mmol) in drytoluene (15 mL) was stirred and heated at 110° C overnight. After the mixture was cooled to room temperature, saturated ammonium chloride solution was added to the reaction solution. The solution was extracted with dichloromethane, dried with MgSO4,and subjected to column chromatography (silica gel, dichloromethane/hexanes = 3:1). A yellow solid was obtained with the following properties: yield, 57percent (0.24 g); mp 160.1–161.5° C; 1HNMR [400 MHz, (CD3)2CO]: δ 7.64 (d, 1H, J = 8 Hz), 7.60–7.57 (m,3H), 7.50–7.48 (m, 2H), 7.43-7.40 (m, 2H), 7.38–7.26 (m, 5H), 7.25(s, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 7.15 (s, 1H), 7.06–7.02 (m, 3H),1.42 (s, 6H). HRMS: m/z calcd. for C33 H26 Br N: 516.1321 [M-H];Found: 516.1337.
Reference：
[1] Patent: KR2016/66308, 2016, A, . Location in patent: Paragraph 0289-0291
[2] Patent: KR2015/131700, 2015, A, . Location in patent: Paragraph 0104; 0143; 0147-0149
[3] Chinese Chemical Letters, 2017, vol. 28, # 2, p. 285 - 292
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 6, p. 681 - 696
[2] Organic Process Research and Development, 2018, vol. 22, # 6, p. 681 - 696
[3] Organic Process Research and Development, 2018, vol. 22, # 6, p. 681 - 696
98
[ 106-37-6 ]
[ 761446-44-0 ]
[ 1191616-45-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 3 h; Inert atmosphere
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 1-methyl-4-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 9.61 mmol), 1 ,4-dibromobenzene (2.30 g, 9.75 mmol), Pd(PPh3)4 (550 mg, 0.48 mmol), potassium carbonate (2.60 g, 18.8 mmol), dioxane (40 ml_) and water (10 ml_). The resulting solution was stirred for 3 h at 80°C. The resulting mixture was evaporated to dryness. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 1.70 g (75percent) of 4-(4- bromophenyl)-1-methyl-1 H-pyrazole as a yellow solid.
To 200 ml toluene, 94g phenol and 80 g 50% caustic soda lye are added and water is azeotropically distilled out. 50 ml DMF and 475 g paradibromo benzene (PDBB) and 5 g cuprous bromide are added to it. The mass is maintained at 160-165C for 5 hours by distilling toluene. The mass is filtered at 80C, washed with toluene and the filtrate fractionally distilled under vacuum to give 229 g 4-bromodiphenyl ether, 99% purity, b.p. - 125C/2 mm
With copper(l) iodide; caesium carbonate; dimethylbiguanide; In N,N-dimethyl-formamide; at 20 - 110℃; for 15.1667h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110?C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
85%
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h;Catalytic behavior;
General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60-120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
81%
With C40H34CuIN6O6; sodium hydroxide; In dimethyl sulfoxide; at 100℃; for 4h;Sealed tube;
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
With potassium hydroxide; at 60℃; for 0.5h;Green chemistry;Catalytic behavior;
General procedure: In a round-bottomed flask equipped with mechanical stirrer,aryl halide (1 mmol), amine (1.2 mmol), catalyst (5 mg) and KOH(2 mmol) were stirred in ethanol (5 ml) under air atmosphere at 60C for 0.5 h. The progress of the reaction was monitored by TLC and GC. After completion of the reaction, CH2Cl2 (15 ml) was added and the catalyst was separated using an external magnet. The organic layer was washed with water (3 x 10 ml) and dried over anhydrous MgSO4. The product was isolated by column chromatography (nhexaneeethylacetate, 5:1) to afford the corresponding products.The products were characterized by their physical properties,melting points, and FT-IR, 1H NMR and 13C NMR [69-71].
56%
With tris-(dibenzylideneacetone)dipalladium(0); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 80℃; for 16h;Sealed tube; Inert atmosphere;
To a 50 mL sealed tube were added R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.20 g, 0.31 mmol), tris(dibenzylideneacetone)dipalladium (0.095 g, 0.10 mmol), sodium tert-butoxide (0.49 g, 5.0 mmol), p-dibromobenzene (1.00 g, 4.15 mmol) and morpholine (0.37 mL, 4.2 mmol), then anhydrous toluene (8 mL) was added under nitrogen protection. The resulting mixture was stirred for 16 h at an oil bath temperature of 80C. The reaction mixture was cooled to rt and to the mixture was added EtOAc (20 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE:EtOAc=15:1, V/V)to give a white solid (0.56 g, 56%). MS(ESI, pos.ion)m/z:242.00(M+1)
47%
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Inert atmosphere; Reflux;
A solution of tris(dibenzylideneacetone)dipalladium(0) (0.093 g, 0.1 mmol) and (±)-BINAP (0.13 g, 0.21 mmol) in toluene (7 mL) was degassed with argon for 10 min and then heated at 110 C for 15 min. The reaction mixture was allowed to cool to room temperature before potassiumtert-butoxide (0.53 g, 4.73 mmol), 1,4-dibromobenzene (80) (0.6 g, 2.54 mmol) and morpholine (332 muL, 3.82 mmol) were added. The resulting mixture was heated at reflux for 16 h, cooled to room temperature and filtered through a pad of Celite, the pad was further washed with toluene (30 mL) and the combined filtrates evaporated under reduced pressure to give the crude product. Purification by flash chromatography on silica eluting with hexane-ethyl acetate (6:1) gave the desired amine81(0.19 g, 47%) as a colourless solid; mp 110-111 C;numax/cm-12965, 2857, 2831, 1589, 1495, 1259, 1236, 1120, 923, 818; deltaH(300 MHz, CDCl3) 7.35 (2 H, d,J9.0 Hz), 6.78 (2 H, d,J9.0 Hz), 3.84 (4 H, t,J6.0 Hz), 3.11 (4 H, t,J6.0 Hz);deltaC(75 MHz, CDCl3) 150.3, 132.0, 117.4, 112.3, 66.8, 49.3;m/z(APCI) 242/244 ([M + H]+, 68/100).
26.96%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; johnphos; In 1,4-dioxane; at 100℃; for 12h;Sealed tube; Inert atmosphere;
To a stirred solution of morpholine (2.0 g, 23.0 mmol), 1, 4-dibromo benzene (19.4 g,82.2 mmol) and 1,4-dioxane (10.0 mL) in sealed tube, 0s2003 (22.4 g, 68.7 mmol)was added and degasified with argon. To the above solution Pd2(dba)3 (0.2 g, 0.22mmol) and 2-(di-tert-butylphosphino)biphenyl (0.6 g, 2.0 mmol) was added andheated at 100 00 for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with water, brine solution and dried. Finally, concentrated under vacuo and purified by the column chromatography to yield the desired product (1 .5 g, 26.96%) as a yellow solid. LCMS: (M+2) =244.0; 1HNMR: (ODd3, 300MHz) 6 7.34-7.37 (d, 2H), 6.76-6.79 (d, 2H), 3.84-3.87 (t, 4H),3.10-3.13 (t, 4H).
With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); johnphos; In 1,4-dioxane; for 20h;Heating / reflux;
EXAMPLE 35; Synthesis of (2S)-N-(Cyanomethyl)-4-methyl-2-[(R)-(4'-morpholin-4-yl-1,1 '-biphenyl-4-yl)(phenyl)methyl]oxy}pentanamide; Step 1; 4-(4-Bromophenyl)morpholine;To a solution of of morpholine (0.85 mmol, 739 mg) in dioxane (12 mL) was added 1,4-dibromobenzene (21.2 mmol, 5 g), 2-(di-t-butylphosphine)biphenyl (1.02 mmol, 304mg), potassium t-butoxide (25.5 mmol, 2.47 g) and Pd2(dba)3 (0.254 mmol, 233 mg). The mixture was degassed under a stream of nitrogen and then heated to reflux for 20 h. The mixture was diluted with EtOAc and washed with water and brine. The organic extract was concentrated under reduced pressure and the residue was chromatographed to give the desired product
With N,N,N,N,-tetramethylethylenediamine; iodine; In tetrahydrofuran; nitrogen; benzene;
1 Synthesis of 4-Decylbromobenzene: In a reaction flask were charged 10.2 g of metallic magnesium, 100 ml of THF, and a small amount of iodine in a nitrogen stream, and a part of 500 ml of a THF solution containing 100 g of 1,4-dibromobenzene was added thereto dropwise to initiate reaction. Then, the rest of the solution was added dropwise at 25 to 30 C. over a 2-hour period, and the mixture was allowed to react at 40 C. for 1 hour, followed by cooling to prepare a Grignard reagent. Separately, 187 g of decyl bromide, 500 ml of benzene, 98.3 g of N,N,N',N'-tetramethylethylenediamine, and 2.1 g of copper (I) chloride were put in a reaction flask, and the atmosphere was displaced with nitrogen. The mixture was heated to 50 C., and the above prepared Grignard reagent was added thereto dropwise at that temperature over 30 minutes. The reaction mixture was allowed to react for 24 hours, cooled, and poured into a saturated aqueous ammonium solution, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate to recover 107 g of a crude product. The crude product was distilled in a Claisen flask equipped with a Vigreaux tube cylinder to obtain 43.7 g of the title compound.
1,4-bis[4-(trans-4-propylcyclohexyl)-cyclohexen-1-yl]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; potassium hydrogen sulphate; In tetrahydrofuran; nitrogen; toluene;
EXAMPLE 26 Preparation of 1,4-bis[4-(trans-4-propylcyclohexyl)-cyclohexen-1-yl]benzene (a compound of the formula (X) wherein R is propyl) A solution of p-dibromobenzene (5.6 g, 0.024 mol) dissolved in tetrahydrofuran (200 ml) was dropwise added to sliced Mg (1.2 g, 0.049 mol) in nitrogen current so as to give soft reflux. After 7 hours, the reaction finished to yield its magnesium bromide, to which a solution of <strong>[82832-73-3]4-(trans-4-propylcyclohexyl)-cyclohexanone</strong> (10.9 g, 0.049 mol) dissolved in tetrahydrofuran (100 ml) was rapidly dropwise added while the temperature was kept at 30 C. or lower. After the addition, the mixture was refluxed for 1.5 hour and 3N hydrochloric acid was added. The reaction liquid was extracted with toluene (100 ml*3), combined toluene layers were washed with water and the solvent was distilled off under reduced pressure. The remaining oily substance was 1,4-bis[4-(trans-4-propylcyclohexyl)-cyclohexan-1-ol]benzene, to which potassium hydrogen sulfate (2.5 g) was added, followed by dehydrating at 200 C. for 2 hours in nitrogen current, cooling, adding toluene (300 ml), filtering off potassium hydrogen sulfate, washing toluene layer with water, distilling off the solvent under reduced pressure and recrystallizing the residue from toluene to obtain an objective product, 1,4-bis[4-(trans-4-propylcyclohexyl)cyclohexen-1-yl]benzene (yield: 0.9 g) having a C-Sm point of 98.5 C. and a Sm-I point of 300 C. or higher.
(i) Production of 8-(4-bromophenyl)-5,6,7,8-tetrahydroimidazo-[1,5-a]pyridin-8-ol The reactions in the same manner as in Example 19 using 1,4-dibromobenzene (4.53 g), a hexane solution (1.6 M; 10.0 ml) of n-butyl lithium and <strong>[426219-51-4]6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one</strong> (1.09 g) afforded the title compound (916 mg) as a pale-yellow powder. 1H-NMR(CDCl3) delta: 1.85-2.05(2H, m), 2.1-2.25(1H, m), 2.3-2.5(1H, m), 3.85-4.05(1H, m), 4.15-4.3(1H, m), 6.67(1H, s), 7.36(2H, d, J=8.8 Hz), 7.46(2H, d, J=8.8 Hz), 7.47(1H, s). IR(KBr): 1485, 1453, 1397, 1208, 1105, 953, 936, 831, 812 cm-1.
Preparation 1 (4-bromophenyl)(3-hydroxy-2-pyridinyl)methanone 48.5 g (205.5 mM) of 1,4-dibromobenzene are added dropwise to a mixture containing one crystal of iodine and 5 g (205.5 mM) of magnesium metal covered with 150 ml of THF. The mixture is stirred at the reflux temperature of the solvent for 2 hours and then cooled to 10 C. 12.34 g (102.7 mM) of 2-cyano-3-pyridinol are then added dropwise. The reaction medium is heated at the reflux temperature of the solvent for 3 hours, then stirred for 18 h at room temperature and then treated with 300 ml of 0.5 N sulfuric acid. The solvents are driven off under reduced pressure and the residual aqueous phase is brought to pH 4 by adding a necessary and sufficient amount of 2 N sodium hydroxide solution. The neutralized mixture is extracted with dichloromethane and the organic phase is dried over magnesium sulfate. After evaporation of the solvent, the expected product is obtained in the form of a yellow solid with a yield of 35%. M.p.=94-95 C.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; for 48h;Inert atmosphere; Reflux;
Example 1 Synthesis of 4,4'-(1,4-phenylene)bis(1-hexylpyridin-1-ium) bis(tetrafluroborate) A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.34 g, 21.2 mmol), 1,4-dibromobenzene (2.00 g, 8.5 mmol), K2CO3 (2.92 g, 21.2 mmol) and Pd(PPh3)4 (0.49 g, 5 mol percent) in PhMe (30 mL) and EtOH (30 mL) under N2 was heated at reflux for 48 h. The resulting mixture was poured into water (50 mL), extracted with dichloromethane (2*100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using MeOH (0-5percent) in dichloromethane as eluent. The solvent was removed under reduced pressure and the residue crystallised from hot EtOAc/hexanes to give 1,4-di(4-pyridyl)benzene (1.52 g, 77percent) as a pale yellow powder.
71%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In N,N-dimethyl-formamide; toluene; at 130℃; for 48h;Inert atmosphere;
Pyridylboronic pinacol ester (3.64 g, 17.8 mmol), 1,4-dibromobenzene (1.40 g, 5.92 mmol), and Cs2CO3 (11.6 g, 35.5 mmol) were added to a 1:1 mixture of dry PhMe/DMF (300 mL), which had been degassed with Ar for 15 min. Next, Pd(PPh3)4 (0.68 g, 0.59 mmol) was added to the reaction mixture and the solution heated to 130° C. under Ar for 48 h. Then, the reaction mixture was cooled to room temperature and the palladium catalyst filtered off using Celite. The organic phase was concentrated under vacuum and then dissolved in CH2Cl2 followed by extraction with H2O three times. The organic layer was made acidic (pH 2-3) by adding dropwise concentrated HCl, which caused the desired product to precipitate from solution. The precipitate was collected by filtration and then dissolved in H2O. Finally, aq. NaOH (10 M) was added dropwise to the water layer until the pH was 8-9, which resulted in precipitation of pure product ExBIPY (973 mg, 71percent) as a white solid. The yield of the product obtained in the reaction was 71percent. 1H NMR (500 MHz, CDCl3, ppm): deltaH 8.72 (AA? of AA?XX?, J=4.6, 1.6 Hz, 4H), 7.80 (s, 4H), 7.59 (XX? of AA?XX?, J=4.6, 1.6 Hz, 4H).
Step 2: Preparation of N-[3-(4-bromophenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide A solution of n-butyllithium in hexanes (1.65M, 4.92 mL) was added dropwise to a solution of 1,4-dibromobenzene (2.05 g) in THF (25 mL) dropwise over the course of 30 min at -78 C. The resulting mixture was stirred at the same temperature for 1 h. To the mixture was added a solution of <strong>[1158098-73-7]2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide</strong> (1.02 g) in THF (5 mL) dropwise over the course of 30 min at -78 C. The reaction mixture was stirred for an additional 30 min. at -78 C. then allowed to warm to room temperature. After being stirred for 1 h at room temperature, the reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes then 5% methanol in ethyl acetate) gave the product (1.85 g, 96%). 1HNMR (CDCl3) 400 MHz delta: 7.55 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.16 (d, J=6.9 Hz, 1H), 5.06 (d, J=6.9 Hz, 1H), 5.02 (d, J=6.9 Hz, 1H), 4.94 (d, J=6.9 Hz, 1H), 4.05 (br s, 1H), 1.22 (s, 9H). LCMS: 332, 334 [M+H].
76%
p-Dibromobenzene (0.8 g, 3 mmol) was dissolved in tetrahydrofuran (30 mL).Add n-butyl lithium (3 mL, 3 mmol),After stirring at -80 C for 1 hour,Add tert-butylsulfinyl-3-oxetanimide (0.6 g, 3 mmol),Stir at room temperature for 2 hours.The reaction solution was concentrated to dryness.Purified by silica gel column chromatography,A white solid (0.6 g, 76%) was obtained.
36%
Step 1: Preparation of N-(3-(4-bromophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide To 1,4-dibromobenzene (0.5 g, 2.12 mmol) in dry THF (8.8 mL) at -78 C. was added a solution of n-butyllithium (1.2 mL, 2.97 mmol). The resulting mixture was stirred for 1 h, then <strong>[1158098-73-7]2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide</strong> (0.371 g, 2.12 mmol) in dry THF (1.8 mL) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred another 1 h. The mixture was then quenched with saturated NH4Cl (aq) and extracted with EtOAc. The organic phase was washed with saturated sodium bicarbonate (aq), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (gradient 0-100% EtOAc in heptane) to afford N-(3-(4-bromophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (284 mg, 36%): LCMS Rt=0.95 min (condition B), MS (M+3)=334.0.
With pyridinium hydrobromide perbromide; In tetrahydrofuran; water; at 20℃; for 0.333333h;
General procedure: The trifluoroborate (1.0 mmol) was dissolved in (1:1 v/v) mixture of tetrahydrofuran and water (10 mL). Pyridinium tribromide (or tetrabutylammonium tribromide) (1.0 mmol) was added to this solution. The mixture was stirred for the appropriate time and temperature (Tables 1and 2) and then diluted with 10 mL of ether. The aqueous layer was extracted twice with ether (5 mL) and the combined organic phase was dried over anhydrous Na2SO4. After evaporation of the solvent the residue was purified by silica gel column chromatography [elute: hexane (or pentane)-ethyl acetate (or Et2O)].
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 8h;Inert atmosphere;
General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 110℃; for 48h;Inert atmosphere;
In the Ar gas protection,Using the intermediate H as a starting material (620 mg; 5 mmol)Were charged into a 50 ml two-necked flask,1,4-dibromobenzene(1.2 g; 5 mmol), 10 mg of Pd (pph3) 4, anhydrous potassium carbonate (1.38 g, 5 mmol)5ml distilled oxygen,40ml anhydrous oxygen-free toluene,110 ° C reflux reaction 48h.Saturated ammonium chloride solution was quenched and extracted with ethyl acetate.The solvent was removed by rotary evaporator,The crude product was then purified by column chromatography to give the substituent (11) as a white solid 700mg(61percent).
26.26%
A 500 mL sealed tube was charged with pyridin-4-ylboronic acid (1.6 g, 13.0 mmol) 1,4-dibromobenzene (3.07 g, 13.0 mmol), sodium carbonate (5 mL, 2M solution) and mixture of toluene (10 mL) and water (10 mL). The reaction mixture was purged with argon for 30 mm. Then, Pd(PPh3)4 (0.75 g, 0.05 eq) was added to the reactionmixture and the said mixture was heated at 90 00 for about 12 h. After cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuo to yield crude product, which was purified by column chromatography to yield title compound (0.8 g, 26.26percent) as a white solid. LCMS: (M+2) = 236.0; 1H NMR:(DMSO-d6, 300MHz) 68.64-8.66 (d, 2H), 7.71- 7.80 (m, 6H).
26.26%
A 500 mL sealed tube was charged with pyridin-4-ylboronic acid (1.6 g, 13.0 mmol)1 ,4-dibromobenzene (3.07 g, 13.0 mmol), sodium carbonate (5 mL, 2M solution) andmixture of toluene (10 mL) and water (10 mL). The reaction mixture was purged withargon for 30 mm. Then, Pd(PPh3)4 (0.75 g, 0.05 eq) was added to the reactionmixture and heated at 90 00 about 12 h. After cooling, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuo to yield crude product, which was purified by column chromatography to yield title compound (0.8 g, 26.26percent) as a white solid. LCMS: (M+2) = 236.0; 1H NMR: (DMSO-d6, 300MHz ) 68.64-8.66 (d, 2H), 7.71- 7.80 (m, 6H).
With potassium carbonate; palladium; In toluene; at 80℃; for 16h;Inert atmosphere;
Under N2 gas purification system, Compound A, 0.9 equivalents of compound B, 0.05 equivalents of Pd (0) and 4.0 equivalents of potassium carbonate into toluene, the mixture at a temperature of 80 deg. C oil bath with stirring. After 16 hours, water was added to the mixture, was extracted, the product was eluted with methylene chloride and hexane (2: 1) through the column to obtain a white solid compound C.
1-benzyl-4-(4-bromo-phenyl)-3,3-dimethyl-piperidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
STEP B: 1-Benzyl-4-(4-bromo-phenyl)-3,3-dimethyl-piperidin-4-ol1,4-Dibromobenzene (9.31 g, 39.5 mmol) was dissolved in dry THF (50 ml) in a two necks round-bottom flask equipped with a stirring bar, a septum, and an addition funnel with nitrogen inlet. The solution was cooled to -78C, and n-BuLi (1.6 M, 24.7 ml, 39.5 mmol) was added dropwise via syringe. The 25 resulting milky suspension was stirred for 1 hour at the same temperature, before a solution of <strong>[173186-91-9]1-benzyl-3,3-dimethyl-piperidin-4-one</strong> (7.15 g, 32.9 mmol) in THF (50 ml) was slowly added from the addition funnel. The clear solution was then stirred for 3 hours allowing the temperature to rise to ambient. The reaction was quenched with saturated NH4Cl (50 ml) and water (100 ml). The organics were extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried over MgSO4, filtered and concentrated to a viscous oil. Purification of the oil over silica gel eluting with a gradient of MeOH in DCM from 0 to 6% yielded the desired product. 1H NMR (300 MHz, CDCl3) ppm 0.72 (s, 3 H), 0.94 (s, 3 H), 1.41 - 1.55 (m, 2 H), 2.29 (d, J=11.2 Hz, 1 H), 2.38 (d, J=11.2 Hz, 1 H), 2.48 (m, 1 H), 2.74 - 2.86 (m, 2 H), 3.47 (d, J=13.4 Hz, 1 H), 3.59 (d, J=13.4 Hz, 1 H), 7.22 - 7.39 (m, 7 H), 7.44 (d, J=8.7 Hz, 2H). MS m/z 374 (M+H)+
With potassium phosphate monohydrate; palladium dichloride; 3-(diphenylphosphino)propionic acid; In dimethyl sulfoxide; at 100℃; for 12h;Schlenk technique;
General procedure: The Schlenk tube (5 mL) equipped with a stir bar was charged with PdCl2 (1.0 molpercent), Ph2P(CH2)2COOH (2.0 molpercent), and K3PO4 ·H2O (4.0 equiv.), then 1,4-dibromobenzene (0.5 mmol), phenylboronic acid (1.20 mmol), and DMSO (2.0 ml) were added, and the mixture was stirred at 100 °C until the substrate was completely consumed. After cooling to room temperature, the solution was quenched with water and extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts were dried over anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE as the eluent to obtain the desired products.
9-(4'-bromo-[1,1'-biphenyl]-3-yl)-9H-carbazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 40 - 100℃; for 5h;Inert atmosphere;
Under a stream of nitrogen 50.0 g (187.18 mmol) of (3 - (9H-carbazol-9-yl) phenyl) boronic acid, 47.53 g (187.18mmol) of 1,4-dibromobenzene, 77.61 g (561.55 mmol) of K2CO3, 1000 ml / 250 ml / stirred into the Toluene / H2O / EtOH in 250 ml. At 40°C into the Pd (PPh3) 4 g of 10.81 (5 molpercent) it was stirred at 100°C for 5 hours. After completion of the reaction and extracted with methylene chloride and the filter insert MgSO4. The solvent of the filtered organic layer was purified by column chromatography to 57.41 g (yield: 77percent) of 9- (4'-bromo- [1,1'-biphenyl] -3-yl) -9H-carbazole was obtained.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 80℃; for 5h;
At 80C, 4-dibenzofuranboronic acid (13.3g), 1,4-dibromobenzene (10g), tetrakis(triphenylphosphine)palladium (3.02g), toluene (158mL), ethanol (65mL), water (65mL), and potassium carbonate (21.69g) were stirred for 5 hours. The reaction was monitored by thin layer chromatography. Upon completion of the reaction, it was quenched with water (100mL) and extracted with ethyl acetate (100mL). The organic layer was extracted with water (3x30mL) and dried over anhydrous sodium sulfate. The ethyl acetate layer was collected through Celite and further purified by column chromatography. Following this, the ethyl acetate layer was evaporated to dryness under vacuum rotavap to yield 13.7g 4-(4'-bromophenyl)dibenzofuran.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; toluene; at 80℃; for 24h;Inert atmosphere;
Under nitrogen environment, compound G was dissolved in tetrahydrofuran / toluene (5: 1) and then 0.9 equivalent of compound F was added. After 4.4 equivalent of Potassium carbonate was dissolved in DI water, 0.05 equivalent of Pd (0) was added. The reaction mixture was then refluxed at 80 C. for 24 hours and the reaction was terminated. After extraction with organic solvent, the organic solvent was removed. Compound H was obtained by reprecipitation after a column.
tert-butyl (R)-(1-(4-bromophenyl)-2-oxopiperidin-3-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium phosphate; copper(l) iodide; N,N-dimethylethylenediamine; In 1,4-dioxane; at 60℃;Sealed tube; Inert atmosphere;
In a 1 L sealed tube, to a solution of <strong>[221874-51-7](R)-tert-butyl (2-oxopiperidin-3-yl)carbamate</strong> (23 g, 110 mmol) in 1,4-dioxane (300 mL) was added 1,4-dibromobenzene (28 g, 120 mmol), potassium phosphate tribasic (34 g, 160 mmol), cuprous iodide (8.2 g, 43 mmol), Nu,Nu'- dimethylethylenediamine (4.7 ml, 43 mmol). The reaction mixture was purged with Argon for 10-15 minutes and then heated to 60 C for overnight. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with brine solution (200 mL). The organic layer was dried over Na2S04 and concentrated to produce the crude product. The crude compound was purified through 330 gm Silica column and was eluted with ethylacetate:pet-ether (40:60) to achieve off white solids of tert-butyl (l-(4- bromophenyl)-2-oxopiperidin-3-yl)carbamate (20 gm). Chiral SFC analysis of the purified product showed -10% epimerization. The compound was then purified via SFC to afford Intermeidate la (15 gm, 40 mmol, 38% yield) as a white solid. MS(ESI) m/z: 369.0/371.0 (M+H). NMR (400 MHz, CDCh): delta ppm 7.48 (d, J = 4.8 Hz, 2H), 7.11 (d, J= 4.8 Hz, 2H), 5.48 (br-s, 1H), 4.25-4.18 (m, 1H), 3.70-3.62 (m, 2H), 2.60-2.52 (m, 1H), 2.08-1.95 (m, 2H), 1.74-1.64 (m, 1H), 1.43 (s, 9H). [a]D25 (c = 0.1, MeOH): +30.0. Chiral Purity (SFC): 99.9%, retention time = 4.15 min (time of Peak-01 (0.105%) = 3.03 min & Retention time of Peak-02 (99.9%) = 4.15 min; Co-Solvent: 0.2%DEA in Methanol; Column: Whelk-01 ( R,R )(250 X 4.6)mm 5u; Column Temperature: 24.5; Total Flow: 3; C02 Flow Rate: 1.8; Co-Solvent Flow Rate: 1.2; Co-Solvent% 40; Back Pressure 100.) Preparative SFC Conditions: Column/dimensions: Whelk(R,R) (250 X 30) mm, 5u; C02%: 70%; Co-solvent%: 30% of (0.2% DEA in methanol); Total Flow: 120 g /min; Back Pressure: 100 bar; Temperature: 30C; UV: 240 nm. Retention time of Peak-01 = 3.20 min & Retention time of Peak-02 = 4.60 min;
38%
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 60℃;Sealed tube; Inert atmosphere;
In a 1 L sealed tube, to a solution of <strong>[221874-51-7](R)-tert-butyl (2-oxopiperidin-3-yl)carbamate</strong> (23 g, 110 mmol) in 1,4-dioxane (300 mL) was added 1,4-dibromobenzene (28 g, 120 mmol), potassium phosphate tribasic (34 g, 160 mmol), cuprous iodide (8.2 g, 43 mmol), Nu,Nu'- dimethylethylenediamine (4.7 ml, 43 mmol). The reaction mixture was purged with Argon for 10-15 minutes and then heated to 60 C for overnight. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with brine solution (200 mL). The organic layer was dried over Na2S04 and concentrated to produce the crude product. The crude compound was purified through 330 g Silica column and was eluted with ethylacetate:pet-ether (40:60) to achieve off white solids of tert-butyl (l-(4- bromophenyl)-2-oxopiperidin-3-yl)carbamate (20 g). Chiral SFC analysis of the purified product showed -10% epimerization. The compound was then purified via SFC to afford Intermediate 1 (15 g, 40 mmol, 38% yield) as a white solid. MS(ESI) m/z: 369.0/371.0 (M+H). NMR (400 MHz, CDCh):? ppm 7.48 (d, J = 4.8 Hz, 2H), 7.11 (d, J= 4.8 Hz, 2H), 5.48 (br-s, 1H), 4.25-4.18 (m, 1H), 3.70-3.62 (m, 2H), 2.60-2.52 (m, 1H), 2.08- 1.95 (m, 2H), 1.74-1.64 (m, 1H), 1.43 (s, 9H). [a]D25 (c = 0.1, MeOH): +30.0. Chiral Purity (SFC): 99.9%, retention time = 4.15 min (time of Peak-01 (0.105%) = 3.03 min & Retention time of Peak-02 (99.9%) = 4.15 min; Co-Solvent: 0.2%DEA in Methanol; Column: Whelk-01 ( R,R )(250 X 4.6)mm 5u; Column Temperature: 24.5; Total Flow: 3; C02 Flow Rate: 1.8; Co-Solvent Flow Rate: 1.2; Co-Solvent% 40; Back Pressure 100.) (0145) Preparative SFC Conditions: Column/dimensions: Whelk(R,R) (250 X 30) mm, 5u; C02%: 70%; Co-solvent%: 30% of (0.2% DEA in methanol); Total Flow: 120 g /min; Back Pressure: 100 bar; Temperature: 30C; UV: 240 nm. Retention time of Peak-01 = 3.20 min & Retention time of Peak-02 = 4.60 min.
38%
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 60℃;Inert atmosphere;
In a 1 L sealed tube, to a solution of (i?)-tert-butyl (2-oxopiperidin-3-yl)carbamate (23 g, 110 mmol) in 1,4-dioxane (300 mL) was added 1,4-dibromobenzene (28 g, 120 mmol), potassium phosphate tribasic (34 g, 160 mmol), cuprous iodide (8.2 g, 43 mmol), Nu,Nu'- dimethylethylenediamine (4.7 ml, 43 mmol). The reaction mixture was purged with Argon for 10-15 minutes and then heated to 60 C for overnight. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with brine solution (200 mL). The organic layer was dried over Na2S04 and concentrated to produce the crude product. The crude compound was purified through 330 gm Silica column and was eluted with ethylacetate:pet-ether (40:60) to achieve off white solids of tert-butyl (l-(4- bromophenyl)-2-oxopiperidin-3-yl)carbamate (20 gm). Chiral SFC analysis of the purified product showed -10% epimerization. The compound was then purified via SFC to afford Intermeidate la (15 gm, 40 mmol, 38% yield) as a white solid. MS(ESI) m/z: 369.0/371.0 (M+H). NMR (400 MHz, CDCh): delta ppm 7.48 (d, J= 4.8 Hz, 2H), 7.11 (d, J= 4.8 Hz, 2H), 5.48 (br-s, 1H), 4.25-4.18 (m, 1H), 3.70-3.62 (m, 2H), 2.60-2.52 (m, 1H), 2.08-1.95 (m, 2H), 1.74-1.64 (m, 1H), 1.43 (s, 9H). [a]D25 (c = 0.1, MeOH): +30.0. Chiral Purity (SFC): 99.9%, retention time = 4.15 min (time of Peak-01 (0.105%) = 3.03 min & Retention time of Peak-02 (99.9%) = 4.15 min; Co-Solvent: 0.2%DEA in (0236) Methanol; Column: Whelk-01 ( R,R )(250 X 4.6)mm 5u; Column Temperature: 24.5; Total Flow: 3; C02 Flow Rate: 1.8; Co-Solvent Flow Rate: 1.2; Co-Solvent% 40; Back Pressure 100.) (0237) Preparative SFC Conditions: Column/dimensions: Whelk(R,R) (250 X 30) mm, 5u; (0238) C02%: 70%; Co-solvent%: 30% of (0.2% DEA in methanol); Total Flow: 120 g /min; Back Pressure: 100 bar; Temperature: 30C; UV: 240 nm. Retention time of Peak-01 = 3.20 min & Retention time of Peak-02 = 4.60 min;
250 ml of a four-necked flask, and 11.8 g was added under an atmosphere of nitrogen gas1,4-dibromobenzene (0.05 mol) and1.33 g Mg powder (0.055 mol), 60 ml of tetrahydrofuran,Heated to reflux for 4 hours, the reaction is complete, the formation of format reagents;11.1 g of <strong>[5447-86-9]10,10-dimethylanthrone</strong> (0.05 mol) was dissolved in 50 ml of tetrahydrofuran,The above-mentioned format reagent was added dropwise and reacted at 60 C for 24 hours to form a large amount of white precipitate,Finally, saturated NHCl4 was added to convert the format salt to alcohol. After completion of the reaction, the ether was extracted,Drying and steaming, petroleum ether: dichloromethane mixed solvent (3: 2) silica gel column,A slightly solid solid tertiary alcohol (yield 88%) was obtained
With trans-di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II); sodium acetate; In N,N-dimethyl acetamide; at 100 - 140℃; for 48h;Schlenk technique; Inert atmosphere;
General procedure: A solution of aryl halide 7a-c (6.37mmol; 1equiv) anddry NaOAc (7.64mmol; 1.2equiv) in N,N-dimethylacetamide (3mL) was placed in a Schlenk tube and repeatedly degassed and purged with argon five times. The styrene derivative 6a-d (1.4equiv) was added and the mixture was heated to 100C. Next, a solution of Herrmann's catalyst (59.68mg, 1mol%) in N,N-dimethylacetamide (2mL) was added and the mixture was heated to 140C during 48h. The product was worked up by addition of H2O and the organic phase was extracted with EtOAc (3×30mL). The combined organic phases were dried over MgSO4. After removal of the solvent, the residue was purified by silica gel column chromatography with cyclohexane/EtOAc (98:02) as the eluent.
With iron(III)-acetylacetonate; magnesium; zinc(II) chloride; In tetrahydrofuran; at 40 - 60℃; for 8h;Inert atmosphere;
General procedure: Under a nitrogen atmosphere, to a two-liter three-necked flask was added 236 g of p-dibromobenzene, 185 g of 1-bromopropane and 1 liter of anhydrous tetrahydrofuran; followed by addition of 204 g of zinc chloride, 36 g of magnesium powder and 18 Grams of acetylacetone iron. The mixture was heated to about 40 °C under stirring, the reaction was initiated after a few minutes, the reaction temperature was controlled at not more than 60 °C for 8 hours. The reaction mixture was then cooled to room temperature and quenched by stirring with 200 ml of water. The tetrahydrofuran solvent was recovered by distillation and the residue was diluted with 500 ml of toluene. The toluene layer was separated and washed twice with 200 ml of saturated brine and dried over anhydrous sodium sulfate Drying, filtration, filtrate recovery of toluene recovery, and then vacuum distillation, collecting at 94-97 °C / 10 mmHg to give 170 g of p-bromopyrophenyl. The yield was 85percent.
3-(4-bromophenyl)-5-chloropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate;
Step 2: 3-(4-bromophenyl)-5-chloropyridin-4-amine A mixture of 3-bromo-5-chloropyridin-4-amine (5 g, 24.10 mmol), bis(pinacolato)diboron (12 g, 48320 mmol), potassium acetate (4.7 g, 48.20 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloride (3.5 g, 4.82 mmol) in dioxane (100 ml) was stirred at 90° C. overnight under nitrogen. TLC showed the reaction was complete. To this mixture solution was added 1,4-dibromobenzene (11.4 g, 48.20 mmol), potassium carbonate (6.7 g, 48.20 mmol) and water (30 ml). tetrakis(triphenylphosphine)palladium (1.4 g, 1.21 mmol) was added and the mixture was stirred at 90° C. overnight under nitrogen. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer was washed with brine (20 ml*2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 20-50percent ethyl acetate in hexane) to afford 3-(4-bromophenyl)-5-chloropyridin-4-amine (2.3 g, yield 34percent) as yellow solid.
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In toluene; at 110℃; for 48h;Inert atmosphere; Sealed tube;
Synthesis of H2bdp Derivatives. (0115) The ligand 1,4-benzenedipyrazole (H2bdp) was synthesized according to a previously reported procedure. The functionalized dibromobenzene analogues used were 1,4-dibromo-2-fluorobenzene, 1,4-dibromo-2,5-difluorobenzene, 1,4-dibromo-2,3-difluorobenzene, 1,4-dibromobenzene-d4, or 1,4-dibromo-2,5-dimethylbenzene. (0116) Functionalized 1,4-dibromobenzene (8.00 mmol, 1.00 equiv), 1-(2-tetrahydropyranyl)-1H-pyrazole-4-boronic acid pinacol ester (5.56 g, 20.0 mmol, 2.50 equiv), and K3PO4 (8.48 g, 40.0 mmol, 5.00 equiv) were suspended in toluene (16 mL) in a 40-mL glass scintillation vial equipped with a magnetic stir bar, which was then sparged with Ar for 10 min. The vial was uncapped quickly to add XPhos Pd G2 (1.26 g, 1.60 mmol, 0.200 equiv) and then briefly purged with Ar, sealed with a PTFE-lined cap, and heated to 110 C. with stirring for 2 days. After 2 days, the reaction mixture was cooled to room temperature, exposed to air, concentrated under reduced pressure, and diluted with 250 mL of diethyl ether. The ether layer was then washed with saturated aqueous NaHCO3 (5×250 mL), dried over MgSO4, and concentrated under reduced pressure to yield a yellow oil, which was used in the subsequent reaction without additional purification. The crude ligand was then dissolved in 60 mL of methanol in a 250-mL round-bottom flask equipped with a magnetic stir bar. To this flask was added 12 mL of concentrated aqueous HCl, and the reaction mixture was stirred at 50 C. for 2 h, during which time a white precipitate formed. The reaction mixture was then filtered, and the filtrate was suspended in water and neutralized with NaHCO3. The precipitate was isolated in a second filtration, washed with water, and dried under reduced pressure to yield a white or beige powder.
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