* 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 aluminum (III) chloride In nitrobenzene at 100℃; for 4 h;
2-bromo-naphthalene (0.5 g, 2.41 mmol), AlCl3 (0.338 g, 2.53 mmol) and AcCl (0.172 mL, 2.41 mmol) weredissolved in 3.4 mL of nitrobenzene, and stirred at 100°C for 4 hours under reflux. After addition of water, the reactionsolution extracted with EtOAc. The organic layer was separated, dried with MgSO4 and purified by column chromatographyto obtain the title compound (0.3 g, 49percent).1H-NMR (CDCl3) δ 8.43 (1H, s), 8.06 (2H, m), 7.82 (2H, t), 7.63 (1H, m), 2.72 (3H, s).
42%
Stage #1: With aluminum (III) chloride In nitrobenzene at 100℃; for 4 h; Stage #2: With water In nitrobenzene
A mixture of 2-bromonaphthalene (950 g, 4589 mmol), acetyl chloride (260 mL,4589 mmol), nitrobenzene (6000 mL) and aluminum chloride (642.2 g, 4818 mmol) was stirred for 4 hours at 100°C. The mixture was poured onto ice water, the resulting slurry was filtrated and the organic phase separated from the filtrate. The organic phase was washed with water (2000 mL), dried over Na2S04 and filtrated. The solvent was removed by distillation. The residue was re-crystallized from a solution of hexane: ethyl acetate (10: 1) resulting in l-(6-bromonaphthalen-2-yl)ethanone (480 g, 42percent yield).
37%
With aluminum (III) chloride In nitrobenzene at 100℃; for 4 h;
Into a four-necked flask of 500 ml,Then, 41.4 g of 2-bromonaphthalene, 15.7 g of acetyl chloride, 28 g of aluminum chloride and 250 mℓ of nitrobenzene were charged and stirred at 100 ° C. for 4 hours.Then, upon reaching below cooling to 30 ° C., the reaction mixture was poured into ice water, was removed and the precipitated precipitate was filtered off.The filtrate after washing twice with water 100 ml, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue is recrystallized from hexane to give 18.42g of 2-bromo-6-acetyl naphthalene. (Yield 37.0percent)1H-NMR (400 MHz, CDCl3): δH 2.71 (s, 3H), 7.63 (dd, 1H), 7.80 (d, 1H), 7.82 (d, 2H), 8.05 (M, 2 H), 8.42 (s, 1 H)
36%
Stage #1: With aluminum (III) chloride In nitrobenzene at 100℃; for 4 h; Stage #2: With water In nitrobenzeneCooling with ice
Alternative for preparation of l-(6-bromonaphthalen-2-yl)ethanone; A mixture of 2-bromonaphthalene (41.4 g, 200 mmol), acetyl chloride (11.3 mL, 160 mmol), nitrobenzene (250 mL) and A1C13 (28g, 210 mmol) was stirred for 4 hours at 100°C (oil bath temperature). The resulting reaction mixture was cooled, poured onto ice /water (100 mL) and filtered. The filtrate was washed with water (100 mL). The solvent (nitrobenzene) was removed by distillation. The resulting residue was crystallized from hexane to afford 18 g of desired product (36percent yield).l-(6-bromonaphthalen-2-yl)ethanone: 1H NMR (400 MHz, ACETONITRILE- 3) δ ppm 2.66 (s, 3 H) 7.66 (dd, J=8.8, 2.0 Hz, 1 H) 7.86 (d, J=8.8 Hz, 1 H) 7.94 (d, J=8.8 Hz, 1 H) 8.02 (dd, J=8.8, 1.8 Hz, 1 H) 8.13 (d, J=2.0 Hz, 1 H) 8.53 (d, J=1.8 Hz, 1 H).
11 g
With aluminum (III) chloride In nitrobenzene at 10 - 40℃; for 18 h;
To a solution of 2-bromonaphthalene (25 g, 121 mmol) and AlCl3(19.32 g, 145 mmol) in nitrobenzene (227 mL) was added AcCl (10.78 mL, 152 mmol) at 10° C. The reaction mixture was heated to 40° C. for 18 h. Then the reaction mixture was cooled to rt and poured into ice containing con. HCl (400 mL). The reaction mixture was extracted with EtOAc and washed with 1.5 N HCl solution, brine, dried over Na2SO4and concentrated. The crude was purified by column chromatography (Silica gel 60-120, 3-5percent EtOAc/petroleum ether) to obtain bromide B-1a (11 g) as light brown solid.1H NMR (CDCl3), δ=7.26 ppm, 400 MHz): δ 8.43 (s, 1H), 8.08-8.04 (m, 2H), 7.84 (d, J=8.8, 1H), 7.81 (d, J=8.8, 1H), 7.64 (dd, J=8.8, 2.0, 1H), 2.72 (s, 3H).
11 g
With aluminum (III) chloride In nitrobenzene at 10 - 40℃; for 10 h;
To a solution of 2-bromonaphthalene (25 g, 121 mmol) and AICI3 (19.32 g,145 mmol) in nitrobenzene (227 mL) was added AcCl (10.78 mL, 152 mmol) at 10 °C. The reaction mixture was heated to 40 °C for 18 h. Then the reaction mixture was cooled to rt and poured into ice containing con. HCl (400 mL). The reaction mixture was extracted with EtOAc and washed with 1.5 N HCl solution, brine, dried over Na2S04and concentrated. The crude was purified by column chromatography (Silica gel 60-120, 3-5percent EtOAc/petroleum ether) to obtain bromide B-la (11 g) as light brown solid.XH NMR (CDC13), δ = 7.26 ppm, 400 MHz): δ 8.43 (s, 1 H), 8.08- 8.04 (m, 2 H), 7.84 (d, J = 8.8, 1 H), 7.81 (d, J = 8.8, 1 H), 7.64 (dd, J = 8.8, 2.0, 1 H), 2.72 (s, 3 H).
Reference:
[1] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0306
[2] Patent: WO2012/13643, 2012, A1, . Location in patent: Page/Page column 25-26
[3] Patent: JP2017/39655, 2017, A, . Location in patent: Paragraph 0044
[4] Patent: WO2011/54834, 2011, A1, . Location in patent: Page/Page column 39
[5] Chemical Communications, 2015, vol. 51, # 38, p. 8153 - 8156
[6] Angewandte Chemie - International Edition, 2016, vol. 55, # 26, p. 7530 - 7533[7] Angew. Chem., 2016, vol. 128, # 26, p. 7656 - 7659,4
[8] Chemische Berichte, 1891, vol. 24, p. 550
[9] Bulletin of the Chemical Society of Japan, 1975, vol. 48, p. 3356 - 3366
[10] Patent: US5877207, 1999, A,
[11] Patent: US5958954, 1999, A,
[12] Patent: US4766127, 1988, A,
[13] Patent: US2012/219594, 2012, A1,
[14] Patent: US2015/23913, 2015, A1, . Location in patent: Paragraph 0993-0994
[15] Patent: WO2015/5901, 2015, A1, . Location in patent: Page/Page column 369
6
[ 75-15-0 ]
[ 7446-70-0 ]
[ 580-13-2 ]
[ 75-36-5 ]
[ 1590-24-5 ]
[ 1590-25-6 ]
Reference:
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 239,241
[2] Journal of Organic Chemistry, 1948, vol. 13, p. 164,165
[3] Journal of Organic Chemistry, 1946, vol. 11, p. 163
[4] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1931, vol. <A>, p. 59,65
7
[ 7446-70-0 ]
[ 580-13-2 ]
[ 98-95-3 ]
[ 75-36-5 ]
[ 1590-24-5 ]
[ 1590-25-6 ]
Reference:
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 239,241
[2] Journal of Organic Chemistry, 1948, vol. 13, p. 164,165
[3] Journal of Organic Chemistry, 1946, vol. 11, p. 163
[4] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1931, vol. <A>, p. 59,65
Reference:
[1] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4326 - 4329
21
[ 580-13-2 ]
[ 2243-58-5 ]
Reference:
[1] Chinese Journal of Chemistry, 2018, vol. 36, # 11, p. 1003 - 1006
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 2994 - 3008
22
[ 580-13-2 ]
[ 78871-05-3 ]
Reference:
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 22, p. 6604 - 6607[2] Angew. Chem., 2015, vol. 127, # 22, p. 6704 - 6707,4
[3] Organic Letters, 2018, vol. 20, # 9, p. 2778 - 2781
23
[ 580-13-2 ]
[ 762-04-9 ]
[ 78871-05-3 ]
Reference:
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 17, p. 4549 - 4553[2] Angew. Chem., 2013, vol. 125, # 17, p. 4647 - 4651,5
[3] Green Chemistry, 2015, vol. 17, # 1, p. 314 - 319
24
[ 580-13-2 ]
[ 474688-73-8 ]
Reference:
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2007, vol. 66, # 3, p. 672 - 675
[2] Journal of Materials Chemistry, 2011, vol. 21, # 34, p. 12969 - 12976
[3] Dyes and Pigments, 2012, vol. 92, # 1, p. 588 - 595
[4] Patent: KR2015/22269, 2015, A,
[5] Patent: KR2015/22270, 2015, A,
[6] Patent: KR101502811, 2015, B1,
[7] Patent: KR2017/49295, 2017, A,
[8] Patent: WO2008/140208, 2008, A1,
25
[ 109-72-8 ]
[ 580-13-2 ]
[ 124-38-9 ]
[ 572-83-8 ]
[ 474688-76-1 ]
Reference:
[1] Patent: US2008/299294, 2008, A1,
26
[ 580-13-2 ]
[ 4612-26-4 ]
[ 918655-03-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 80℃; for 2 h;
2-bromo-naphthalene (2.07g, 10mmol), benzene-1,4-diBoronic acid(2.49g, 15mmol), Pd (PPh3) 4 (0.58 g, 0.5mmol), potassium carbonate (4.15g, 30mmol) and THF: H2O = 2:1 solution dissolved in 200ml 80 After 2 hours reflux agitation. Thereafter it was added and extracted three times with 40ml ethyl ether H2O40ml drying the obtained organic layer with magnesium sulfate, and separating the residue obtained by evaporating the solvent was subjected to silica gel column chromatography purification Intermediate B-1 (1.98g, 80percent yield) It was obtained.
Reference:
[1] Patent: KR2016/30001, 2016, A, . Location in patent: Paragraph 0327-0330
27
[ 580-13-2 ]
[ 934545-80-9 ]
Reference:
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 841 - 846
[2] Patent: WO2016/36207, 2016, A1,
[3] Patent: WO2016/64227, 2016, A1,
[4] Patent: KR2016/29399, 2016, A,
[5] Patent: KR2015/21171, 2015, A,
With copper (II)-fluoride; N,N,N,N,-tetramethylethylenediamine; In HMPA (hexamethylphosphoramide); at 180℃; for 3h;Product distribution / selectivity;
A mixture of 2-bromonaphthalene (0.08 g), copper (II) fluoride (0.04 g), TMEDA (0.31 mL), and HMPA (1.5 mL) was vigorously stirred at 180 C. for 3 hrs. After the mixture was allowed to cool to room temperature, water (5 mL) and hexanes (2 mL) were added. The mixture was vigorously shaken for extraction into the hexane phase, which was then filtered through a short silica gel plug. Analysis of the filtrate by 19F NMR indicated the formation of 2-fluoronaphtalene. The characteristic multiplet at -116 ppm was identical with that observed for an authentic sample of 2-fluoronaphthalene (Aldrich).
Step 2 8-Benzyl-3-Naphthalen-2-yl-8-Aza-Bicyclo[3.2.1]Octan-3-Ol To a -78 C. solution of 10.75 g (50.35 mmol) 2-bromonaphthalene in 200 mL THF was added 20.1 mL (50.25 mmol) of n-BuLi (2.5 M in hexanes) in drops over 5 min. After 35 min, a solution of 10.51 g (48.82 mmol) 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one in 25 mL THF was added via cannula, and then allowed to warm to room temperature. After 17 h, the mixture was transferred to a separatory funnel containing 200 mL brine. The aqueous layer was extracted with EtOAc (3*150 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered and evaporated to an orange oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2Cl2/EtOAc (40:1 to 20:1 to 8:1 to 4:1 to 2:1 to 1:1). The appropriate fractions were combined and evaporated to afford 7.07 g (20.6 mmol, a 42% yield) of the title compound as a yellow oil. MS (ES) m/z: 345 (MH)+.
With n-butyllithium; In tetrahydrofuran; ethyl acetate;
8-Benzyl-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol To a -78 C. solution of 10.75 g (50.35 mmol) 2-bromonaphthalene in 200 mL THF was added 20.1 mL (50.25 mmol) of n-BuLi (2.5 M in hexanes) in drops over 5 min. After 35 min, a solution of 10.51 g (48.82 mmol) 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one in 25 mL THF was added via cannula, and then allowed to warm to room temperature. After 17 h, the mixture was transferred to a separatory funnel containing 200 mL brine. The aqueous layer was extracted with EtOAc (3*150 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered and evaporated to an orange oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2Cl2/ EtOAc (40:1 to 20:1 to 8:1 to 4:1 to 2:1 to 1:1). The appropriate fractions were combined and evaporated to afford 7.07 g (20.6 mmol, a 42% yield) of the title compound as a yellow oil. MS (ES) m/z 345 (MH)+.
8-Benzyl-3-Naphthalen-2-yl-8-Aza-Bicyclo[3.2.1]octan-3-ol To a -78 C. solution of 10.75 g (50.35 mmol) 2-bromonaphthalene in 200 mL THF was added 20.1 mL (50.25 mmol) of n-BuLi (2.5 M in hexanes) in drops over 5 min. After 35 min, a solution of 10.51 g (48.82 mmol) 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one in 25 mL THF was added via cannula, and then allowed to warm to room temperature. After 17 h, the mixture was transferred to a separatory funnel containing 200 mL brine. The aqueous layer was extracted with EtOAc (3*150 mL), then the combined organics were washed with water (100 mL), brine (100 mL), dried over MgSO4, filtered and evaporated to an orange oil. The crude material was purified by flash chromatography on SiO2, using a gradient elution of CH2CI2/EtOAc (40:1 to 20:1 to 8:1 to 4:1 to 2:1 to 1:1). The appropriate fractions were combined and evaporated to afford 7.07 g (20.6 mmol, a 42% yield) of the title compound as a yellow oil. MS (ES) m/z: 345 (MH)+.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;
Reference Example 23 4,6-Dichloro-3-hydroxy-3-(2-naphthyl)oxindole To a solution of 2-bromonaphthalene (2.952 g) in anhydrous THF (25 mL) was added portion wise a solution of n-butyl lithium in n-hexane (1.55 N, 10.12 mL) at -78 C. The reaction solution was stirred for 30 minutes. To the mixture was then added portion wise a solution of <strong>[18711-15-4]4,6-dichloroisatin</strong> (1.54 g) in anhydrous THF (25 ml) for 50 minutes. The reaction mixture was stirred for 2 hours. Then the mixture was allowed to warm to room temperature. To the mixture was added 1N HCl and extracted by ethyl acetate. The organic phase was separated, washed with 1N HCl and brine and dried over MgSO4 and concentrated. Purification was carried out by silica gel chromatography (hexane:ethyl acetate, 2:1 to 1:1 gradient) to give the title compound (0.652 g, yield: 27%). 1H NMR (DMSO-d6, 300 MHz) delta 6.93 (1H, s), 6.96 (1H, d, J=1.7 Hz), 7.12 (1H, d, J=1.7 Hz), 7.23 (1H, m), 7.49 (2H, m), 7.80-7.94 (4H, m), 10.80 (1H, brs).
EXAMPLE 5 3-(naphth-2-yl)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene Beginning with 18.0 gm (91 mMol) 8-ethoxycarbonyl-8-azabicyclo[3.2.1]oct-3-one and 18.9 gm (91 mMol) 2-bromonaphthalene, 9.02 gm (32%) of the title compound was recovered as a yellow oil by the procedure described in detail in Example 3.
(1) Synthesis of Intermediate 1-1 (0232) 20.0 g (20 mmol) of 2-bromonaphthalene was dissolved in 50 mL of tetrahydrofuran (THF), and then 8.8 mL (22.0 mmol) of n-BuLi (2.5 M in hexane) was slowly dropwise added thereto at about -78 C. After the reaction solution was stirred at the same temperature for about 1 hour, 4.65 mL (25.0 mmol) of 2-isoproxy-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane was slowly dropwise added to the reaction solution, stirred at about -78 C. for about 1 hour, and then further stirred at ambient temperature for about 24 hours. After termination of the reaction, 30 mL of a 10% HCl aqueous solution and 30 mL of H2O were added thereto, followed by extraction three times with 50 ml of diethyl ether. An organic phase was collected and dried using magnesium sulfate, followed by evaporating the solvent. The resulting residue was purified by silica gel column chromatography to obtain 3.7 g of Intermediate 1-1 (Yield: 73%). This compound was identified by liquid chromatography-mass spectrometry (LC-MS). C16H19BO2: M+ 255.1
41%
To a 500 mL 3 -necked round bottomed flask, charged were THF (300 mL) and 2-bromonaphthalene (10 g, 48.3 mmol) , and the mixture was chilled to -78C by using liquefied nitrogen. Then, n-BuLi (14.73 g, 53.1 mmol) was slowly added dropwise thereto. After stirring at ambient temperature for 1 hour, 2- isopropoxy-4, 4, 5, 5-tetramethyl- [1, 3, 2] -dioxaborolane (9.87 g) was slowly added dropwise at -78C to the mixture. After 12 hours, water is poured thereto, to quench the reaction. The reaction mixture was extracted with ether, dried over MgSO4 and evaporated by using a rotary evaporator to remove the solvent. The product was isolated via column chromatography (eluent: hexane/EA = 5/1) .Yield: 4.05 g (41%) m.p. : 93 C1H NMR (300 MHz, CDCl3, ppm): 7.81 (d, 4H), 7.29 (t, 3H), 1. 26 (m , 12H).
With hydrogenchloride; stannous chloride; In tetrahydrofuran; acetic acid; acetone;
Synthesis of 2-Bromo-9,10-di(naphthalen-2-yl)anthracene 4.3 g (21 mmole) of 2-bromonaphthalene was placed in an 100 ml round bottom flask, and was dissolved in dry THF. The solution was cooled down to 31 70 C. by dry-ice/acetone, then 1.6M n-Butyllithium 13 ml (21 mmole) was added slowly over 30 minutes. The reaction was stirred for 2 hours while the reaction temperature was maintained at -70 C., 2-bromoanthraquinone 2 g (6.9 mmole; manufactured by Tokyo Chemical Industry Co., LTD.,) was added to the cooled reaction mixture, the reaction was stirred for overnight at room temperature. Then, 30 ml of 10% HCl was added to the resulting solution, and stirred for 30 minutes, the organic layer was separated, and was evaporated to dryness, the brown color residue was dissolved in 50 ml of acetic acid, and 1.6 g of SnCl2. 2H2O were added to the brown solution. The reaction mixture was heated to reflux for 6 hours, and then, cooled down to room temperature. Thus, the Brown product was collect by filtration. (2.47 g, 70.4%)
(Preparation of a compound represented by Chemical Formula 2-4) To a solution of 2-bromo naphthalene (5.78 g, 28.0 mmol) in dry THF (40 mL) under a nitrogen atmosphere was added dropwise cooled t-butyl lithium (21 mL, 1.7 M pentane solution) at -78C. After stirring at the same temperature for 40 minutes, the compound of the Chemical Formula a prepared in Preparation Example 1 (2.93 g, 8.00 mmol) was added at the same temperature. After removing the cooling bath, the mixture was stirred at room temperature for 3 hours. An ammonium chloride solution (40 mL) was slowly added to the reaction mixture and the mixture was stirred at room temperature for 40 minutes. The precipitate was filtered off with suction, washed with water and petroleum, and dried to obtain the dialcohol (4.10 g, 82%).
66%
[Preparation Example 2] Preparation of Compound (203); Preparation of Compound (A); In a reaction vessel, 2-bromonaphthalene (27.16 g, 0.131 mol) was completely dissolved with stirring in tetrahydrofuran (1.2 L) at room temperature for 10 minutes. After chilling the solution to -78C, 2.5 M butyllithium (68.2 mL, 0.17 mol) was slowly added dropwise thereto. After 1 hour, <strong>[633-70-5]2,6-dibromoanthraquinone</strong> (20 g, 0.055 mol) was added, and the resultant mixture was slowly warmed to room temperature with stirring for 20 hours. To the reaction mixture, 10% HCl solution (0.3 L) was added, and the resultant mixture was stirred for 2 hours and filtered under reduced pressure. The organic layer separated was evaporated, and the residue was recrystallized from ethyl acetate (100 mL) and n-hexane (500 mL). After filtration, the solid compound obtained was dried to obtain Compound (A) (22.44 g, 66%).
54%
3 2-bromonaphthalene multi function cap to opening 500 ml (8.5g, 0.04mol) THF and he and agitating the added under nitrogen. Reaction temperature and in -78 C n-BuLi (25.6 ml, 0.04mol) is slowly added to the polymerization reaction mixture to visitor is checked through a stirring time 1. 2, 6-dibromoanthracene-9 herein, 10-dione (5g, 0.01mol) adding an 4-5 time was reacted at ambient. After reaction is completed, water are added after vacuum distilling a reaction mixture, out by extracting with distilled water and a Methylene Chloride. Extracted Methylene Chloride layer MgSO 4 after for holding a order to form an exterior, of methanol removing the solvent by the string grudge liquid obtained. An Column Chromatography method using yellow solid (11) separated the. (4.5g, 54%)
54%
Three-necked added 2-bromonaphthalene (8.5g, 0.04mol) in 500ml THF and the flask under nitrogen and the mixture was stirred. And added slowly to the reaction temperature at -78 n-BuLi (25.6mL, 0.04mol) and stirred 1 hour. To this was added a <strong>[633-70-5]2,6-dibromoanthracene-9,10-dione</strong> (5g, 0.01mol) and allowed to react at room temperature for 4 to 5 hours. After completion of the reaction, after addition of water, and distilled under reduced pressure, the reaction solution was extracted with Methylene Chloride with distilled water. After japahjun moisture Methylene Chloride the extracted layer with MgSO4, the solvent was removed by distillation under reduced pressure to give a viscous liquid. The liquid to a yellow solid (11) was isolated using Column Chromatography method. (4.5g, 54%)
In dry tetrahydrofuran solvent (500 mL), dissolved was 2-bromonaphthalene (44.1 g, 270.7 mmol), and n-buthyllithium (2.5 M solution in n-hexane) (130.0 mL, 324.9 mmol) was slowly added thereto at -78C. After stirring for 1 hour, <strong>[633-70-5]2,6-dibromoanthracene-9,10-dione</strong> (30.0 g, 108.3 mmol) was added thereto, and the resultant mixture was stirred while slowly raising the temperature to room temperature. After 17 hours, water was added, and the mixture was stirred for 30 minutes, and extracted with ethyl acetate (500 mL). The extract was washed with water (500 mL), and the organic layer obtained was dried over magnesium sulfate. Distillation under reduced pressure and drying gave Compound (B) (21.3 g, 47.8 mmol).
1) Operation: To the 10L three-necked flask equipped with mechanical stirrer, low temperature thermometer and drying tube, turn into argon lOmin, then add 2-bromonaphthalene, 516g, THF 4740ml, stir, dissolve completely and then cool with liquid nitrogen -85 C to -78 C, through the funnel dropping butyl lithium 1486ml, dropping process temperature control -85 C ~ -78 C, after the drop after the insulation _85 C ~ -78 C Reaction lh, began to add <strong>[633-70-5]2,6-dibromoanthraquinone</strong> 338g, batch interval 15min, plus finished after -85 C ~ -78 C continue to heat the reaction 3.5h, and then remove the low temperature bath, natural warming, 0 ~ 30 C reaction 1h, every 1h sampling, when the raw materials 2,6 - dibromoanthraquinone LC 50% to stop the reaction, the reaction equation is as follows. 2) After the treatment: stirring about 1 1L of dilute hydrochloric acid to step 1) in the reaction solution, the acidification system to acid (rhoH- = 4 ~ 5), stirring 30min, and then the reaction solution into the Sheng 5160ml water bucket, stirring 5min, adding dichloroethane 5160ml, stirring lOmin, liquid, organic phase temporarily, the water phase and then 2580ml dichloroethane extraction time, combined organic phase, organic phase with 10320ml water washed Neutral, separated, organic phase under reduced pressure (55 C ~ 78 C, -0.08MPa ~-0.09MPa) to no longer solvent drop, the concentrate is reddish brown solid solution mixture, filter, filter abandoned , The filter cake was rinsed with 1158 ml of petroleum ether and dried to obtain 419.7 g of a yellowish solid,(78 C, -0.08 MPa) to about 1.2 L, and the solution was reduced to room temperature (25 C) and cooled to 60 C. The filtrate was concentrated under reduced pressure (78 C, -0.08 MPa) (50 C, -0.08MPa ~ -0.09MPa, 5h), the main content of LC> 95% of the light yellow solid (50 C, -0.08MPa ~ -0.09MPa, 5h), the main content of LC> 95% of the light yellow solid 329.3g, namely dihydroxy dibromo ADN (see Figure 1, the main content of LC = 96.3806%)
With palladium diacetate; potassium carbonate; triphenylphosphine; Trimethylacetic acid; In N,N-dimethyl-formamide; at 130℃; for 12h;Inert atmosphere;
General procedure: A stirred mixture of <strong>[874-14-6]1,3-dimethyluracil</strong> (1a, 140 mg, 1.0 mmol), bromobenzene (2a, 315 mg, 2.0 equiv), Pd(OAc)2 (22 mg, 10 mol percent), PPh3 (52 mg, 20 mol percent), PivOH (30 mg, 30 mol percent), K2CO3 (415 mg, 3.0 equiv) in DMF (1.5 mL) was heated to 130 °C for 12 h under nitrogen atmosphere. After the usual aqueous extractive workup with chloroform and column chromatographic purification process (hexanes/THF, 4:1) compounds 3a (171 mg, 79percent) and 4a (21 mg, 10percent) were obtained as white solids.5
With copper; potassium carbonate; In Tetraethylene glycol dimethyl ether; at 195℃;Inert atmosphere;
In a 200-ml three-necked flask that had been deaerated and filled with nitrogen were placed 10.0 g (0.036 mole) of the white powder A obtained in Example 1, 12.9 g (0.093 mole) of potassium carbonate, 5.7 g (0.090 mole) of copper powder, and 50.0 g of tetraglyme and stirred under flow of nitrogen. To the flask was added dropwise a solution of 9.87 g (0.047 mole) of 2-bromonaphthalene in 10.0 g of tetraglyme over 10 minutes. After the dropwise addition, the mixture was stirred at 195C for 1 hour. The mixture was then cooled to room temperature and the insoluble matters were separated by filtration. To the filtrate were added 30 g of methanol and 150 g of water and the mixture was stirred for 2 hours. Thereafter, a precipitate was collected by filtration, washed twice by reslurrying with 100 g of water, then washed once by reslurrying with 100 g of methanol, dried under reduced pressure, and purified by column chromatography to give 13.0 g (0.034 mole, 94.7% yield) of a white powder D.
With sodium t-butanolate;PtBu3*HBF4; palladium diacetate; In toluene; at 120 - 121℃; for 18h;Reflux;
Tri-2-NaphythylamineScheme 2[0050] With reference to Scheme 2, a 100 mL round bottom flask was charged with Pd(oAc)2 (5.4 mg, 0.024 mmols), HPtBu3 BF4, (9.0 mg, 0.031 mmols), and NaOtBu (0.241 g, 2.51 mmols) all suspended in toluene (5.0 mL). Next, hydroxylamine O-benzyl ether (0.06 mL, 0.6 mmol) and 2-bromo naphthalene (0.417g, 2.0 mmols) were added to the reaction flask. The reaction was then heated (120-121 C) and allowed to reflux for 18 hours in an oil bath and then set to cool at room temperature followed by quenching with addition of 1M HC1 (6 mL, 6 mmol). The aqueous layer was extracted with CH2C12 (2 x 20 ml). The organic layer was combined and dried with sodium sulfate. The product was then filtered under high vacuum and reduced pressure to give a brown solid which was purified by column chromatography (Si02, ethyl acetate :hexanes 20:80) respectively to give tri-2- naphythylamine as an off-white powder: 0.0838 g (37%) m.p. 230.3 - 238.6 C; 1H NMR (400 MHz, CDC13) delta 7.81-7.76 (m, 6H), 7.60 -7.58 (m, 3H), 7.52 (d, J = 2 Hz, 3H), 7.43- 7.37 (m, 9H); 13C NMR (100 MHz, CDC13) delta 145.4, 134.4, 130.3, 129.0, 127.6, 127.0, 126.3, 124.7, 124.6, 120.8. LCMS (M+H)+ Calc'd for C30H22N 396.1752, found 396.1753.
N-(3-(naphthalen-2-ylsulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 NN-( 3-( naphthalen-2-ylsulfonyl)benzyl)imidazo [ 1 ,2-al pyridine-6-carboxamideTo a mixture of sodium 4-(acetamidomethyl)benzenesulfmate (0.2 M MeOH, 100 mu, 20 muiotaetaomicron) and zinc chloride (0.5 M THF, 40 mu, 20 muiotaetaomicron), cesium carbonate (1.43 M MeOH, 25 muEpsilon, 35 muiotaetaomicron) then 2-bromonapthelene (0.2 M Toluene, 110 mu, 22 muiotaetaomicron) were added. A toluene solution of XantPhos and Pd2dba (0.01 M XantPhos/0.005 M Pd2dba , 50 mu,, 2.5 mol%) was added and the reaction was heated for 4 h at 95 C under nitrogen. The reaction was cooled to room temperature and 70% i-PrOH (0.35 mL) and 3N HC1 (0.35 mL, 1.05 mmol) were added and was heated at 95 C for 4 hours then concentrated to dryness. The residue was treated with triethylamine (5%> in ACN (v/v), 100 mu) and imidazo[l,2-a]pyridine-6-carboxylic acid (0.2 M in DMA w/ 10% TEA (v/v), 120 mu, 24 muiotaetaomicron) and BOP (0.2 M DCE, 130 mu, 26 muiotaetaomicron). The solution was heated to 40 C for 4 h then cooled to room temperature and partitioned between NaOH and EtOAc. The organic layer was separated and deposited on a SCX-SPE cartridge which was eluted to two fractions: the Is with 25% MeOH/EtOAc (v/v), the 2nd with Et3N/MeOH/EtOAc (1 : 1 : 10 v/v/v). The second fraction was concentrated to dryness and was purified by LC/MS to afford the title compound as white solid.1H NMR (400 MHz, CDC13): delta 8.85 (s, 1H), 8.55 (s, 1H), 7.93 (m, 4H), 7.87 (d, J=8 Hz, 1H), 7.81 (dd, J=8.8 Hz, J'=1.6 Hz, 1H), 7.63 (m, 5H), 7.47 (d, J=8.4 Hz, 2H), 7.34 (m, 1H), 6.81 (m, 1H), 4.70 (d, J=5.6 Hz, 2H).LC-MS: 442.13 (M+l)
With bis(benzonitrile)palladium(II) dichloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 24h;Inert atmosphere;
General procedure: Pd(PhCN)2Cl2 (1.9 mg, 5.00 mumol, 1 mol%), Xantphos 1.9 mg, 10.0 mumol, 2 mol%), bromoarene (0.500 mmol), 123)(226 mg, 1.00 mmol, 2.0 eq), and toluene (1.0 mL) were addedto a 10 mL test tube with a septum containing a magnetic stirring bar. The tube was evacuated and backfilled with Ar three times. DBU (150 muL, 1.00 mmol, 2.0 eq) was added to the mixture using a syringe through the septum. The tube was screw-capped and warmed to 80C in an oil bath. The mixture was stirred for 24 h. After cooling to r.t., the mixture was quenched with aq. citric acid (10% (w/v)), diluted with CH2Cl2and H2O, extracted with CH2Cl2 from aqueous layer, washed with H2O, aq. Na2CO3 (0.5 M), and brine, dried over Na2SO4,filtered, and concentrated. The obtained residue was purified by preparative TLC (SiO2, hexane-EtOAc 30 : 1) to afford the desired ester.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.5h;Microwave irradiation;
General procedure: A mixture of aromatic trithiol (1 mmol), aryl bromide (3 mmol), K2CO3 (2.5 mmol) and PdnpnSTDP(0.05 mol% Pd) in DMF (3 mL) was stirred at 80 oC or subjected to MW irradiation(230 W, 80 oC) for the appropriate time according to Table 4. The work-up was performed asmentioned for synthesis of disulfides and the pure trisulfide was obtained by recrystallizationof the crude product from ethyl acetate.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; at 80℃; for 5h;Inert atmosphere;
(1)In a 250mL three-vial bottle,With nitrogen,Add 0.02mol 2-bromonaphthalene dissolved in 100ml tetrahydrofuran (THF),Then add 0.024 mol of bis(pinacolato)diboron,0.0002mol(1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) and 0.05 mole of potassium acetate were added,Stir the mixture,The above mixed solution of the reactants was heated to reflux at a reaction temperature of 80C for 5 hours;After the reaction is over,Cool and add 100 ml of water,The mixture was filtered and dried in a vacuum oven.The residue obtained is separated and purified through a silica gel column.Obtained 2-naphthaleneboronic acid pinacol ester; HPLC purity 99.8%, yield87.8%.
83%
With meso-tetra(p-tolyl)porphinato-palladium(II); potassium acetate; In 1,4-dioxane; at 110℃; for 6h;
General procedure: Aryl/heteroaryl bromide 1 (1 mmol), B2pin2(2), B2npg2(4) orBpin (6, 1.2 mmol), and dioxane (5 mL) are taken into a 25 mLround-bottomed flask. KOAc (2 mmol) was added and stirredthe resultant mixture at room temperature for 5 min, PdII-TpTP(0.15 mol%) was added, and the contents were refluxed on preheatedoil bath at 110 C under constant stirring in open-air.The reaction progress was ensured by TLC. After completion ofthe reaction, the mixture was cooled, dilute with water (20 mL)and extracted with tertbutylmethyl ether (3 × 10 mL). The combinedn-hexane layers were concentrated, and the crudeproduct obtained was purified by column chromatography (CC)on silica gel using a mixture of ethyl acetate and hexane (1:30)as eluent.
75%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 24h;
Sub B (3) (4.14g, 20mmol) then dissolved in toluene, bis pinacolato Todai boron ( 5.58g , 22mmol ) , Pd ( dppf ) Cl2 catalyst(0.44g, 0.6mmol), KOAc (5.89g, 60mmol) was added to a stirred for 24 hours and then by synthesizing the borate compound and then in the orderIn , then the resulting compound was separated through a silicagel column and recrystallized to obtain 3.8g of Sub B - 3 . (Yield: 75%)
75%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 24h;
Sub 2-1-3 (4.14g, 20mmol) was dissolved in toluene, bis-pinacolato diboron (5.58g, 22mmol), Pd(dppf)Cl2 catalyst (0.44g, 0.6mmol), KOAc (5.89g, 60mmol )was added. A borate compound was synthesized by stirring for 24 hours after the addition, as, after the thus obtained compound was separated over a silicagel column and recrystallized to obtain 3.8g of Sub 2 (3). (Yield: 75%)
61%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 120℃; for 8h;Inert atmosphere;
Fill a dry 500mL double-neck round bottom flask with nitrogen.Add 2-naphthalene bromide (20.6g, 0.1mol),Bis (pinacolato) diboron (25.4g, 0.1mol),Potassium acetate (19.6g, 0.2mol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.005mol),1,4-dioxane (200 mL), reacted at 120 C for 8 hours;After the reaction was completed, it was cooled to room temperature, quenched with water, and extracted with dichloromethane (three times with 200 mL extraction). The extract was dried over anhydrous magnesium sulfate and spin-dried.The crude product was separated by silica gel column chromatography.2-naphthoboronic acid pinacol ester (15.5 g, yield 61%) was obtained.
47%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,2-dimethoxyethane; for 4h;Inert atmosphere; Reflux;
2eBromonaphthalene (299 mg, 1.14 mmol) KAcO (416 mg,4.24 mmol) and bis(pinacolato)diboron (558 mg,2.20 101 mmol) were dissolved in 50 mL of 1,2-dimethoxyethane (DME) and the mixture was purged with N2 gas. [1,10-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (Pd(dppf)Cl2CH2Cl2) (49 mg,5.94 102 mmol)was added to the resulting solution and refluxedfor 4 h. The mixture was extracted with ethyl acetate. The solutionwas washed withwater, and passed through phase separator paper.After the solvent was removed, the crude mixture was purified bysilica gel column chromatography (ethyl acetate:hexane 1:40) togive 1 as a yellow solid (170 mg, yield: 47%). 1H NMR (400 MHz,CDCl3): delta 8.37 (s, 1H), 7.89 (d, J 7.6 Hz 3H), 7.86e7.79 (m, 3H), 1.39(s, 12H). HRMS (ESI-TOF) calculated for C16H19BO2 [MNa] :276.1421, found: 276.1407.
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 20 - 80℃;Inert atmosphere;
General procedure: The appropriate 2-iodothiophene (100mg,0.47mmol), bis(pinacolato)diboron(137mg, 0.57mmol), andbis(triphenylphosphine)palladium (II) dichloride (33.4mg,0.04mmol) were dissolved in dry 1,4-dioxane in an inertatmosphere. Potassium acetate (93.4mg,0.9521mmol) was then added at room temperature, and the mixturewas heated at 80C for 5-6 h. After solvent evaporation, water was added to theresidue extracted with ethyl acetate. The organic layer was washed with brine,and dried by distillation to obtain a crude product, which was used withoutfurther purification. Other aryl halide, 2-bromonaphthalene andbromoahthracene, also followed same procedure with 2-iodothiophene.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 2h;
2-bromo-naphthalene (2.07g, 10mmol), benzene-1,4-diBoronic acid(2.49g, 15mmol), Pd (PPh3) 4 (0.58 g, 0.5mmol), potassium carbonate (4.15g, 30mmol) and THF: H2O = 2:1 solution dissolved in 200ml 80 After 2 hours reflux agitation. Thereafter it was added and extracted three times with 40ml ethyl ether H2O40ml drying the obtained organic layer with magnesium sulfate, and separating the residue obtained by evaporating the solvent was subjected to silica gel column chromatography purification Intermediate B-1 (1.98g, 80% yield) It was obtained.
With potassium phosphate; copper; In N,N-dimethyl-formamide; at 200℃;
5,12-dihydro-indole[3,2-a] carbazole (5,12-dihydro-indolo [3,2-a] carbazole) 20g (78mmol), iodo- benzene (iodobenzene) 50ml Cu powder 5g (80mmol), insert the K3PO4 24.8g (117mmol) was stirred at 200 . After cooling the reaction solution to room temperature under a reduced pressure to obtained after filtering the precipitated solid by dissolving it again in an organic solvent and separating the Cu powder. The obtained organic layer followed by drying under reduced pressure was purified by column chromatography. Method as the compound obtained in 2-a 18g (54mmol) in iodo-benzene instead ofUsing 2-bromo-naphthalene 12.2g (59mmol), and the solvent is dimethylformamideIt was stirred at 200 use.Dissolving the reaction product in the organic solution obtained was dried under reduced pressure to obtain the compound b-2 19g (41mmol, 75% yield) by column chromatography, the resulting organic solution was separated off and the Cu powder.
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); lithium carbonate; In N,N-dimethyl acetamide; at 160℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added <strong>[2164-61-6]pyridazine-3-carboxylic acid</strong> (0.6 mmol, 1.0 eq), aryl- and heteroaryl-bromides (1.2 mmol, 2.0 eq), Pd(PPh3)4 (35 mg, 0.03 mmol, 5.0 mol %), Cu2O (84 mg, 0.6 mmol, 1.0 eq), Li2CO3 (107 mg, 1.8 mmol, 3.0 eq), 3A MS (200 mg) and DMA (4.0 mL). The mixture was stirred at 160 C for 24 h under N2. After the reaction was complete, the mixture was washed with brine and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/1), the eluent need bubbled NH3 five seconds. The eluent of TLC (ethyl acetate / petroleum ether 1:1) need bubbled NH3 two seconds.
dicyclohexyl(2',6'-di(naphthalen-2-yl)-2-yl)phosphine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 140℃; for 36h;Schlenk technique; Inert atmosphere;
In a 25 mL Schlenk tube,A solution of 70.1 mg (0.2 mmol) of 2-dicyclohexylphosphino biphenyl (<strong>[247940-06-3]CyJohnPhos</strong>)(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.2-bromonaphthalene99.4 mg (0.48 mmol). After stirring at 140 C for 36 hours, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The solvent was separated on a 200-300 mesh silica gel column. The petroleum ether: ethyl acetate = 100: 1And the product was dried in vacuo to give 108.7 mg of product as a white solid in 90% yield.
With potassium phosphate; copper(l) iodide; In 5,5-dimethyl-1,3-cyclohexadiene; for 24h;Inert atmosphere; Reflux;
Under the protection of nitrogen,To 500ml of three bottles,33.2 g of compound A (100 mmol) was added,18.5 g of compound J (90 mmol),3.8 g of cuprous iodide (20 mmol),42.4 g of tripotassium phosphate (200 mmol),200 g xylene,Heated to reflux for 24 hours,TLC was tracked to no compound.Reaction finished,Cooling to 30 ,filter,Xylene 50ml * 3 leaching,The filtrate was washed with 200 g * 3 to pH = 7,After the organic phase is dried,Normal pressure on silica gel column.After the column,Xylene 50ml * 2 eluted silica gel column,Leaching finished,The eluent and the column with the pressure combined with pressure from the solvent,De-solvent was added to 300 ml of methanol and 50 ml of toluene mixed solution to recrystallize twice,After drying, 30.5 g of compound K,Yield: 74%, HPLC: 98.5%.
With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
General procedure: The halo aryl (1.0 equiv) was dissolved in a mixture of water:dioxane (1:1). The boronic acid or ester(1.5 equiv) and potassium phosphate (5.0 equiv) were added. The solution was degassed byvacuum/argon cycles (10 times) before addition of PdCl2(PPh3)2 (10 mol%) and further degassed (5times). The resulting mixture was stirred at 95 C under argon atmosphere for 16-20 hours. Thereaction mixture was filtered through Celite and diluted with water (approx. 30 mL) before washingwith chloroform (3 x 30 mL). If not stated otherwise, the aqueous phase was concentrated underreduced pressure and applied to a C18 precolumn before purification on a 10g or 60 g C18 column witha gradient of acetonitrile in water (10-100%) to yield the desired product.
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; for 24h;Inert atmosphere; Reflux;
General procedure: 250ml three-necked flask, under an atmosphere of nitrogen, was added 0.01mol 2-bromo-4,6-dichloropyrimidine, 0.015mol N-phenyl- [1,1'- biphenyl] -4-amine, 0.03 mol sodium tert-butoxide,1 × 10-4mol Pd2 (dba) 3, 1 × 10-4mol tri-tert-butylphosphine, 150ml toluene, heated to reflux for 24 hours, sampling plate, the reaction was complete;Natural cooling, filtration, rotary evaporation of the filtrate, passed through a silica gel column gave Intermediate A14, HPLC purity 99.5%, yield 82.7%.