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Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25 h; Inert atmosphere Stage #2: at -78℃; Inert atmosphere Stage #3: With n-butyllithium In tetrahydrofuran; hexane at -78 - 25℃; for 12 h; Inert atmosphere
General procedure: A solution of butyllithium (1 equiv, 1.6 M in hexanes) or tert-butyllithium (2 equiv, 1.7 M in pentanes) was added dropwise to a solution of aryllithium precursor (1 equiv) in dry THF (2.5 mL/mmol) under argon at -78 °C. The mixture was stirred at -78 °C for 15 min and was then warmed up to the desired temperature. Either a rt solution of aryne precursor (1 or 1.2 equiv) in dry THF (2.5 mL/mmol) or the neat aryne precursor was added dropwise. If required, butyllithium (0.2 equiv) was added dropwise to the reaction medium. The mixture was stirred for 15 h from the desired temperature to 25 °C, quenched with water and extracted with Et2O. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The crude product was puried by column chromatography on silica gel, eluting with hexane/EtOAc or pentane/EtOAc mixtures. Compound 23e was prepared following the general procedure from 22b (246 mg, 1.1 mmol) and 2d (406 mg, 1.1 mmol, 1 equiv) using BuLi as the base and adding a -78 °C solution of 2d in THF onto the reaction medium at -78 °C, followed by 0.2 equiv of BuLi. 23e was obtained as a mixture of two atropo-diastereoisomers with a diastereoisomeric ratio of 66:34. The crude residue was purified by column chromatography (eluent: hexane/AcOEt 8/2) to give 23e as a pale yellow oil (84.5 mg, 0.165 mmol, 15percent) and 24d as a yellow solid byproduct (23.2 mg, 0.0770 mmol, 7percent).
Reference：
[1] Tetrahedron, 2016, vol. 72, # 34, p. 5208 - 5220
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 4, p. 725 - 732
2
[ 54245-41-9 ]
[ 4269-17-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
for 12 h; Reflux
To a 500 mL reaction flask, 50 mL of benzonitrile was added successively,70.7 g (0.3 mol) of o-dibromobenzene,68.4 g (0.45 mol) of cesium fluoride,Catalyst purged with argon was added bis (dibenzylideneacetone) palladium 0.86g (15mmol),Thiophene-2-carboxylate 2.86 g (15 mmol)And 7.0 g (15 mmol) of 1,1'-bis (di-t-butylphosphine) ferrocene,150 reaction 24h,filter,The filtrate was distilled to remove benzonitrile to give crude 2-bromo-2'-carbonitrile biphenyl.A 500 mL reaction flask was charged with crude 2-bromo-2'-carbonitrile biphenyl,Glacial acetic acid 80mL,Concentrated sulfuric acid 80mL.After heating and refluxing for 12 h,Cooled to room temperature,filter,To give a dark yellow solid,100 mL of water,100 mL of methanol,Recrystallization from 200 mL of cumene afforded 61.9 g of 4-bromofluorenone as a yellow solid in 80percent yield.
Reference：
[1] Patent: CN105237379, 2016, A, . Location in patent: Paragraph 0006; 0016
[2] Organic Letters, 2013, vol. 15, # 11, p. 2742 - 2745
[3] Australian Journal of Chemistry, 1974, vol. 27, p. 2209 - 2228
3
[ 69200-16-4 ]
[ 4269-17-4 ]
Yield
Reaction Conditions
Operation in experiment
36 g
at 0 - 50℃; for 2 h;
To the crude intermediate 2 (70 g, 0.2525 mol), cone. H0SO4 (1400 mL) was slowly added at 0 °C. The reaction mixture was heated to 50 °C and stirred for 2 h. After 2 h, LCMS monitoring showed complete conversion of starting material. After cooling to room temperature, the mixture was carefully poured into ice water (1000 mL) and stirred for an hour. The precipitated solid was filtered and washed with water (500 mL). The crude product was purified twice by hot acetone crystallization to get 36 g intermediate 3 with 99.54 percent HPLC purity
Reference：
[1] Journal of the Chemical Society, 1952, p. 299,301
[2] Journal of the American Chemical Society, 1935, vol. 57, p. 2443,2446
[3] Yuki Gosei Kagaku Kyokaishi, 1958, vol. 16, p. 304,308[4] Chem.Abstr., 1958, p. 18339
10
[ 121772-84-7 ]
[ 4269-17-4 ]
Reference：
[1] Patent: CN108658932, 2018, A,
[2] Patent: CN108689972, 2018, A,
11
[ 98-80-6 ]
[ 4269-17-4 ]
Reference：
[1] Patent: CN108658932, 2018, A,
[2] Patent: CN108689972, 2018, A,
12
[ 583-55-1 ]
[ 4269-17-4 ]
Reference：
[1] Australian Journal of Chemistry, 1974, vol. 27, p. 2209 - 2228
To a 500 mL reaction flask, 50 mL of benzonitrile was added successively,70.7 g (0.3 mol) of o-dibromobenzene,68.4 g (0.45 mol) of cesium fluoride,Catalyst purged with argon was added bis (dibenzylideneacetone) palladium 0.86g (15mmol),Thiophene-2-carboxylate 2.86 g (15 mmol)And 7.0 g (15 mmol) of 1,1'-bis (di-t-butylphosphine) ferrocene,150 reaction 24h,filter,The filtrate was distilled to remove benzonitrile to give crude 2-bromo-2'-carbonitrile biphenyl.A 500 mL reaction flask was charged with crude 2-bromo-2'-carbonitrile biphenyl,Glacial acetic acid 80mL,Concentrated sulfuric acid 80mL.After heating and refluxing for 12 h,Cooled to room temperature,filter,To give a dark yellow solid,100 mL of water,100 mL of methanol,Recrystallization from 200 mL of cumene afforded 61.9 g of 4-bromofluorenone as a yellow solid in 80% yield.
With potassium acetate;palladium diacetate; In N,N-dimethyl-formamide; at 70℃; for 1h;Inert atmosphere;
Stage 1: In a 250 mL three-necked flask, introduce successively 2 g of <strong>[4269-17-4]4-bromo-fluoren-9-one</strong>, which can be obtained according to J. Amer. Chem. Soc. 57, 2443-6 (1935), 175 mg of palladium (II) acetate, 3.8 g of potassium acetate, 4.8 g of 4,4,5,5,4',4',5',5'-octamethyl-2,2'-bi[1,3,2-dioxaborolanyl] and 150 mL of dimethylformamide. Pass an argon stream into the solution obtained for 1 hour, then heat at about 70 C. for 1 hour. After cooling, filter the mixture on Celite, add 200 mL of water to the filtrate, extract with 3×50 mL of ethyl acetate, dry over magnesium sulphate and concentrate at reduced pressure. Purify the solid obtained by chromatography on silica gel (40-63 mum), eluting with a mixture of cyclohexane and ethyl acetate (95/05 by volume). We thus obtain 2 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-fluoren-9-one, in the form of a yellow solid, which is used as it is in the next stage, and has the following characteristics:Mass spectrum (E/I): m/z=306 (M+)1H spectrum (400 MHz-DMSO-d6) delta in ppm: 1.40 (s, 12H); 7.39 (t broad, J=7.5 Hz, 2H); from 7.59 to 7.66 (m, 2H); 7.71 (d broad, J=7.5 Hz, 1H); 7.87 (dd, J=1.0 and 7.5 Hz, 1H); 8.47 (d broad, J=7.5 Hz, 1H).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In ethanol; at 140℃; for 0.3h;Microwave irradiation;
Stage 1: In a microwave tube, dissolve 0.5 g of <strong>[4269-17-4]4-bromo-fluoren-9-one</strong>, which can be obtained according to J. Amer. Chem. Soc, 57, 2443-6, 1935, in 12 mL of ethanol, then add successively 0.27 g of bis(triphenylphosphine) palladium (II) chloride, 0.25 g of pyrimidino-5-boronic acid and 0.54 mL of triethylamine. After reaction at 140 C. for 18 minutes, concentrate to dryness, take up in dichloromethane and in water, dry over magnesium sulphate, filter and concentrate to dryness. Purify the raw solid obtained by flash chromatography on silica gel (20-40 mum), eluting with a mixture of cyclohexane and ethyl acetate (80-20 by volume). We thus obtain 0.3 g of 4-(pyrimidin-5-yl)-fluoren-9-one in the form of a yellow solid, to be used as it is in the next stage and having the following characteristics:Melting point (Kofler): 188 C.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 20h;
Stage 1: In a 50 mL three-necked flask, introduce successively 1.062 g of <strong>[4269-17-4]4-bromo-fluoren-9-one</strong>, which can be obtained according to J. Amer. Chem. Soc. 57, 2443-6 (1935), 1 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, 947 mg of palladium (0) tetrakis (triphenylphosphine) and 2.003 g of caesium carbonate in 32 mL of anhydrous dimethylformamide. After heating for 20 hours at 120 C., concentrate the dimethylformamide at reduced pressure and then pour it into 25 mL of water, and extract with 2×30 mL of ethyl acetate. After drying over magnesium sulphate and concentrating at reduced pressure, purify the raw solid obtained by flash chromatography on 100 g of silica gel (40-60 mum), eluting with cyclohexane and then with a mixture of cyclohexane and ethyl acetate (70-30 by volume). We thus obtain 455 mg of 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-fluoren-9-one, in the form of a light brown solid with the following characteristics:Mass spectrum (E/I): m/z=296 (M+)
4-bromo-9-(2'-bromobiphenyl-2-yl)-9H-fluoren-9-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In a nitrogen atmosphere, 2,2?-dibromo-1,1?-biphenyl (31.7 grams (g), 101.6 millimoles, mmol) and diethyl ether (500 milliliters, mL) were added to a three-neck flask and cooled to a temperature of -80 C. n-BuLi (34.7 mL of 2.66 molar (M) hexane solution, 92.4 mmol) was added dropwise thereto for 10 minutes. The mixture was stirred at a temperature of -80 C. for 5 minutes. Then, <strong>[4269-17-4]4-bromo-9H-fluorene-9-one</strong> (25.0 g, 97 mmol) was added thereto and stirred at a temperature of -80 C. for 5 minutes. The mixture was heated to room temperature for 30 minutes and stirred at room temperature for 3 hours. The mixture was quenched with a small amount of water, and diluted with chloroform (500 mL), and washed with pure water twice. The organic layer obtained therefrom was dried by using anhydrous magnesium sulfate and filtered and concentrated by using a silica gel pad to obtain Intermediate 1-1, which was used to synthesize Intermediate 1-2 without purification.
To the crude intermediate 2 (70 g, 0.2525 mol), cone. H0SO4 (1400 mL) was slowly added at 0 C. The reaction mixture was heated to 50 C and stirred for 2 h. After 2 h, LCMS monitoring showed complete conversion of starting material. After cooling to room temperature, the mixture was carefully poured into ice water (1000 mL) and stirred for an hour. The precipitated solid was filtered and washed with water (500 mL). The crude product was purified twice by hot acetone crystallization to get 36 g intermediate 3 with 99.54 % HPLC purity
Example 1; Synthesis of Example Compound D01; Synthesis of Compound 01; A Grignard reagent was prepared by putting 1.5 g (61.8 mmol) of magnesium in a reaction vessel, replacing the atmosphere inside the reaction vessel with argon, and then dropping 11.7 g (50.2 mmol) of 2-bromobiphenyl dissolved in 55 mL of dehydrated diethyl ether into the reaction vessel with stirring.[0098] The following reagent and solvent: dehydrated diethyl ether: 50 mL, and2-bromofluorenone : 10 g (38.6 mmol)were put in another reaction vessel. The Grignard reagent prepared in advance was dropped into this reaction vessel, followed by stirring for 30 min. It was confirmed by thin layer chromatography that the raw materials disappeared, and instead, a new compound was produced.[0099] The reaction solution was cooled to 0C and was subjected to extraction with a saturated ammonium chloride aqueous solution and ethyl acetate, and the organic layer was collected. After drying with sodium sulfate, the solvent was distilled off to obtain an intermediate of Compound 01.[0100] The intermediate of Compound 01 and 200 mL of acetic acid were put in another reaction vessel. This reaction solution was heated to 120C, and 20 mL ofconcentrated hydrochloric acid was dropped thereto over 10 min with stirring, followed by stirring at 120C for 1 hr. It was confirmed by thin layer chromatography that the raw materials disappeared, and instead, a new compound was produced.[0101] The reaction vessel was cooled to 0C, and the precipitate was collected and was washed with water and ethanol to obtain 13.0 g (33.1 mmol, yield: 85.8%) ofCompound 01. The resulting compound was detected as a peak at m/z = 394 by gas chromatography-mass spectrometer (GS-MS) and was thereby confirmed to be the target compound.
Under nitrogen protection,4-Bromo-triphenylamine (1.6 g; 5 mmol) was placed in a 200 ml Schlenk flask,40 ml of ether was then added, cooled to -78 C in a cryogenic reactor,3 ml (2 M; 6 mmol) of n-butyllithium was added dropwise,After 1 h at low temperature,4-Bromo-9-propanone (1.3 g; 5 mmol), which had been dissolved in anhydrous anaerobic ether, was slowly added dropwise to the Hiranque bottle,Reaction 1h after removal.Slowly returned to room temperature,The reaction flask was purged with dry ammonia (200 ml)Remove the gas device, adding lithium wire 200mg, reaction 0.5h, open the bottle to ammonia gas.The remaining solvent was quenched with saturated ammonium chloride,Ethyl acetate extraction, rotary evaporator will be solvent evaporated,The remaining crude product was purified by column chromatography to give 1 g (49%) of the intermediate C product.
Under an argon atmosphere, o-bromotriphenylamine (1. 6 g; 5 mmol) was added to a 200 ml jar bottle,Anhydrous tetrahydrofuran 60ml, low-temperature cooling to -78 C, dropping 3ml n-butyl lithium (2m; 6mmol),After reaction at low temperature for 1 hour, the solution was dissolved in anhydrous tetrahydrofuran (THF) under Ar gas4-bromo-9-propanone (1.2 g; 5 mmol),Continue low temperature reaction 1h after the removal of stirring at room temperature overnight.The reaction was then quenched with saturated ammonium chloride solution and dried over anhydrous sodium sulphate.The solvent was evaporated on a rotary evaporator, and the product was isolated by column chromatography (1.1 g, 50%).
9- (2-bromo-phenyl) -9H- carbazole (9- (2-bromophenyl) -9H-carbazole, 3-1) was dissolved 9.4g (29mmol) in 80mL of anhydrous tetrahydrofuran cooled to -78 It was. Normal to the cooled solution - and then put the semi-butyl lithium (2.5M) 13mL (32mmol) slowly and stirred for 30 minutes at the same temperature. 4-bromo--9H- fluorene-9-one (<strong>[4269-17-4]4-bromo-9H-fluoren-9-one</strong>) To a mixture of the cold put 7.5g (29mmol, 3-2). When the reaction is complete, the mixture gives the temperature up to room temperature and stirred was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and treated with anhydrous magnesium sulfate and concentrated after filtration. It was added to an excess of hexane and a small amount of ethyl acetate to the compound of the concentrated state after stirring was filtered to give 10.6g of the desired compound 3-3 (72%) of white solid.
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