* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
15
[ 13534-89-9 ]
[ 13534-99-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
16
[ 13534-89-9 ]
[ 35486-42-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
17
[ 13534-89-9 ]
[ 136-95-8 ]
[ 261-96-1 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 9, p. 1420 - 1422[2] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 9, p. 1521 - 1524,3
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24 h; Inert atmosphere
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol percent), PPh3 (26 mg, 10 mol percent) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97percent) as a white solid.
83%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24 h; Sealed tube; Inert atmosphere
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol percent) and Pd(OAc)2 (23 mg,5 mol percent) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane–EtOAc, 30:1) to provide pure pyridines 2a–j. 3-Bromo-2-phenylpyridine (2a).53 Yield 387 mg(83percent), colorless oil.
Reference：
[1] Tetrahedron, 2013, vol. 69, # 51, p. 10996 - 11003
[2] Chemistry of Heterocyclic Compounds, 2017, vol. 53, # 10, p. 1103 - 1113[3] Khim. Geterotsikl. Soedin., 2017, vol. 53, # 10, p. 1103 - 1113,11
[4] Synlett, 2009, # 7, p. 1081 - 1086
20
[ 13534-89-9 ]
[ 128071-75-0 ]
Reference：
[1] Journal of Organometallic Chemistry, 1990, vol. 382, # 3, p. 319 - 332
21
[ 13534-89-9 ]
[ 68-12-2 ]
[ 128071-91-0 ]
Reference：
[1] Journal of Organometallic Chemistry, 1990, vol. 382, # 3, p. 319 - 332
22
[ 13534-89-9 ]
[ 131747-43-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
23
[ 13534-89-9 ]
[ 75-05-8 ]
[ 122851-60-9 ]
Yield
Reaction Conditions
Operation in experiment
22%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 1.5 h;
To the solution of MeCN (87 mg, 2.13 mmol) in THF (8 mL) was added n-BuLi (1.78 mL, 4.26 mmol) at -78 oC and stirred at -78 oC for 1 h. Then B2.1 (500 mg, 2.13 mmol) in THF (2 mL) was added slowly at -78 oC. The reaction was stirred at -78 oC for 1.5 h, and warmed to rt, quenched with saturated NH4Cl solution, extracted with EA (100 mL × 3), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC (Mobile Phase: MeCN/H2O (10 nM) NH4HCO3)) to give the title compound (110 mg, 22percent) as a white solid. LCMS: [MH]+ = 197.
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 1h;
Stage #2: benzaldehyde at 20℃; for 2h;
92%
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 1h;
Stage #2: benzaldehyde In tetrahydrofuran at 20℃; for 18h;
78 %Chromat.
Stage #1: 2,3-dibromopyridine With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1.52778E-05h;
Stage #2: benzaldehyde In tetrahydrofuran; hexane at 0℃; for 0.0025h;
78 %Chromat.
Stage #1: 2,3-dibromopyridine With n-butyllithium In hexane at 0℃; for 1.52778E-05h;
Stage #2: benzaldehyde In tetrahydrofuran; hexane at 0℃; for 0.0025h;
Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75h;
Stage #2: 2,3-dibromopyridine In tetrahydrofuran; hexane at -78 - 20℃; for 2.5h;
22%
Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran at -78℃; for 1h;
Stage #2: 2,3-dibromopyridine In tetrahydrofuran at -78℃; for 1.5h;
2-(3-Bromopyridin-2-yl)acetonitrile (B2.2)
To the solution of MeCN (87 mg, 2.13 mmol) in THF (8 mL) was added n-BuLi (1.78 mL, 4.26 mmol) at -78 oC and stirred at -78 oC for 1 h. Then B2.1 (500 mg, 2.13 mmol) in THF (2 mL) was added slowly at -78 oC. The reaction was stirred at -78 oC for 1.5 h, and warmed to rt, quenched with saturated NH4Cl solution, extracted with EA (100 mL × 3), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC (Mobile Phase: MeCN/H2O (10 nM) NH4HCO3)) to give the title compound (110 mg, 22%) as a white solid. LCMS: [MH]+ = 197.
Stage #1: acetonitrile With n-butyllithium In tetrahydrofuran; hexanes at -78 - -60℃; for 0.75h;
Stage #2: 2,3-dibromopyridine In tetrahydrofuran; hexanes at -78℃; for 1.5h;
i
Dry THF (100 mL) was cooled to -78° C. and n-butyllithium (2.5 M in hexanes; 23 mL, 58 mmol) was added. Acetonitrile (3.3 mL, 64 mmol) was added dropwise maintaining the temperature below -60° C. A white precipitate formed and the reaction mixture was stirred at -78° C. for 45 min. A solution of 2,3-dibromopyridine (2.0 g, 8 4 mmol) in dry THF (10 mL) was added dropwise and the reaction mixture stirred at -78° C. for 1.5 h then allowed to warm to room temperature. The reaction was quenched by the dropwise addition of water. The aqueous was extracted with DCM (×3) and the combined organics washed with brine, dried (MgSO4) and concentrated in vacuo. (3-Bromo-pyridin-2-yl)-acetonitrile (Intermediate 1) was purified by flash column chromatography.
Stage #1: 2,3-dibromopyridine With n-butyllithium In diethyl ether at -78℃; for 1h;
Stage #2: With Triisopropyl borate In diethyl ether at -78 - 20℃;
Stage #3: 2,3-dimethyl-2,3-butane diol With acetic acid In diethyl ether at 20℃; for 2h;
With chloro-trimethyl-silane; sodium iodide; for 75h;Reflux;
2,3-dibromopyridine 10g (42.21mmol), chlorotrimethylsilane 4.59g (42.21mmol), sodium iodide 19g (126.64mmol), propionitrile 10mL was added and refluxed for 75 hours. After the reaction was completed was recrystallized with hexane (Hexane) to give the title compound 8.87g 351-1 (74%)
pyrido[3',2':4,5]imidazo[2,1-a]isoquinoline[ No CAS ]
pyrido[3',2':4,5]imidazo[2,3-a]isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With tris(dibenzylideneacetone)dipalladium (0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,2-dimethoxyethane at 140℃; for 30h;
With potassium carbonate In lithium hydroxide monohydrate; acetonitrile at 80℃; for 72h;
1221
Example 1221 Compound 1221A (1.0g, 4.22 mmol), cyclopropyl boronic acid (326 mg, 3.80 mmol) and [PdCI2(dppf)]CH2CI2 (150, 0.21 mmol) in CH3CN (15 mL) was treated with potassium carbonate (5 mL, 5 mmol, 1 M in H2O). The mixture was subjected to vacuum and refilled with Nitrogen three times. The reaction mixture was stirred at 80 0C (oil bath) for 3 days. Additional [PdCl2(dppf)]CH2CI2 (150 mg) was added in day two. After cooling down, the water layer was separated and extracted with EtOAc (20 mL) once. The organic layers were combined, filtered through a Celite pad, and concentrated. The product was purified by silica gel chromatography (Hexane/EtOAc, 1 :0 to 10:1 to 5:1) to give 1221B (280 mg, 33.5%)
With tripotassium phosphate tribasic; palladium diacetate; tricyclohexylphosphine at 100℃;
88
22. The required 3-bromo-2-cyclopropylpyridine was prepared via reaction of 2,3-dibromopyridine with cyclopropylboronic acid at 100 °C in the presence of palladium(ll) acetate,tricyclohexylphosphine and potassium phosphate.
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 95℃; for 2h; Inert atmosphere;
1.1 Step 1:
A mixture of 4-bromonaphthalen-2-ol (3.0 g, 13.4 mmol) , bis (pinacolato) diboron (4.1 g, 16.1 mmol) , Pd (dppf) Cl2(0.98 g, 1.35 mmol) and KOAc (3.9 g, 40.3 mmol) in 1, 4-dioxane (30 mL) was stirred at 95 C for 2 hours under nitrogen atmosphere. The mixture was cooled and diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and filtered. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to afford 20-1.
3-bromo-N-(2-methoxyphenyl)pyridine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.8%
With caesium carbonate In toluene at 115℃; for 1.5h;
26.1
In a 5-ml screw-capped vial, palladium acetate (5.1 mg,0.021 mmol) , 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) (24.4 mg, 0.042 mmol), cesium carbonate (275 mg, 0.84 mmol), 2, 3-dibromopyridine (100 mg, 0.42 mmol) and degassed toluene (1 ml) were mixed, and to this, o-anisidine (52.4 mg, 0.42 mmol) was added. Then, argon gas was enclosed in the vial, and the vial was stoppered tightly and the mixture was stirred with heating at an external temperature of 1150C for 1.5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, toluene (5 ml) and water (5 ml) were added thereto, and the insoluble was filtered off through Celite. The filtrate was washed with toluene (10 ml) , and then the obtained organic layer was washed with saturated brine (5 ml) , dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue, a mixture (6 ml) of hexane/ethyl acetate (5/1) was added. The mixture was stirred at room temperature for 10 minutes, and then the insoluble was filtered off. The filtrate was concentrated under reduced pressure, and dried under reduced pressure at 5O0C, to yield the title compound (107 mg, 0.38 mmol) as a white solid (yield 90.8%).1H-NMR (CDCl3, TMS, 300 MHz) δ (ppm) : 3.95 (s, 3H), 6.61 (dd, IH, J = 7.7, 4.8 Hz), 6.90-7.01, 7.73 (dd, IH, J = 7.7,1.6 Hz), 7.83 (brs, IH), 8.14 (dd, IH, J = 4.8, 1.6 Hz), 8.57- 8.63 (m, IH) .13C-NMR (CDCl3, TMS, 300 MHz) δ (ppm): 56.03, 107.20, 110.08, 115.35, 118.33, 121.02, 121.66, 129.97, 140.11, 146.43, 148.28, 151.96.High resolution mass spectrometry (012HuBrN2O) Theoretical value: 278.0055 [M+] Measured value: 278.0048 [M+] Melting point: 93.8°C
Stage #1: 2,3-dibromopyridine; 4-methoxyphenylboronic acid With sodium carbonate In ethanol; water; toluene at 90℃; for 12h;
Stage #2: phenylboronic acid With sodium carbonate In ethanol; water; toluene at 90℃; for 12h; Further stages.;
With lithium chloride In DMF (N,N-dimethyl-formamide) at 100℃; for 18h;
3-bromo-2-vinylpyridine. A solution of 2,3-dibromopyridine (2.0 g, 8.44 mmol) in DMF (10 mL) was treated with tributyl(vinyl)tin (2.94 g, 9.29 mmol), LiCl (1.07 g, 25.32 mmol), and PdCl2(PPh3)2 (0.296 g, 0.422 mmol). The reaction mixture was heated at 100° C. for 18 hours. The mixture was extracted with hexanes (3×50 mL). The combined hexane layers were extracted with 1N HCl. The aqueous layer was neutralized with 1N NaOH, extracted with hexanes, and the extracts were dried (MgSO4), filtered, and concentrated to provide the desired product as a yellowish oil (0.83 g, 53% yield). MS m/z 184(MH+); 1H NMR (300 MHz, CD3OD) δ 5.53 (dd, J=10.80, 2.01 Hz, 1H), 6.33 (dd, J=16.83, 1.83 Hz, 1H), 7.08-7.26 (m, 2H), 7.96 (dd, J=8.05, 1.46 Hz, 1H), 8.44 (dd, J=4.76, 1.46 Hz, 1H); 13C NMR (300 MHz, CD3OD) δ 121.9, 122.4, 125.7, 134.9, 142.8, 149.5, 154.5.
53%
Stage #1: 2,3-dibromopyridine; tri-n-butyl(vinyl)tin With bis-triphenylphosphine-palladium(II) chloride; lithium chloride In N,N-dimethyl-formamide at 100℃;
Stage #2: With potassium fluoride In N,N-dimethyl-formamide for 4h;
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: 1-phenylmethyl-4-piperidone In tetrahydrofuran for 0.75h;
1-benzyl-4-(2-bromopyridin-3-yl)piperidin-4-ol
To a solution of 2,3-dibromopyridine (12.0 g, 50.7 mmol) in tetrahydrofuran (250 ml) was added isopropylmagnesium chloride (26 ml, 52.0 mmol). The mixture was stirred for 30 mm at 20 °C. 1-benzylpiperidin-4-one (9.5 g, 50.2 mmol) was added and the mixture was stirred for 45mm, then poured into water (25 ml) and extracted with methyl tert-butyl ether (3 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography (amine-silica, split in 3x40 g, 0% to 50% ethyl acetate in heptane) gave the title compound (5.8 g, 16.8 mmol, 33% yield) as light brown solid.MS mle: 347.1 ([M+Hj+)
23%
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 1h;
Stage #2: 1-phenylmethyl-4-piperidone In tetrahydrofuran at 20℃; for 16h;
a
a) 1'-Benzyl-2-bromo-2',3',5',6'-tetrahydro-1'H-[3,4']bipyridinyl-4'-ol To a solution of 10 g (42 mmol) 2,3-dibromopyridine in 210 ml dry tetrahydrofuran at room temperature were added 22 ml (44 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was stirred for 1 h at room temperature. A solution of 7.9 g (44 mmol) 1-benzyl-4-piperidone in 40 ml tetrahydrofuran was added, and stirring was continued for 16 h. The reaction mixture was quenched with water, basified to pH 9 with aqueous 2 M sodium hydroxide solution and extracted with tert-butyl methyl ether (3*). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (3.4 g, 23%) as an orange amorphous solid. MS m/e (%): 349, 347 (M+H+, 100, 97).
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-arylation of 2,5- and 2,3-dibromopyridines
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
81%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; triphenylphosphine In tetrahydrofuran; water at 80℃;
With palladium on activated charcoal; potassium carbonate; triphenylphosphine In water; toluene at 100℃;
83%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-arylation of 2,5- and 2,3-dibromopyridines
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
72%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; Sealed tube;
72%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; triphenylphosphine In tetrahydrofuran; water at 80℃;
80%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-arylation of 2,5- and 2,3-dibromopyridines
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
77%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
71%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; Sealed tube;
71%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
With palladium diacetate; potassium carbonate; triphenylphosphine; In methanol; acetonitrile; at 50℃; for 24h;Inert atmosphere;
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
83%
With palladium diacetate; potassium carbonate; triphenylphosphine; In methanol; acetonitrile; at 50℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j. 3-Bromo-2-phenylpyridine (2a).53 Yield 387 mg(83%), colorless oil.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; acetonitrile; at 50℃; for 24h;Inert atmosphere;
Weigh molecular 1 (4.2 mmol, 1 g), phenylboronic acid (4.2 mmol, 515 mg), potassium carbonate (8.4 mmol, 1165 mg), tetrakis (triphenylphosphonium) palladium (0.2 mmol, 240 mg) on an analytical balance and add to In a 150 ml round-bottomed flask, evacuate and bubble nitrogen for three cycles. A mixed solution of acetonitrile and methanol (2: 1, v / v) was injected after 30 minutes of deoxygenation under a nitrogen atmosphere, stirred to dissolve, and then reacted at 50 C for 24 hours. After the reaction was completed, it was cooled to room temperature. Filtration gave a solid. PE: DCM = 10: 1 was used as eluent for column chromatography. The product was a yellow liquid.
Stage #1: 2,3-dibromopyridine With hydrazine In 1,4-dioxane at 85℃; for 8h;
Stage #2: acetyl chloride With triethylamine In dichloromethane at -78 - 20℃; for 0.333333h; Inert atmosphere;
64.A
To a solution of 0.800 g (3.38 mmol) of 2,3-dibromopyridine in 10 mL of anhydrous 1,4-dioxane was added 0.325 g (10.1 mmol) of anhydrous hydrazine and the resulting mixture was heated to 85° C. for 8 h. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo. The crude residue was dissolved in anhydrous dichloromethane and cooled to -78° C. in a dry ice acetone bath under an atmosphere of nitrogen. Next, 1.0 mL (6.8 mmol) of triethylamine was added followed by 0.210 g (2.72 mmol) of acetyl chloride. The resulting mixture was allowed to warm to ambient temperature over 20 min then all volatiles were removed in vacuo. The residue was suspended in 20 mL of water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (0.18 g, 23%). LC-MS: m/z (ES) 230, 232 (MH)+ and 188, 190 (MH-COCH3)+.
4.2. Methylation of 2,3-dibromopyridine (5) and 3-bromo-2-chloroquinoline (9)
General procedure: A flame dried round-bottomed flask was charged with the respective dihalo compound (10 mmol), methyl trifluoromethanesulfonate (1.2 mL, 10.6 mmol) (CAUTION: Causes burns by all exposure routes.) and dry toluene (15 mL). The resulting solution was stirred under Ar atmosphere for the time indicated at room temperature. A white precipitate was formed, which was collected on a fritted filter, rinsed well with dry toluene (50 mL), and dried under reduced pressure.
In tetrahydrofuran at 20 - 40℃; for 19h; Inert atmosphere;
3
Tetrakis(triphenylphosphine)palladium(0) (2.0 g) is added to a flask charged with a stir bar, phenethylzinc bromide (0.5 mol/L in tetrahydrofuran, 100 mL), 2,3-dibromopyridine (10.50 g), and tetrahydrofuran (100 ml) and kept under argon atmosphere at room temperature. The resulting mixture is stirred at room temperature for 3 h and at 40° C. for another 16 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→75:25) to afford the title compound as an oil that solidified upon treatment with ether. Yield: 9.32 g (81% of theory); LC (method 1): tR=4.28 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
81%
In tetrahydrofuran at 20 - 40℃; for 19h; Inert atmosphere;
1.3; 2.3
Step 3: 3-bromo-2-phenethyl-pyridineTetrakis(triphenylphosphine)palladium(0) (2.0 g) is added to a flask charged with a stir bar, phenethylzinc bromide (0.5 mol/L in tetrahydrofuran, 100 mL), 2,3-dibromopyridine (10.50 g), and tetrahydrofuran (100 ml) and kept under argon atmosphere at room temperature. The resulting mixture is stirred at room temperature for 3 h and at 40 °C for another 16 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→75:25) to afford the title compound as an oil that solidified upon treatment with ether. Yield: 9.32 g (81 % of theory); LC (method 1 ): tR = 4.28 min; Mass spectrum (ESI+): m/z = 262/264 (Br) [M+H]+.
81%
In tetrahydrofuran at 20 - 40℃; for 19h; Inert atmosphere;
Step 3: 3-bromo-2-phenethyl-pyridineTetrakis(triphenylphosphine)palladium(0) (2.0 g) is added to a flask charged with a stir bar, phenethylzinc bromide (0.5 mol/L in tetrahydrofuran, 100 ml_), 2,3-dibromopyridine (10.50 g), and tetrahydrofuran (100 ml) and kept under argon atmosphere at room temperature. The resulting mixture is stirred at room temperature for 3 h and at 40 °C for another 16 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→75:25) to afford the title compound as an oil that solidified upon treatment with ether. Yield: 9.32 g (81 % of theory); LC (method 1 ): tR = 4.28 min; Mass spectrum (ESI+): m/z = 262/264 (Br) [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide In tetrahydrofuran; water at 70℃; for 4h; Schlenk technique; Inert atmosphere; chemoselective reaction;
92%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; potassium hydroxide In tetrahydrofuran; water for 72h; Inert atmosphere; Reflux;
92%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; potassium hydroxide In tetrahydrofuran; water for 72h; Reflux;
85%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; potassium hydroxide In tetrahydrofuran; water at 70℃; for 18h; Schlenk technique;
General procedure for preparation of 3-bromo-2-(2-bromophenyl)pyridine 1a
2,3-Dibromopyridine (2 g, 8.44 mmol), 2-bromophenyl boronic acid (1.7 g, 8.44mmol), Pd(PPh3)4 (488 mg, 0.422 mmol), were added to a 250 mL Schlenk flask. Themixture was back-filled several times with Argon. To the mixture K2CO3 (1M, 25 ml),5 drops of aqueous KOH (10%) and 35 ml of THF were added, then back-filledseveral times with Argon. The reaction was heated at 70 C for 18h. The solvent wasevaporated in vacuo. The residue was extracted with ethyl acetate and water. Theorganic layer was dried over MgSO4, filtered and the solvent was evaporated in vacuo.The yellow residue was purified by column chromatography (silica gel,hexane/ethylacetate 20:1) to yield 3-bromo-2-(2-bromophenyl)pyridine1 1a (2.2 g, 85%) as colorless syrup.
With palladium diacetate; 2,2'-bis(diphenylphosphino)biphenyl; copper(l) chloride In N,N-dimethyl-formamide at 80℃; for 14h; Inert atmosphere;
4.2.2. Pd(OAc)2/CuCl system22d
General procedure: The triolborate, dibromides (0.2 mmol), palladium acetate (10 mol %), BIPHEP (11 mol), and CuCl (0.4 equiv) were placed in a flask under an atmosphere of nitrogen. DMF (15 mL) was added, and heated at 80 °C for 14 h. After cooling to room temperature, 15 mL water was added, extracted with dichloromethane, dried over MgSO4, and then purified by chromatography on silica gel.
Stage #1: tert-butyl-3-iodoazetidine-1-carboxylate With chloro-trimethyl-silane; ethylene dibromide; zinc In dimethyl amine at 20 - 65℃; for 1.41667h; Inert atmosphere;
Stage #2: 2,3-dibromopyridine With copper(l) iodide In dimethyl amine at 80℃; for 17h; Inert atmosphere;
1.1
A 5L 3 -neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (138 g, preactivated according to the above Preparation 1, 2.11 mol, 2 eq.) and DMA (370 mL, anhydrous). 1, 2-dibromoethane (13 mL, 0.158 mol, 0.15 eq, Aldrich) was then added over 5 min, followed by TMSCl (20 mL, 0.158 mol, 0.15 eq, Acros) over 5 min. The reaction mixture was stirred for 20 min at RT. A solution of N-Boc-3-iodoazetidine (2) (448 g, 1.583 mol, 1.5 eq, CNH Technologies) in DMA (925 mL, anhydrous) was added over 25 min keeping the internal temperature below 65 °C using a water bath. The suspension was stirred for 1 h at RT at which point it was degassed with nitrogen. Stirring was stopped and the suspension was allowed to stand. A 12L 3 -neck round bottom flask fitted with a mechanical stirrer was charged with 2, 3-dibromopyridine (1) (250 g, 1.055 mol, 1.0 eq, Frontier Scientific),PdCl2dppf-CH2Cl2 (25.8 g, 31.65 mmol, 0.03 eq, Aldrich), Cul (12.5 g, 65.41 mmol, 0.062 eq, Aldrich), and DMA (925 mL, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 12L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80 °C for 17 h at which point LCMS indicated complete conversion of 2, 3-dibromopyridine (1). The reaction mixture was transferred to brine (2 L) in 22L separatory funnel. Water (2 L) and EtOAc (4 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 3 L). The combined organics were washed with water (3 x 3 L) and brine (2 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate = 9:1 to 5: 1) to obtain 289 g of impure tert-butyl 3-(3-bromopyridin-2- yl)azetidine-l-carboxylate (3) which was distilled under high vacuum to remove the impurity (N- Boc-azetidine) to give 281 g of pure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-l-carboxylate. Yield: 85%.
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; regioselective reaction;
4.1 General procedure for the copper-catalyzed coupling reaction of 2,x-dihalopyridines and phenols
General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product.
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; regioselective reaction;
4.1 General procedure for the copper-catalyzed coupling reaction of 2,x-dihalopyridines and phenols
General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product.
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; regioselective reaction;
4.1 General procedure for the copper-catalyzed coupling reaction of 2,x-dihalopyridines and phenols
General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product.
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; regioselective reaction;
4.1 General procedure for the copper-catalyzed coupling reaction of 2,x-dihalopyridines and phenols
General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product.
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; regioselective reaction;
4.1 General procedure for the copper-catalyzed coupling reaction of 2,x-dihalopyridines and phenols
General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 °C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product.
With sulfuric acid In isopropyl alcohol at 80℃; for 96h;
B10 Preparation of compound 10:
Intermediate 25 (0.482 g, 2 mmol) was dissolved in iPrOH (24 mL), then 2,3- dibromopyridine (0.948 g, 4 mmol) and sulfuric acid (0.533 mL, 10 mmol) were added. The reaction mixture was stirred for 4 days at 80°C. The reaction was allowed to cool down, then DCM and a sat. aq. NaHC03 solution were then added. The phases were separated and the organic layer was dried and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (silica gel; elueng : 7M solution of ammonia in methanol/DCM 0/100 to 10/90). The desired fractions were collected and further purified by preparative SFC (Chiralpak Daicel AS 20 microhm 500 gr). Mobile phase (C02, iPrOH with 0.2% iPrNH2), to yield compound 10 (0.135 g, 17% FontWeight="Bold" FontSize="10" )
17%
With sulfuric acid In isopropyl alcohol at 80℃; for 96h;
B.10 Preparation of Compound 10
Intermediate 25 (0.482 g, 2 mmol) was dissolved in iPrOH (24 mL), then 2,3-dibromopyridine (0.948 g, 4 mmol) and sulfuric acid (0.533 mL, 10 mmol) were added. The reaction mixture was stirred for 4 days at 80° C. The reaction was allowed to cool down, then DCM and a sat. aq. NaHCO3 solution were then added. The phases were separated and the organic layer was dried and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (silica gel; elueng: 7M solution of ammonia in methanol/DCM 0/100 to 10/90). The desired fractions were collected and further purified by preparative SFC (Chiralpak Daicel AS 20 microhm 500 gr). Mobile phase (CO2, iPrOH with 0.2% iPrNH2), to yield compound 10 (0.135 g, 17%)
N-(3-bromopyridin-2-yl)isoquinolin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
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 10h;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.
4-benzyl-N-(3-bromopyridin-2-yl)isoquinolin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 10h; Inert atmosphere;
General procedure for the synthesis of N-arylisoquinolin-3-amines
General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol % ), ligand (10 mol%), 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 palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-arylation of 2,5- and 2,3-dibromopyridines
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
93.6%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
82%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-arylation of 2,5- and 2,3-dibromopyridines
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
52%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; Sealed tube;
52%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane at 80℃; for 0.166667h; Inert atmosphere; Microwave irradiation;
25.1 Step 1
[00161] In a 2-5 mL Smith Process Vial, 2,3-dibromopyridine (300.0 mg, 1.266 mmol), 4-fluorophenyl boronic acid (177.2 mg, 1.266 mmol, 1 equiv) and Pd(PPh3)4 (73.2 mg, 0.063 mmol, 0.05 equiv) were placed. The mixture was suspended in 1,4-dioxane (3 mL) and 2M-Na2C03 (1 mL) under a nitrogen atmosphere. The mixture was heated at 80°C for 10 min using the microwave reactor. To the mixture were added EtOAc (70 mL) and water (30 mL). The whole was filtered through Celite (3 g) and the filtrate was washed with brine (30 mL), dried over Na2S04 and concentrated under a reduced pressure. Obtained crude material was purified by Gilson preparative HPLC to give 3-bromo-2-(4-fluorophenyl)pyridine. [00162] CuH7BrFN. MS. m/z 241.0 (M-l+1), 243.0 (M+l+1).
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; Sealed tube;
68%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
62%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
46%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-arylation of 2,5- and 2,3-dibromopyridines
General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 °C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid.
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 0.75h;
Stage #2: acetone In tetrahydrofuran at 20℃;
2-(2-Bromopyridin-3-yl)propan-2-ol
To a solution of 2,3-dibromopyridine (5.5 g, 23 mmol) in tetrahydrofuran (77 ml) was added isopropylmagnesium chloride, 2 M in tetrahydrofuran (15 ml, 30 mmol) at room temperature. The reaction mixture was stirred for 45 minutes. Acetone (2.7 g, 3.4 ml, 46 mmol) was added in a quick fashion at room temperature. The reaction mixture was stirred for 16 h and the quenched with 2 M aqueous hydrogen chloride solution (15 ml). The solvent was evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated. The aqueous layer was extracted with one 100-ml portion of ethyl acetate. The combined organic layers were washed with one 50-ml portion of saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography with w-heptane/ethyl acetate gave the title compound (2.4 g, 48%) as light brown viscous oil. MS m/e: 216, 218 [(M+H)+].
di-tert-butyl 2,2'-(pyridine-2,3-diyl)bis(1H-pyrrole-1-carboxylate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: 2,3-dibromopyridine; N-boc-2-pyrroleboronic acid With potassium carbonate In ethanol; water; toluene for 0.25h; Inert atmosphere;
Stage #2: With tetrakis(triphenylphosphine) palladium(0) at 90℃; for 24h;
Synthesis of di-tert-butyl 2,2'-(pyridine-2,3-diyl)bis(1H-pyrrole-1-carboxylate)
General procedure: 2,3-Dibromopyridine (0.40 g, 1.7 mmol) and 2 (1.8 g, 8.4 mmol) was placed in the flaskunder an argon atmosphere, and then toluene (36 ml), EtOH (12 ml) and 2.0 M K2CO3aq. (16 ml) was added. The resulting solution was degassed by bubbling for 15 minwith argon and then Pd(PPh3)4 (97 mg, 0.084 mmol) was added. The reaction mixturewas heated at 90 C for 24 h. After cooling to room temperature, water was added. The mixture was extracted with EtOAc and the separated organic layer was dried overNa2SO4. After removal of the solvent, the residue was purified by silica gel columnchromatography (EtOAc:hexane = 1:3) to give di-tert-butyl2,2'-(pyridine-2,3-diyl)bis(1H-pyrrole-1-carboxylate) as yellow oil. Yield: 88% (0.61 g,1.5 mmol).
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl acetamide; water at 120℃; for 7h; Inert atmosphere;
2,3-Dibromopyridine (20 g, 84 mmol), 2-Chlorophenylboronic acid (13.2 g, 84 mmol) and potassium phosphate tribasic (35.8 g, 169 mmol) were charged into the reaction flask with 240 mL of dimethylacetamide and 60 mL of water. This mixture was degassed with nitrogen for 15 minutes followed by the addition of tetrakis(triphenylphosphine)palladium(0) (9.76 g, 8.44 mmol). This mixture was then stirred and heated at 120° C. for 7 hours. Heating was discontinued. Then, the reaction mixture was diluted with water and was extracted with ethyl acetate. The organic extracts were dried then were filtered and concentrated under vacuum. The crude residue was passed through a silica gel column eluting the column with 5-15% ethyl acetate/heptanes. Product fractions yielded 3-bromo-2-(2-chlorophenyl)pyridine (17.2 g, 64.1 mmol, 76% yield).
63%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl acetamide; water at 130℃; for 0.25h; Sealed tube;
3-bromo-2-(4-ethyloxyphenylethynyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(l) iodide; palladium(II) trifluoroacetate; palladium diacetate; diisopropylamine; In methanol; acetonitrile; for 24h;Reflux; Inert atmosphere;
General procedure: 2,5-dibromopyridine (119 mg, 0.50 mmol), phenylacetylene (61 mg, 0.6 mmol), i-Pr2NH (101 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %), and CuI (9.5 mg, 5 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at reflux under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 200:1) to give the desired product 3i (117 mg, 91%) as a white solid.
3-bromo-2-(4-chlorophenylethynyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(l) iodide; palladium(II) trifluoroacetate; palladium diacetate; diisopropylamine In methanol; acetonitrile for 24h; Reflux; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-alkynylation of 2,5- and 2,3-dihalopyridines
General procedure: 2,5-dibromopyridine (119 mg, 0.50 mmol), phenylacetylene (61 mg, 0.6 mmol), i-Pr2NH (101 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %), and CuI (9.5 mg, 5 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at reflux under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 200:1) to give the desired product 3i (117 mg, 91%) as a white solid.
3-bromo-2-(4-bromophenylethynyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With copper(l) iodide; palladium(II) trifluoroacetate; palladium diacetate; diisopropylamine In methanol; acetonitrile for 24h; Reflux; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-alkynylation of 2,5- and 2,3-dihalopyridines
General procedure: 2,5-dibromopyridine (119 mg, 0.50 mmol), phenylacetylene (61 mg, 0.6 mmol), i-Pr2NH (101 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %), and CuI (9.5 mg, 5 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at reflux under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 200:1) to give the desired product 3i (117 mg, 91%) as a white solid.
3-bromo-2-(2-methyloxyphenylethynyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With copper(l) iodide; palladium(II) trifluoroacetate; palladium diacetate; diisopropylamine In methanol; acetonitrile for 24h; Reflux; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-alkynylation of 2,5- and 2,3-dihalopyridines
General procedure: 2,5-dibromopyridine (119 mg, 0.50 mmol), phenylacetylene (61 mg, 0.6 mmol), i-Pr2NH (101 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %), and CuI (9.5 mg, 5 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at reflux under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 200:1) to give the desired product 3i (117 mg, 91%) as a white solid.
With copper(l) iodide; palladium(II) trifluoroacetate; palladium diacetate; diisopropylamine In methanol; acetonitrile for 24h; Reflux; Inert atmosphere; regioselective reaction;
Typical procedure for the 2-alkynylation of 2,5- and 2,3-dihalopyridines
General procedure: 2,5-dibromopyridine (119 mg, 0.50 mmol), phenylacetylene (61 mg, 0.6 mmol), i-Pr2NH (101 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %), and CuI (9.5 mg, 5 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at reflux under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 200:1) to give the desired product 3i (117 mg, 91%) as a white solid.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine at 20℃;
With tert.-butyl lithium; In toluene; at -78℃; for 4h;Inert atmosphere;
To a solution of 2,3-dibromopyridine (10 g, 42.2 mmol) in toluene (100 mL) was dropwise added t-BuLi (20.26 mL, 50.7 mmol) at -78C under N2. After the resulting mixture was stirred at -78C for 2h, DMF (3.92 mL, 50.7 mmol) was added dropwise. The mixture was stirred at -7 8C for another 2h. The mixture was then quenched with water at -7 8C andextracted with EtOAc (300 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by combiflash (25% EtOAc in petroleum ether) to give the title compound. LRMS m/z (M+H) 186.1 found, 186.1 required.
To a solution of 2,3-dibromopyridine (10 g, 42.2 mmol) in toluene (100 mL) was dropwise added n-BuLi (20.26 mL, 50.7 mmol) at -78oC under N2. After the resulting mixture was stirred at -78oC for 2h, DMF (3.92 mL, 50.7 mmol) was added dropwise. The mixture was stirred at -78oC for another 2h. TLC (50% EtOAc in petroleum ether) indicated the reaction was finished. The mixture was quenched with water at -78oC and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. 5 The residue was purified by combiflash (25% EtOAc in petroleum ether) to give the title compound as yelow oil. LRMS m/z (M+H) 186.1 found, 186.1 required.
Intermediate Q 2-(2,2,2-trifluoroethyl)nicotinic acid Intermediate Q Step 1: 2-(2.2-difluoroethyl)benzoic acid (01) To a solution of 2,3-dibromopyridine (10 g, 42.2 mmol) in toluene (100 mL) was dropwise added t-BuLi (20.26 mL, 50.7 mmol) at -78C under N2. After the resulting mixture was stirred at -78C for 2h, DMF (3.92 mL, 50.7 mmol) was added dropwise. The mixture was stirred at -78C for another 2h. The mixture was then quenched with water at -78C and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo. The residue was purified by combiflash (25% EtOAc in petroleum ether) to give the title compound. LRMS m/z (M+H) 186.1 found, 186.1 required.
To a solution of 2,3-dibromopyridine (10 g, 42.2 mmol) in toluene (100 mL) was dropwise added nBuLi (20.26 mL, 50.7 mmol) at -78 C under N2. After the resulting mixture was stirred at -78C for 2 h, DMF (3.92 mL, 50.7 mmol) was added dropwise and the mixture was stirred at -78C for another 2 h. TLC analysis of the reaction mixture (50% EtOAc in petroleum ether) indicated the reaction was finished. The mixture was quenched with water at -78C and extractedwith EtOAc (3 x 300 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (25% EtOAc in petroleum ether) to give K1 as an oil. LRMS mlz (M+H) 186.1 found, 186.1 required.
To a solution of 2,3-dibromopyridine (5 g, 21 .1 1 mmol) in toluene (50 mL), t-BuLi (1 .3 M, 19.50 mL) was dropwise added at -78C under N2. The resulting mixture was stirred at -78C for 2 hours. DMF (1 .9 g, 25.33 mmol) was added dropwise at -78C. The mixture was stirred at -78C for another 2 hours. The solution was quenched with NH4CI (aq. 1 mL) at -78C, and the mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (Petroleum ether /ethyl acetate=10/1 to 1 /1 ) to afford 3- bromopicolinaldehyde.
To a solution of 2,3-dibromopyridine (5 g, 21.11 mmol) in toluene (50 mL), t-BuLi (1.3 M, 19.50 mL)was dropwise added at -78C under N2. The resulting mixture was stirred at -78C for 2 hours. DMF(1.9 g, 25.33 mmol) was added dropwise at -78C. The mixture was stirred at -78C for another 2hours. The solution was quenched with NH4CI (aq. 1 mL) at -78C, and the mixture was concentratedunder vacuum. The residue was purified by column chromatography on silica gel (Petroleum ether/ethyl acetate=10/1 to 1/1) to afford 3-bromopicolinaldehyde.
To a solution of 451 2,3-dibromopyridine (5 g, 21.11 mmol) in 119 toluene (50 mL), 452 t-BuLi (1.3 M, 19.50 mL) was dropwise added at -78 C. under N2. The resulting mixture was stirred at -78 C. for 2 hours. 28 DMF (1.9 g, 25.33 mmol) was added dropwise at -78 C. The mixture was stirred at -78 C. for another 2 hours. The solution was quenched with 255 NH4Cl (aq. 1 mL) at -78 C., and the mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (Petroleum ether/ethyl acetate=10/1 to 1/1) to afford 453 3-bromopicolinaldehyde.
To a solution of 2,3-dibromopyridine (5 g, 21.11 mmol) in toluene (50 mL), t-BuLi (1.3 M, 19.50 mL) was dropwise added at -78C under N2. The resulting mixture was stirred at -78C for 2 hours. DMF (1.9 g, 25.33 mmol) was added dropwise at -78C. The mixture was stirred at -78C for another 2 hours. The solution was quenched with NH4CI (aq. 1 mL) at -78C, and the mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (Petroleum ether /ethyl acetate=10/l to 1/1) to afford 3-bromopicolinaldehyde.
With tris-(dibenzylideneacetone)dipalladium(0); copper(l) iodide; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,2-dimethoxyethane at 140℃; for 24h;
1.1 Sub 1-1 synthesis
Tris (d it cuts qualitative the acetone which is burnt) d palladium (Pd2(dba)3) (0.08g, 0.1mmol), 9, 9-dimethyl -4, 5-bis ([...]) xanthone- H -9 (9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene- H -9) (0.11g, 0.2mmol) [...]in round bottom flask of 1, 2-(1, 2-dimethoxyethane) (hereinafter, the hereinafter to DME) layer covering the both to 10 minutes stirring section. Furthermore, is the starting material a [...] 2, 3-(2, 3-dibromopyridine) (1.02g, 4.3mmol), 5-chloro-pyridine-2-amine (5-chloropyridin-2-amine) (0.66g, 5.2mmol), (CuI) copper most iodide (0.08g, 0.4mmol), cesium cyclocarbonate (Cs2CO3) (5.61g, 17.2mmol) prior paste has better mouth feeling and the pressure tube (pressure tube) the Pd catalyst solutions (Pd2(dba)3, XANTPHOS in DME) 160 °C by the addition of 24 (internal temperature: 140 °C) in adaptation stirring time. After complete after and concentrating the cooled to a room temperature, the resulting compound is a silica gel column (silicagel column) the products and recrystallization 0.73g a obtained (yield: 83%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 4h;Reflux;
2,3-dibromo-pyridine 10g (42.21 mmol), <strong>[190788-59-1]4,4,5,5-tetramethyl-2-(2-nitrophenyl)-1,3,2-dioxaborolane</strong>3.50g (14.07 mmol), tetrakis(triphenylphosphine)palladium, 0.32g (0.28 mmol),potassium carbonate 5.83g (42.21 mmol) and toluene, H2O, ethanol, insert themixed solution was refluxed for 4 hours. When the reaction was complete andextracted with MC and the organic layer was dried over MgSO4. To a MC / Hexeluant separated by column chromatography to give the title compound a-3 2.67g(68%).
(3-bromopyridin-2-yl)(4-chlorophenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: 2,3-dibromopyridine With 2-(N,N-dimethylamino)ethanol; trimethylsilylmethyllithium In toluene; pentane at -30℃; for 0.666667h;
Stage #2: 4-chlorobenzaldehyde In toluene at -30℃; for 0.5h;
10.8 Step 8. Synthesis of (3-bromopyridin-2-yI)(4-chlorophenyl)methanol (C42).
This compound was synthesized using the method of P. C. Gros and F. Elaachbouni, Chem. Commun. 2008, 4813-4815. [(Trimethylsilyl)methyl]lithium (1.0 Msolution in pentane, 12.7 mL, 12.7 mmol) was added drop-wise to a 0 °C solution of 2- (dimethylamino)ethanol (423 pL, 4.22 mmol) in toluene (14 mL), and the mixture was stirred for 20 minutes. It was then cooled to -30 °C and treated with a solution of 2,3- dibromopyridine (1.0 g, 4.2 mmol) in toluene (6 mL). After the reaction mixture had been stirred for 40 minutes at -30 °C, a solution of 4-chlorobenzaldehyde (99%, 899 mg, 6.33 mmol) in toluene (5 mL) was added in a drop-wise manner, and stirring was continued for 30 minutes at -30 °C. At this point, the reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (25 mL), and the mixturewas allowed to warm to room temperature. It was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 40% ethyl acetate in heptane) afforded the product as a white solid. Yield: 949 mg, 3.18 mmol, 76%. LCMS m/z 298.0, 300.0,302.0 [M+H]. 1H NMR (400 MHz, CDCI3) ö 8.60 (dd, J=4.7, 1.3 Hz, 1H), 7.88 (dd, J=8.0, 1.5 Hz, 1H), 7.26-7.32 (m, 4H), 7.20 (dd, J=8.0, 4.7 Hz, 1H), 5.95 (5, 1H), 5.27 (brs, 1H).
bromo-2<hydroxy-1(chloro-4' benzyl)-1>-3 pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
Stage #1: 2,3-dibromopyridine With n-butyllithium; butyl magnesium bromide In tetrahydrofuran; diethyl ether; hexane at -78℃; for 0.5h;
Stage #2: 4-chlorobenzaldehyde In tetrahydrofuran; diethyl ether; hexane at -78 - 0℃; for 0.333333h;
9.1 Step 1. Synthesis of (2-bromopyridin-3-yl)(4-chlorophenyl)methanol (C32).
n-Butyllithium (2.5 M in hexanes, 0.56 mL, 1.4 mmol) was added drop-wise to a0 °C solution of n-butylmagnesium chloride (2.0 M in diethyl ether, 0.35 mL, 0.70 mmol)in tetrahydrofuran (2 mL). After it had stirred for 10 minutes, the mixture was cooled to-78 °C and treated drop-wise with a solution of 2,3-dibromopyridine (474 mg, 2.00mmol) in tetrahydrofuran (2 mL). The reaction mixture was allowed to stir at -78 °C for30 minutes, whereupon 4-chlorobenzaldehyde (422 mg, 3.00 mmol) was added; stirringwas continued at -78 °C for 10 minutes, then at 0 °C for 10 minutes. Saturatedaqueous sodium bicarbonate solution was added, and the mixture was extracted withethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered,and concentrated in vacuo. Silica gel chromatography (Gradient: 5% to 45% ethylacetate in heptane) afforded the product as a colorless gum. Yield: 0.28 g, 0.94 mmol,47%. LCMS m/z 297.9, 299.9, 301.9 [M+H]. 1H NMR (400 MHz, CDCI3) ö 8.31 (ddd, J=4.7, 2.0, 0.3 Hz, 1 H), 7.90 (ddd, J=7.7, 2.0, 0.6 Hz, 1 H), 7.34-7.35 (m, 4H), 7.33 (ddd, J=7.7, 4.7, 0.5 Hz, 1H), 6.13 (brs, 1H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; dimethyl sulfoxide; at 20℃;
The titled compound was prepared by the reaction of 2,3-dibromopyridine (1.0 g, 4.22 mmol) with 4-nitrophenylboronic acid pinacol ester (1.26 g, 5.06 mmol) using potassium carbonate (1.75 g, 12.66 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium (II) (172 mg, 0.21 mmol) in a mixture of DMSO and water (25 mL, 4: 1) at RT as per the procedure described in Step 1 of Intermediate 1 to yield 658 mg of the product; 1H NMR (300 MHz, CDCI3) delta 7.21-7.28 (m, 1H), 7.88 (d, = 9.0 Hz, 2H), 8.06 (d, = 7.8 Hz, 1H), 8.34 (d, = 8.7 Hz, 2H), 8.68 (d, = 4.5 Hz, 1H).
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
378 mg
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In water; dimethyl sulfoxide
34.1 Step 1 : 3-Bromo-2-(4-chlorophenyl)pyridine
The titled compound was prepared by the reaction of 2,3-dibromopyridine (803 mg, 3.39 mmol) with 4-chlorophenylboronic acid (530 mg, 3.39 mmol) using sodium carbonate (1.06 g, 10.16 mmol) and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium (II) (124 mg, 0.17 mmol) in a mixture of DMSO and water (10 mL, 1 : 1) as per the procedure described in Step 1 of Intermediate 1 to yield 378 mg of the product; 1H NMR (300 MHz, CDC13) δ 7.12- 7.19 (m, 1H), 7.43 (d, = 8.7 Hz, 2H), 7.63 (d, = 8.4 Hz, 2H), 7.99 (d, = 7.8 Hz, 1H), 8.61 (d, J = 4.5 Hz, 1H); APCI-MS (m/z) 268 (M)+, 270 (M+2H)+.
thieno[3,2-b]thiophene-2,5-diylbis((2-bromopyridin-3-yl)methanol)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With lithium diisopropyl amide; In tetrahydrofuran; diethyl ether; hexane; at -78 - 24℃; for 12h;
Thienothiophene dicarbaldehyde (5 g, 25.48 mmol) is dissolved in 250 mL of dry diethylether and dry tetrahydrofuran and then, cooled down to -78 C. 42.12 mL of lithium diisopropylamine (a 2.0 M hexane solution) is slowly added thereto in a dropwise fashion, and 2,3-dibromopyridine (13.3 g, 56.16 mmol) is added thereto. The temperature is slowly increased, and the mixture is stirred at room temperature (24 C.) for 12 hours. Then, 100 mL of an ammonium chloride-saturated solution is added thereto, and an extract is obtained by using chloroform and several times washed with water. The extract is dried with magnesium sulfate and filtered, and the chloroform solvent is removed to obtain a compound 1a. (a yield of 75%)
With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 65℃; for 1h; Inert atmosphere;
Compound 39: 3-bromo-2-propylpyridine
Under inert atmosphere, to a solution of 2,3-dibromopyridine (1.0 equiv.) and tetrakistriphenylphosphine palladium (0.05 equiv.) in THF (0.10 mol.L-1), a solution of propylzinc bromide (0.5M in THF, 1.5 equiv.) was added dropwise. The reaction mixture was heated at 65 °C for 1 hour, before being neutralized by addition of a saturated aqueous solution of K2CO3 and extracted twice with Et2O. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The crude yellow oil was purified by flash column chromatography on silica gel (EtOAc in cyclohexane, 0 to 10%) to afford compound 39 as a colorless oil in 77% yield. M/Z (M[79Br]+H)+ = 200.0.
With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 70℃; for 4h; Inert atmosphere;
1.1 Step 1: 3-bromo-2-cyclopropylpyridine
To a solution of 2,3-dibromopyridine (3g,12.8mmol) and cyclopropylzinc(II) bromide (76 mL, 0.5 M in THF) in THF (30mL) was added Pd(PPh3)4 (740 mg, 0.64mmol). The mixture was stirred at 70 °C under N2 for 4 hours, then diluted with water (50ml) and extracted with EtOAc (3x 50mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 3-bromo-2-cyclopropylpyridine as a yellow oil (1.2g). Yield 48% (ESI 198(M+H) +).
12%
With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 65℃; for 2h; Inert atmosphere;
36.36-1 Example 36: 1-[2-cyano-4-(trifluoromethyl)phenyl]-4-{2'-cyclopropyl-[2,3'-bipyridin]-5-yl}- N-[(3S)-1-methylpyrrolidin-3-yl]piperidine-4-carboxamide (Compound 1-180)
Step 36-1, preparation of 3-bromo-2-cyclopropylpyridine : Into a 100-mL vial, was placed 2,3-dibromopyridine (1.5 g, 6.3 mmol), tetrakis(triphenylphosphine)palladium (0) (0.22 g, 0.19 mmol), and THF (10 mL) under N2. The resulting solution was treated with cyclopropylzinc(II) bromide (17 ml, 1.5 Eq) in THF. The reaction was stirred at 65 C for 2h. The reaction was cooled to rt and concentrated. The residue was purified by a silica gel column chromatography to afford the title compound (150 mg, 12%) as yellow solid. LCMS (M+H)+= 197.9.
With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 65℃; for 1h; Inert atmosphere;
Compound 40: 3-Bromo-2-cyclopropylpyridine.
Under inert atmosphere, to a solution of 2,3-dibromopyridine (1.0 equiv.) and tetrakistriphenylphosphine palladium (0.05 equiv.) in THF (0.10 mol.L-1), a solution of cyclopropylzinc bromide (0.5M in THF, 1.5 equiv.) was added dropwise. The reaction mixture was heated at 65 °C for 1 hour, before being neutralized by addition of a saturated aqueous solution of K2CO3 and extracted twice with Et2O. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. Compound 40 was obtained as a crude yellow oil and taken to the next step without purification. M/Z (M[79Br]+H)+ = 198.0.
N-[1-adamantyl(phenyl)methyl]-3-bromopyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In 1,4-dioxane Inert atmosphere; Reflux;
Palladium-Catalyzed Amination of Dihalogenopyridines; GeneralProcedure
General procedure: A flask flushed with dry argon and equipped with a magnetic stirrerand condenser was charged with appropriate dihalogenopyridine(0.25-1 mmol), Pd(dba)2 (2-8 mol%), the phosphine ligand (2.5-9mol%), the corresponding amine 1-5 (0.25-0.75 mmol), and absolute1,4-dioxane (2.5 mL). t-BuONa (0.37-0.75 mmol) was added, and themixture was stirred under reflux for 6-12 h (the progress of the reactionwas monitored by 1H NMR spectroscopy), cooled down to r.t.,1,4-dioxane was evaporated under vacuum, and the residue was chromatographedon silica gel using a sequence of eluents: PE, PE-CH2Cl2,4:1 to 1:2; CH2Cl2; CH2Cl2-MeOH, 200:1 to 50:1
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
4-(3-bromopyridin-2-yl)-N,N-dimethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; acetonitrile at 50℃; for 24h; Sealed tube; Inert atmosphere;
Synthesis of 2-aryl-3-bromopyridines 2a-j (Generalmethod).
General procedure: A mixture of MeCN and MeOH (2:1, 15 ml) wasadded to a mixture of 2,3-dibromopyridine (1) (474 mg,2.0 mmol), arylboronic acid (2.1 mmol), K2CO3 (560 mg,4.0 mmol), PPh3 (52 mg, 10 mol %) and Pd(OAc)2 (23 mg,5 mol %) in a screw-cap vial. Reaction mixture was flushedwith argon, sealed, and stirred at 50°C for 24 h in an oilbath. Then the reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentratedunder reduced pressure, the residue was dissolved in CH2Cl2(20 ml), washed with water (3×10 ml) and dried overNa2SO4. Solvent was evaporated under reduced pressure,and the residue was purified by column chromatography on silica (hexane-EtOAc, 30:1) to provide pure pyridines 2a-j.
3,3'-[pyridine-2,3-diylbis(prop-2-yne-3,1-diyl)]bis(5,5-dimethyloxolan-2-one)[ No CAS ]
3-[3-(3-bromopyridin-2-yl)prop-2-yn-1-yl]-5,5-dimethyloxolan-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 56%
2: 10%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; tricyclohexylphosphine tetrafluoroborate In N,N-dimethyl-formamide at 100℃; for 8h; Inert atmosphere; Schlenk technique;
General procedure for the Sonogashira reaction of compounds 1a and 1b with dihaloarenes
General procedure: A Schlenk flask was charged under argon with 1 equiv of dihaloarene, 0.2 equiv of CuI, 0.22 equiv of Cy3PHBF4, and 0.1 equiv of PdCl2(PPh3)2. The flask was closed, evacuated, and filled with argon (the procedure was repeated thrice), 8 mL of DMF (per millimole of dihaloarene), 4 equiv of triethylamine, and 3 equiv of lactone 1a or 1b were added with a syringe, and the mixture was heated for 8 h at 100°C. The mixture was cooled and concentrated under reduced pressure, and the products were isolated by column chromatography using heptane-ethyl acetateas eluent.
3-bromo-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: 2,3-dibromopyridine With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 60℃; for 0.416667h; Inert atmosphere;
Stage #2: 3-(tetrahydropyran-2'-yloxy)propyne With triethylamine In tetrahydrofuran at 60℃; for 20h; Inert atmosphere;
3-Bromo-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (S38)
To a solution of 2,3-dibromopyridine (2.0 g, 8.44 mmol) in freshly distilled THF (24 mL) andEt3N (12 mL) under argon were added PdCl2(PPh3)2 (178 mg, 3 mol%) and CuI (96 mg, 6mol%). The mixture was then stirred at 60 °C. After 25 min, a solution of THP-protectedpropargylic alcohol (1.18 g, 8.44 mmol) in freshly distilled THF (6 mL) and Et3N (3 mL) wasadded to the mixture. After 20 h, the crude reaction mixture was cooled down to roomtemperature, diluted with Et2O, filtered through a pad of Celite and then the solvent wasevaporated under reduced pressure. The crude product was purified by flash chromatographyon silica gel (0-40% EtOAc/pentane) to give S38 (2.08 g, 93% based on the substrate reacted).
With bis(tri-t-butylphosphine)palladium(0) In tetrahydrofuran at 60℃; for 12h; Inert atmosphere;
5
In a 250 ml four-necked flask, 0.01 mol of 3a, 0.011 mol of 2,3-dibromopyridine was added.5*10-5 mol Pd(PtBu3)2 [di(tri-tert-butylphosphine) palladium], 100 ml THF,The gas was protected by nitrogen, the temperature was raised to 60 ° C, and the reaction was stirred for 12 hours, and the reaction was confirmed to be complete.The reaction solution was suction filtered, and the filtrate was steamed.After passing through a silica gel column, a white powder 4b was obtained with a purity of 98.70% and a yield of 81.8%.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene Inert atmosphere; Reflux;
21 Example 21
Example 21 Synthesis of 1,1"-dihexyl-[4,2':3',4"-terpyridine]-1,1"-diium bis(tetrafluoroborate) A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.32 g, 11.3 mmol), 2,3-dibromopyridine (1.22 g, 5.0 mmol), Pd(PPh3)4 (0.30 g, 0.25 mmol, 5 mol %) and K2CO3 (1.56 g, 11.3 mmol) in degassed EtOH (25 mL) and PhMe (25 mL) under N2 was heated at reflux for 10 days, cooled, diluted with water (100 mL) and extracted with dichloromethane (4*50 mL). The organic portions were dried with anhydrous sodium sulfate and solvent removed in vacuo to yield a brown oil which was chromatographed on silica, eluting with MeOH (10%) in ethyl acetate. The solvent was removed and the residue dissolved in hot hexane/ethyl acetate, decanted, cooled and the solvent removed to yield 4,2':3',4"-terpyridine as a pale orange oil (0.90 g, 77.2%).
di-tert-butyl 2,2'-pyridine-2,3-diyldiacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); lithium hexamethyldisilazane In toluene at 20℃; for 1h; Inert atmosphere;
6.1 Step 1. Synthesis of di-tert-butyl 2,2'-pyridine-2,3-diyldiacetate (C31).
A flask containing 2,3-dibromopyridine (1.52 g, 6.42 mmol) and chloro(2- dicyclohexylphosphino-2',6'-dimethoxy-1, 1 '-biphenyl)[2-(2'-amino-1, 1 '- biphenyl)]palladium(ll) (SPhos Pd G2; 231 mg, 0.321 mmol) was evacuated and charged with nitrogen. Toluene (40 ml_) was added, followed by a fairly rapid drop-wise addition of lithium bis(trimethylsilyl)amide (1 M solution in toluene; 38.5 ml_, 38.5 mmol) and then a fairly rapid drop-wise addition of fe/f-butyl acetate (2.58 mL, 19.1 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour, whereupon it was quenched with saturated aqueous ammonium chloride solution (75 mL) and then extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a thick yellow oil. Yield: 986 mg, 3.21 mmol, 50%. 1 H NMR (400 MHz, CDCI3) δ 8.47 (dd, J=4.7, 1.6 Hz, 1H), 7.57 (dd, J=7.6, 1.4 Hz, 1H), 7.18 (dd, J=7.6, 4.9 Hz, 1H), 3.87 (s, 2H), 3.59 (s, 2H), 1.45 (s, 9H), 1.44 (s, 9H).
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 15 - 30℃;Inert atmosphere;
Under the protection of argon, add tetrahydrofuran (980mL) and diethylzinc (591ml, 0.591mol, 1eq) to the reaction flask, and control the temperature at 15-25 C; stir for 5 minutes, and then add tetrakis(triphenylphosphine)palladium (13.6 g, 0.012 mol, 0.02 eq). dissolve 2,3-dibromopyridine (140g, 0.591mol, 1eq) in compound 1 in tetrahydrofuran (420ml), and slowly add it to the above reaction solution. The dropping time is 0.5 to 1 hour. The reaction was carried out at a temperature of 20-30 C for 1 hour. After the reaction is completed, slowly pour the reaction solution into iced sodium bicarbonate aqueous solution (1.5L), warm to room temperature, and extract with ethyl acetate (1L * 2). Combine the organic phases with saturated brine (1L * 1) After washing, concentrating, and mixing the sample through the column, 73 g of the product was obtained with a yield of 66.4%. The NMR spectrum of the product is shown in Figure 1. Its structure is 3-bromo-2-ethylpyridine, and its purity by HPLC is> 99%.
[0209] A mixture of magnesium turnings (612 mg, 25.5 mmol) and cyclobutyl bromide (3.4g, 25.5 mmol) in anhydrous THF(50mL) was heated for 3 hours at 60 C until complete dissolution of the magnesium. The solution was cooled to -78 C and treated with ZnCl2 (3.48g, 25.5 mmol) in THF (50mL). The resulting white suspension was warmed gradually to room temperature and stirred for 1 hour. Then a solution of 2,3-dibromopyridine (4g, 17 mmol) and Pd(PPh3)4 (983 mg, 0.85 mmol) in THF (30mL) was added to the reaction. The mixture was stirred at 60 C for 1 hour under N2, then diluted with water (100mL) and extracted with EtOAc (3x 50mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc=10:1) to give the desired product 3-bromo-2-cyclopropylpyridine as a yellow oil (2.3g). Yield 94% (ESI 212(M+H) +).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 4h; Inert atmosphere;
98.1 Step 1-Synthesis of Compound 98.2:
To a solution of 98 (0.5 g, 2.11 mmol, 1.0 eq) in 1,4-dioxane (15 mL) were added 98.1 (0.429 g, 3.16 mmol, 1.5 eq), caesium carbonate (2.4 g, 7.38 mmol, 3.5 eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.193 g, 0.21 mmol, 0.1 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.243 g, 0.42 mmol, 0.2 eq) were added, again degassed for 5 min. The reaction mixture was stirred at 110° C. for 4 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred into water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by combi flash using 18% ethyl acetate in hexane as eluant to obtain pure 98.2 (0.460 g, Yield: 85.43%; MS (ES): m/z 255.12 [M+H]+).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 4h; Inert atmosphere;
113 Synthesis of Compound 113.2.
To a solution of 113 (6.0 g, 25.42 mmol, 1.0 eq) in 1,4-dioxane (200 mL) was added 113.1 (2.8 g, 25.42 mmol, 1.0 eq), cesium carbonate (20.6 g, 63.55 mmol, 2.5 eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (1.1 g, 1.27 mmol, 0.05 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (1.4 g, 2.54 mmol, 0.1 eq) were added, and again degassed for 5 min. The reaction mixture was stirred at 110° C. for 4 h. After completion, reaction mixture was cooled to room temperature, transferred into water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by combi flash using 2.2% methanol in dichloromethane as eluant to obtain pure 113.2. (4.2 g, Yield: 61.39%). MS(ES): m/z 270.1 [M+H]+
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 4h; Inert atmosphere;
117 Synthesis of Compound 117.6.
To a solution of 117.5 (10.0 g, 42.37 mmol, 1.0 eq) in 1,4-dioxane (300 mL) was added 117.4 (7.7 g, 42.37 mmol, 1.0 eq), cesium carbonate (34.4 g, 105.92 mmol, 2.5 eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (1.9 g, 2.11 mmol, 0.05 eq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (2.4 g, 4.23 mmol, 0.1 eq) were added, and degassed for 5 min. The reaction was stirred at 11 0° C. for 4 h. After completion of reaction, reaction mixture was cooled to room temperature, transferred into water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by combi flash using 2.8% methanol in dichloromethane as eluant to obtain pure 117.6. (5.2 g, Yield: 36.21%). MS(ES): m/z 341.2 [M+H]+
4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidin-1-ium 2,2,2-trifluoroacetate[ No CAS ]
5-((1-(3-bromopyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)-1-(4-fluorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 20h;
1-(4-fluorophenyl)-5-((4-hydroxy-1-(pyridin-2-yl)piperidin-4-yl)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (L1)
General procedure: A mixture of 5 (88 mg, 0.2 mmol), 2-bromopyridine (21 µL, 0.22 mmol) and K2CO3 (102 mg, 0.74 mmol) in DMF (2 mL) was stirred at 120 for 20 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3), and the organic layer was washed with water (10 mL × 3) and brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to give compound L1 (37 mg, 34% yield) as a white solid.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene for 24h; Reflux;
3 <Synthesis of Intermediate 72-6>
After dissolving 150.73g (254.92mmol) of Intermediate 72-4 and 60.39g (254.92mmol) of Intermediate 72-5 in 700ml of toluene, 2M K2CO3382ml (764.75mmol), 70ml of EtOH, Pd(PPh3)414.73g (12.75mmol) were added. The mixture was stirred under reflux for 24 hours. After confirming the completion of the reaction, the water layer was removed and the solvent was distilled off. After the column, 65.84 g of the intermediate 72-6 was obtained in a yield of 83%.
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 1h;
Stage #2: dimethylmonochlorosilane for 1h;
Preparation of 2-bromo-3-dimethylsilylpyridine:
In a 500mL three-necked flask fitted with a stirrer, a reflux condenser and a dropping funnel was placed 10.474g (44.2mmol) of 2,3-dibromopyridine in 150mL of dry THF. To this mixture was added dropwise a THF solution of 26.5mL (53.0mmol) of 2.0M isopropylmagnesium chloride at room temperature. After the mixture was stirred for 1h at room temperature, 5.166g (54.7mmol) of chlorodimethylsilane was added. The mixture was stirred for 1h. It was hydrolyzed and the organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled under reduced pressure to give 6.749g (71% yield) of 2-bromo-3-dimethylsilylpyridine: bp 48°C/2Torr; HR-MS: calcd for C7H10NSiBr: (M+): 214.9766, found: 214.9756. MS m/z 215 (M+); 1H NMR δ(CDCl3) 0.45 (d, 6H, Me2Si, J=3.6Hz), 4.49 (sep, 1H, HSi, J=3.6Hz), 7.24 (dd, 1H, pyridyl ring proton, J=7.2, 5.0Hz), 7.74 (dd, 1H, pyridyl ring proton, J=7.2, 2.4Hz), 8.34 (dd, 1H, pyridyl ring proton, J=5.0, 2.4Hz); 13C NMR δ (CDCl3) -4.2 (Me2Si), 122.4, 136.9, 145.4, 149.0, 150.7 (pyridyl ring carbons); 29Si NMR δ (CDCl3) -13.7.
71%
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃;
Stage #2: dimethylmonochlorosilane
3-(3-bromopyridin-2-yl)-9-ethyl-9H-carbazole[ No CAS ]
3,3’-(pyridine-2,3-diyl)bis(9-ethyl-9H-carbazole)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 80%
2: 8%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; for 17h; Inert atmosphere;
3-(3-Bromopyridin-2-yl)-9-ethyl-9H-carbazole (4b) and 3,3'-(pyridine-2,3-diyl)bis(9-ethyl-9H-carbazole) (5b)
A stirred mixture of 2,3-dibromopyridine 3b (119 mg, 0.5 mmol), 9-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (161 mg, 0.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), K2CO3 (345 mg, 2.5 mmol), 1,4-dioxane (8 mL) and water (4 mL) was heated at 100 °C for 17 h under argon. After evaporation ofthe reaction mixture the residue was diluted with water (100 mL) and extracted with CH2Cl2 (3 x 15 mL). The extract was dried over Na2SO4. Flashcolumn chromatography on silica gel (3.5 55 cm) was then carried out using CH2Cl2 as the eluent. From the colorless fraction with Rf 0.3 compound4b was isolated (142 mg, 80%). The yellowish fraction with Rf 0.2 gave compound 5b (20 mg, 8%).
tert-butyl (2S)-2-methyl-4-oxo-pyrrolidine-1-carboxylate[ No CAS ]
tert-butyl (2S)-4-(2-bromopyridin-3-yl)-4-hydroxy-2-methylpyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
Stage #1: 2,3-dibromopyridine With isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 1h;
Stage #2: tert-butyl (2S)-2-methyl-4-oxo-pyrrolidine-1-carboxylate In tetrahydrofuran at 20℃;
1.79 Compound 79.1: tert-Butyl (2S)-4-(2-bromopyridin-3-yl)-4-hydroxy-2- methylpyrrolidine-1-carboxylate:
Isopropylmagnesium chloride (2.0M in THF, 11.6 ml, 23.0 mmol) was dropwise added to a solution of 2,3-dibromopyridine (5.0 g, 21.0 mmol) in THF (50 ml) at rt and the mixture stirred at rt for 1h. To the mixture, a solution of tert-butyl (S)-2-methyl-4-oxopyrrolidine-1-carboxylate (4.25 g, 21.0 mmol) in THF (15 ml) was added. The mixture was then stirred at rt overnight. The reaction was quenched with aq. NH4Cl, extracted with EtOAc (3x). The combined organic layer was then washed with water, brine, then dried and concentrated. The crude was purified by chromatography on silica gel to give the title compound (3.1 g, yield 41%). LCMS (ESI): [M+H] 357. (Ref. US20080161332, page18, by Roche)
9,9'-(pyridine-2,3-yl-bis(3,1-phenylene)bis(9H-carbazole))[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran at 150℃; Inert atmosphere;
Synthesis of P-8:
2,3-dibromopyridine (2.0 g, 8.4 mmol) and (3-(9H-carbazol-9-yl)phenyl)boronic acid (5.1 g, 17.7 mmol) were prepared Put in a 250ml two-necked round-bottom flask, dissolved in 100 ml of tetrahydrofuran, 2M potassium carbonate (3.5 g, 25.3 mmol) was added to 30 ml. Thereafter, tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.9 mmol) was added, followed by stirring under reflux for 24 hours. After cooling to room temperature, the reactant was extracted with methylene chloride and distilled water, and the organic layer was dried with magnesium sulfate and then the solvent was removed by distillation under reduced pressure. The reaction product was further purified by column chromatography using a methylene chloride/hexane mixed solvent, and after drying, a pure white solid 9,9'-(pyridine-2,3-diylbis(3,1-phenylene) bis(9H-carbazole)) 1.9 g of (P-8) were obtained. [Yield: 40%, MS (FD+) m/z 487]
With potassium phosphate; copper(II) iodide; rac-diaminocyclohexane In 1,4-dioxane at 180℃; Inert atmosphere;
Synthesis of Intermediate-3:
2,3-dibromopyridine (15.0 g, 63.32 mmol) and carbazole (8.8 g, 52.56 mmol) were placed in a 500 ml 2-neck round-bottom flask, and 1,4-dioxane 400 ml After dissolving in , CuI2 (0.60 g, 3.17 mmol) and tripotassium phosphate (13.1 g, 95.0 mmol) were added. Then, 1,2-diaminocyclohexane (1.45 g, 12.6 mmol) was injected and stirred under reflux for 24 hours. After completion of the reaction and cooling to room temperature, the reaction product was extracted with methylene chloride and distilled water, and the organic layer was dried with magnesium sulfate and the solvent was removed by distillation under reduced pressure. The reaction product was further purified by column chromatography using a methylene chloride/hexane mixed solvent, and after drying, 9-(3-bromopyridin-2-yl)-9H-carbazole as a pure white solid 10.5 g of (Intermediate 3) was obtained. [Yield: 51%, MS (FD+) m/z 323]
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