* 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] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 631 - 634
2
[ 626-55-1 ]
[ 87199-17-5 ]
[ 127406-55-7 ]
Yield
Reaction Conditions
Operation in experiment
87%
With potassium phosphate tribasic heptahydrate; C18H24N3O2Pd In ethanol; water at 60℃; for 4 h;
General procedure: The reaction vessel was charged with heteroaryl bromides (1.0mmol), arylboronic acid (1.2mmol), K3PO4·7H2O (1.5mmol), and the catalyst 1 (0.5molpercent) in EtOH/H2O (1:2, v/v 3mL). The reaction mixture was heated at 60°C in air and the progress of the reaction was monitored by TLC. At the end of the reaction, the reaction mixture was diluted with water (20mL) and then extracted with EtOAc (2×20mL). The combined organic layers were washed with brine (10mL) and then dried over anhydrous Na2SO4. After removal of the solvent, the crude product was purified by flash chromatography over silica gel using ethyl acetate/hexane as an eluent to afford the pure product.
25%
With sodium carbonate In ethanol; water; toluene for 8 h; Heating / reflux
Tetrakis (TRIPHENYLPHOSPHINE) palladium (0. 65 g, 0. 56 MMOL), 4-FORMYLPHENYLBORIC acid (2. 81 g, 18. 7 MMOL), 2M aqueous sodium carbonate (18. 7 ml, 37. 4 mmol) and ethanol were added to the nitrogen-saturated solution of 3-bromopyridine (2. 66 g, 16. 8 mmol) in toluene and refluxed under nitrogen for 8 hrs. Water was added to the solution and extracted with ethyl acetate, washed with water and brine and dried. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent ; hexane/ethyl acetate = 1/1. 5) to give 4- (3-PYRIDYL) benzaldehyde (0. 78 g, 25percent).
With copper(l) iodide; C37H51ClFeNPPd; cesium fluoride In N,N-dimethyl-formamide at 80℃; for 12 h; Inert atmosphere
General procedure: 4.3.10 4-(Pyridin-3-yl)benzaldehyde (3ja) White solid, mp 50-51 °C; 1H NMR (400 MHz, CDCl3): δ=10.09 (s, 1H), 8.90 (d, J=1.76 Hz, 1HAryl halide (0.5 mmol), base (1 mmol), CuI (20 mol percent), alkylstannylpyridine(0.75 mmol), and catalyst (1 mol percent) were dissolvedin DMF (2 mL) in a 10 mL vial and heated at a specific temperatureunder N2 for 12 h. After the reaction was complete, and thenquenched with water. The mixture was diluted with ethyl acetate(10 mL), filtered through a pad of Celite, and followed by extractionwith ethyl acetate for three times. The combined organic layer wasdried over anhydrous Na2SO4, filtered, and evaporated under reducedpressure. The residual was purified by flash chromatographyon silica gel (ethyl acetate/hexane) to give the desired product.), 8.68-8.66 (m, 1H), 8.00 (d, J=8.24 Hz, 2H), 7.93 (d, J=7.88 Hz, 1H), 7.76 (d, J=8.20 Hz, 2H), 7.41-7.44 (m, 1H); 13C NMR (100 MHz, CDCl3): δ=123.8, 127.8, 127.8, 130.5, 130.5, 134.6, 135.3, 135.8, 143.8, 148.4, 149.6, 191.8; HRMS-ESI (m/z): [M+H]+ calcd for C12H10NO+: 184.0757, found: 184.0758.
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h;
Anhydrous zinc chloride (6.8 g, 0.05.0 moles) and then 3-bromopyridine (26.4 g, 0.167 mol) are added with agitation under an inert atmosphere, to a solution constituted by toluene (78 g) and tetrahydrofuran (66 g). [00117] Palladium tetrakistriphenylphosphine (0.102 g, 0.089 mmol) and then, over a period of 2 hours, a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (169.3 g of solution, equal to 0.197 mol), prepared analogously to Example 1, are added to the suspension maintained at 50° C. with agitation and under an inert atmosphere. [00118] The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 25° C. [00119] 4-(3'-pyridyl)benzaldehyde (25.6 g, 0.14 mol) is obtained with a yield of 84percent in moles relative to the 3-bromopyridine added, turnover of the catalyst (Pd): 1576. [00120] IR: 1701.6 cm-1 (aldehyde C-O stretching) [00121] m.p.: 52°-53° C. [00122] 1H-NMR (300 MHz, CDCl3): ppm 10.1 (1H, s); 8.9 (1H, d, J=2.2 Hz); 8.7 (1H, dd, J=1.6 Hz, J=4.9 Hz); 8.02 (2H, part A of an AB system, J=8.2 Hz); 7.97 (1H, ddd, J=2.2 Hz, J=7.9 Hz, J=1.6 Hz); 7.78 (2H, part B of an AB system, J=8.2 Hz); 7.45 (1H, dd, J=4.9 Hz, J=7.9 Hz)
3%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Stage #2: at 50℃; for 2.5 h;
Example 24 was repeated but in the absence of zinc chloride. The yield in moles of 4-(3'-pyridyl)benzaldehyde relative to the 3-bromopyridine added was 3percent, turnover of the catalyst (Pd) 56.
Reference：
[1] Patent: US6765097, 2004, B1, . Location in patent: Page column 14
[2] Patent: US6765097, 2004, B1, . Location in patent: Page column 14
[3] Patent: US5849911, 1998, A,
5
[ 1692-25-7 ]
[ 1122-91-4 ]
[ 127406-55-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2009, # 13, p. 2051 - 2054
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[3] Dalton Transactions, 2007, # 35, p. 3952 - 3958
[4] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 453 - 462
6
[ 16518-17-5 ]
[ 1122-91-4 ]
[ 127406-55-7 ]
Yield
Reaction Conditions
Operation in experiment
45%
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); 1,10-Phenanthroline In N,N-dimethyl acetamide at 60 - 180℃; for 4 h; Inert atmosphere; Glovebox; Microwave irradiation
General procedure: In an argon-filled glovebox, a 10 mL microwave vial was charged with Pd(PPh3)4 (14.35 mg,0.0125 mmol), Cu2O (21.3 mg, 0.15 mmol), 1,10-phenanthroline (8.95 mg,0.05 mmol), the potassium pyridylcarboxylate (0.50 mmol), aryl bromide(0.75 mmol) and anhydrous DMA (3.0 mL). The resulting solution wasirradiated in a microwave reactor (Biotage Initiator Eight EXP) with a 2 minprestirring period, followed by 10 min at 60 C. The reaction was then heatedat 180 C for 3 h 50 min. The maximum pressure noted was 3 bar. Aftercompletion of the reaction, H2O was added to the mixture which was thenextracted with EtOAc (3 10 mL). The combined organic layers were washedwith brine (5 mL), dried over Na2SO4, filtered, and the volatiles removed invacuo. The residue was purified by column chromatography on silica gel,yielding the corresponding biaryl product.
4-bromobenzaldehyde dimethyl acetal (9.5 g, 41.1 mmoles) and palladium tetrakistriphenyl phosphine (50 mg, 0.04 mmoles) were added to a mixture of anhydrous zinc chloride (2.1 g 15.4 mmoles) in anhydrous tetrahydrofuran (23 g), with stirring, in an inert atmosphere. A solution of Grignard A (40.3 g) was added over 4 hours to the resulting mixture, which was kept at 50°C with stirring, in an inert atmosphere. The reaction mixture was kept at 50°C for 30 minutes and then cooled to 20-25°C. An 85percent yield of 4- (3APOS;-PYRIDYL)- BENZALDEHYDE-DIMETHYL acetal, relative to the 4- bromobenzaldehyde dimethyl acetal loaded, was obtained. After acid hydrolysis, an 85percent yield of 4- (3APOS;-PYRIDYL)- BENZALDEHYDE was obtained.
85%
Acidic aqueous solution
4-bromobenzaldehyde dimethyl acetal (9.5 g, 41.1 mmoles) and palladium tetrakistriphenyl phosphine (50 mg, 0.04 mmoles) were added to a mixture of anhydrous zinc chloride (2.1 g 15.4 mmoles) in anhydrous tetrahydrofuran (23 g), with stirring, in an inert atmosphere. A solution of Grignard A (40.3 g) was added over 4 hours to the resulting mixture, which was kept at 50° C. with stirring, in an inert atmosphere. The reaction mixture was kept at 50° C. for 30 minutes and then cooled to 20-25° C. An 85percent yield of 4-(3'-pyridyl)-benzaldehyde-dimethyl acetal, relative to the 4-bromobenzaldehyde dimethyl acetal loaded, was obtained. After acid hydrolysis, an 85percent yield of 4(3'-pyridyl)-benzaldehyde was obtained.
Reference：
[1] Patent: WO2004/37790, 2004, A1, . Location in patent: Page 7
[2] Patent: US2006/264640, 2006, A1, . Location in patent: Page/Page column 3
[3] Patent: US5714496, 1998, A,
8
[ 626-60-8 ]
[ 87199-17-5 ]
[ 127406-55-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259,12
[2] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259
[3] Advanced Synthesis and Catalysis, 2017, vol. 359, # 4, p. 616 - 622
9
[ 104-88-1 ]
[ 1692-25-7 ]
[ 127406-55-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2009, # 13, p. 2051 - 2054
[2] Advanced Synthesis and Catalysis, 2008, vol. 350, # 6, p. 846 - 862
10
[ 1120-90-7 ]
[ 87199-17-5 ]
[ 127406-55-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 11-12, p. 1889 - 1896
11
[ 1122-91-4 ]
[ 160688-99-3 ]
[ 127406-55-7 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 6, p. 2210 - 2212
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 130℃;Microwave irradiation; Sealed tube;
General procedure: To a solution of a 3- or 4-bromobenzaldehyde in a mixture DMF/water (3:1; 14.8mL/mmol) were added boronic acid derivative (1.5 equiv.), Pd(PPh3)4 (5mol%), and K2CO3 (2 equiv.). The reaction mixture was heated under microwave irradiation (130C) until TLC showed complete conversion of the starting material (0.5-1h). After cooling, the mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered off, and concentrated under reduced pressure to afford the corresponding crude product 2. (0027) Compounds 2a-2p were synthesized following the procedure described above from the corresponding boronic acids.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; for 0.416667h;Heating / reflux;
[0331] Cis/trans 4-(pyridin-3-yl)phenyl-1-carbaldehyde oximes (53). To a solution of 52 (547 mg, 2.99 mmol) in 95 % ethanol (6 mL) was added hydroxylamine hydrochloride (228 mg, 3.28 mmol), sodium acetate (269 mg, 3.28 mmol) and the resultant slurry was heated to reflux and stirred for 25 min. The solvent was removed in vacuo and the residue was triturated with CH2Cl2. The white solid (TLC: CH30H/CHCl3, 5/95, Rf = 0.22) was collected by filtration to afford the cisltrans mixture of the title compound 53 (580 mg, 98% yield) as a yellow solid: mp = 160-165 C dec.; 1H NMR (DMSO-D6) 8 11. 39 (s, 1H), 8.98 (s, 1H), 8.63 (m, 1H), 8.21 (m, 2H), 7.79 (m, 2H) 7.72 (m, 2H), 7.57 (m, 1H), 7.57 (m, 1H); LRMS (ESI) nilz calcd for C12H11N2O [M + H] + 199, found 199.
(a) 4-Pyridin-3-yl-benzaldehyde This aldehyde was prepared using the procedure for 4-pyridin-2-yl-benzaldehyde in Example 126 from 3-bromopyridine and 4-formylboronic acid to give a white crystalline solid (94%): mp=53-55 C.; Rf=0.08 (30% EtOAc/hexanes); IR (KBr) 1700, 1605, 1219 cm-1; 1H NMR (CDCl3) delta 7.55-7.60 (m, 1H), 7.76-7.79 (m, 2H), 8.01-8.05 (m, 2H), 8.08-8.12 (m, 1H), 8.69-8.71 (m, 1H), 8.94-8.95 (m, 1H), 10.10 (s, 1H). LRMS 184 (M+H).
87%
With potassium phosphate tribasic heptahydrate; C18H24N3O2Pd; In ethanol; water; at 60℃; for 4h;
General procedure: The reaction vessel was charged with heteroaryl bromides (1.0mmol), arylboronic acid (1.2mmol), K3PO4·7H2O (1.5mmol), and the catalyst 1 (0.5mol%) in EtOH/H2O (1:2, v/v 3mL). The reaction mixture was heated at 60C in air and the progress of the reaction was monitored by TLC. At the end of the reaction, the reaction mixture was diluted with water (20mL) and then extracted with EtOAc (2×20mL). The combined organic layers were washed with brine (10mL) and then dried over anhydrous Na2SO4. After removal of the solvent, the crude product was purified by flash chromatography over silica gel using ethyl acetate/hexane as an eluent to afford the pure product.
25%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 8h;Heating / reflux;
Tetrakis (TRIPHENYLPHOSPHINE) palladium (0. 65 g, 0. 56 MMOL), 4-FORMYLPHENYLBORIC acid (2. 81 g, 18. 7 MMOL), 2M aqueous sodium carbonate (18. 7 ml, 37. 4 mmol) and ethanol were added to the nitrogen-saturated solution of 3-bromopyridine (2. 66 g, 16. 8 mmol) in toluene and refluxed under nitrogen for 8 hrs. Water was added to the solution and extracted with ethyl acetate, washed with water and brine and dried. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent ; hexane/ethyl acetate = 1/1. 5) to give 4- (3-PYRIDYL) benzaldehyde (0. 78 g, 25%).
4-bromobenzaldehyde dimethyl acetal (9.5 g, 41.1 mmoles) and palladium tetrakistriphenyl phosphine (50 mg, 0.04 mmoles) were added to a mixture of anhydrous zinc chloride (2.1 g 15.4 mmoles) in anhydrous tetrahydrofuran (23 g), with stirring, in an inert atmosphere. A solution of Grignard A (40.3 g) was added over 4 hours to the resulting mixture, which was kept at 50C with stirring, in an inert atmosphere. The reaction mixture was kept at 50C for 30 minutes and then cooled to 20-25C. An 85% yield of 4- (3'-PYRIDYL)- BENZALDEHYDE-DIMETHYL acetal, relative to the 4- bromobenzaldehyde dimethyl acetal loaded, was obtained. After acid hydrolysis, an 85% yield of 4- (3'-PYRIDYL)- BENZALDEHYDE was obtained.
85%
Acidic aqueous solution;
4-bromobenzaldehyde dimethyl acetal (9.5 g, 41.1 mmoles) and palladium tetrakistriphenyl phosphine (50 mg, 0.04 mmoles) were added to a mixture of anhydrous zinc chloride (2.1 g 15.4 mmoles) in anhydrous tetrahydrofuran (23 g), with stirring, in an inert atmosphere. A solution of Grignard A (40.3 g) was added over 4 hours to the resulting mixture, which was kept at 50 C. with stirring, in an inert atmosphere. The reaction mixture was kept at 50 C. for 30 minutes and then cooled to 20-25 C. An 85% yield of 4-(3'-pyridyl)-benzaldehyde-dimethyl acetal, relative to the 4-bromobenzaldehyde dimethyl acetal loaded, was obtained. After acid hydrolysis, an 85% yield of 4(3'-pyridyl)-benzaldehyde was obtained.
In hydrogenchloride;
This diacetal (5.0 g) was stirred in 1M aqueous hydrochloric acid (30 ml) for 45 minutes and the mixture neutralised with 1M aqueous sodium hydroxide solution (30 ml) and extracted with ether (3*60 ml). The ether extracts were combined, washed with saturated brine, dried (Na2 SO4) and evaporated to give 4-(3-pyridyl)benzaldehyde (3.41 g) as an oil which gave a solid on standing, m.p 48-51 C.; NMR(CDCl3): 7.43(1H,q), 7.76(2H,m), 7.92(1H,m), 8.01(2H,m), 8.65(1H,dd), 8.90(1H,d) and 10.09(1H,s).
Methyl iodide (0. 8 ml, 12. 9 mmol) was added to a solution of 4- (3-PYRIDYL) benzaldehyde (0. 78 g, 4. 3 mmol) in dichloromethane and stirred 2 days. Additional methyl iodide (0. 8 ml, 12. 9 mmol) was added and stirred for 3 hr. After removal of the solvent, methanol was added to the residue and ice-cooled. Sodium tetrahydroborate (6. 4 g, 17. 0 mmol) was added to the solution and stirred for 1. 5 hr with warming to room temperature. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. After removal of the solvent under reduced pressure, residue was purified by silica gel chromatography (eluent ethyl acetate to methanol) to give 3-(4-HYDROXYMETHYLPHENYL)-1-METHYL-1, 2, 5, 6- TETRAHYDROPYRIDINE (0. 63 g, 72%).
With potassium carbonate; In isopropyl alcohol; at 85℃; for 24h;
General procedure: [0039] According to one aspect of the present subject matter, the method may be employed to obtain a molecule of biaryl using aryl halide and phenyl boronic acid assubstrates, potassium carbonate as base, isopropanol as solvent and GO-PdNPs as catalyst. The following equation shows the reaction.[00401 According to a further embodiment, the catalyst (GO-PdNPs)(io mg), aryl halide (i mmol), boronic acid (1.5 mmol), K2C03 (2 mmol) and isopropanol ( mL) are combined to obtain a mixture and refluxed at about 90 C for 24 hour. As discussed above the time for boiling may be determined based on the quantity of the mixture. At about 90 degree Celsius, isopropanol boils and initiates the catalytic reaction. The mixture is then cooled at room temperature. The catalyst may be extracted employing filtration through a membrane paper and washing of the reaction mixture and the desired biaryl molecule may be then purified employing vaporization under reduced pressure and short column chromatography (silica gel 100-200 mesh).
[4-(6-Ethyl-thieno[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-(4-pyridin-3-yl-phenyl)-methanone The target acid was obtained (50 mg) by essentially following Step 1 of Example 437 using <strong>[127406-55-7]4-pyridin-3-yl-benzaldehyde</strong> in place of 4-pyridin-4-yl-benzaldehyde. ES-MS: (M+H)+200
(b) Title Compound: The product was prepared according to the procedure described in Example 19 from diamine g and <strong>[127406-55-7]4-pyridin-3-yl-benzaldehyde</strong> to give a cream-colored solid (97%): mp=284-286 C.; Rf=0.16 (10% MeOH/EtOAc); IR (KBr) 1656, 1468, 1399, 1306 cm-1; 1H NMR (DMSO-d6) delta 3.55-3.58 (m, 2H), 4.51-4.54 (m, 2H), 7.37 (t, 1H, J=7.8 Hz), 7.51-7.56 (m, 1H), 7.87-8.02 (m, 6H), 8.17-8.21 (m, 1H), 8.42-8.46 (m, 1H), 8.62 (dd, 1H, J=1.5, 4.8 Hz), 9.00 (d, 1H, J=1.8 Hz). HRMS calcd for C21H16N4O 340.1324 (M+), found 340.1313. Anal. (C21H16N4O) C, H, N.
1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-3-yl-benzylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; sodium cyanoborohydride; acetic acid; In methanol; hexane; dichloromethane; ethyl acetate;
Step 1F 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-3-yl-benzylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2.1]hept-7-yl)-2-methyl-propan-1-one (20 mg in 1.5 mL dry, degassed tetrahydrofuran) was added 9.4 mg <strong>[127406-55-7]4-pyridin-3-yl-benzaldehyde</strong> followed by 43 mg titanium (IV) isopropoxide and the mixture stirred at room temperature. After 60 hours, the reaction was cooled to 0 C. and a solution of sodium cyanoborohydride (9.0 mg in 0.50 mL methanol) was added along with 0.026 mL acetic acid and the mixture stirred at low temperature. The reaction was quenched after 45 minutes by the addition of saturated aqueous ammonium chloride and brine. This was then extracted with ethyl acetate and the organics washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash chomatography on silica gel (ethyl acetate:hexane, 75:25; then methylene chloride:10% ammonium hydroxide in methanol, 98:2; then 97:3; then 95:5) gave the title compound (8.0 mg). MASS: 597 (M+H).
Step EEE: 4-Pyridin-3-yl-benzaldehyde To a solution of (4-pyridin-3-yl-phenyl)-methanol (20 mg in 1.0 mL methylene chloride) was added 25 mg 4-methylmorpholine N-oxide, 20 mg 4 A molecular sieves and 4 mg tetrapropylammonium perruthenate and the mixture stirred at room temperature. After 2 hours, the mixture was applied to a silica gel column and purified by flash chromatography (hexane:ethyl acetate, 40:60; then 60:40) to give the title compound (11.2 mg).
In dichloromethane;
4-Pyridin-3-yl-benzaldehyde To a solution of (4-pyridin-3-yl-phenyl)-methanol (20 mg in 1.0 mL methylene chloride) was added 25 mg 4-methylmorpholine N-oxide, 20 mg 4 A molecular sieves and 4 mg tetrapropylammonium perruthenate and the mixture stirred at room temperature. After 2 hours, the mixture was applied to a silica gel column and purified by flash chromatography (hexane:ethyl acetate, 40:60; then 60:40) to give the title compound (11.2 mg).
3-{2-[Bis-(4-pyridin-3-yl-benzyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisopropylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In methanol; acetic acid;
Step 3E 3-{2-[Bis-(4-pyridin-3-yl-benzyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisopropylamide To a solution of 2.5 equivalents <strong>[127406-55-7]4-pyridin-3-yl-benzaldehyde</strong> in a mixture of methanol and glacial acetic acid is added 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid diisopropylamide followed by 3 A powdered molecular seives. To this mixture, an excess of sodium cyanoborohydride is added and the pH adjusted to 5.5 by the addition of 10% methanolic acetic acid. After completion, the reaction is quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion is washed successively with saturated ammonium chloride, sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-[3-{2-[bis-(4-pyridin-3-yl-benzyl)amino]-ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methyl-propan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In methanol; acetic acid;
Step 1F 1-(7-Aza-bicyclo[2.2.1]hept-7-yl)-2-[3-{2-[bis-(4-pyridin-3-yl-benzyl)amino]-ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methyl-propan-1-one To a solution of 2.5 equivalents <strong>[127406-55-7]4-pyridin-3-yl-benzaldehyde</strong> in a mixture of methanol and glacial acetic acid is added 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo[2.2.1]hept-7-yl)-2-methyl-propan-1-one followed by 3 A powdered molecular seives. To this mixture, an excess of sodium cyanoborohydride is added and the pH adjusted to 5.5 by the addition of 10% methanolic acetic acid. After completion, the reaction is quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion is washed successively with saturated ammonium chloride, sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound. MASS: 764 (M+H)
Anhydrous zinc chloride (6.8 g, 0.05.0 moles) and then 3-bromopyridine (26.4 g, 0.167 mol) are added with agitation under an inert atmosphere, to a solution constituted by toluene (78 g) and tetrahydrofuran (66 g). [00117] Palladium tetrakistriphenylphosphine (0.102 g, 0.089 mmol) and then, over a period of 2 hours, a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (169.3 g of solution, equal to 0.197 mol), prepared analogously to Example 1, are added to the suspension maintained at 50 C. with agitation and under an inert atmosphere. [00118] The reaction mixture is maintained at 50 C. for 30 minutes and then cooled to 25 C. [00119] 4-(3'-pyridyl)benzaldehyde (25.6 g, 0.14 mol) is obtained with a yield of 84% in moles relative to the 3-bromopyridine added, turnover of the catalyst (Pd): 1576. [00120] IR: 1701.6 cm-1 (aldehyde C-O stretching) [00121] m.p.: 52-53 C. [00122] 1H-NMR (300 MHz, CDCl3): ppm 10.1 (1H, s); 8.9 (1H, d, J=2.2 Hz); 8.7 (1H, dd, J=1.6 Hz, J=4.9 Hz); 8.02 (2H, part A of an AB system, J=8.2 Hz); 7.97 (1H, ddd, J=2.2 Hz, J=7.9 Hz, J=1.6 Hz); 7.78 (2H, part B of an AB system, J=8.2 Hz); 7.45 (1H, dd, J=4.9 Hz, J=7.9 Hz)
3%
Example 24 was repeated but in the absence of zinc chloride. The yield in moles of 4-(3'-pyridyl)benzaldehyde relative to the 3-bromopyridine added was 3%, turnover of the catalyst (Pd) 56.
With magnesium; In tetrahydrofuran;
39a 4-(Pyridin-3-yl)-benzaldehyde Analogously to Example 37b, the title compound is obtained from 6.39 g (29.9 mmol) of 4-bromobenzaldehyde dimethyl acetal (prepared in accordance with Example 37a), 0.8 g (31.6 mmol) of magnesium turnings, 2.77 ml (28.2 mmol) of 3-bromopyridine (Fluka, Buchs, Switzerland) and 0.4 g (0.74 mmol) of DPPP in 150 ml of THF. HPLC20-100: tRet =5.50. 1H NMR (CD3 OD; 200 MHz): 10.04/s (1H); 8.87/d, J=2.5 (1H); 8.58/d*d, J=about 1.5 and 5 (1H); 8.17/m ia. J=7.5 (1H); 8.05 and 7.88/each d, J=9 (2*2H); 7.56/d*d, J=7.5 and 5 (1H).
With copper(l) iodide; C37H51ClFeNPPd; cesium fluoride; In N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere;
General procedure: 4.3.10 4-(Pyridin-3-yl)benzaldehyde (3ja) White solid, mp 50-51 C; 1H NMR (400 MHz, CDCl3): delta=10.09 (s, 1H), 8.90 (d, J=1.76 Hz, 1HAryl halide (0.5 mmol), base (1 mmol), CuI (20 mol %), alkylstannylpyridine(0.75 mmol), and catalyst (1 mol %) were dissolvedin DMF (2 mL) in a 10 mL vial and heated at a specific temperatureunder N2 for 12 h. After the reaction was complete, and thenquenched with water. The mixture was diluted with ethyl acetate(10 mL), filtered through a pad of Celite, and followed by extractionwith ethyl acetate for three times. The combined organic layer wasdried over anhydrous Na2SO4, filtered, and evaporated under reducedpressure. The residual was purified by flash chromatographyon silica gel (ethyl acetate/hexane) to give the desired product.), 8.68-8.66 (m, 1H), 8.00 (d, J=8.24 Hz, 2H), 7.93 (d, J=7.88 Hz, 1H), 7.76 (d, J=8.20 Hz, 2H), 7.41-7.44 (m, 1H); 13C NMR (100 MHz, CDCl3): delta=123.8, 127.8, 127.8, 130.5, 130.5, 134.6, 135.3, 135.8, 143.8, 148.4, 149.6, 191.8; HRMS-ESI (m/z): [M+H]+ calcd for C12H10NO+: 184.0757, found: 184.0758.
methyl 2-(4-(pyridin-3-yl)benzylamino)-1,3-thiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a 250 mL round-bottomed flask was added 4-(pyridin-3-yl)benzaldehyde (4 g, 21.8 mmol), <strong>[6633-61-0]methyl 2-aminothiazole-5-carboxylate</strong> (3.45 g, 21.83 mmol) and acetic acid (0.375 ml, 6.55 mmol) in toluene (109 ml). The reaction mixture was heated at reflux under Dean-Stark conditions for 3 hours, cooled to room temperature, and the volatiles were removed by rotary evaporation. Methanol was added, the solution was cooled to 0 C, and sodium borohydride (1.322 g, 34.9 mmol) was carefully added. The reaction was stirred at 0 C for 15 minutes and allowed to warm to room temperature while stirring for an additional 2 hour. The solids were filtered off, washed with water and dried under high vaccuum to give the title compound which was used in the next step without further purification.
Example 2A methyl 2-(4-(pyridin-3-yl)benzylamino)thiazole-5-carboxylate To a 250 mL round-bottomed flask was added 4-(pyridin-3-yl)benzaldehyde (4 g, 21.8 mmol), <strong>[6633-61-0]methyl 2-aminothiazole-5-carboxylate</strong> (3.45 g, 21.83 mmol) and acetic acid (0.375 ml, 6.55 mmol) in toluene (109 ml). The reaction mixture was heated at reflux under Dean-Stark conditions for 3 hours, cooled to room temperature, and the volatiles were removed by rotary evaporation. Methanol was added, the solution was cooled to 0 C., and sodium borohydride (1.322 g, 34.9 mmol) was carefully added. The reaction was stirred at 0 C. for 15 minutes and allowed to warm to room temperature while stirring for an additional 2 hour. The solids were filtered off, washed with water and dried under high vacuum to give the title compound which was used in the next step without further purification.
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); 1,10-Phenanthroline; In N,N-dimethyl acetamide; at 60 - 180℃; for 4h;Inert atmosphere; Glovebox; Microwave irradiation;
General procedure: In an argon-filled glovebox, a 10 mL microwave vial was charged with Pd(PPh3)4 (14.35 mg,0.0125 mmol), Cu2O (21.3 mg, 0.15 mmol), 1,10-phenanthroline (8.95 mg,0.05 mmol), the potassium pyridylcarboxylate (0.50 mmol), aryl bromide(0.75 mmol) and anhydrous DMA (3.0 mL). The resulting solution wasirradiated in a microwave reactor (Biotage Initiator Eight EXP) with a 2 minprestirring period, followed by 10 min at 60 C. The reaction was then heatedat 180 C for 3 h 50 min. The maximum pressure noted was 3 bar. Aftercompletion of the reaction, H2O was added to the mixture which was thenextracted with EtOAc (3 10 mL). The combined organic layers were washedwith brine (5 mL), dried over Na2SO4, filtered, and the volatiles removed invacuo. The residue was purified by column chromatography on silica gel,yielding the corresponding biaryl product.
2-(4,5-dimethoxy-2-nitrophenyl)-1-(4-(pyridin-3-yl)phenyl)ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
General procedure: To a glass vessel capable of being sealed with Teflon cap (for microwave vials) were added 1 and benzaldehyde derivative (3 equiv.). The vessel was capped and then, evacuated and backfilled with N2 (process repeated 3X). Anhydrous DMF (3.5mL/mmol) was introduced and the solution was vigorously stirred for 20min at-20C. TDAE was added slowly and the mixture was stirred for 1h. Then, the reaction was stirred at room temperature overnight. After LC-MS analysis clearly showed that the chloride had been totally consumed, the reaction was hydrolysed with distilled water. The mixture was then extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to afford the corresponding crude product 3.
0.915 g (0.005 mol) of <strong>[127406-55-7]4-(pyridin-3-yl)benzaldehyde</strong> dissolved in dichloromethane, 1.58 g (0.005 mol) of 1-(1-bromo-4,4,4-trifluorobut-2-yl)-2-(nitrovinyl)imidazolidine, 30 mL of anhydrous acetonitrile, and a catalytic amount of HCl were placed in a 50 ml round bottom flask. Stirring at room temperature, about 4h after a large number of bright yellow solid precipitation, the reaction was stopped and filtered. The resulting filtered solid, 25 mL of methanol, and 2 equivalents of sodium borohydride were placed in a 50 ml round bottom flask. The mixture was stirred at room temperature. TLC plate to track the reaction process. The product had Rf = 0.25 (dichloromethane: acetone = 7: 1). After completion of the reaction, the solvent was dried. The residual sticky material was extracted three times with dichloromethane and water. The dichloromethane layer was taken, washed three times with a saturated NaCl solution, and dried over Na2SO4 overnight. Filtered and spin dried the solvent to give crude product. Recrystallization from ethanol afforded the pure product of compound IB-13 as a white powdery solid 1.626 g, yield of about 67%.
General procedure: L1 Tris(2-aminoethyl)-amine (100mg, 0.68mmol) in 10mL of ethanol was added to a solution of 4-(4-formylphenyl)pyridine (400mg, 2.18mmol)) in 20mL of ethanol leading to a clear yellow solution. The mixture was heated to reflux for 3h and then the resulting yellow solution was left at 60C with overnight stirring. The residue obtained after the removal of the solvent was dissolved in acetonitrile mixture for recrystallization. The crystallized product was washed with cold acetonitrile (3×5mL) to give a yellow solid in 73% yield.
<strong>[127406-55-7]4-(pyridin-3-yl)benzaldehyde</strong> (151 mg, 0.827 mmol) was added to a DMF (Volume: 1378 m Density: 0.944 g/ml) solution of Crude amine (2141 -022) (H2mg, 0.276 mmol) at rt. Acetic acid (15.77 m, 0.276 mmol) was added and the mixture was stirred for 30 min before sodium Iriacetoxyhydroboraie (234 mg, 1 102 mmol) was added and the mixture was stirred at rt overnight or until LC/MS indicates conversion into product. Saturated aq sodium bicarbonate solution was slowly added until gas evolution ceased. The reaction mixture was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtO Ac (3x). The combined organic layers were washed with brine, dried with MgSOq, filtered, and concentrated. The residue was purified via 1SCO (0.5-7% MeOH in CH2C12, 13 min) to afford the product as a yellow solid in 24% yield (38 mg) over 2 s teps. (M+H)+ calculated ::: 574.3388 (M+H)? average (3 ESI replicates) = 5.74.3394 ± 0.85
General procedure: In a oven-dried flask and under nitrogen flow, benzenediazonium o-benzenedisulfonimide (1a, 161mg, 0.5mmol) was added to a suspension of 4-methoxyphenylboronic acid (3a, 91mg, 0.6mmol), [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) (2:1) toluene adduct (39mg, 0.025mmol, 5mol%), Cs2CO3 (325mg, 1mmol) in THF (5mL). The resulting mixture was stirred at room temperature for 2h; the completion of the reaction was confirmed by the absence of azo coupling with 2-naphthol. Then, the reaction mixture was poured into diethyl ether/water (100mL, 1:1). The aqueous layer was separated and extracted with diethyl ether (50mL). The combined organic extracts were washed with water (50mL), dried with Na2SO4 and evaporated under reduced pressure. GC-MS analyses of the crude residue showed 4-methoxybiphenyl (4a), MS (EI): m/z 184 (M+) as the major product, besides traces of biphenyl, MS (EI): m/z 154 (M+), 4,4'-dimethoxybiphenyl, MS (EI): m/z 214 (M+), N-phenyl-o-benzenedisulfonimide, MS (EI): m/z 295 (M+). The crude residue was purified on a short column, eluting with petroleum ether/diethyl ether (9:1). The only isolated product was the title compound (4a, 81mg, 88% yield).
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