| 74% |
With potassium phosphate; In ethanol; water; at 100℃; for 8h; |
General procedure: A dried round bottomed flask equipped with a magnetic stirring bar was charged with 10mg Polymer anchored-Pd(II) D catalyst (PS-NPPZ-Pd) (0.0045mmol/Pd), 2-halopyridine (0.5mmol), phenylboronic acid (0.6mmol) and K3PO4 (1.0mmol) were added to a reaction vessel. The mixture was stirred in 4mL of H2O: EtOH (1:1) at 100C for 8h and then cooled to room temperature. The catalyst was filtered and the filtrate was extracted with ethyl acetate (3×10mL). The combined organic layers were extracted with water, and dried over anhydrous Na2SO4. The organic layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography by using ethyl acetate/hexane (10:90) as eluent to give the corresponding coupled products. The products were characterized by 1H NMR, 13C NMR and HRMS analysis. |
| 68% |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 3h; |
After mixing 2-bromo-5-methylpyridine (15g, 87mmol), phenylboronic acid (14g, 114mmol), Pd(PPh3)4 (3g, 2.6mmol), Na2CO3 (36g, 260mmol), toluene (300mL), EtOH (150mL) and H2O (130mL), the mixture was stirred at 100C for 3 hours. After the reaction, the mixture was extracted with EA, dried with MgSO4, and distilled under reduced pressure. The resultant was subjected to column chromatography with MC/Hx = 1/2 to obtain compound 2-1 (10g, 68%, white solid). |
| 68% |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 100℃; for 3h; |
2-Bromo-5-methylpyridine (15.0 g, 87.0 mmol), phenylboronic acid (14.0 g, 114.0 mmol), Pd(PPh3)4(3.0 g, 2.6 mmol), K2CO3(36.0 g, 260.0 mmol), toluene (300.0 mL), EtOH (150.0 mL), and H2O (130.0 mL) in a flask were stirred at 100C for 3 hrs. After completing the reaction, the mixture was extracted with EA, the remaining moisture was removed by using MgSO4and the mixture was distilled under reduced pressure. By column chromatography with MC/Hx = 1/2, compound 2-1 (10.0 g, 68 %) was obtained as white solid. |
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With barium dihydroxide;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water; |
Step B 2-Phenyl-5-methylpyridine A mixture of 2-bromo-5-methylpyridine (2.00 g, 11.63 mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50 g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672 mg, 0.58 mmol) was added, and the resultant solution was stirred at 80 C. for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HCl. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5% aq. Na2 S2 O3, dried (Na2 SO4), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, CH2 Cl2) to afford the title compound. 1 H NMR (CDCl3, 400 MHz) delta 8.52 (1H, s), 7.96(2H, d, J=7.0 Hz), 7.63(1H, d, J=8.0 Hz), 7.55(1H, brd, J=8.0 Hz), 7.50-7.35(3H, m), and 2.37(3H, s) ppm. |
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With potassium phosphate monohydrate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In water; toluene; for 18h;Inert atmosphere; Reflux; |
Step 1 Synthesis of 5-Methyl-2-phenylpyridine In a 1 L round bottom flask was added 2-bromo-5-methylpyridine (30 g, 174 mmol), phenylboronic acid (25.5 g, 209 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (2.86 g, 6.98 mmol) and potassium phosphate tribasic monohydrate (120 g, 523 mmol) with toluene (600 mL) and water (60 mL). The reaction mixture was degassed with N2 for 20 min. Pd2(dba)3 (3.19 g, 3.49 mmol) was added and the reaction mixture was refluxed for 18 h. The reaction mixture was cooled, the aqueous layer was removed and the organic layer was concentrated to dryness to leave a residue. The residue was dissolved in EtOAc:hexane (1:3) and passed through a small silica gel plug and eluted with EtOAc:hexane (1:3). The solvent was removed and the crude product was purified by Kugelrohr at 150 C. to yield 26 g of 5-methyl-2-phenylpyridine, which was obtained as a white solid (HPLC purity: 99.2%). |
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With palladium diacetate; diisopropylamine; In water; at 100℃; for 16h; |
General procedure: 2-Bromopyridine (191 muL, 2 mmol), Pd(OAc)2 (10 mg, 0.02 mmol), and arylboronic acid (4 mmol) were added to a 25-mL round-bottom flask in air without any precautions. Subsequently, i-Pr2NH (1 mL)and H2O (4 mL) were added into the flask. Then a condenser was set on the round-bottom flask and the reaction was heated to reflux for16 h. The mixture was then transferred to a 100-mL separation funnel and EtOAc (20 mL) and H2O (20 mL) were added. The organic layer were collected and the solvent was removed used a rota-vapor. The crude product was purified by column chromatography. |
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With potassium phosphate tribasic heptahydrate; palladium diacetate; In water; isopropyl alcohol; at 80℃; |
General procedure: A mixture of 2-bromopyridines (2 mmol), boronic acids (3 mmol), Pd(OAc)2 (6.8 mg, 1.5 mol%), K3PO4·7H2O (1.35 g, 4 mmol) in mixture of isopropanol (10 mL) and water (10 mL) was stirred at 80C overnight. The mixture was added brine (40 mL) and extracted four times with ethyl acetate (4 x 25 mL), the solvent was evaporated under reduced pressure and the product was isolated by short column chromatography using ethyl acetate and petroleum as eluent. |
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General procedure: A Schlenk flask containing a magnetic stir bar was charged sequentially with Pd(OAc)2 (0.074 g, 0.33 mmol), dppf (0.19 g,0.34 mmol), 2-bromopyridine (0.79 g, 5 mmol), aryl boronic acid (6 mmol), and degassed dioxane (20 ml). The mixture was stirred atroom temperature for 15 min. A solution of Cs2CO3 (3.26 g,10 mmol) in 5ml of degassed H2O was added. The mixture was heated to reflux for 3 h. The organic layer was separated and extracted with EtOAc twice, and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification was performed by a silica gel column, eluted with hexane/EtOAc to give desired products. |
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With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 90℃;Heating; |
EXAMPLE 12A 5-methyl-2-phenylpyridine Phenylboronic acid (732 mg, 6 mmol), 2-bromo-5-methylpyridine (1.03g, 5.99 mmol), and Pd (PPh3)4 (350 mg, 0.303 mmol) were heated in 0.4 M K2CO3 (30 mL, 12 mmol) and CH3CN (30 mL) at 90 overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The organic layer was separated, dried (Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 hexanes:ethyl acetate) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) delta 8.50 (m, 1H), 8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.68-7.71 (m, 1H), 7.37-7.50 (m, 3 H), 2.34 (s, 3H); MS (APCI+) m/z 170 (M+H)+. |
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