* 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.
Example 92; 4-(lH-Benzoimidazol-5-yloxy)-N-(4-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4- ylamino)-benzamide; Example 92A; lH-Benzoimidazol-5-ol; [0458] A solution of 5-methoxybenzimidazole (500 mg, 3.374 mmol) in 48percent hydrobromic acid (10 mL) was refluxed for 2 hours. The reaction was cooled to room temperature, the solvent removed by rotary evaporation under vacuum, and the residue azeotroped with toluene (50 mL) to provide the title compound as a tan solid (701 mg, 96percent).
Reference：
[1] Patent: WO2007/76034, 2007, A2, . Location in patent: Page/Page column 125
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 5192
[3] Synthetic Communications, 2010, vol. 40, # 12, p. 1765 - 1771
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 7, p. 2620 - 2623
2
[ 22019-71-2 ]
[ 4887-80-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With triethylsilane; palladium 10% on activated carbon In tetrahydrofuran at 20℃; for 18 h; Inert atmosphere
General procedure: A 16 mL vial with a PTFE/silicone septum and a nitrogen-bubbler line was charged with N-benzylbenzimidazole (208.1 mg, 1.0 mmol), Pd/C (10 wt percent, dry powder, reduced) (20 mg) and THF (5 mL). The mixture was treated at rt with triethylsilane (320 µL, 2.0 mmol) and then stirred under nitrogen for 14 h at rt. The mixture was filtered through a 0.45 µM PTFE syringe filter and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (0 to 10percent MeOH/ dichloromethane) to afford benzimidazole as a colorless solid (117.6 mg, 0.996 mmol 99percent). The reactions generally exhibit an induction period of 5 to 30 min as indicated by the initiation of gas release (i.e., bubbling) from the reaction mixture. The use of Pd/C on a dry matrix is imperative as wet Pd/C results in decreased yield or no reaction.
With sodium hydroxide In ethanol; water at 70℃; for 1.5 h; Green chemistry
General procedure: TUD (20 mmol) was added in batches to a solution of substituted 2‑nitroanilines (5 mmol) and NaOH (20 mmol) in H2O (15 mL) and EtOH (5 mL) at 70 °C. The reaction mixture was stirred for a certain period of time as required to complete the reaction (monitored byTLC). After cooling, 10percent NaOH solutions were added until pH = 9–10, the precipitated solid was filtered off and washed with water to obtain crude product. The crude product was recrystallised from water to give a white solid. The physical and spectra data of the compounds 2a–h were as follows.
Reference：
[1] Journal of Chemical Research, 2014, vol. 38, # 2, p. 118 - 120
4
[ 68-12-2 ]
[ 102-51-2 ]
[ 4887-80-3 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 120℃; for 6 h;
General procedure: To a 10mL three-necked round bottle was charged with 1a (0.54 g, 5 mmol), imidazolium chloride (0.09 g, 0.5 mmol) and N,N-dimethylformamide 2 mL. The resulting solution was warmed to120 °C and stirred at this temperature for 6 h. When the reaction was completed, 25 mL water was added and the resulting mixture was extracted with 25 mL ethyl acetate twice. The combined organic layer was successively washed with H2O (50 mL) and then brine (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether and ethyl acetate or recrystallized from petroleum ether/EA to give the title products.
With bromine; potassium acetate; In water; at 20℃; for 4h;
Into a suspension of <strong>[4887-80-3]5-methoxy-1H-benzimidazole</strong> (3.76 g, 25.4 mmol) and potassium acetate (10 g, 102 mmol) in 250 ml of water was added dropwise a bromine solution (1.3 ml, 25.4 mmol in 300 ml of water) at room temperature in the period of 1 h. The reaction mixture was stirred for 3 h and extracted with ethyl acetate 3 times. The organics were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The brown solid residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a brown solid and the 4-bromo isomer as a beige solid.5-Bromo-6-(methyloxy)-1H-benzimidazole: 1H NMR (400 MHz, CDCl3) delta ppm 3.80 (s, 3H) 7.06 (s, 1H) 7.80 (s, 1H) 8.20 (s, 1H) 12.40 (s, 1H); LC-MS: 228.95 (M+1), 0.83 min (LC/MS method A)
With sodium hydroxide; In ethanol; water; at 70℃; for 1.5h;Green chemistry;
General procedure: TUD (20 mmol) was added in batches to a solution of substituted 2-nitroanilines (5 mmol) and NaOH (20 mmol) in H2O (15 mL) and EtOH (5 mL) at 70 C. The reaction mixture was stirred for a certain period of time as required to complete the reaction (monitored byTLC). After cooling, 10% NaOH solutions were added until pH = 9-10, the precipitated solid was filtered off and washed with water to obtain crude product. The crude product was recrystallised from water to give a white solid. The physical and spectra data of the compounds 2a-h were as follows.
To a solution of NaH (972 mg, 40.5 mmol) in DMF (20 mL) was added 5- methoxy-lH-benzo[d] imidazole (2.0 g, 13.5 mmol) at 27C. After stirring for 5 minutes, Mel (2.3 g, 16.2 mmol) was added and the resulting mixture was stirred for 16 h. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated to give the crude product (1.2 g, 54.5%) as a grown solid. This crude was used in next step without further purification. LCMS (m/z): 163.1 (M+l).
To a solution of NaH (972 mg, 40.5 mmol) in DMF (20 mL) was added <strong>[4887-80-3]5-methoxy-1H-benzo[d]imidazole</strong> (2.0 g, 13.5 mmol) at 27 C. After stirring for 5 minutes, MeI (2.3 g, 16.2 mmol) was added and the resulting mixture was stirred for 16 h. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product (1.2 g, 54.5%) as a grown solid. This crude was used in next step without further purification. LCMS (m/z): 163.1 (M+1).
In methanol; water; at 20℃; for 7h;Inert atmosphere;
Under the protection of nitrogen, the 5-methoxy-benzimidazole 14.8g added to the dry round-bottom flask, add 50 ml methanol stirring to dissolve, then add N, N- two butyl amines 16.7g and quality concentration 37% aqueous solution of formaldehyde (wherein the amount of formaldehyde 0.18mol). Stirring the mixture at room temperature for 7 hours in the two-phase, then adding an amount of ether is mixed with organic phase in the aqueous phase, heating reflow 12h. TLC detection after the reaction, the mixture is poured in ice, extraction five times with ethyl ether, the organic phase is dried with anhydrous sodium sulfate. After filtration, the filtrate is transferred to the round-bottom flask, concentrated under reduced pressure, vacuum drying under and the colorless product is close to.
<strong>[4887-80-3]5-Methoxybenzimidazole</strong> (0.50 g, 3.37 mmol) was dissolved in acetonitrile (5 mL), potassium hydroxide (0.39 g, 6.95 mmol) was added, and the mixture was refluxed for 30 min. 2-(Bromomethyl)naphthalene (0.76 g, 3.44 mmol) was added, and the mixture was refluxed overnight.
With triethylsilane; palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; for 18h;Inert atmosphere;
General procedure: A 16 mL vial with a PTFE/silicone septum and a nitrogen-bubbler line was charged with N-benzylbenzimidazole (208.1 mg, 1.0 mmol), Pd/C (10 wt %, dry powder, reduced) (20 mg) and THF (5 mL). The mixture was treated at rt with triethylsilane (320 muL, 2.0 mmol) and then stirred under nitrogen for 14 h at rt. The mixture was filtered through a 0.45 muM PTFE syringe filter and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (0 to 10% MeOH/ dichloromethane) to afford benzimidazole as a colorless solid (117.6 mg, 0.996 mmol 99%). The reactions generally exhibit an induction period of 5 to 30 min as indicated by the initiation of gas release (i.e., bubbling) from the reaction mixture. The use of Pd/C on a dry matrix is imperative as wet Pd/C results in decreased yield or no reaction.
With triethylsilane; palladium 10% on activated carbon; In tetrahydrofuran; at 20℃; for 18h;Inert atmosphere;
General procedure: A 16 mL vial with a PTFE/silicone septum and a nitrogen-bubbler line was charged with N-benzylbenzimidazole (208.1 mg, 1.0 mmol), Pd/C (10 wt %, dry powder, reduced) (20 mg) and THF (5 mL). The mixture was treated at rt with triethylsilane (320 muL, 2.0 mmol) and then stirred under nitrogen for 14 h at rt. The mixture was filtered through a 0.45 muM PTFE syringe filter and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (0 to 10% MeOH/ dichloromethane) to afford benzimidazole as a colorless solid (117.6 mg, 0.996 mmol 99%). The reactions generally exhibit an induction period of 5 to 30 min as indicated by the initiation of gas release (i.e., bubbling) from the reaction mixture. The use of Pd/C on a dry matrix is imperative as wet Pd/C results in decreased yield or no reaction.
With sodium hydrogencarbonate; In acetonitrile; at 70℃; for 12h;
5 g of methoxybenzimidazole (44.5 mg, 0.3 mmol), NaHCO3 (12.6 mg, 50 mol%), NFSI (142 mg, 1.5 equiv.) Were added to 2.0 mL of acetonitrile and the reaction was stopped for 12 h at 70 C , Column chromatography (silica gel column; eluent: petroleum ether / ethyl acetate = 25/2) to give 2 g of sulfonylated <strong>[4887-80-3]5-methoxybenzimidazole</strong>. The product was a white solid in 67% yield
9-methoxy-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]oxazine-12-one[ No CAS ]
8-methoxy-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]oxazine-12-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(I) bromide; In para-xylene; at 120℃; for 36h;Schlenk technique; Green chemistry;
CuBr 6 mg (0.04 mmol), TEMPO 5 mg (0.03 mmol), compounded in a 25 mL Schlenk reaction tube<strong>[4887-80-3]5-methoxybenzimidazole</strong> 60 mg (0.4 mmol),28 mg (0.2 mmol) of salicylic acid (0.2 mmol) and p-xylene (0.5 mL), followed by 33 muL of pyridine (0.4 mmol) were added and the reaction was stirred at 120C for 36 hours under reflux.Cool to room temperature, transfer all to a 25 mL flask, spin off the solvent on a rotary evaporator, add an appropriate amount of silica gel to spin dry, and then use a 300-400 mesh silica gel column. The developing solvent used is petroleum ether:ethyl acetate=16: 1 to 6:1, namely 27 mg of compound III-4, with a yield of 51%. white solid
General procedure: An excess of 5-substituted benzoimidazoles 4a-d (1.5 equiv.) were dissolved in 8 mL of anhydrous acetonitrile and 1.7 equiv. NaH 95% were added portionwise under stirring in a Schlenk tube at room temperature, applying mechanical vacuum until complete evolution of hydrogen gas. After 15 minutes, 1 g (7.14 mmol) of the 4-hydroxy-2-cyclopentenone acetate (±)-1 was dissolved in the minimum amount of anhydrous acetonitrile and added to the solution under stirring. The reactions are left under stirring at room temperature overnight. The reactions were quenched with ice mixed with NaCl/NH4Cl 1:3 and the water phase extracted with DCM. The organic phases were dried over Na2SO4 and, upon evaporation of the solvent, the residues were submitted to chromatographic separation to isolate the purified products 5/6a-d
With [bis(acetoxy)iodo]benzene; In 1,2-dichloro-ethane; at 20 - 80℃; for 6h;Schlenk technique;
General procedure: PhI(OAc)2 (0.5 mmol) was added to a mixture of 1H-benzimidazole(1a; 0.5 mmol), isochroman (2a; 2.0 mmol), and DCE (2.0mL) in a Schlenk tube at r.t. The mixture was stirred at 80 C for6 h then cooled. H2O (10 mL) was added, and the mixture wasextracted with CH2Cl2 (3 × 10 mL). The combined organic layerwas dried (Na2SO4) and concentrated under reduced pressure.The residues were purified by flash column chromatography(silica gel, hexane-EtOAc) to give a colorless oil; yield: 115 mg(92%).
General procedure: To a 10mL three-necked round bottle was charged with 1a (0.54 g, 5 mmol), imidazolium chloride (0.09 g, 0.5 mmol) and N,N-dimethylformamide 2 mL. The resulting solution was warmed to120 C and stirred at this temperature for 6 h. When the reaction was completed, 25 mL water was added and the resulting mixture was extracted with 25 mL ethyl acetate twice. The combined organic layer was successively washed with H2O (50 mL) and then brine (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether and ethyl acetate or recrystallized from petroleum ether/EA to give the title products.
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