* 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.
With sodium hydride In N,N-dimethyl-formamide at 20 - 100℃;
1500 ml of dry dimethylformamide (DMF) are placed in a 1000 ml four-necked flask while passing nitrogen over it and 72.67 g (0.6 mol) of 4-fluorocyanobenzene and 61.2 g (0.9 mol) of imidazole and finally 21.6 g (0.9 mol) of sodium hydride are added. The reaction mixture is heated to 100° C., stirred at this temperature for 4 hours and subsequently overnight at room temperature. The reaction mixture is then poured into water and the resulting mixture is extracted a number of times with dichloromethane. The organic phase is dried, evaporated on a rotary evaporator and finally dried further at 60° C. under reduced pressure. The yield is 94 g (93percent of theory).1H-NMR (400 MHz, CDCl3): δ=7.27 (s, 1H); 7.35 (s, 1H); 7.54 (d, J=8.8 Hz, 2H); 7.81 (d, J=8.8 Hz, 2H); 7.95 (s, 1H).
Reference：
[1] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[2] Patent: WO2006/56418, 2006, A2, . Location in patent: Page/Page column 57
[3] Patent: US2009/18330, 2009, A1, . Location in patent: Page/Page column 14
[4] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[5] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[6] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154
[7] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 3879 - 3887
[8] Tetrahedron Letters, 2009, vol. 50, # 12, p. 1286 - 1289
[9] Journal of Materials Chemistry A, 2017, vol. 5, # 2, p. 535 - 543
2
[ 288-32-4 ]
[ 623-03-0 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 12.1667 h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110∘C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[2] Synthesis, 2009, # 15, p. 2517 - 2522
[3] RSC Advances, 2015, vol. 5, # 112, p. 92121 - 92127
[4] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[5] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[6] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[7] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 4, p. 515 - 517
[8] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[9] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[10] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[11] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[12] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[13] Polyhedron, 2012, vol. 34, # 1, p. 143 - 148
[14] Synthesis, 2010, # 9, p. 1505 - 1511
[15] Journal of Organic Chemistry, 2009, vol. 74, # 20, p. 7951 - 7954
[16] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[17] Synlett, 2006, # 14, p. 2195 - 2198
3
[ 288-32-4 ]
[ 3058-39-7 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 8.16667 h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110∘C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
95%
With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h;
General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
93%
With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
91%
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 22 h; Inert atmosphere
To the three-neck flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanoiodobenzene (229 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 ml) were added under argon atmosphere. The reaction was allowed to proceed at room temperature for 22 hours until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a white solid in 91percent yield.
96%Chromat.
With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[2] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[3] Synlett, 2004, # 1, p. 128 - 130
[4] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[5] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[6] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[7] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0145-0156
[8] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
[9] Catalysis Science and Technology, 2017, vol. 7, # 19, p. 4401 - 4412
4
[ 288-32-4 ]
[ 126747-14-6 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
With copper(I) 3-metthylsalicylate; potassium carbonate In methanol at 65℃; for 3 h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
52%
With 4,4'-dimethyl-2,2'-bipyridines; oxygen; copper diacetate In water at 20℃; for 24 h;
General procedure: Under an O2 atmosphere, a mixture of 4-methoxyphenylboroic acid (1a, 60.8 mg, 0.40 mmol), imidazole (2a, 13.6 mg, 0.20 mmol), Cu(OAc)2 (3.6 mg, 0.020 mmol), ligand I (3.7 mg, 0.020 mmol), and Triton X-100 (38.8 mg, 0.060 mmol) in H2O (4 mL) was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with AcOEt (30 mL.x.3). The organic layer was washed with H2O (10 mL.x.3) and dried over MgSO4. The solvent was removed under the reduced pressure and the residue was purified by SiO2 column chromatography using AcOEt to give N-(4-methoxyphenyl)imidazole (3aa) (23.0 mg, 66percent).
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h;
General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60–120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
88%
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 24 h; Inert atmosphere
To the three-necked flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-bromobenzonitrile (181 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 mL) were added under argon atmosphere. The reaction was continued for 24 hours at 80 °C until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a pale yellow oil in 88percent yield.
88%
With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
85%
With copper(l) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 85℃;
To a mixture of 4-bromobenzonitrile (40 g, 222 mmol) and imidazole (60g, 888 mmol) in DMSO (150 ml) was added L-proline (15.2 g, 132 mmol), CuI (12.6 g, 67 mmol) and K2CO3 (60 g, 444 mmol). The resulting mixture was degassed and heated to 85 °C overnight, then cooled to room temperature and diluted with EA (1 L) and water (300 ml). The aqueous layer was extracted with EA (100 ml x 2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford 19-1 as a white solid (32 g, yield 85percent).
84%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5 h;
General procedure: The reaction flask, containing 0.02 g Cu(II) nanocatalyst(contains 0.4 molpercent of Cu(II)), imidazole (2.0 mmol),K2CO3 (1.0 mmol), and corresponding aryl halide(1.0 mmol) in 2.5 cm3 DMF, was immersed in a preheated oil bath and the reaction mixture was stirred under air atmosphere at 120 C until no further conversion of the starting aryl halide was observed by thin-layer chromatography(TLC). After completion of the reaction, the resulting mixture was allowed to cool to room temperature,and then the catalyst was separated out by an external permanent magnet, washed with ethyl acetate (EtOAc) anddried. The residue mixture was diluted by H2O and extracted with EtOAc (3 9 10 cm3). The extracted organic phases were dried over anhydrous Na2SO4, filtrated, concentrated and, finally, purified by silica gel chromatography using petroleum ether/ethyl acetate to afford the corresponding pure N-arylimidazole.
80%
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 120℃; for 2 h; Inert atmosphere
General procedure: A 25-mL Schlenk tube was flame-dried under vacuum and filled with argon after cooling to room temperature. To this tube were added phenol (1.0 mmol), t-BuOK (2.0 mmol). The tube was then evacuated and backfilled with argon (3 cycles). A dry DMSO solution (1.0 mL) of aryl bromides(2.0 mmol) was loaded into a plastic syringe. After the tube was purged with argon, this solutionwas injected into bottom of the tube using a long needle syringe. The mixture was stirred under Ar atmosphere in sealed Schlenk tubes at the corresponding temperature. When the reaction was cooled down to room temperature, the mixture was filtered through a short plug of silica gel and washed with 100 mL dichloromethane and water. The combined organic phase was concentrated under vacuum. The product was purified through flash column chromatography on 200-300 mesh silica gel with petroleum ether/ethyl acetate as eluent with a suitable ratio according to the TLC experiments. The identity and purity of the product were ascertained by GC-MS, HRMS, 1H and 13C NMR spectroscopy.
80%
With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 130℃; for 24 h; Inert atmosphere
General procedure: To a suspension of 4-bromobenzonitrile (1 equiv), CuI (0.2 equiv) in DMF (10 mL) were added Cs2CO3 (2 equiv) and imidazole (1.4 equiv). The mixture was stirred at 130 °C under N2 for 24 h. After cooling to room temperature, H2O (50 mL) wasadded and the mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3) and dried over Na2SO4. After concentration, the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the desired products 30 and 31.
74%
With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h;
General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
92 %Chromat.
With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[2] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[3] Applied Catalysis A: General, 2016, vol. 513, p. 53 - 66
[4] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[5] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[6] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[7] Green Chemistry, 2012, vol. 14, # 5, p. 1268 - 1271
[8] Journal of Organic Chemistry, 2008, vol. 73, # 21, p. 8639 - 8642
[9] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[10] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[11] Synthesis, 2010, # 9, p. 1505 - 1511
[12] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0211-0222
[13] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[14] European Journal of Organic Chemistry, 2011, # 14, p. 2692 - 2696
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
[16] Polyhedron, 2012, vol. 34, # 1, p. 143 - 148
[17] Synthesis, 2002, # 11, p. 1597 - 1600
[18] Monatshefte fur Chemie, 2018, vol. 149, # 6, p. 1101 - 1109
[19] Inorganic Chemistry, 2015, vol. 54, # 20, p. 9885 - 9895
[20] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[21] Chemistry - A European Journal, 2009, vol. 15, # 36, p. 8971 - 8974
[22] Tetrahedron Letters, 2012, vol. 53, # 33, p. 4288 - 4292
[23] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5861 - 5872
[24] Synthesis, 2011, # 23, p. 3915 - 3924
[25] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[26] RSC Advances, 2015, vol. 5, # 12, p. 8571 - 8578
[27] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[28] Inorganic Chemistry, 2016, vol. 55, # 12, p. 6085 - 6094
[29] Chemical Communications, 2007, # 45, p. 4809 - 4811
[30] Chemical Communications, 2013, vol. 49, # 31, p. 3230 - 3232
[31] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
6
[ 557-21-1 ]
[ 51581-54-5 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc In acetonitrile at 60℃; for 20 h; Inert atmosphere; Sealed tube
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn(CN)2 (0.8mmol) , 93.9mg), p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88percent, and 1H NMR purity was greater than 98percent.
Reference：
[1] Organic Letters, 2017, vol. 19, # 8, p. 2118 - 2121
[2] Patent: CN108623495, 2018, A, . Location in patent: Paragraph 0043; 0045; 0157-0159
7
[ 1194-02-1 ]
[ 18156-74-6 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With cesium fluoride In N,N-dimethyl-formamide for 0.166667 h; Inert atmosphere Stage #2: at 60℃; for 20 h;
Under a nitrogen atmosphere 362 mg (2.38 mmol) of CsF, previously activated with NaOH, were suspended in 5 ml of DMF and stirred for 30 min. Then, 1.00 g (8.26 mmol) of 4-fluorobenzonitrile was added. After 10 min 1.20 ml (8.18 mmol) N-trimethylsilylimidazole were added and the mixture was stirred at 60° C. for 20 hr. For workup, most of the solvent was removed under vacuum (oil pump), and then 5 ml of water and 5 ml of CH2Cl2 were added to the reaction mixture. The organic phase was separated, the aqueous phase was extracted with CH2Cl2, the organic phases were combined, washed several times with water and dried over MgSO4. The solvent was removed under vacuum, and the resulting solid was rinsed twice with pentane.Yield: 1.07 g (6.31 mmol, 77percent), appearance: colorless solid. 1H NMR (CDCl3, 25° C., 400.13 MHz): δ=7.25 (s, 1H, ImH), 7.33 (s, 1H, ImH), 7.51-7.53 (m, 2H, PhH), 7.79-7.81 (m, 2H, PhH), 7.94 (s, 1H, ImH). 13C NMR (CDCl3, 25° C., 100.61 MHz): δ=111.3 (C-1), 117.7 (C-9), 117.9 (-CN), 121.5 (C-3, C-5), 131.6 (C-8), 134.2 (C-2, C-6), 135.4 (C-7) 140.6 (C-4).
A mixture 4-fluorobenzonitrile (3 g, 25 MMOL) and imidazolyl sodium (2. 48 g, 27.5 MMOL) in DMF (50 mL) was stirred at 80 C under Ar for 12 h. Progress of reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 mL water and stirred. The aqueous mixture was extracted with EtOAc (2 x 50 mL). Combined EtOAc extracts was dried over anhydrous MGS04, concentrated, and the 4- (1-imidazolyl)-benzonitrile was isolated by column chromatography (3.6 g, 78percent). LCMS: MH+ = 170 ;'H NMR (CDCI3) 8 8.0 (s, 1 H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)
With lithium aluminium hydride; In tetrahydrofuran; for 3h;Inert atmosphere; Reflux;
In 50mL two-neck flask was added LiAlH4 (450mg, 11.8mmol), purged with nitrogen, was added via syringe of tetrahydrofuran (10 mL), the A40-1(500mg, 2.96mmol) was dissolved in tetrahydrofuran (10 mL), was added slowly by syringe to the above solution and stirred at reflux for 2 hours. Cooled to room temperature,In an ice bath was slowly added dropwise a saturated aqueous sodium sulfate solution until no bubbles, stirred for 1 hour, filtration, the filtrate was dried over anhydrous sodium sulfate, and sodium sulfate was filtered,Spin-dry the solvent to give a brown oil (570mg, 100percent).
80%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 25℃; for 2h;Heating / reflux;
4- (1-IMIDAZOLYL)-BENZONITRILE (1G, 5.92 MMOL) was dissolved in anhydrous THF (10 mL) and added drop-wise to a stirring solution of LAH-THF (1 M in THF, 18 mL) at room temperature. The reaction mixture was refluxed under Ar for 2 h and the progress was monitored by TLC. The mixture was cooled to 0 C and quenched by drop-wise addition of a saturated NA2SO4-H2O solution. The mixture was stirred for 1 h and filtered to remove lithium salts. The filtrate was dried over anhydrous MGS04 and concentrated to obtain 4- (1-IMIDAZOLYL)- benzylamine (0.8 g, 80percent). LCMS: MH+ = 174.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 80℃; for 2h;Inert atmosphere;
General procedure: To a solution of lithium aluminum hydride (4 equiv) in tetrahydrofuran (5 mL) was added a solution of 30 or 31 (1 equiv) in tetrahydrofuran (2 mL). The reaction was refluxed at 80 °C for 2 h under N2. After cooling to room temperature, excess Na2SO4*10H2O was added. The mixture was filtered and the filtrate was concentrated to give the desired products 32 and 33, which was used directly in the next step without further purification.
With C40H34CuIN6O6; sodium hydroxide; In dimethyl sulfoxide; at 100℃;
General procedure: The optimum reaction conditions were as follows: sodium hydroxide as base (2mmol), dimethyl sulfoxide as solvent (3mL), reaction temperature of 100 , catalyst such as methylene bridged 1,8-naphthyridine copper () The amount of the complex was 0.01 mmol, and the catalytic expansion experiments were carried out with different substituted aryl bromides and iodide substrates. The results are shown in Table 2.The catalyst system is capable of tolerating a C-N coupling reaction of various functionalized aryl halides, including nitrile, nitro, acetyl and ether groups, wherein the catalytic yield of iodide is between 91percent and 99 percentbetween.In addition, when the catalytic reaction is highly selective and the substrate is a hydroxyl group or an amino-substituted aryl bromide, the formation of the diaryl ether compound and the diphenylamine compound can be avoided.Reaction conditions: aryl halide (1.0 mmol), imidazole (1.0 mmol), sodium hydroxide (2.0 mmol), complex (0.01 mmol), dimethyl sulfoxide (3 mL), 100 ° C air atmosphere, B. Isolated yield; c.2-bromopyridine aryl halide.
88%
With C40H34CuIN6O6; sodium hydroxide; In dimethyl sulfoxide; at 100℃;
General procedure: The optimum reaction conditions were as follows: sodium hydroxide as base (2mmol), dimethyl sulfoxide as solvent (3mL), reaction temperature of 100 , catalyst such as methylene bridged 1,8-naphthyridine copper () The amount of the complex was 0.01 mmol, and the catalytic expansion experiments were carried out with different substituted aryl bromides and iodide substrates. The results are shown in Table 2.The catalyst system is capable of tolerating a C-N coupling reaction of various functionalized aryl halides, including nitrile, nitro, acetyl and ether groups, wherein the catalytic yield of iodide is between 91percent and 99 percentbetween.In addition, when the catalytic reaction is highly selective and the substrate is a hydroxyl group or an amino-substituted aryl bromide, the formation of the diaryl ether compound and the diphenylamine compound can be avoided.Reaction conditions: aryl halide (1.0 mmol), imidazole (1.0 mmol), sodium hydroxide (2.0 mmol), complex (0.01 mmol), dimethyl sulfoxide (3 mL), 100 ° C air atmosphere, B. Isolated yield; c.2-bromopyridine aryl halide.
87%
With potassium phosphate; In N,N-dimethyl-formamide; at 110℃;
General procedure: 1 mmol of the compound of the formula II-1 and 2 mmol of the compound of the formula III are sequentially added to the reaction.0.5mmolpercent catalyst CS Cu2O,3mmol potassium phosphate and 0.5ml N,N-dimethylformamide solution, heated to 110 ° C to stir the reaction,After the TLC reaction was completed, the reaction was quenched with water and filtered for ethyl acetate.Washed with saturated brine, dried and concentrated.The product was obtained by silica gel column chromatography.
3
[ 288-32-4 ]
[ 623-00-7 ]
[ 25372-03-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h;Catalytic behavior;
General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60?120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
88%
With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;Inert atmosphere;
To the three-necked flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-bromobenzonitrile (181 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 mL) were added under argon atmosphere. The reaction was continued for 24 hours at 80 °C until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a pale yellow oil in 88percent yield.
88%
With C40H34CuIN6O6; sodium hydroxide; In dimethyl sulfoxide; at 100℃; for 4h;Sealed tube;
General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
85%
With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 85℃;
To a mixture of 4-bromobenzonitrile (40 g, 222 mmol) and imidazole (60g, 888 mmol) in DMSO (150 ml) was added L-proline (15.2 g, 132 mmol), CuI (12.6 g, 67 mmol) and K2CO3 (60 g, 444 mmol). The resulting mixture was degassed and heated to 85 °C overnight, then cooled to room temperature and diluted with EA (1 L) and water (300 ml). The aqueous layer was extracted with EA (100 ml x 2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford 19-1 as a white solid (32 g, yield 85percent).
84%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.5h;Catalytic behavior;
General procedure: The reaction flask, containing 0.02 g Cu(II) nanocatalyst(contains 0.4 molpercent of Cu(II)), imidazole (2.0 mmol),K2CO3 (1.0 mmol), and corresponding aryl halide(1.0 mmol) in 2.5 cm3 DMF, was immersed in a preheated oil bath and the reaction mixture was stirred under air atmosphere at 120 C until no further conversion of the starting aryl halide was observed by thin-layer chromatography(TLC). After completion of the reaction, the resulting mixture was allowed to cool to room temperature,and then the catalyst was separated out by an external permanent magnet, washed with ethyl acetate (EtOAc) anddried. The residue mixture was diluted by H2O and extracted with EtOAc (3 9 10 cm3). The extracted organic phases were dried over anhydrous Na2SO4, filtrated, concentrated and, finally, purified by silica gel chromatography using petroleum ether/ethyl acetate to afford the corresponding pure N-arylimidazole.
80%
With potassium tert-butylate; In dimethyl sulfoxide; at 120℃; for 2h;Inert atmosphere;
General procedure: A 25-mL Schlenk tube was flame-dried under vacuum and filled with argon after cooling to room temperature. To this tube were added phenol (1.0 mmol), t-BuOK (2.0 mmol). The tube was then evacuated and backfilled with argon (3 cycles). A dry DMSO solution (1.0 mL) of aryl bromides(2.0 mmol) was loaded into a plastic syringe. After the tube was purged with argon, this solutionwas injected into bottom of the tube using a long needle syringe. The mixture was stirred under Ar atmosphere in sealed Schlenk tubes at the corresponding temperature. When the reaction was cooled down to room temperature, the mixture was filtered through a short plug of silica gel and washed with 100 mL dichloromethane and water. The combined organic phase was concentrated under vacuum. The product was purified through flash column chromatography on 200-300 mesh silica gel with petroleum ether/ethyl acetate as eluent with a suitable ratio according to the TLC experiments. The identity and purity of the product were ascertained by GC-MS, HRMS, 1H and 13C NMR spectroscopy.
80%
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere;
General procedure: To a suspension of 4-bromobenzonitrile (1 equiv), CuI (0.2 equiv) in DMF (10 mL) were added Cs2CO3 (2 equiv) and imidazole (1.4 equiv). The mixture was stirred at 130 °C under N2 for 24 h. After cooling to room temperature, H2O (50 mL) wasadded and the mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3) and dried over Na2SO4. After concentration, the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the desired products 30 and 31.
74%
With copper(I) oxide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a?3t.
92%Chromat.
With C16H12ClN3OPdS; potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 10h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 100℃;
1500 ml of dry dimethylformamide (DMF) are placed in a 1000 ml four-necked flask while passing nitrogen over it and 72.67 g (0.6 mol) of 4-fluorocyanobenzene and 61.2 g (0.9 mol) of imidazole and finally 21.6 g (0.9 mol) of sodium hydride are added. The reaction mixture is heated to 100° C., stirred at this temperature for 4 hours and subsequently overnight at room temperature. The reaction mixture is then poured into water and the resulting mixture is extracted a number of times with dichloromethane. The organic phase is dried, evaporated on a rotary evaporator and finally dried further at 60° C. under reduced pressure. The yield is 94 g (93percent of theory).1H-NMR (400 MHz, CDCl3): delta=7.27 (s, 1H); 7.35 (s, 1H); 7.54 (d, J=8.8 Hz, 2H); 7.81 (d, J=8.8 Hz, 2H); 7.95 (s, 1H).
Compound 19-1 (22 g, 130 mmol) was dissolved in anhydrous THF (250 ml) and cooled to -78 °C. A solution of n-BuLi in hexane (143 mmol, 57.2 ml) was added dropwise while keeping the solution below -60 °C. When the addition was complete, the mixture was stirred at -78 °C for 30 min. Iodine (39.7 g, 156 mmol) was added in 3 portions. The reaction was stirred at -78 °C for 1 h, allowed to warm to room temperature within 2 h, quenched with saturated ammonium chloride (250 ml) and extracted with ethyl acetate (500 ml x 2). The combined organic layers were washed with saturated Na2S2O3 (100 ml x 2) and brine (100 ml), dried over Na2SO4, filtered and concentrated to afford yellow oil, which was purified by column chromatography (PE : EA = 5 : 1 to 1 : 1) to afford 19-2 as a yellow solid (6.2 g, yield 16percent).
With copper(l) iodide; caesium carbonate; dimethylbiguanide; In N,N-dimethyl-formamide; at 20 - 110℃; for 12.1667h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110?C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
A mixture 4-fluorobenzonitrile (3 g, 25 MMOL) and imidazolyl sodium (2. 48 g, 27.5 MMOL) in DMF (50 mL) was stirred at 80 C under Ar for 12 h. Progress of reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 mL water and stirred. The aqueous mixture was extracted with EtOAc (2 x 50 mL). Combined EtOAc extracts was dried over anhydrous MGS04, concentrated, and the 4- (1-imidazolyl)-benzonitrile was isolated by column chromatography (3.6 g, 78percent). LCMS: MH+ = 170 ;'H NMR (CDCI3) 8 8.0 (s, 1 H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)
(b) Alternatively, the product can be obtained as follows: To a mixture of imidazole (5.13 g, 75.35 mmol), K2 CO3 (11.45 g) and DMSO (50 ml) at room temperature was added to 4-fluorobenzonitrile (10.04 g) in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then was warmed on a steam for 2 hours. The reaction mixture was cooled to room temperature, and poured into cold water. A precipitate formed which was collected by filtration and washed with water and recrystallized from CHCl3 /hexane to afford 4.07 g of 4-(1-imidazolyl)benzonitrile, m.p. 146°-148° C.
56 g (0.33 mol) of 1-(4-cyanophenyl)imidazole are dissolved in 560 ml water-free tetrahydrofuran in a 2000 ml one-necked flask with condenser, admixed with 234.2 g (1.65 mol) of methyl iodide, stirred briefly and allowed to stand for 48 hours without further stirring. The solid contents of the flask are subsequently slurried with ethanol, filtered off with suction and washed with ethanol until the washings are virtually colorless. The residue is dried at 70° C. under reduced pressure. The yield is 81.54 g (80percent of theory).1H-NMR (400 MHz, DMSO): delta=3.97 (s, 3H); 8.00-8.04 (m, 3H); 8.22 (d, J=9.0 Hz, 2H); 8.40 (dd, J=1.8, 1.8 Hz, 1H); 9.91 (s, 1H). Elemental analysis: calculated for C11H10IN3: C, 42.4; H, 3.3; N, 13.5; I 40.0, found: C, 42.6; H, 2.9; N, 13.6; I 40.9.
Step A A mixture 4-fluorobenzonitrile (3 g, 25 mmol) and imidazolyl sodium (2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80° C. under Ar for 12 h. Progress of reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 mL water and stirred. The aqueous mixture was extracted with EtOAc (2*50 mL). Combined EtOAc extracts was dried over anhydrous MgSO4, concentrated, and the 4-(1-imidazolyl)-benzonitrile was isolated by column chromatography (3.6 g, 78percent). LCMS: MH+=170; 1H NMR (CDCl3) delta 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H)
Step B 4-(1-imidazolyl)-benzonitrile (1 g, 5.92 mmol) was dissolved in anhydrous THF (10 mL) and added drop-wise to a stirring solution of LAH-THF (1 M in THF, 18 mL) at room temperature. The reaction mixture was refluxed under Ar for 2 h and the progress was monitored by TLC. The mixture was cooled to 0° C. and quenched by drop-wise addition of a saturated Na2SO4-H2O solution. The mixture was stirred for 1 h and filtered to remove lithium salts. The filtrate was dried over anhydrous MgSO4 and concentrated to obtain 4-(1-imidazolyl)-benzylamine (0.8 g, 80percent). LCMS: MH+=174.
With copper(I) 3-metthylsalicylate; potassium carbonate; In methanol; at 65℃; for 3h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
52%
With 4,4'-dimethyl-2,2'-bipyridines; oxygen; copper diacetate; In water; at 20℃; under 760.051 Torr; for 24h;
General procedure: Under an O2 atmosphere, a mixture of 4-methoxyphenylboroic acid (1a, 60.8 mg, 0.40 mmol), imidazole (2a, 13.6 mg, 0.20 mmol), Cu(OAc)2 (3.6 mg, 0.020 mmol), ligand I (3.7 mg, 0.020 mmol), and Triton X-100 (38.8 mg, 0.060 mmol) in H2O (4 mL) was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with AcOEt (30 mL.x.3). The organic layer was washed with H2O (10 mL.x.3) and dried over MgSO4. The solvent was removed under the reduced pressure and the residue was purified by SiO2 column chromatography using AcOEt to give N-(4-methoxyphenyl)imidazole (3aa) (23.0 mg, 66percent).
Under a nitrogen atmosphere 362 mg (2.38 mmol) of CsF, previously activated with NaOH, were suspended in 5 ml of DMF and stirred for 30 min. Then, 1.00 g (8.26 mmol) of 4-fluorobenzonitrile was added. After 10 min 1.20 ml (8.18 mmol) N-trimethylsilylimidazole were added and the mixture was stirred at 60° C. for 20 hr. For workup, most of the solvent was removed under vacuum (oil pump), and then 5 ml of water and 5 ml of CH2Cl2 were added to the reaction mixture. The organic phase was separated, the aqueous phase was extracted with CH2Cl2, the organic phases were combined, washed several times with water and dried over MgSO4. The solvent was removed under vacuum, and the resulting solid was rinsed twice with pentane.Yield: 1.07 g (6.31 mmol, 77percent), appearance: colorless solid. 1H NMR (CDCl3, 25° C., 400.13 MHz): delta=7.25 (s, 1H, ImH), 7.33 (s, 1H, ImH), 7.51-7.53 (m, 2H, PhH), 7.79-7.81 (m, 2H, PhH), 7.94 (s, 1H, ImH). 13C NMR (CDCl3, 25° C., 100.61 MHz): delta=111.3 (C-1), 117.7 (C-9), 117.9 (-CN), 121.5 (C-3, C-5), 131.6 (C-8), 134.2 (C-2, C-6), 135.4 (C-7) 140.6 (C-4).
CPI (0.338 g, 2 mmol) was added slowly to a solution of [PdCl2(C6H5CN)2] (0.383 g, 1 mmol) in 30 mL CH3OH:CH2Cl2 (50:50 V/V) mixture at room temperature. The resulting mixture was stirred at room temperature for 24 h, during this the color of the solution changed from light yellow to dark turbid yellow. Finally, the yellow color solid precipitated out, and was filtered, washed with diethyl ether and dried.
[RuCl3(1-(4-cyanophenyl)imidazole)2(NO)][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
In ethanol; for 12h;Reflux;
General procedure: To a stirring solution of 4-CNPy (104 mg, 1.0 mmol, 2 equiv) in ethanol (25 ml), Ru(NO)Cl3·2H2O (136 mg, 0.5 mmol, 1 equiv) was added and contents of the flask heated under reflux for 12 h. After cooling to room temperature a red solid separated which was isolated by filtration, washed with ethanol, diethylether and dried under vacuo. Crystals suitable for X-ray diffraction analyses were obtained by slow diffusion of hexane into dichloromethane solution of the complex. Yield: 138 mg (62percent),
With air; heterogeneous copper Schiff-base modified SBA-15 catalyst; In N,N-dimethyl-formamide; at 80℃; for 6h;Catalytic behavior;
At first diphenyliodonium tetrafluoroborate was synthesizedaccording to procedure reported previously [31] and characterizedby1H and13C NMR and mass spectral analysis (see Supplementarycontent). A mixture of N-heteroarene (1.0 mmol), diphenyliodo-nium salt (1.5 mmol), catalyst and DMF (3 mL) was stirred at 80Cfor a desired time in air. After cooled down to room tempera-ture, heterogeneous catalyst was separated out by centrifugation.The liquid part was then subjected to rotary evaporation andthe residue obtained was passed through a silica gel column(dichloromethane/acetone = 5:1?2:1 v/v) to afford the desired ary-lazolium salt. The product was analyzed by1H and13C NMR andmass spectroscopy.
A mixture of CuI (0.0381g, 0.2mmol), NaN3 (0.0065g, 0.1mmol), <strong>[25372-03-6]4-(1H-imidazol-1-yl)benzonitrile</strong> (0.0169g, 0.1mmol) and H2O (15mL) was sealed in a 25mL Teflon-lined stainless steel container. The reactor was heated to 120°C for 3days, and then slowly cooled down to room temperature. Colorless block crystals were isolated in 53percent yield (based on CuI). C10H7N6ICu2 (465.20): Calc. C, 26.28; H, 1.84; N, 25.54; Found C, 26.21; H, 1.87; N, 25.61percent. FT-IR (KBr pellet, cm?1): 3442(br), 1616(m), 1539(s), 1512(m), 1494(w), 1447(w), 1398(w), 1382(w), 1305(m), 1263(w), 1232(w), 1187(w), 1063(m), 953(w), 823(m), 749(m), 718(w), 652(w), 496(w).
4-(2-bromo-1H-imidazol-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.79 g
With N-Bromosuccinimide; In 1,4-dioxane; at 60℃; for 2h;
4-Imidazol-1-yl-benzonitrile (5.0 g, 29.6 mmol) was dissolved in dioxane and N-bromosuccinimide (5.26 g, 29.6 mmol) was added. The solution was heated at 60° C. for 2 h. The solution was decanted from a gummy residue and evaporated to give a yellow solid. This was triturated with EtOAc to give a cream solid which was further purified by chromatography using EtOAc as eluant to afford Intermediate 11 (0.79 g) as a pale yellow solid. LCMS (Method 1) Rt=2.44 min., m/z 248 and 250 (Br isotopes)
0.79 g
With N-Bromosuccinimide; In 1,4-dioxane; at 60℃; for 2h;
4-imidazol-1-yl-benzonitrile (5.0 g, 29.6 mmol) was dissolved in dioxane and N-bromosuccinimide (5.26 g, 29.6 mmol) was added. The solution was heated at 60° C. for 2 h. The solution was decanted from a gummy residue and evaporated to give a yellow solid. This was triturated with EtOAc to give a cream solid which was further purified by chromatography using EtOAc as eluant to afford Intermediate 11 (0.79 g) as a pale yellow solid. LCMS (Method 1) Rt=2.44 min., m/z 248 and 250 (Br isotopes)
0.79 g
With N-Bromosuccinimide; In 1,4-dioxane; at 60℃; for 2h;
Intermediate 1E. 4-(2-bromo-1H-imidazol-1-yl)benzonitrile 4-Imidazol-1-yl-benzonitrile (5.0 g, 29.6 mmol) was dissolved in dioxane and N-bromosuccinimide (5.26 g, 29.6 mmol) was added. The solution was heated at 60° C. for 2 h. The solution was decanted from a gummy residue and evaporated to give a yellow solid. This was triturated with EtOAc to give a cream solid which was further purified by chromatography using EtOAc as eluant to afford Intermediate 1E (0.79 g) as a pale yellow solid. LCMS (Method 1) Rt=2.44 min., m/z 248 and 250 (Br isotopes)
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc; In acetonitrile; at 60℃; for 20h;Inert atmosphere; Sealed tube;
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn(CN)2 (0.8mmol) , 93.9mg), p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88percent, and 1H NMR purity was greater than 98percent.
1-(4-cyanophenyl)-5'-methyl-2'-oxo-1'-(3-trifluoromethylphenyl)-1',2'-dihydro-1H-[2,4']biimidazolyl-3'-carboxylic acid [1-(2-dimethylaminoacetyl)piperidin-4-yl]amide[ No CAS ]
[2-(4-[1-(4-cyanophenyl)-5'-methyl-2'-oxo-1'-(3-trifluoromethylphenyl)-1',2'-dihydro-1H-[2,4']biimidazolyl-3'-carbonyl]amino}piperidin-1-yl)-2-oxo-ethyl]trimethylammonium benzenesulfonate[ No CAS ]
1-(4-cyano-phenyl)-1H-imidazole-2-carboxylate lithium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
429 mg
With n-butyllithium; In tetrahydrofuran; hexane; at -75 - -70℃; for 1h;Inert atmosphere;
Intermediate 7A. 1-(4-Cyano-phenyl)-1H-imidazole-2-carboxylate lithium salt A solution of n-butyl lithium (1.38 mL of a 1.6 M solution in hexanes, 2.2 mmol) was added dropwise to a cold (-75° C.) solution of 4-imidazol-1-yl-benzonitrile in THF (10 ml) in an argon purged flask. The addition was at such a rate that the internal temperature did not exceed -70° C. The mixture was stirred at -75° C. for 1 h and the resultant orange suspension was poured onto ca. 3 g of ground dry ice. The resultant mixture was stirred for 1 h, a thick white precipitate forming over time. The solvent was evaporated in vacuo and the residue was triturated with diethyl ether (15 mL). The solid was recovered by filtration and dried in vacuo to afford Intermediate 7A (429 mg, 1.96 mmol). 1H NMR (400 MHz, d6-DMSO): delta 7.90 (2H, d, J=8.7 Hz), 7.59 (2H, d, J=8.7 Hz), 7.33 (1H, d, J=1.3 Hz), 6.97 (1H, d, J=1.3 Hz).
5-[1-(4-cyano-phenyl)-1H-imidazol-2-yl]-1-methyl-3-oxo-2-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid cyclopentyl-amide[ No CAS ]
1-(4-cyano-phenyl)-1H-imidazole-2-carboxylate lithium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
429 mg
A solution of n-butyl lithium (1.38 mL of a 1.6 M solution in hexanes, 2.2 mmol) was added dropwise to a cold (?75° C.) solution of 4-imidazol-1-yl-benzonitrile in THF (10 ml) in an argon purged flask. The addition was at such a rate that the internal temperature did not exceed ?70° C. The mixture was stirred at ?75° C. for 1 h and the resultant orange suspension was poured onto ca. 3 g of ground dry ice. The resultant mixture was stirred for 1 h, a thick white precipitate forming over time. The solvent was evaporated in vacuo and the residue was triturated with diethyl ether (15 mL). The solid was recovered by filtration and dried in vacuo to afford Intermediate 72A (429 mg, 1.96 mmol). (0302) 1H NMR (400 MHz, d6-DMSO): delta 7.90 (2H, d, J=8.7 Hz), 7.59 (2H, d, J=8.7 Hz), 7.33 (1H, d, J=1.3 Hz), 6.97 (1H, d, J=1.3 Hz).
1-(4-cyanophenyl)-2-{3-(cyclopentylcarbamoyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-methyl-1H-imidazol-3-ium benzene sulfonate[ No CAS ]
1-(4-cyanophenyl)-2-{3-(cyclopentylcarbamoyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-benzyl-1H-imidazol-3-ium bromide[ No CAS ]
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