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CAS No. : | 534-85-0 | MDL No. : | MFCD00007685 |
Formula : | C12H12N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NFCPRRWCTNLGSN-UHFFFAOYSA-N |
M.W : | 184.24 | Pubchem ID : | 68297 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 60.39 |
TPSA : | 38.05 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.45 cm/s |
Log Po/w (iLOGP) : | 1.94 |
Log Po/w (XLOGP3) : | 2.78 |
Log Po/w (WLOGP) : | 3.02 |
Log Po/w (MLOGP) : | 2.68 |
Log Po/w (SILICOS-IT) : | 2.02 |
Consensus Log Po/w : | 2.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.24 |
Solubility : | 0.107 mg/ml ; 0.000581 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.24 |
Solubility : | 0.107 mg/ml ; 0.000582 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.61 |
Solubility : | 0.00455 mg/ml ; 0.0000247 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.01 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: With triethylamine In dichloromethane at 0 - 20℃; Stage #2: With trichlorophosphate In 1,4-dioxane at 115℃; for 1 h; |
Compound 1 (Ge, Z.; Hayakawa, T.; Ando, S.; Ueda, M.; Akiike, T.; Miyamoto, H.; Kajita, T.; Kakimoto, M. Chem. Mater. 2008, 20(7), 2532-2537) was prepared as follows: to a chilled (ca. 0° C.), stirring solution of N-phenyl-o-phenylene-1,2-diamine (21.41 g, 116.2 mmol) in anhydrous dichloromethane (CH2Cl2) (575 mL) was added 4-bromobenzoyl chloride (25.00 g, 113.9 mmol) portion-wise, followed by dropwise addition of triethylamine (Et3N) (31.8 mL). The reaction was allowed to warm to room temperature and stirring continued until TLC (SiO2, 4:1 hexanes-ethyl acetate) indicated consumption of the starting material. Upon completion, the reaction was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude was then dissolved in anhydrous 1,4-dioxane (500 mL) and heated to about 80° C. Upon completely dissolving, phosphorus oxychloride (31.2 mL, 335 mmol) was added to the solution slowly via syringe and the reaction then maintained at about 115° C. Upon completion (ca. 1 h), the solution was cooled to room temperature (RT) and poured over CH2Cl2 (ca. 3 L) and washed with brine. The organics were then dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by recrystallization from CH2Cl2 and hexanes provided Compound 1 (37.5 g, 94percent) as an off-white solid: confirmed by LCMS (APCI): calculated for C19H13BrN2 (M+): 349; Found: 349. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydrogensulfite In N,N-dimethyl-formamide for 1 h; | A solution of Ν-(4-phenyl)benzene-1,2-diamine (3.68 g, 20 mmol), 4-bromobenzaldehyde (3.70 g, 20 mmol) and sodium bisulfite (2.04 g, 10mmol) was dissolved in DMF (80 mL) and stirred in air for 1 h. After the completion of the reaction, the reaction solution was poured into water to precipitate the product. After standing for some time, the product was filtered and washed with a small amount of methanol. Finally, the crude product was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (1: 5) as eluent to give a white powdery solid product. Yield: 6.40 g, 92percent. |
89% | With sodium hydrogensulfite In N,N-dimethyl-formamide for 1 h; Reflux | willN- (4-phenyl) benzene-1,2-diamine(3.68 g, 20 mmol),4-bromobenzaldehyde (3.70 g, 20 mmol) and sodium bisulfite (2.04 g, 10 mmol)Of the mixture was dissolved in DMF (80 mL)Mix in air for 1 h.Point plate test After the end of the reaction cooled to room temperature,The reaction solution was poured into water,Precipitation products.After standing for some time,Filter out the product,Wash with a small amount of methanol.At last,The crude product was mixed with n-hexane and ethyl acetate (1: 3)As a eluent by silica gel column chromatography to obtain a white powder solid product.Yield: 6.18 g, 89percent. |
60% | at 180℃; for 6 h; | 4-bromo-benzaldehyde (8.3g, 45mmol) was dispersed in the benzene in 10ml of N-phenyl-1,2-phenylenediamine (N-phenyl-1,2-phenylenediamine, 8.3g, 45mmol ), which was heated at 180 °C for 6 hours. After cooling to room temperature, and then removed by distillation under reduced pressure to nitrobenzene, the resulting solid was filtered and dried in vacuo, washed with ethyl ether to obtain a compound A. |
57.71% | With toluene-4-sulfonic acid In toluene for 16 h; Heating / reflux | Synthesis of 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazoleN-Phenyl-o-phenylenediamine 13.27 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 14.51 g of product (yield=57.71percent). |
49% | for 12 h; Reflux | Acetic acid (20 mL) was added to a flask containing N-phenyl-o-phenylenediamine (1.50 g, 8.14 mmol) and 4-bromobenzaldehyde (1.66 g, 8.96 mmol). After the mixture was refluxed for 12 h, distilled water was added and the organic layer was extracted with dichloromethane. The organic layer was washed with sodium bicarbonate and brine and dried using anhydrous sodium sulfate. The filtrate was concentrated in vacuo to give a crude mixture, which was then subjected to column chromatography on silica gel using ethyl acetate and hexane (v/v 1:20) as the eluent. Analytically pure 2-(4-bromophenyl)-1-phenyl-1H-benz[d]imidazole was isolated as a white solid (1.39 g, 49percent). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 1H), 7.53-7.42 (m, 7 H), 7.35-7.21 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 151.21, 142.90, 137.25, 136.75, 131.55, 130.84, 130.01, 128.90, 128.77, 127.37, 124.04, 123.58, 123.15, 119.90, 110.48. MALDI-TOF MS: calcd for C19H13BrN2 348.03, found 349.20. |
35% | With Oxone In N,N-dimethyl-formamide at 20 - 40℃; Inert atmosphere | c) 2-(4-Bromophenyl)-1-phenyl-1H-benzimidazole N-Phenyl-o-phenylenediamine (50 g, 0.27 mol) is dissolved in anhydrous DMF (400 ml) under N2, and 4-bromobenzaldehyde (45.5 g, 0.25 mol) is added dropwise. The reaction mixture is warmed to 40° C., and Oxone (potassium hydrogen monopersulfate, 98.1 g, 0.16 mol) is added in portions. After the mixture has been stirred at room temperature for 120 min., 1 l of water is added. The precipitated product is filtered off, washed with water and dried in vacuo. Recrystallisation from acetonitrile gives a cream-coloured solid (31 g, 35percent). |
23.6% | at 140℃; Inert atmosphere | 2.1Weigh 7.36 g of 4-bromobenzaldehyde and 7.3 g of o-aminodiphenylamine in 200 mL of acetic acid.After charging and discharging nitrogen for 3 times, the temperature was set to 140 ° C to start the reaction;2.2After the reaction, the temperature was lowered to room temperature, and a large amount of gray solid was precipitated after pouring into water, and filtered.After the filter cake was added with 5 g of silica gel, the column was passed to obtain 3.2 g of a white solid powder, the yield was 23.6percent, HPLC 99.7percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; | |
99% | With platinum(IV) oxide; hydrogen In methanol | |
99% | With hydrazine hydrate In ethanol at 70℃; for 4h; chemoselective reaction; | 2.4. general procedure for the reduction of nitroarenes General procedure: In a typical reaction, 5.0 mg of Pd-gCN (5.0 wt% of Pd) catalyst was added to the solution of 1.0 mM of nitroarene in ethanol (2 mL)and 2 mM (1.2 equiv. 0.07 mL) of 60% of hydrazine hydrate. The mixture was placed into a 10 mL round-bottom flask at the reflux temperature (70° C) for the 4 h and then allowed to cool at room temperature. The resultant material was filtered and the filtrate was subjected to column chromatography over silica gel to obtain the corresponding products. For di-nitroarenes substrates 4.0 mM(2.4 equiv. 0.14 mL) of 60% of hydrazine hydrate solution was used. |
93% | With vasicine In water at 120℃; for 24h; chemoselective reaction; | |
92% | With hydrogenchloride; indium In water at 100℃; for 1h; | |
91% | With palladium 10% on activated carbon; hydrazine In ethanol at 80℃; for 0.5h; Inert atmosphere; | |
90% | With Aminoiminomethanesulfinic acid; sodium hydroxide In ethanol; water at 50℃; for 1.5h; | General procedure for the synthesis of 4 in Table 3 General procedure: A mixture of 3 (10 mmol) and NaOH (4.0 g, 100 mmol) was prepared in EtOH (5 mL) and H2O (15 mL). TDO (5.4 g, 50 mmol) was added in batches within 15 minutes to the mixture followed by stirring at 50 °C. After completion of the reaction as indicated by TLC, cooled to room temperature, the precipitated solid was filtered out and washed with water to obtain compound 4. |
82% | With hydrogenchloride; hydroxylamine hydrochloride; iron In ethanol; water for 2h; Reflux; | Preparation of N1-phenylbenzene-1,2-diamine (b4) General procedure: A mixtureof iron powder (5.2 g, 92.0 mmol), hydrochloric acid (1 mL),ammonium chloride (0.6 g, 11.0 mmol) and 60% ethanol (100 mL)was stirred at 70 C for 30 min, then the intermediate a4 (5.0 g,23.0 mmol) was added, the mixture was heated to reflux for 2 h.After that, filtered through a Celite pad, the filtrate was concentratedand adjusted to pH 8-9 with saturated sodium carbonatesolution. The resulting precipitate was filtered, washed with waterand dried under reduced pressure to yield the title compound as ared solid (3.5 g, 82%). MS [M+H]+ m/z: 185. |
82% | With hydrogenchloride; iron; ammonium chloride In ethanol at 70℃; for 2h; Reflux; | 10.4.2 10.4.2. Preparation of intermediate 2-amino-N-phenylaniline (b4) 5.2g (0.092mol) of iron powder,1 mL of hydrochloric acid and 0.6 g (0.011 mol) of ammonium chloride were added to 60 mL of ethanol and 40 mL of water, stirred at 70 ° C. for 30 minutes, 5 g (0.023 mol) of intermediate a4 was added, and the reaction was carried out under reflux for 2 h. The reaction was completed. Filtered with diatomaceous earth while hot, concentrated the filtrate, adjusted the pH to 8 with 10% sodium hydroxide solution, solids precipitated, stirred for 30min, filtered with suction, washed the filter cake with water, and dried the cake to obtain 3.47 g of red solid, yield 82% |
81% | With tin(ll) chloride In ethyl acetate at 80℃; for 2h; | |
76% | With iron; acetic acid In water; ethyl acetate for 6h; Reflux; | J Take intermediate h 8.0 g (37.3 mmol) in 80 mL of ethyl acetate.Add 30 mL of water to the solution, iron powder10.43 g (186.7 mmol) and glacial acetic acid 22.4 g (373.4 mmol), refluxed for 6 h, filtered hot.The ethyl acetate layer is separated, Wash twice with water and dry over anhydrous sodium sulfate.Evaporation to dryness under reduced pressure gave 5.2 g of brown product.The yield was 76%. |
44% | With acetic acid; zinc In ethanol; water for 12h; Reflux; | |
With ammonium sulfide at 120℃; | ||
With hydrogenchloride; ethanol; tin(ll) chloride | ||
With sodium sulfide; ethanol | ||
With platinum Hydrogenation; | ||
With iron; acetic acid Hydrogenation; | ||
With ethanol; nickel Hydrogenation; | ||
With ethanol; sulfuric acid (electrochemical reduction); | ||
1.6 g | With hydrazine hydrate In ethanol for 2h; Heating; | |
With sodium dithionite; potassium carbonate In ethanol; water at 23℃; Yield given; | ||
With hydrogen; acetic acid In methanol; ethyl acetate | ||
With 10% palladium on carbon; hydrogen In ethanol at 20℃; for 2h; | ||
With 5% Pd(II)/C(eggshell); hydrogen In methanol | ||
With palladium 10% on activated carbon; hydrogen In ethyl acetate for 2h; | ||
With acetic acid; zinc In ethanol Reflux; | ||
With palladium 10% on activated carbon; hydrogen In toluene at 20℃; | ||
With sodium tetrahydroborate; nickel(II) chloride hexahydrate In methanol at 0 - 20℃; for 0.5h; | ||
95 %Chromat. | With Pt-TiO2; isopropyl alcohol at 32℃; for 4h; UV-irradiation; Inert atmosphere; | The photocatalytic and catalytic synthesis was carried out using the following procedure. Appropriate amounts of catalyst and 2-nitrodiphenylamine or 2-aminodiphenylamine in 25 mL of alcohol were taken in a reaction tube. The reaction tube was sealed with a rubber septum and purged with nitrogen for 30 min. The reaction mixture was irradiated with UV (365 nm) medium-pressure mercury lamp (Sankyo Denki, Japan; intensity I = 1.381 × 10-6 einstein L-1 s-1)/ solar light at constant stirring. The temperature of the reaction medium during UV irradiation was 32 °C and it was nearly constant. With solar light, the temperature of the solution changed gradually from 32 to 48 °C for all the experiments. The progress of the reaction was monitored using thin layer chromatography (TLC). Product analysis was performed by GC analysis, Perkin-Elmer GC-9000 with a capillary column of DB-5 and flame ionization detector was used. GC-MS analysis was carried out using Varian 2000 Thermo with the following features: capillary column VF5MS (5% phenyl-95% methylpolysiloxane), 30 m length, 0.25 mm internal diameter, 0.25 μm film thickness, temperature of column range from 50-280 °C (10 °C/min) and injector temperature 250 °C, attached with mass spectrometer model SSQ 7000. The isolation was performed by column chromatography on a silica gel column by eluting with a co-solvent of dichloromethane and methanol (volume ratio: 8:2). For solar experiments, all reactions have been carried out under similar conditions on sunny days of different months of 2008-2009 between 10 A.M. and 2 P.M. The intensity of solar light was measured using a LT Lutron LX-10/A digital Lux meter and it was found to be 1250 × 100 (+/-100) lux. The intensity was nearly constant during the experiments. |
With ammonium formate; zinc In ethanol at 60℃; for 2h; | ||
With palladium on activated charcoal; ammonium formate Reflux; | ||
With tin(II) chloride dihdyrate In ethanol for 24h; Reflux; | ||
With tin(II) chloride dihdyrate | ||
With hydrogenchloride; iron In water at 90℃; | 1.2.3. Synthesis of N1-phenylbenzene-1,2-diamine (4a-j) General procedure: To a slurry containing iron powder (94.5 mmol) and distilled water(20 mL), the crude 2-nitro-N-phenylanilinewas added at room temperature. Upon dropwise addition of concentratedhydrochloric acid (0.3 mL), the mixture was stirred at 90 C for 1-2 hours.Reaction completion was confirmed via TLC and the mixture was cooled to roomtemperature. The mixture was extracted with ether (5 x 20 mL) and the organicphase was evaporated in vacuo toobtain intermediates 4a-j.3 | |
With iron; acetic acid In water; ethyl acetate for 6h; Reflux; | 6.3. General procedure for preparation of N1- substituted-benzene-1,2-diamine (16a-16n) General procedure: A mixture of N-substituted-2-nitroanilines (50 mmol), ironpowder (250 mmol), acetic acid (500 mmol), water (35 ml) andethyl acetate (80 ml) was heated to reflux for 6 h. After completionof the reaction as indicated by TLC, the mixture was filtered immediately.The organic layer of the filtrate was separated, washedwith water, dried over anhydrous Na2SO4 and concentrated underreduced pressure to obtain diamines (16a-16n) as a brown solid. | |
With iron; ammonium chloride In ethanol; water at 90℃; for 3h; | 4.2.2. General procedure for the synthesis of target compounds 9a, 9b and 9c General procedure: The main procedure is shown in Scheme 2. The raw products of compound 7 were synthesized via one-pot method in a flask containing compounds 5 (30 mmol), 6 (30 mmol), K2CO3 (15 mmol) and PEG1000 (0.45 mmol). The reactions were carried out under stirring at 185 °C and were monitored by TLC. After reactions completion, the desired diphenylamine derivatives 7 were obtained via column chromatographic purification. Next, compounds 7 (20 mmol), reductive iron powder (60 mmol), solid NH4Cl (60 mmol) and ethanol aqueous solution (75%, 50 mL) were added. The reactions proceeded with refluxing for 3 h at 90 °C and compounds 8 were obtained. Then, compound 3 (30 mmol) and SOCl2 (thionylchloride, 30 mL) were added. The mixture was heated to reflux at 90 °C for 3 h. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 4. Finally, the primary amines 8 (10 mmol) dissolved in dichloromethane (CH2Cl2, 5 mL) and triethylamine(Et3N, 10 mL) were added. The mixture was cooled to 0 °C and compound 4 (20 mmol) dissolved in dichloromethane (CH2Cl2, 10 mL) was added dropwise under stirring at a temperature not exceeding 5 °C. The final mixture was stirred at room temperature for 10 h and the target compounds 9a, 9b and 9c were purified via column chromatography and recrystallization. | |
With sodium dithionite In tetrahydrofuran; ethanol; water at 0 - 20℃; for 3h; | 4.1.2. General procedure for synthesis of b1-b5 General procedure: In the ice bath conditions, a mixture of compound a1 (6.09g, 20.0mmol) and anhydrous ethanol (50mL) in tetrahydrofuran (100mL) was added into sodium dithionite aqueous solution (55.71g, 320mmol). The mixture was stirred at room temperature for 3h, then saturated NaHCO3 solution and extracted with ethyl acetate. Collect the organic layer, wash with saturated NaHCO3 solution, dry with anhydrous sodium sulfate and concentrate to obtain crude compound b1. Compounds b2-b5 were prepared by performing the method above. | |
With hydrazine hydrate In ethanol at 70 - 80℃; | 1.01-1.03 Step S101, taking a three-neck bottle, adding 400 parts of absolute ethanol and 100 parts of o-nitrodiphenylamine to the three-necked bottle, and dissolving the o-nitrodiphenylamine in the absolute ethanol by stirring or shaking. , the first liquid is prepared.Specifically, the structural formula of the o-nitrodiphenylamine is as follows:Step S102,Adding 3 parts of iron hydroxide to the first liquid,After heating to 70 to 80 ° C, 58.4 parts of hydrazine hydrate was added to the first liquid.Stir for 3-8 hours with heat.The o-nitrodiphenylamine is sufficiently reacted with the hydrazine hydrate to prepare a second liquid.Specifically, the hydrazine hydrate has a molecular formula of N2H4.H2O; the hydrazine hydrate has a purity of 80%; and the iron hydroxide is used as a catalyst for the reaction in the step S102.Step S103,Cooling the second liquid to 60-70 ° C,Filtering the second liquid,Then take the filtrate and evaporate and concentrate.Then filter again,And drying the filtrate,A first intermediate is obtained.Specifically, when filtering the second liquid, silica gel is used as a filter aid; the temperature of the evaporation concentration is 40 to 50 ° C; the temperature of the drying treatment is 55 to 60 ° C, and the drying time is 12 hours; The amount of the first intermediate was 82 parts. | |
Stage #1: 2-nitro-N-phenylaniline With iron; ammonium chloride; acetic acid In methanol; water at 50℃; for 0.416667h; Stage #2: With sodium carbonate In methanol; water | ||
5.2 g | With iron; acetic acid In water; ethyl acetate for 6h; Reflux; | 1.5 Step 5: Preparation of N-phenyl o-phenylenediamine Take 8.0 g of the intermediate 2-nitro-N-phenylaniline and dissolve it in 80 mL of ethyl acetate. Add 30 mL of water, 10.43 g of iron powder and 22.4 g of glacial acetic acid to the solution, reflux for 6 hours, and filter while hot. The ethyl acetate layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 5.2 g of a brown product |
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 1.5h; | ||
With iron; acetic acid In water; ethyl acetate for 6h; Reflux; | ||
With hydrogenchloride; tin(II) chloride dihdyrate In methanol; water for 0.5h; Reflux; | 4.1.2.5. N-isobutylbenzene-1,2-diamine 7. 3.20 g (16.5 mmol) of N-isobutyl-2-nitroaniline 3 and a solution of 22.30 g (98.8 mmol)SnCl2 Χ 2H2O in methanol (43 mL) and concentrated HCl (43 mL)were heated under reflux for 0.5 h. After cooling, the reaction mixture was evaporated under vacuum and dissolved in water(70 mL). The resulting solution was treated with 20% NaOH to pH 14. The resulting precipitate was filtered off and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and concentrated at reduce pressure to give the product as brown oil (2.19 g, 81%). 1H NMR (DMSO-d6, 300 MHz): δ/ppm 6.53 (dd, 1H, J1 1.60 Hz, J2 7.70 Hz, Harom), 6.47 (dd, 1H,J1 1.97 Hz, J2 7.13 Hz, Harom), 6.43-6.32 (m, 2H, Harom), 4.48 (s,2H, NH2), 4.33 (bs, 1H, NH), 2.82 (t, 2H, J 6.05 Hz, CH2), 1.95-1.78(m, 1H, CH), 0.95 (d, 6H, J 6.63 Hz, CH3); Anal. Calcd. for C10H16N2:C, 73.13; H, 9.82; N, 17.06. Found: C, 73.25; H, 9.89; N, 16.86%. | |
With hydrogenchloride; indium In water for 2h; | 7.2. General protocol for synthesis of ethyl benzo[d]imidazole-2-carboxylates General procedure: The mixture of 1 (141 mg, 1 mmol) and 2 (1 equiv) in water (2 mL)was stirred magnetically under reflux (oil bath, 110 ) for 2 h (TLCshows complete consumption of starting materials). To this mixture wasadded 2 N aq. HCl (2.5 mL, 5 equiv) and indium powder (287 mg, 2.5equiv) and the resultant mixture was stirred magnetically for 2 h. Next, 5(204 mg, 2 mmol, 2 equiv) was added to this reaction mixture and themagnetic stirring was continued for another 1 h. The reaction mixturewas cooled to rt and treated with solid NaHCO3 (~140 mg) to neutralize(ceasing of effervescence) the acid. The reaction mixture was extractedwith EtOAc (2 × 5 mL), the combined EtOAc extracts were dried (anhMgSO4), and filtered through a cotton plug. The filtrate was concentratedin vacuo and the crude product was subjected to column chromatographypurification on silica gel G (230-400) using (hexane:EtOAc, 85:15) as the eluent to afford analytically pure 6. | |
With iron; acetic acid at 60℃; for 1h; | General procedure for reduction with iron powder in acetic acid2 (2 and 2′): General procedure: 2-Nitroaniline (5 mmol) was dissolved in acetic acid (10 mL), and Fe powder (1.4g) was added. The reaction mixture was heated at 60 °C for 1h, then concentrated and quenched with sat. aq. Na2CO3. The slurry formed was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the amine, which was purified with flash chromatography if necessary. | |
5.2 g | With iron; acetic acid In water; ethyl acetate for 6h; Reflux; | 1.6 Step 6: Preparation of N-phenyl o-phenylenediamine Take 8.0g of intermediate 2-nitro-N-phenylaniline and dissolve it in 80mL ethyl acetate,Add 30mL of water, 10.43g of iron powder and 22.4g of glacial acetic acid to this solution,Reflux for 6h, filter while hot, separate the ethyl acetate layer, wash twice with water,Dry with anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain 5.2 g of brown product N-phenyl o-phenylenediamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | |
90% | In water monomer at 100℃; for 2h; | |
90% | In water monomer; N,N-dimethyl-formamide at 80℃; | Synthesis of benzimidazoles via metal-free aerobic oxidation in wet DMF (Table 5) General procedure: An ortho-phenylenediamine derivative 3 (1.0 mmol; 1.0 equiv) and an aldehyde 4 (1.0 mmol; 1.0 equiv) were dissolved in wet DMF (DMF 9.0 mL, H2O 1.0 mL). The resulting reaction mixture was stirred at 80°C in an open flask, and the reaction progress was monitored by TLC. On the complete consumption of 3, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel to afford the corresponding benzimidazole 5. |
80% | With oxygen; 1-hexadecylpyridinium bromide In water monomer at 20℃; for 0.0833333h; | |
73% | With dodecatungstosilicic acid In ethyl acetate at 20℃; for 0.5h; | |
72% | In 2-ethoxy-ethanol | |
62% | With disodium metabisulfite In N,N-dimethyl-formamide at 100℃; for 0.1h; Microwave irradiation; | |
55% | at 110℃; for 1h; Neat (no solvent); | 3 Synthesis of Dpb The synthesis of 1,2-diphenyl-1H-benzoimidazole (Dpb) is outlined in Scheme 3. To a round round-bottom flask (50 mL) was added N-phenyl-1,2-phenylene diamine (10 mmol) and benzaldehyde (20 mmol) which was allowed to react in a Kugelrohr oven at 110° C. for one hour. After the unreacted benzaldehyde was removed under vacuum, the crude product of high purity was obtained by raising the temperature to 180° C. Recrystallization of the crude product from Hexane/CH2Cl2 gave a white crystal of the title compound in 55% yield. |
53% | In 2-methoxy-ethanol for 30h; Inert atmosphere; Reflux; | |
46% | With acetic acid In 2-ethoxy-ethanol for 24h; Inert atmosphere; Reflux; | |
With nitrobenzene | ||
With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | 2.5.General procedure for the catalytic synthesis of benzimidazolederivatives (1-6) General procedure: A mixture of corresponding aldehyde (1 mmol1 (1 mmol), ammonium acetate (2.5 mmol) and cobalt hydroxide (II) (10 or 15mol %) was refluxed at 80 °C in ethanol for 1 hour. The reaction was monitored by TLC and purified by column chromatography using petroleum ether as the eluent. | |
2 g | In 2-methoxy-ethanol for 48h; Reflux; | Synthesis of 1,2-diphenyl-1H-benzo [d] imidazole N1-phenylbenzene-1,2-diamine (4.15 g, 22 mmol) and benzaldehyde (2.1 g, 20 mmol) were mixed with methoxyethanol (60 ml) in a three-necked flask. this The mixture was heated to reflux for 48 hours. After cooling to room temperature, the solvent was evaporated. The residue was purified by column chromatography using dichloromethane as eluent and 5% ethyl acetate in dichloromethane Purification. 2 g of the desired product was obtained. |
Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux 2: iodine; potassium carbonate / dichloromethane / 3 h / 20 °C | ||
99.9 %Chromat. | With erbium trifluoromethanesulfonate In neat (no solvent) at 60℃; for 0.0833333h; Microwave irradiation; Green chemistry; | 3.2. General Procedure for the Synthesis of 1-phenyl-2-Aryl(alkyl) Benzimidazoles 1a-11a General procedure: To the N-phenil-o-phenilendiammine (1 mmol) and Er(OTf)3 (1% mol) in a 3 mL glass,aryl o alkyl aldehyde (1 mmol) was added. The mixture reacted for 5 min in a Synthos3000 microwave instrument, fixed on a temperature value of 60 °C (IR limit). The reactionwas monitored by TLC and GC/MS analyses. After the completion of the conversionof N-phenil-o-phenilendiammine, the Er(OTf)3 was separated from the reaction mixtureby adding water (to separate the catalyst from the reaction mixture) and extracting theorganic product with ethyl acetate (4 3 mL). The products were isolated after its organicphases and was dried over Na2SO4, followed by evaporation under reduced pressure(1a-10a in 91-99% yields). Spectral data were in accordance with the literature [71]. SeeSupplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With disodium metabisulfite In N,N-dimethyl-formamide at 100℃; for 0.1h; Microwave irradiation; | |
66% | In ethanol for 72h; Reflux; | 2.5.1. 2,6-di-tert-butyl-4-(1-phenyl-1H-benzimidazol-2-yl) phenol (L 1 ) General procedure: A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.200 g, 0.821 mmol) and N- phenyl-o-phenylene diamine (0.151g, 0.821 mmol) in ethanol (5 mL) were stirred and the reaction mixture was refluxed for 3 days. The solution was cooled to room temperature and the solid products were precipitated. Filtration was performed for the resulting solid, and then dried under vacuum. Final product was crystallized from the dichloromethane / hexane solution. The crystals formed have a pale yellow color. |
With disodium metabisulfite In N,N-dimethyl-formamide for 2h; Reflux; |
91.1 %Chromat. | With erbium trifluoromethanesulfonate In neat (no solvent) at 60℃; for 0.25h; Microwave irradiation; Green chemistry; | 3.2. General Procedure for the Synthesis of 1-phenyl-2-Aryl(alkyl) Benzimidazoles 1a-11a General procedure: To the N-phenil-o-phenilendiammine (1 mmol) and Er(OTf)3 (1% mol) in a 3 mL glass,aryl o alkyl aldehyde (1 mmol) was added. The mixture reacted for 5 min in a Synthos3000 microwave instrument, fixed on a temperature value of 60 °C (IR limit). The reactionwas monitored by TLC and GC/MS analyses. After the completion of the conversionof N-phenil-o-phenilendiammine, the Er(OTf)3 was separated from the reaction mixtureby adding water (to separate the catalyst from the reaction mixture) and extracting theorganic product with ethyl acetate (4 3 mL). The products were isolated after its organicphases and was dried over Na2SO4, followed by evaporation under reduced pressure(1a-10a in 91-99% yields). Spectral data were in accordance with the literature [71]. SeeSupplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With calcium oxide at 600℃; for 0.666667h; | |
With lead(II) oxide bei der Destillation; | ||
With lead(II) oxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In 1,4-dioxane Heating; | |
79% | In isopropyl alcohol for 0.333333h; Heating; | |
73% | In isopropyl alcohol for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; sodium acetate In ethanol; water; acetic acid at 23℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N,N-dimethyl acetamide at 20℃; Inert atmosphere; | |
95% | With triethylamine In tetrahydrofuran at 20℃; for 32h; | |
95% | In N,N-dimethyl acetamide at 0℃; for 2.5h; | 6 Preparation of Compound F-1 Preparation of Compound F-1[181] N1-phenylbenzene-1,2-diamine (48g, 260mmol) was completely dissolved in N,N-Dimethyl acetamide (DMAC, 100mL) at 0, and then 4-bromobenzoyl chloride (63g, 287mmol) was dropped thereinto and stirred. After 2 hours 30 minutes, pyridine (60mL) and water (100mL) were added thereto. After stirring the mixture for 30 minutes, the prepared solid was filtered while being washed with methanol, thereby obtaining Compound F-1 (95g, 95%) as a white solid. |
93% | With triethylamine In dichloromethane at 20℃; | 1.3.1 Example 1.3.1; [0085] 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (8): To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-l,2-diamine (10.2 g, 55 mmol), then triethylamine (17 ml, 122 mmol) slowly. The whole mixture was then stirred at room temperature (r.t.) overnight. Subsequent filtration gave a white solid (Compound 8) (6.5 g). The filtrate was worked up with water (300 ml), and then extracted with DCM (300ml) three times. The resulting organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid (Compound 8) (10.6 g). The total amount of product (Compound 8) was 17.1 g, in 93% yield. |
93% | With triethylamine In dichloromethane at 20℃; | 1 [0074] 4-Bromo-N-(2-(phenyIamino)phenyl)benzamide (1): To a solution of 4-bromo-benzoyl chloride (l lg, 50 mmol) in anhydrous dichloromethane (100 ml), was added N-phenylbenzene-l,2-diamine (10.2 g, 55 mmol), then triethylamine (17 ml, 122 mmol) slowly. The whole was stirred at room temperature overnight. Filtration gave a white solid (6.5 g). The filtrate was worked up with water (-300 ml) and extracted with dichloromethane (DCM) (~300ml) three times. The organic phase was collected and dried over MgS04, concentrated and recrystallized in DCM/hexanes to give another portion of white solid (10.6 g). Total amount of product was 17.1 g, in 93% yield. |
93% | With triethylamine In dichloromethane at 20℃; | 1.3.1 Example 1.3.1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (8): To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (17 ml, 122 mmol) slowly. The whole mixture was then stirred at room temperature (r.t.) overnight. Subsequent filtration gave a white solid (Compound 8) (6.5 g). The filtrate was worked up with water (300 ml), and then extracted with DCM (300 ml) three times. |
93% | With triethylamine In dichloromethane at 20℃; | 1.1.BE-2 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (Compound 3) [120] 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (Compound 3): To a solution of 4-bromo-benzoyl chloride (1 1 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1 ,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 3 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300 mL) three times. The organic phase was collected and dried over MgS04, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 3 (10.6 g). Total amount of product 3 is 17.1 g, in 93% yield. |
93% | With triethylamine In dichloromethane at 20℃; | 1.1.1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (Compound 1) Example 1.1.1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (Compound 1) To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 mL, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid (1, 6.5 g). The filtrate was worked up with water (300 mL), then extracted with DCM (300 mL) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 1 (10.6 g). |
90% | In N,N-dimethyl acetamide at 20℃; for 14.5h; | Synthesis of intermediate 4-bromo-N-(2-(phenylamino)phenyl)benzamide (11) A 1-L round bottom flask was charged with 4-bromobenzoylchloride 13 (24.0 g, 110 mmol) and N,N-dimethylacetamide (DMAc, 200 mL). A solution of N-phenylbenzene-1,2- diamine (9) (20.0 g, 109 mmol) in DMAc (300 mL) was added dropwise into the flask over 30 min using an addition funnel. Upon complete addition (>95% conversion), the reaction solution was stirred overnight (14 h) at room temperature. The dark colored reaction mixture was transferred into a 250-mL Erlenmyer flask into which was added 200 mL of deionized water causing a precipitate to form (color changes to red). This mixture was stirred for 1 h at room temperature then filtered over a course porosity fritted filter. The filtrate was washed with hexanes (3 x 200 mL) and dried in a vacuum oven (60 °C) for 24 h to give 36.0 g (90% yield) of the desired amide 14 in -98% purity as determined by NMR and LC-MS (Waters e2695 system equipped with a Waters 2424 ELS Detector, Waters 2998 Photodiode Array Detector, and a 3100 mass detector in positive ion mode). *H NMR (500 MHz, CDC13) δ 8.36 (s, 1H), 8.23 (d, J = 7.1 Hz, 1H), 7.54 - 7.45 (m, 4H),7.27 - 7.21 (m, 4H), 7.19 - 7.13 (m, 1H), 6.91 (tt, / = 7.5, 1.0 Hz, 1H), 6.80 (dt, / = 8.8, 1.6 Hz, 2H), 5.62 (s, 1H); 13C NMR (126 MHz, CDC13) δ 164.62, 144.72, 133.50, 132.87, 132.74, 131.91, 129.55, 128.58, 126.53, 125.57, 125.48, 124.70, 121.93, 120.62, 116.07. |
90% | In N,N-dimethyl acetamide | 4-Bromo-indole-(2-(anilino)phenyl)benzinzan (precursor 1) A four-neck, 2 L round bottom flask equipped with a thermocouple, a 500 mL addition funnel, a nitrogen needle inlet, and an overhead stirrer. 4-Bromobenzylidene chloride (23.8 g, 108.4 mmol) and iV, -dimethylacetamide (DMAC, 125 mL) were added to the flask. A DMAC solution of phenyl-o-phenylenediamine (300 mL) was added dropwise via an addition funnel over 40 min, which was recrystallized from heptane (20·0 g, 108.6 mmol) before use. Once the addition was complete, the reaction was stirred at room temperature for 1 h. Add 1.1 L of deionized water to the flask with vigorous agitation, resulting in the formation of a precipitate. The mixture was stirred at room temperature for 1 h, and then filtered by a course porosity fritted filter to separate the solid. The solid was washed with hexanes (3×200 mL) and dried in EtOAc (EtOAc) |
75% | In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; Schlenk technique; | |
75% | for 2.5h; | 1 Synthesis of Intermediate 1-1 4-bromobenzoyl chloride (25 g, 114 mmol) in a 500 mL three neck flask and diethyl acetamide (40 mL) was added and stirred for 30 minutes. Then 2-aminodiphenyl amine(2-aminodiphenyl amine) (21 g, 114 mmol) was dissolved in diethyl acetamide (100 mL), slowly added dropwise to the reaction vessel, stirred for 2 hours, and then H2O (800 mL) was added thereto. The reaction was terminated. The resulting solid compound was washed with water and methanol, recrystallized under DMF/H2O conditions, and confirmed by 1H NMR.Yield: 31.4 g, 75% |
75% | In N,N-dimethyl acetamide at 20℃; for 1h; Inert atmosphere; | |
67.7% | With triethylamine In dichloromethane at 0 - 20℃; for 3.5h; | 5.6 In a 500 mL round-bottom flask, 25 g (0.136 mol) of 4-bromo-benzol chloride, 32.8 g (0.149 mol) of en-phenylbenzene-1,2-diamine,After adding 34.3 g (0.339 mol) of triethyla, dichloromethane was added at 0° C. and stirred for 30 minutes.When the reaction was completed, the reaction solution was stirred at room temperature for 3 hours, and the precipitated solid was filtered and dried with hexane to obtain 33.6 g (yield 67.7%) of a compound represented by [Chemical Formula 70-f]. |
61.2% | Stage #1: 4-chlorobenzoyl chloride; N-phenyl-1,2-benzenediamine In dichloromethane for 0.5h; Stage #2: With triethylamine In dichloromethane for 3h; Reflux; | 10.2 25 g (136 mmol) of 4-bromobenzyl chloride in a 500 mL round bottom flask,32.76 g (149 mmol) of N-phenylbenzene-1,2-diamine was diluted in 250 mL of dichloromethane, stirred for 30 minutes, and then 34.33 g (339 mmol) of triethylamine was added and refluxed for 3 hours.When the reaction was completed, the resulting solid was filtered to obtain 29 g (yield 61.2%) of a compound represented by [Chemical Formula 38-b]. |
In 1-methyl-pyrrolidin-2-one at 20℃; | 1.1 (1) Synthesis of 2-(4-bromop;henyl)-1-phenyl-1H-benzimidazole Suspending 3.0 g (15 mmol) of 4-bromobenzoic acid into 30 milliliter of 1,2-dichloroethane, adding 2.7 g (23 mmol) of thionyl chloride and 3 drops of N,N-dimethylformamide, the resultant solution was stirred with heating at the temperature of about 50 °C for 1 hour and 30 minutes until benzoic acid as the material disappeared. After completion of the reaction, removing the solvent and excess thionyl chloride by distillation, dissolving the resultant acid chloride into 30 milliliter of N-methylpyrrolidone, adding 2.8 g (15 mmol) of N-phenyl-1,2-phenylenediamine, the resultant solution was stirred at room temperature for a night. After completion of the reaction, adding water and filtering the precipitated solid, further washing with water and by drying under reduced pressure, 5.2 g of 4-bromo-N-(2-phenylamino-phenyl)-benzamide was obtained. The benzamide was stirred with heating under reduced pressure (about 20 mmHg) and at the temperature of about 300 °C for 30 minutes. After completion of the reaction, the resultant solution was further dissolved in dichloro-methane, and by refining with the use of silicagel column chromatography, 3.5 g of 2-(4-bromophenyl-1-phenyl-1H) -benzimidazole was obtained (yield: 80 %). | |
With triethylamine In dichloromethane (DCM) | 1.3.1 Example 1.3.1 Example 1.3.1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (8): To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (17 ml, 122 mmol) slowly. The whole mixture was then stirred at room temperature (r.t.) overnight. Subsequent filtration gave a white solid (Compound 8) (6.5 g). The filtrate was worked up with water (300 ml), and then extracted with DCM (300 ml) three times. | |
With triethylamine In dichloromethane; water | 1 Synthesis of Host-1 Example 1 Synthesis of Host-1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (1): To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (17 ml, 122 mmol) slowly. The whole was stirred at room temperature overnight. Filtration gave a white solid (6.5 g). The filtrate was worked up with water (~300 ml) and extracted with dichloromethane (DCM) (~300 ml) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid (10.6 g). Total amount of product was 17.1 g, in 93% yield. | |
3.56 g | With 1-methyl-pyrrolidin-2-one at 20℃; | |
With triethylamine In 1-methyl-pyrrolidin-2-one at 20℃; | 1 Synthesis of Compound 15-3 and 15-4 Synthesis of Compound 15-3 and 15-4 Adding in the flask N-phenyl -1, 2-phenylenediamine (9.2g, 50mmol) and NMP (80 ml, N-methyl pyrrolidone), then adding 4-bromophenylacetic formyl chloride (10.9g, 50mmol) stirring the reaction overnight at room temperature. Reaction end, in the reaction solution is poured into the water, a large number of solid precipitation, filtration, because (tetrahydrofuran) and methanol THF recrystallization, the get white solid (compound 15-3) by adding acetic acid (100 ml) heating to reflux for 12 hours, the reaction end, reduced pressure to remove the solvent, by adding methanol (50 ml), filtered, get 12g white solid (compound 15-4), yield of 69% | |
With triethylamine In 1-methyl-pyrrolidin-2-one at 20℃; | 1 N- phenyl-1,2-phenylenediamine was added in the flask (9.2g, 50mmol) and NMP (80ml, N- methylpyrrolidone), was added 4-bromobenzoyl chloride (10.9g, 50mmol) at room temperature The reaction was stirred overnight.After the reaction, the reaction mixture was poured into water, there are large amount of solid precipitated, was filtered, the filter cake washed with THF (tetrahydrofuran), and recrystallized from methanol to give the white solid (Compound 15-3) Acetic acid (100ml) was heated under reflux for 12 hours, the reaction after, the solvent was removed under reduced pressure, methanol (50ml), filtered to give a white solid 12g (compound 17-1), in a yield of 69%. | |
In 1-methyl-pyrrolidin-2-one at 20℃; for 1h; Inert atmosphere; | 1 Example 1 First, under a nitrogen atmosphere, N-phenyl-O-phenylenediamine (5.7 g, 30.9 mmol) was dissolved in N-methylpyrrolidone (NMP) (23 ml). Thereafter, the NPOP solution is cooled to 10° C., 4-bromobenzoyl chloride (4BC) (6.8 g, 30.9 mmol) was dissolved in NMP (3 ml), and this 4BC solution was added dropwise in the NPOP solution. Thereafter, the reaction solution was stirred at room temperature for 1 hour. Thereafter, water (50 ml) was added dropwise therein, to thereby terminate the reaction, and the reaction solution was extracted with ethyl acetate (100 ml). Thereafter, the organic layer was washed with a saturated saline solution, and was dried over anhydrous sodium sulfate. Thereafter, the organic layer was concentrated under a reduced pressure, to thereby obtain the compound represented by the aforementioned formula (3). | |
With triethylamine In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In dichloromethane; at 0℃; for 6h; | N-phenyl-1,2-phenylenediamine (1.84 g, 10 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was then added, and the mixture was cooled to 0 C. <strong>[72482-64-5]2,4-Difluoro-benzoyl chloride</strong> (1.94 g, 11 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2,4-difluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=1.83 g, 60%). |
With triethylamine; In dichloromethane; | EXAMPLE 2 Organometallic compound (2): Iridium(III) bis[2-(2,4-difluoro-phenyl)-1-phenyl-1H-benzoimidazole] (tetrakis(1-pyrazolyl) borate) N-phenyl-1,2-phenylenediamine (1.84 g, 10 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was added, and the mixture was cooled to 0 C. <strong>[72482-64-5]2,4-Difluoro-benzoyl chloride</strong> (1.94 g, 11 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitate. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2,4-difluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=1.83 g, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; ethyl acetate; | EXAMPLE 6 Synthesis of 1-phenyl-2-(3-methoxyphenyl)benzimidazole The titled intermediate was prepared essentially as described in Journal of Medicinal Chemistry, 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and m-methoxybenzoic acid (1.52 g, 10 mmol) was stirred at room temperature in methylene chloride (80 ml). <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> (2.97 g) was added dropwise and the reaction was refluxed for about 16 hours. Additional <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> was added and the reaction was refluxed for an additional 18 hours. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer (pH~14) was extracted with ethyl acetate (3*150 ml). The combined organic fractions were dried over potassium carbonate, filtered and concentrated in vacuo. Crude red oil was purified by chromatography using hexanes/ethyl acetate (9:1) as the eluent. White solid crystallized out of several fractions. mp 118-120 C. | |
With sodium hydroxide; In dichloromethane; ethyl acetate; | EXAMPLE 6 Synthesis of 1-phenyl-2-(3-methoxyphenyl)benzimidazole The titled intermediate was prepared essentially as described in Journal of Medicinal Chemistry, 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and m-methoxybenzoic acid (1.52 g, 10 mmol) was stirred at room temperature in methylene chloride (80 ml). <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> (2.97 g) was added dropwise and the reaction was refluxed for about 16 hours. Additional <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> was added and the reaction was refluxed for an additional 18 hours. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer (pH~14) was extracted with ethyl acetate (3*150 ml). The combined organic fractions were dried over potassium carbonate, filtered and concentrated in vacuo. Crude red oil was purified by chromatography using hexanes/ethyl acetate (9:1) as the eluent. White solid crystallized out of several fractions. mp 118-120 C. | |
With sodium hydroxide; In dichloromethane; ethyl acetate; | Example 6 Synthesis of 1-phenyl-2-(3-methoxyphenyl)benzimidazole The titled intermediate was prepared essentially as described in Journal of Medicinal Chemistry, 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and m-methoxybenzoic acid (1.52 g, 10 mmol) was stirred at room temperature in methylene chloride (80 ml). <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> (2.97 g) was added dropwise and the reaction was refluxed for about 16 hours. Additional <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> was added and the reaction was refluxed for an additional 18 hours. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer (pH 14) was extracted with ethyl acetate (3 x 150 ml). The combined organic fractions were dried over potassium carbonate, filtered and concentrated in vacuo. Crude red oil was purified by chromatography using hexanes/ethyl acetate (9:1) as the eluent. White solid crystallized out of several fractions. mp 118-120C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In tetrahydrofuran; | EXAMPLE 30 Synthesis of 1-phenyl-2-(3-nitro-4-chlorophenyl)-benzimidazole A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and 4-chloro-3-nitro-benzoic acid (2.07 g, 10 mmol) in anhydrous tetrahydrofuran was stirred at room temperature as <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> (3.71 g, 15 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for about 72 hours. The reaction mixture was alkalinized with 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate (4*100 ml). The organic fractions were combined, dried over potassium carbonate, filtered, and the solvents removed in vacuo to yield the crude product. | |
With sodium hydroxide; In tetrahydrofuran; | EXAMPLE 30 Synthesis of 1-phenyl-2-(3-nitro-4-chlorophenyl)benzimidazole A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and 4-chloro-3-nitro-benzoic acid (2.07 g, 10 mmol) in anhydrous tetrahydrofuran was stirred at room temperature as <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> (3.71 g, 15 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for about 72 hours. The reaction mixture was alkalinized with 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate (4*100 ml). The organic fractions were combined, dried over potassium carbonate, filtered, and the solvents removed in vacuo to yield the crude product. | |
With sodium hydroxide; In tetrahydrofuran; | Example 30 Synthesis of 1-phenyl-2-(3-nitro-4-chlorophenyl)-benzimidazole A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and 4-chloro-3-nitro-benzoic acid (2.07 g, 10 mmol) in anhydrous tetrahydrofuran was stirred at room temperature as <strong>[16357-59-8]N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline</strong> (3.71 g, 15 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for about 72 hours. The reaction mixture was alkalinized with 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate (4 x 100 ml). The organic fractions were combined, dried over potassium carbonate, filtered, and the solvents removed in vacuo to yield the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.5% | With sodium hydroxide; In dichloromethane; | EXAMPLE 3 Synthesis of 1-phenyl-2-phenylmethylbenzimidazole The title intermediate was synthesised in substantial accordance with Journal of Medicinal Chemistry 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (12 mmol, 2.97 g) was stirred in methylene chloride (60 ml) at room temperature. Phenylacetic acid (10 mmol, 1.36 g) in methylene chloride (30 ml) was added via dropping funnel and stirred at room temperature over a drying tube overnight. The resulting reaction mixture was partitioned with 6N sodium hydroxide. The methylene chloride layer was removed and the aqueous layer was extracted with ethyl acetate (3*100). The organic fractions were combined, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 5.28 grams of a dark red/brown crude product. The crude product was recrystallized from ethyl acetate and then diethyl ether to yield a white crystalline product (1.77 g, 58.5%) of the title product. mp 108-110 C. |
58.5% | With sodium hydroxide; In dichloromethane; | EXAMPLE 3 Synthesis of 1-phenyl-2-phenylmethylbenzimidazole The title intermediate was synthesised in substantial accordance with Journal of Medicinal Chemistry, 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (12 mmol, 2.97 g) was stirred in methylene chloride (60 ml) at room temperature. Phenylacetic acid (10 mmol, 1.36 g) in methylene chloride (30 ml) was added via dropping funnel and stirred at room temperature over a drying tube overnight. The resulting reaction mixture was partitioned with 6N sodium hydroxide. The methylene chloride layer was removed and the aqueous layer was extracted with ethyl acetate (3*100). The organic fractions were combined, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 5.28 grams of a dark red/brown crude product. The crude product was recrystallized from ethyl acetate and then diethyl ether to yield a white crystalline product (1.77 g, 58.5%) of the title product. mp 108-110 C. |
58.5% | With sodium hydroxide; In dichloromethane; | EXAMPLE 3 Synthesis of 1-phenyl-2-phenylmethylbenzimidazole The title intermediate was synthesised in substantial accordance with Journal of Medicinal Chemistry, 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (12 mmol, 2.97 g) was stirred in methylene chloride (60 ml) at room temperature. Phenylacetic acid (10 mmol, 1.36 g) in methylene chloride (30 ml) was added via dropping funnel and stirred at room temperature over a drying tube overnight. The resulting reaction mixture was partitioned with 6N sodium hydroxide. The methylene chloride layer was removed and the aqueous layer was extracted with ethyl acetate (3*100). The organic fractions were combined, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 5.28 grams of a dark red/brown crude product. The crude product was recrystallized from ethyl acetate and then diethyl ether to yield a white crystalline product (1.77 g, 58.5%) of the title product. mp 108-110 C. |
58.5% | With sodium hydroxide; In dichloromethane; | Example 3 Synthesis of 1-phenyl-2-phenylmethylbenzimidazole The title intermediate was synthesised in substantial accordance with Journal of Medicinal Chemistry , 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (12 mmol, 2.97 g) was stirred in methylene chloride (60 ml) at room temperature. Phenylacetic acid (10 mmol, 1.36 g) in methylene chloride (30 ml) was added via dropping funnel and stirred at room temperature over a drying tube overnight. The resulting reaction mixture was partitioned with 6N sodium hydroxide. The methylene chloride layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100). The organic fractions were combined, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 5.28 grams of a dark red/brown crude product. The crude product was recrystallized from ethyl acetate and then diethyl ether to yield a white crystalline product (1.77 g, 58.5%) of the title product. mp 108-110C. |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid; In tetrahydrofuran; THF-saturated aqueous sodium hydrogen carbonate; ethanol; N,N-dimethyl-formamide; | 1 Ethyl 6-(1-phenylbenzimidazol-2-yl)hexanoate Monoethyl heptanedioate (10.35 g) was dissolved in THF (55 ml) followed by addition of DMF (1 drop) and oxalyl chloride (11.73 ml), and the mixture was stirred at room temperature for 15 minutes. The excess oxalyl chloride was distilled off under reduced pressure and the residue was added to a solution (100 ml) of N-phenyl-1,2-phenylenediamine (9.21 g) in THF-saturated aqueous sodium hydrogen carbonate solution (1:1). The mixture was stirred at room temperature for 1 hour and, then, extracted with ethyl acetate (50 ml). The organic layer was washed with 1N HCl and 1N NaOH serially and dried. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to give crystals (14.72 g). After this crystal crop (13.54 g) was dissolved in ethanol (50 ml), sulfuric acid (1 ml) was added and the reaction was conducted under reflux for 3 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with 1N-sodium hydroxide (100 ml) and extracted with ethyl acetate (100 ml). The extract was dried and concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to provide ethyl 6-(1-phenylbenzimidazol-2-yl)hexanoate (6.49 g). 1 H-NMR (CDCl3) delta: 1.22 (3H, t, J=7.1 Hz), 1.31-1.42 (2H,m), 1.52-1.68 (2H, m), 1.73-1.90 (2H, m), 2.25 (2H, t, J=7.4 Hz), 2.79 (2H, t, J=7.7 Hz), 4.09 (2H, q, J=7.1 Hz), 7.07-7.39 (5H, m), 7.48-7.64 (3H, m), 7.75-7.81 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In 1-methyl-pyrrolidin-2-one; at 160℃; for 12h; | 6-Bromo-2-naphthoic acid (5.0g,20ml) in thionyl chloride (SOCl2, 20mL) and dimethylformamide (DMF, 1mL) wasrefluxed with stirring for 4 hours. After removal of excess thionyl chloride(SOCl2) in a vacuum distillation, N- methylpyrrolidine (NMP, 20 mL) was added tothe reaction mixture, N-phenyl-1,2-diaminobenzene (3.7g,20mmol) was stirred at 160C for 12hours. The resulting mixture was cooled to room temperature, excess of waterwas added to form a solid. The resulting mixture was filtered, washed with waterand ethanol and dried to obtain compound B-18 (6.2g, yield: 78%). |
With 1-Methylpyrrolidine; In N,N-dimethyl-formamide; at 160℃; for 12h; | To 6-bromo-2-naphthoic acid (5.0 g, 20 mmol), 20 mL of thionyl chloride (SOCl ), and dimethylformaldehyde (DMF, 1 mL) were added, and the mixture was stirred under heating for 4 hours. An excessive amount of thionyl chloride (SOCl ) was distilled off in vacuum, and then to the reaction mixture, 20 mL of N- methylpyrrolidine (NMP), and N-phenyl-l,2-diaminobenzene(3.7 g, 20 mmol) were added, and the mixture was stirred at 160 0C for 12 hours. The mixture was cooled to ambient temperature, and then an excessive amount of water was added thereto to form a solid. The solid was filtered, washed with water and then ethanol, and dried to prepare a compound B-9 (6.2 g, yield 78 %).[132] MS [M+H]+ = 399 |
Yield | Reaction Conditions | Operation in experiment |
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78% | With acetic acid In toluene at 150℃; for 12h; | II.13 To the compound B- 12-1 of Preparation Example 11-12 (6.Og, 20 mmol), N- phenyl-l,2-diamino benzene (3.7 g, 20 mmol), 30 mL of toluene and 10 mL of acetic acid were added and stirred at 150 0C for 12 hours. The mixture was cooled to ambient temperature and an excessive amount of water was added thereto to form a solid. The solid was filtered, washed with water and then ethanol, and dried to prepare a compound B-13-1. (7.2 g, yield 78 %): MS [M+H]+ = 463 |
78% | With acetic acid In toluene at 150℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
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82% | With sodium metabisulfite In N,N-dimethyl-formamide at 1155℃; for 8h; | 1 Example 1 Synthesis of Intermediate M1 Anthracene-9-formaldehyde (10.0g, 48.5mmol)With o-aminodiphenylamine (8.9g, 48.5mmol)Placed in dry DMF (100ml),Sodium metabisulfite (11.0 g, 58.2 mmol) was added.Reaction at 155 ° C for 18 h,After the reaction is over,Cool to room temperature,Washed with water, extracted with ethyl acetate,Dry, evaporate the solvent,The toluene was recrystallized to give Intermediate M1 (14.7 g, y=82%). |
82% | With sodium metabisulfite In N,N-dimethyl-formamide at 155℃; for 18h; | 1 Example 1 Synthesis of Intermediate M1 9-anthraldehyde(10.0 g, 48.5 mmol) and o-aminodiphenylamine (8.9 g, 48.5 mmol) were placed in dry DMF (100 mL).Sodium metabisulfite (11.0 g, 58.2 mmol) was added, and the mixture was reacted at 155 ° C for 18 h. After the reaction was completed, the mixture was cooled to room temperature, washed with water, ethyl acetate was evaporated, evaporated and evaporated =82%). |
82% | With sodium metabisulfite In N,N-dimethyl-formamide at 155℃; for 18h; | 1 Example 1 Synthesis of Intermediate M1 9-anthracene formaldehyde (10.0 g, 48.5 mmol) and o-aminodiphenylamine (8.9 g, 48.5 mmol) were placed in dry DMF (100 ml)In the middle, sodium metabisulfite (11.0 g, 58.2 mmol) was added, and the reaction was carried out at 155 ° C for 18 h. After the reaction was completed, it was cooled to room temperature.Washed with water, extracted with ethyl acetate, dried, evaporated to dryness.Recrystallization of toluene,Intermediate M1 (14.7 g, y = 82%) was obtained. |
78% | In acetic acid; toluene at 160℃; for 12h; | 11.1 9-Anthracenecarboxaldehyde (3.3 g, 15.9 mmol) and N-phenyl-l,2-diaminobenzene(2.93 g, 15.9 mmol) were added to a mixed solution of 60 mL of toluene and 20 ml of acetic acid. The mixture was stirred at 160°C for 12 hours, and cooled to normal temperature. The solvent was distilled off in vacuo, and the resultant was purified by column chromatography to prepare a compound K-I (4.6 g, yield 78 %).[207] MS: [M+H]+ = 371 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydrogensulfite; In N,N-dimethyl-formamide; for 1h; | A solution of Ν-(4-phenyl)benzene-1,2-diamine (3.68 g, 20 mmol), 4-bromobenzaldehyde (3.70 g, 20 mmol) and sodium bisulfite (2.04 g, 10mmol) was dissolved in DMF (80 mL) and stirred in air for 1 h. After the completion of the reaction, the reaction solution was poured into water to precipitate the product. After standing for some time, the product was filtered and washed with a small amount of methanol. Finally, the crude product was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate (1: 5) as eluent to give a white powdery solid product. Yield: 6.40 g, 92%. |
89% | With sodium hydrogensulfite; In N,N-dimethyl-formamide; for 1h;Reflux; | willN- (4-phenyl) benzene-1,2-diamine(3.68 g, 20 mmol),4-bromobenzaldehyde (3.70 g, 20 mmol) and sodium bisulfite (2.04 g, 10 mmol)Of the mixture was dissolved in DMF (80 mL)Mix in air for 1 h.Point plate test After the end of the reaction cooled to room temperature,The reaction solution was poured into water,Precipitation products.After standing for some time,Filter out the product,Wash with a small amount of methanol.At last,The crude product was mixed with n-hexane and ethyl acetate (1: 3)As a eluent by silica gel column chromatography to obtain a white powder solid product.Yield: 6.18 g, 89%. |
80% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere; | Amixture of 1-N-phenylbenzene-1,2-diamine (3.29 g, 17.86 mmol), pbromobenzaldehyde(3.30 g, 17.84 mmol) and Na2S2O5 (7.21 g, 37.93mmol) was dissolved in DMF (50 mL), and heated at 90 C under a nitrogenatmosphere for 5 h. After cooling to room temperature, themixture was poured into the distilled water (200 mL) and then extractedwith dichloromethane (3 × 100 mL). The organic phase was dried overanhydrous Na2SO4 and concentrated in vacuum. The crude product waspurified by silica gel column chromatography with dichloromethane toobtain a white solid (5.0 g, 80%). 1H NMR (500 MHz, DMSO-d6, , ppm):7.80 (d, J = 7.9 Hz, 1H), 7.60-7.54 (m, 5H), 7.46-7.42 (m, 4H),7.34-7.26 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H). 13C NMR (126 MHz, CDCl3,, ppm): 151.2, 142.9, 137.3, 136.8, 131.6, 130.9, 130.1, 128.9, 128.8,127.4, 124.1, 123.6, 123.2, 119.9, 110.5 |
60% | In benzene; at 180℃; for 6h; | 4-bromo-benzaldehyde (8.3g, 45mmol) was dispersed in the benzene in 10ml of N-phenyl-1,2-phenylenediamine (N-phenyl-1,2-phenylenediamine, 8.3g, 45mmol ), which was heated at 180 C for 6 hours. After cooling to room temperature, and then removed by distillation under reduced pressure to nitrobenzene, the resulting solid was filtered and dried in vacuo, washed with ethyl ether to obtain a compound A. |
57.71% | With toluene-4-sulfonic acid; In toluene; for 16h;Heating / reflux; | Synthesis of 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazoleN-Phenyl-o-phenylenediamine 13.27 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 14.51 g of product (yield=57.71%). |
49% | In acetic acid; for 12h;Reflux; | Acetic acid (20 mL) was added to a flask containing N-phenyl-o-phenylenediamine (1.50 g, 8.14 mmol) and 4-bromobenzaldehyde (1.66 g, 8.96 mmol). After the mixture was refluxed for 12 h, distilled water was added and the organic layer was extracted with dichloromethane. The organic layer was washed with sodium bicarbonate and brine and dried using anhydrous sodium sulfate. The filtrate was concentrated in vacuo to give a crude mixture, which was then subjected to column chromatography on silica gel using ethyl acetate and hexane (v/v 1:20) as the eluent. Analytically pure 2-(4-bromophenyl)-1-phenyl-1H-benz[d]imidazole was isolated as a white solid (1.39 g, 49%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 1H), 7.53-7.42 (m, 7 H), 7.35-7.21 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 151.21, 142.90, 137.25, 136.75, 131.55, 130.84, 130.01, 128.90, 128.77, 127.37, 124.04, 123.58, 123.15, 119.90, 110.48. MALDI-TOF MS: calcd for C19H13BrN2 348.03, found 349.20. |
35% | With Oxone; In N,N-dimethyl-formamide; at 20 - 40℃;Inert atmosphere; | c) 2-(4-Bromophenyl)-1-phenyl-1H-benzimidazole N-Phenyl-o-phenylenediamine (50 g, 0.27 mol) is dissolved in anhydrous DMF (400 ml) under N2, and 4-bromobenzaldehyde (45.5 g, 0.25 mol) is added dropwise. The reaction mixture is warmed to 40 C., and Oxone (potassium hydrogen monopersulfate, 98.1 g, 0.16 mol) is added in portions. After the mixture has been stirred at room temperature for 120 min., 1 l of water is added. The precipitated product is filtered off, washed with water and dried in vacuo. Recrystallisation from acetonitrile gives a cream-coloured solid (31 g, 35%). |
23.6% | With acetic acid; at 140℃;Inert atmosphere; | 2.1Weigh 7.36 g of 4-bromobenzaldehyde and 7.3 g of o-aminodiphenylamine in 200 mL of acetic acid.After charging and discharging nitrogen for 3 times, the temperature was set to 140 C to start the reaction;2.2After the reaction, the temperature was lowered to room temperature, and a large amount of gray solid was precipitated after pouring into water, and filtered.After the filter cake was added with 5 g of silica gel, the column was passed to obtain 3.2 g of a white solid powder, the yield was 23.6%, HPLC 99.7%; |
With Oxone; In N,N-dimethyl-formamide; for 12h;Heating / reflux; | [Exemplary embodiment 2] Synthesis of compound 3 Compound 3 <n="67"/>[Reaction formula 2]OxoneDMF, reflux 12hr 4-bromobenzaldehyde (5g, 27mmol), Nl-phenylbenzene- 1,2-diamine (5.47g, 29.7mmol) and oxone (18.25g,29.7mmol) were put into a reactor, melted by DMF of 80ml and agitated for 10 hours at 120C to thereby synthesize2- (4-bromophenyl) -1-phenyl-lH-benzo [d] imidazole. The synthesized 2- (4-bromophenyl) -1-phenyl-lH- benzo [d] imidazole (β.98g, 20mmol) was melted by THF of50ml, gradually added with 2Mn-BuLi (11ml, 22mmol) at -78 C and agitated for one hour at low temperatures. The mixture was added with (Z) -3- (5-bromothiophene-2-yl) -2- cyanoacrylic acid (5.1βg, 20mmol) at -78C, agitated for one hour at low temperatures and then additionally agitated for 30 minutes at 0C to complete the reaction. <n="68"/>After extracting an organic layer from the mixture with dichloromethane and distilled water, the solvent was removed through a distiller, the organic layer was recrystallized by n-hexane, and dried and purified after filtering sediment (yield 48%) .1H NMR(CDCl3) : 11.0 (s, IH), 8.16 (s, IH), 7.70 (m, 3H), 7.54 (dd, 3JHH = 8Hz, 4H), 7.3 (s, IH), 7.26 (m, 7H) . |
Yield | Reaction Conditions | Operation in experiment |
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88% | With zinc(II) acetate dihydrate In neat (no solvent) at 120℃; for 18h; Autoclave; Inert atmosphere; Green chemistry; | Benzimidazole Derivatives; General Procedure General procedure: Zn(OAc)2·2H2O (5.0 mol%) was transferred to a 100 mL autoclavereactor equipped with an overhead stirrer and an automatic temperature-control system. The appropriate benzene-1,2-diamine 1 (2 mmol), DMF (10.0 mmol), and PMHS (5.0 mmol)were successively introduced. The reactor was sealed, flushedthree times with N2 (10 atm), and heated to the required temperature with vigorous stirring (600 rpm). During the course ofthe reaction, an increase of pressure was observed, due to thegeneration of Me2NH and HCHO at 120 °C.15 (For this reason, the protocol needs to be performed in a sealed high-pressurereactor.) When the reaction was complete, the autoclave wascooled to r.t., and the pressure generated during the reactionwas carefully released. Basic hydrolysis was then carried out atr.t. for 30 min to remove unreacted PMHS from the mixture.13aThe mixture was then extracted with EtOAc (3 × 20 mL). Thecombined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude products were further purified bycolumn chromatography [silica gel (100-200 mesh), PE-EtOAc(20:4 to 10:2)]. The spectroscopic data for the products wereconsistent with those reported in the literature. |
30% | Stage #1: N-phenyl-1,2-benzenediamine With n-butyllithium In diethyl ether at 20℃; for 48h; Stage #2: N,N-dimethyl-formamide In diethyl ether for 1h; Further stages.; | |
68 %Spectr. | With Triethoxysilane; carbon dioxide; tris(pentafluorophenyl)borate at 120℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
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74% | In tetrahydrofuran; at 20℃;Inert atmosphere; | General procedure: To a solution of starting materials 13, 14, or 15 (1 mmol) in THF was added 1,1'-carbonyldiimidazole (1.4 mmol) under argon atmosphere and the mixture was stirred at room temperature overnight. Thereafter, the crude reaction product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | |
90% | With disodium metabisulfite In N,N-dimethyl-formamide at 100℃; for 0.1h; Microwave irradiation; | |
85% | With oxygen; 1-hexadecylpyridinium bromide In water monomer at 20℃; for 0.5h; |
51% | With potassium carbonate; 3-butyl-1-methyl-1H-imidazol-3-ium iodide In o-dimethylbenzene; para-xylene; 1,3-dimethylbenzene at 120℃; for 10h; Green chemistry; | General procedure B General procedure: Into a 15*150 mm tube was layered 6b 1mmol (184 mg), corresponding aromatic aldehyde (1mmol), NHC precursor G (10 mol%), K2CO3 (25 mol%), the mixture was stirred under pre-heated 120 °C oil-bath for 10 hours, after finished, the solution was transferred into a 25 mL recovery flask, and concentrated under reduced pressure, the residue was applied on flash silica column chromatograph, which afforded the targeted products. |
With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | 2.5.General procedure for the catalytic synthesis of benzimidazolederivatives (1-6) General procedure: A mixture of corresponding aldehyde (1 mmol1 (1 mmol), ammonium acetate (2.5 mmol) and cobalt hydroxide (II) (10 or 15mol %) was refluxed at 80 °C in ethanol for 1 hour. The reaction was monitored by TLC and purified by column chromatography using petroleum ether as the eluent. | |
99.6 %Chromat. | With erbium trifluoromethanesulfonate In neat (no solvent) at 60℃; for 0.116667h; Microwave irradiation; Green chemistry; | 3.2. General Procedure for the Synthesis of 1-phenyl-2-Aryl(alkyl) Benzimidazoles 1a-11a General procedure: To the N-phenil-o-phenilendiammine (1 mmol) and Er(OTf)3 (1% mol) in a 3 mL glass,aryl o alkyl aldehyde (1 mmol) was added. The mixture reacted for 5 min in a Synthos3000 microwave instrument, fixed on a temperature value of 60 °C (IR limit). The reactionwas monitored by TLC and GC/MS analyses. After the completion of the conversionof N-phenil-o-phenilendiammine, the Er(OTf)3 was separated from the reaction mixtureby adding water (to separate the catalyst from the reaction mixture) and extracting theorganic product with ethyl acetate (4 3 mL). The products were isolated after its organicphases and was dried over Na2SO4, followed by evaporation under reduced pressure(1a-10a in 91-99% yields). Spectral data were in accordance with the literature [71]. SeeSupplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To <strong>[5773-80-8]6-bromo-2-naphthoic acid</strong> (5.0 g, 20 mmol), were added 20 mL of thionyl chloride (SOCl ), and dimethylformamide (DMF, 1 mL), and the mixture was heated under stirring for 4 hours. An excessive amount of thionyl chloride (SOCl ) is distilled off in vacuo, and to the reaction mixture, were added 20 mL of N-methylpyrrolidine (NMP), and N-phenyl-l,2-diamino benzene (3.7 g, 20 mmol). The mixture was stirred at 160C for 12 hours, and cooled to normal temperature, and an excessive amount of water was added thereto to form a solid. The solid was filtered, washed with water and then ethanol, and dried to prepare a compound L-I (6.2 g, yield 78 %).[216] MS [M+H]+ = 399 | |
78% | Thionyl chloride (SOC12) (20 mL) and dimethylformamide (DMF) (1 mL) were put into <strong>[5773-80-8]6-bromo-2-naphthoic acid</strong> (5.0 g, 20 mmol), and agitated and refluxed for 4 hours. After an excessive amount of thionyl chloride (SOC12) was removed by the vacuum distillation, N-methylpyrolidyne (NMP) (20 mL), and N-phenyl-1,2-diaminobenzene (3.7 g, 20 mmol) were put into the reaction mixture and agitated at 160C for 12 hours. The temperature was lowered to normal temperature, and an excessive amount of water was added thereto to form a solid. It was filtered, washed with water and ethanol, and dried to prepare the compound B-18 (6.2 g, 78%). MS:[M]+=399 | |
78% | PREPARATION EXAMPLE II-9 Preparation of Compound B-9 (0096) (0097) To <strong>[5773-80-8]6-bromo-2-naphthoic acid</strong> (5.0 g, 20 mmol), 20 mL of thionyl chloride (SOCl2), and dimethylformaldehyde (DMF, 1 mL) were added, and the mixture was stirred under heating for 4 hours. An excessive amount of thionyl chloride (SOCl2) was distilled off in vacuum, and then to the reaction mixture, 20 mL of N-methylpyrrolidine (NMP), and N-phenyl-1,2-diaminobenzene (3.7 g, 20 mmol) were added, and the mixture was stirred at 160 C. for 12 hours. The mixture was cooled to ambient temperature, and then an excessive amount of water was added thereto to form a solid. The solid was filtered, washed with water and then ethanol, and dried to prepare a compound B-9 (6.2 g, yield 78%). (0098) MS [M+H]+=399 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With polyphosphoric acid at 180℃; | 1.2.1 Example 1.2.1; [0081] A mixture of 4-hydroxy lbipheny 1-1 -carboxylic acid (2.14 g, 10 mmol) and N-phenyl-l,2-diaminobenzene (1.84 g, 10 mmol) in polyphosphoric acid (10 ml) was degassed by vacuum then heated at 1800C at 10 torr overnight. After cooling to room temperature, the mixture was poured into water. Filtration and washing with water gave a dark solid (6.8 g, 84%) as the desired product (Compound 4), which was confirmed by LCMS (calculated for C25H18N2O4P (M-H): 441, found m/e: 441). |
53% | With polyphosphoric acid at 180℃; | 1.2.1 Example 1.2.1 A mixture of 4-hydroxylbiphenyl-1-carboxylic acid (2.14 g, 10 mmol) and N-phenyl-1,2-diaminobenzene (1.84 g, 10 mmol) in polyphosphoric acid (10 ml) was degassed by vacuum then heated at 180° C. at 10 torr overnight. After cooling to room temperature, the mixture was poured into water. Filtration and washing with water gave a dark solid (6.8 g, 84%) as the desired product (Compound 4), which was confirmed by LCMS (calculated for C25H18N2O4P (M-H): 441, found m/e: 441). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Compound 1 (Ge, Z.; Hayakawa, T.; Ando, S.; Ueda, M.; Akiike, T.; Miyamoto, H.; Kajita, T.; Kakimoto, M. Chem. Mater. 2008, 20(7), 2532-2537) was prepared as follows: to a chilled (ca. 0 C.), stirring solution of N-phenyl-o-phenylene-1,2-diamine (21.41 g, 116.2 mmol) in anhydrous dichloromethane (CH2Cl2) (575 mL) was added 4-bromobenzoyl chloride (25.00 g, 113.9 mmol) portion-wise, followed by dropwise addition of triethylamine (Et3N) (31.8 mL). The reaction was allowed to warm to room temperature and stirring continued until TLC (SiO2, 4:1 hexanes-ethyl acetate) indicated consumption of the starting material. Upon completion, the reaction was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude was then dissolved in anhydrous 1,4-dioxane (500 mL) and heated to about 80 C. Upon completely dissolving, phosphorus oxychloride (31.2 mL, 335 mmol) was added to the solution slowly via syringe and the reaction then maintained at about 115 C. Upon completion (ca. 1 h), the solution was cooled to room temperature (RT) and poured over CH2Cl2 (ca. 3 L) and washed with brine. The organics were then dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by recrystallization from CH2Cl2 and hexanes provided Compound 1 (37.5 g, 94%) as an off-white solid: confirmed by LCMS (APCI): calculated for C19H13BrN2 (M+): 349; Found: 349. | |
81.6% | In 1-methyl-pyrrolidin-2-one; at 160℃;Inert atmosphere; | Weigh 10.95g p-bromobenzoyl chloride,9.15g o-aminodiphenylamine dissolved in 200ML of NMP,After filling and releasing nitrogen 3 times,Set the temperature to 160,Start the reaction; after the reaction,Cool down to room temperature,A large amount of gray solid precipitated after being poured into water,filter,The filter cake was slurried with methanol to obtain 14.2g of brown-gray solid powder,The yield was 81.6% and HPLC was 98.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 20℃; Cooling with water bath; | 2 [0078] 2-bromo-N-(2-(phenyIamino)phenyl)benzamide (5): To a solution of N-phenylbenzene-l,2-diamine (6.08g, 30 mmol) in anhydrous dichloromethane (-100 mL), was added 2-bromobenzoylchloride (6.585 g, 33 mmol), followed by triethylamine (7.0 mL, 50 mmol) slowly with water bath cooling. After the additions, the whole was stirred at room temperature overnight. The resulting mixture was poured into water (-150 mL) and extracted with dichloromethane (-100 mL) twice. The organic phase was collected, dried over Na2S04, concentrated and recrystallized in dichloromethane/hexanes to give a white solid (10.7 g, in 92% yield). |
92% | With triethylamine In dichloromethane | 2 Synthesis of Host-2, Host-3 Example 2 Synthesis of Host-2, Host-3 2-bromo-N-(2-(phenylamino)phenyl)benzamide (5): To a solution of N-phenylbenzene-1,2-diamine (6.08 g, 30 mmol) in anhydrous dichloromethane (~100 mL), was added 2-bromobenzoylchloride (6.585 g, 33 mmol), followed by triethylamine (7.0 mL, 50 mmol) slowly with water bath cooling. After the additions, the whole was stirred at room temperature overnight. The resulting mixture was poured into water (~150 mL) and extracted with dichloromethane (~100 mL) twice. The organic phase was collected, dried over Na2SO4, concentrated and recrystallized in dichloromethane/hexanes to give a white solid (10.7 g, in 92% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dimethyl sulfoxide; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 0 - 25℃; for 4h; Inert atmosphere; chemoselective reaction; | General procedure for the one-pot synthesis of benzimidazoles and benzothiazoles: General procedure: to a solution of alcohol (1.1 mmol) in a mixture of solvents ethyl acetate (4 mL) and DMSO (2 mL), was added T3P (2 mmol, 50% solution in ethyl acetate) at 0 °C and the resulting reaction mixture was stirred at room temperature for 1-2 h under nitrogen atmosphere. The reaction was monitored by TLC, 1,2-phenylenediamine (1 mmol) was added and stirred further for 1-2 h. After completion of the reaction, the mixture was diluted with water (20 mL) and neutralized with 10% NaHCO3 solution. The product was extracted with ethyl acetate (10 mL) and the combined organic phase was washed with water (10 mL) and brine solution. The organic phase was dried over anhydrous Na2SO4. The solvent was dried under reduced pressure to afford a crude product, which was purified on silica gel using ethyl acetate and petroleum ether. For the conversion of alcohols to benzothiazoles the same procedure as above was followed except the use of o-aminothiophenol, instead of 1,2-phenylenediamine. |
98 %Chromat. | With Pt-TiO2 at 32℃; for 4h; UV-irradiation; Inert atmosphere; | The photocatalytic and catalytic synthesis was carried out using the following procedure. Appropriate amounts of catalyst and 2-nitrodiphenylamine or 2-aminodiphenylamine in 25 mL of alcohol were taken in a reaction tube. The reaction tube was sealed with a rubber septum and purged with nitrogen for 30 min. The reaction mixture was irradiated with UV (365 nm) medium-pressure mercury lamp (Sankyo Denki, Japan; intensity I = 1.381 × 10-6 einstein L-1 s-1)/ solar light at constant stirring. The temperature of the reaction medium during UV irradiation was 32 °C and it was nearly constant. With solar light, the temperature of the solution changed gradually from 32 to 48 °C for all the experiments. The progress of the reaction was monitored using thin layer chromatography (TLC). Product analysis was performed by GC analysis, Perkin-Elmer GC-9000 with a capillary column of DB-5 and flame ionization detector was used. GC-MS analysis was carried out using Varian 2000 Thermo with the following features: capillary column VF5MS (5% phenyl-95% methylpolysiloxane), 30 m length, 0.25 mm internal diameter, 0.25 μm film thickness, temperature of column range from 50-280 °C (10 °C/min) and injector temperature 250 °C, attached with mass spectrometer model SSQ 7000. The isolation was performed by column chromatography on a silica gel column by eluting with a co-solvent of dichloromethane and methanol (volume ratio: 8:2). For solar experiments, all reactions have been carried out under similar conditions on sunny days of different months of 2008-2009 between 10 A.M. and 2 P.M. The intensity of solar light was measured using a LT Lutron LX-10/A digital Lux meter and it was found to be 1250 × 100 (+/-100) lux. The intensity was nearly constant during the experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | |
73% | With disodium metabisulfite In N,N-dimethyl-formamide at 100℃; for 0.1h; Microwave irradiation; | |
70% | With disodium metabisulfite In N,N-dimethyl-formamide at 150℃; for 3h; |
25% | In 2-(2-methoxyethoxy)ethyl alcohol at 160℃; for 3h; Microwave irradiation; Inert atmosphere; | Preparation of 2-(1-phenyl-1H-benzoimidazol-2-yl)phenol (HBIZ) A mixture of N-phenylbenzene-1,2-diamine (0.92 g, 5 mmol) and 2-hydroxybenzaldehyde (0.61 g, 5 mmol) in 2-(2-methoxyethoxy)ethanol (10 mL) was microwave heated at 160 °C for 3 h under N2[24]. The reaction mixture was cooled to room temperature, and poured into water (200 mL), then filtered. The residue was redissolved in dichloromethane and purified by column chromatography on silica gel with dichloromethane as eluent. Further recrystallization from hexane-dichloromethane (v/v = 1:1) afforded 0.35 g of white crystals (25% yield). 1H NMR (500 MHz, DMSO-d6, δH, ppm): 6.56 (t, 1H), 6.88 (dd, 1H), 7.14 (t, 2H), 7.28 (m, 2H), 7.39 (t, 1H), 7.45 (m, 2H), 7.64 (m, 3H), 7.85 (d, 1H). Anal. Calc. for HBIZ·1.3H2O(C19H16.6N2O2.3): C, 73.68; H, 5.36; N, 9.04. Found: C, 73.24; H, 5.63; N, 9.14%. |
With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | 2.5.General procedure for the catalytic synthesis of benzimidazolederivatives (1-6) General procedure: A mixture of corresponding aldehyde (1 mmol1 (1 mmol), ammonium acetate (2.5 mmol) and cobalt hydroxide (II) (10 or 15mol %) was refluxed at 80 °C in ethanol for 1 hour. The reaction was monitored by TLC and purified by column chromatography using petroleum ether as the eluent. | |
96.3 %Chromat. | With erbium trifluoromethanesulfonate In neat (no solvent) at 60℃; for 0.166667h; Microwave irradiation; Green chemistry; | 3.2. General Procedure for the Synthesis of 1-phenyl-2-Aryl(alkyl) Benzimidazoles 1a-11a General procedure: To the N-phenil-o-phenilendiammine (1 mmol) and Er(OTf)3 (1% mol) in a 3 mL glass,aryl o alkyl aldehyde (1 mmol) was added. The mixture reacted for 5 min in a Synthos3000 microwave instrument, fixed on a temperature value of 60 °C (IR limit). The reactionwas monitored by TLC and GC/MS analyses. After the completion of the conversionof N-phenil-o-phenilendiammine, the Er(OTf)3 was separated from the reaction mixtureby adding water (to separate the catalyst from the reaction mixture) and extracting theorganic product with ethyl acetate (4 3 mL). The products were isolated after its organicphases and was dried over Na2SO4, followed by evaporation under reduced pressure(1a-10a in 91-99% yields). Spectral data were in accordance with the literature [71]. SeeSupplementary Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dimethyl sulfoxide; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 0 - 25℃; for 3h; Inert atmosphere; chemoselective reaction; | General procedure for the one-pot synthesis of benzimidazoles and benzothiazoles: General procedure: to a solution of alcohol (1.1 mmol) in a mixture of solvents ethyl acetate (4 mL) and DMSO (2 mL), was added T3P (2 mmol, 50% solution in ethyl acetate) at 0 °C and the resulting reaction mixture was stirred at room temperature for 1-2 h under nitrogen atmosphere. The reaction was monitored by TLC, 1,2-phenylenediamine (1 mmol) was added and stirred further for 1-2 h. After completion of the reaction, the mixture was diluted with water (20 mL) and neutralized with 10% NaHCO3 solution. The product was extracted with ethyl acetate (10 mL) and the combined organic phase was washed with water (10 mL) and brine solution. The organic phase was dried over anhydrous Na2SO4. The solvent was dried under reduced pressure to afford a crude product, which was purified on silica gel using ethyl acetate and petroleum ether. For the conversion of alcohols to benzothiazoles the same procedure as above was followed except the use of o-aminothiophenol, instead of 1,2-phenylenediamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In dichloromethane at 20℃; | 1.1.1 Example 1.1.1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (1): To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 1 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300 ml) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 1 (10.6 g). Total amount of product 1 is 17.1 g, in 93% yield. |
93% | With triethylamine In dichloromethane at 20℃; | 1.1.1 Example 1.1.1N-phenylbenzene- 1 ,2-diamine4-bro1[0042] 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (1): To a solution of 4- bromo-benzoyl chloride (l lg, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was added N-phenylbenzene- 1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 1 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300ml) three times. The organic phase was collected and dried over MgS04, concentrated and recrystallized in DCM/hexanes to give another portion of white solid 1 (10.6 g). Total amount of product 1 is 17.1 g, in 93% yield.Exam le 1.1.2 |
93% | With triethylamine In dichloromethane at 20℃; | 1.1.1 4-Bromo-N-(2-(phenylamino)phenyl)benzamide (1) To a solution of 4-bromo-benzoyl chloride (11 g, 50 mmol) in anhydrous dichloromethane (DCM) (100 ml), was addedN-phenylbenzene-1,2-diamine (10.2 g, 55 mmol), then triethylamine (TEA) (17 ml, 122 mmol) slowly. The whole was stirred at room temperature (RT) overnight. Filtration gave a white solid 1 (6.5 g). The filtrate was worked up with water (300 ml), then extracted with DCM (300 ml) three times. The organic phase was collected and dried over MgSO4, concentrated and recrystallized in DCMlhexanes to give another portion of white solid 1(10.6 g). Total amount of product 1 is 17.1 g, in 93% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 3-bromobenzoyl chloride; N-phenyl-1,2-benzenediamine With triethylamine In dichloromethane at 20℃; for 23h; Stage #2: With trichlorophosphate In 1,4-dioxane at 75 - 115℃; for 2h; | 1.1.1 2-(3-bromophenyl)-1-phenyl-1H-benzo[d]imidazole (1) Compound 1 was prepared as follows: to a stirring solution of N-phenyl-o-phenylene-1,2-diamine (4.470 g, 24.26 mmol) in anhydrous CH2Cl2 (116 mL) was added 3-bromobenzoyl chloride (3.14 mL, 23.8 mmol) dropwise via syringe, followed by dropwise addition of triethylamine (Et3N) (6.78 mL). Stirring was continued at room temperature (RT) until thin layer chromatography (TLC) (SiO2, 4:1 hexanes-ethyl acetate) indicated consumption of the starting material (23 h.). The reaction was then washed with saturated NaHCO3, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude intermediate was then dissolved in anhydrous 1,4-dioxane (105 mL) and heated to 75° C. Upon completely dissolving, phosphorus oxychloride (6.70 mL, 69.9 mmol) was added to the solution slowly via syringe and the reaction then maintained at 115° C. Upon completion (2 h.), the solution was cooled to RT and poured over a mixture of ethyl acetate (about 500 mL) and water (about 400 mL). The organics were then washed with saturated NaHCO3, H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by flash chromatography (SiO2, 9:1 hexanes-acetone) provided compound 1 (8.30 g, 99%) as an off-white solid. |
96% | With triethylamine; trichlorophosphate In 1,4-dioxane; dichloromethane; water | 4 Synthesis of Host-5 Example 4 Synthesis of Host-5 2-(3-bromophenyl)-1-phenyl-1H-benzo[d]imidazole (13). To a stirring solution of N-phenyl-o-phenylene-1,2-diamine (0.967 g, 5.25 mmol) in anhydrous CH2Cl2 (25 mL) was added 3-bromobenzoyl chloride (0.66 mL, 5 mmol) dropwise via syringe, followed by dropwise addition of Et3N (1.4 mL). Stirring was continued at room temperature until TLC (SiO2, 4:1 hexanes-ethyl acetate) indicated consumption of the starting material (19 h). The reaction was then poured over water (~300 mL) and extracted with CH2Cl2 (3*~40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude intermediate was then dissolved in anhydrous 1,4-dioxane (~22 mL) and heated to about 115° C. Upon completely dissolving, phosphorus oxychloride (1.37 mL, 15 mmol) was added to the solution slowly via syringe and the reaction maintained at about 115° C. Upon completion (~2 h), the reaction was cooled to room temperature and poured over CH2Cl2 (~150 mL). The combined organics were then washed with saturated NaHCO3, H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 4:1 hexanes-acetone) to afford 13 (1.68 g, 96%) as a light yellow solid. |
78.6% | In 1-methyl-pyrrolidin-2-one at 160℃; Inert atmosphere; | 1 Synthesis of TM-9: Similar to TM-8 synthesis steps,Weigh 10.95g of m-bromobenzoyl chloride,9.15g o-aminodiphenylamine dissolved in 200ML of NMP,After filling and releasing nitrogen 3 times,Set the temperature to 160,Start reactionAfter the reaction,Cool down to room temperature,A large amount of gray solid precipitated after being poured into water,After filtering, the filter cake was slurried with methanol to obtain 13.2g of brown-gray solid powder,The yield is 78.6%, HPLC 98.5%. |
Stage #1: 3-bromobenzoyl chloride; N-phenyl-1,2-benzenediamine With triethylamine In tetrahydrofuran at 20℃; for 24h; Stage #2: With acetic acid In tetrahydrofuran at 110℃; for 12h; | ||
Stage #1: 3-bromobenzoyl chloride; N-phenyl-1,2-benzenediamine In N,N-dimethyl acetamide at 20℃; for 1h; Stage #2: With acetic acid at 120℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | [0143] 2-(5-bromopyridin-2-yl)-l-phenyl-lH-benzo[i/]imidazole (13). To a stirring solution of N-phenyl-o-phenylenediamine (2.10 g, 11.4 mmol) in anhydrous CH2CI2 (55 mL) was added <strong>[137178-88-2]5-bromopyridine-2-carbonyl chloride</strong> (2.50 g, 11.3 mmol) portion-wise, followed by drop-wise addition of Et3N (3.16 mL) via syringe. Stirring was continued at RT until TLC (S1O2, 7:3 CH2Cl2-hexanes) indicated no further consumption of the starting material (10 days). The reaction was then poured over water (300 mL) and extracted with CH2CI2 (150 mL). The combined organics were washed with sat. NaHC03, H2O and brine, dried over MgS04, filtered and concentrated. The resulting solid was then partially purified via flash chromatography (S1O2, 17:3 hexanes:EtOAc) to afford the crude intermediate. Anhydrous 1 ,4-dioxane (50 mL) was added to the crude solid and the mixture heated to about 70 C. Upon forming a solution, phosphorus oxychloride (3.11 mL, 33.3 mmol) was added slowly, dropwise via syringe and the reaction maintained at about 115 C. Upon completion (lh), the reaction was cooled to RT, quenched by pipet-wise addition of sat. NaHC03 and poured over CH2CI2 (300 mL). The organic phase was then washed with sat. NaHC(¾ (2x), H2O and brine, dried over MgS04, filtered and concentrated in vacuo. Purification of the crude product via flash chromatography (Si02, 100 % CH2C12 to 19: 1 CH2Cl2-acetone) afforded 13 (2.20 g, 55 %) as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-trimethyl-pyridine at 120 - 130℃; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 20% 2: 3% | With 2,4,6-trimethyl-pyridine at 120 - 140℃; for 120h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With 2,4,6-trimethyl-pyridine at 160℃; for 72h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In ethanol at 20℃; for 1.5h; | 1 4.4. N1-(5-Fluoro-2,4-dinitrophenyl)-N2-(4-substitutedphenyl)benzene-1,2-diamine (30, 31) General procedure: General procedure: 1,5-Difluoro-2,4-dinitrobenzene (10.86 mmol) and TEA (10.94 mmol) were added to a solution of the proper N1-((4-substituted)phenyl)benzene-1,2-diamine (10.86 mmol) in 40 ml of ethanol. The mixture was stirred at rt for 1.5 h. The formed suspension was filtered and the resulting solid washed with ethanol. 4.4.1 N1-(5-Fluoro-2,4-dinitrophenyl)-N2-phenylbenzene-1,2-diamine (30) Yield: 93%. Mp 163.6-164.7 °C (lit. 9 165-167 °C). 1H NMR (CDCl3) δ: 9.60 (br s, 1H, collapsed with D2O); 9.13 (d, 1H, J = 7.70 Hz); 7.36-7.24 (m, 5H); 7.07-6.99 (m, 4H); 6.65 (d, 1H, J = 13.20 Hz); 5.65 (br s, 1H, collapsed with D2O). |
89.9% | With triethylamine In ethanol at 20℃; for 3h; | |
With triethylamine In ethanol at 20℃; for 3h; | 4.1.2. General procedures for synthesis of compounds 6a-h General procedure: To a solution of refined N-(4-clorophenyl)-1,2-benzenediamone (2a, 45.9 mmol) in ethanol (120 mL), DFDNB (1.1 equiv) and TEA (1.1equiv) were added successively, and the mixture was stirred at rtfor 3 h. The formed precipitate was filtered, and the solid waswashed with water (50 mL x 2) and ethanol (60 mL x 2) successivelyto give the intermediate 3a as an orange solid in a 97% yield. |
With triethylamine In ethanol at 20℃; for 3h; | 4.1.2. General procedures for synthesis of compounds 6a-h General procedure: To a solution of refined N-(4-clorophenyl)-1,2-benzenediamone (2a, 45.9 mmol) in ethanol (120 mL), DFDNB (1.1 equiv) and TEA (1.1equiv) were added successively, and the mixture was stirred at rtfor 3 h. The formed precipitate was filtered, and the solid waswashed with water (50 mL x 2) and ethanol (60 mL x 2) successivelyto give the intermediate 3a as an orange solid in a 97% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | |
70% | With sodium metabisulfite In N,N-dimethyl-formamide at 100℃; for 0.1h; Microwave irradiation; | |
50% | With ammonium acetate In ethanol at 80℃; | General procedure for the synthesis of 2-(4-fluorophenyl)-1-phenyl-1H-benzo[d]imidazole A mixture of 4-Fluoro benzaldehyde (1 mmol), N-phenyl-o-phenylenediamine (1 mmol) and ammonium acetate (2.5 mmol) was refluxed at 80 °C in ethanol. The reaction was monitored by TLC and purified by column chromatography using petroleum ether (60-80°) as the eluent. Yield: 50%. mp = 96 °C, Anal. calcd. for C19H13FN2: 1H NMR (400 MHz, CDCl3): δ6.98-7.02 (T, 2H), 7.26-7.36 (m, 4H), 7.50-7.55 (m, 6H), 7.87-7.88 (d, 1H). 13C NMR (100 MHz, CDCl3): δ110.50, 115.44, 115.64, 119.83, 123.13, 123.47, 126.14, 126.18, 127.43, 128.75, 130.01, 131.41, 131.49, 136.84, 137.19, 142.90, 151.47, 162.16, 164.65. MS: m/e 289.17, calcd 289.11 [M+1]. |
32% | In 2-methoxy-ethanol for 30h; Inert atmosphere; Reflux; | |
With ammonium acetate; cobalt(II) hydroxide In ethanol at 80℃; for 1h; | 2.5.General procedure for the catalytic synthesis of benzimidazolederivatives (1-6) General procedure: A mixture of corresponding aldehyde (1 mmol1 (1 mmol), ammonium acetate (2.5 mmol) and cobalt hydroxide (II) (10 or 15mol %) was refluxed at 80 °C in ethanol for 1 hour. The reaction was monitored by TLC and purified by column chromatography using petroleum ether as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium metabisulfite In N,N-dimethyl-formamide at 100℃; for 0.1h; Microwave irradiation; | |
58% | In water for 22h; Inert atmosphere; Reflux; | |
41% | With potassium carbonate; 1-methyl-3-(n-butyl)imidazolium iodide In o-xylene; para-xylene; m-xylene at 120℃; for 10h; Green chemistry; | General procedure B General procedure: Into a 15*150 mm tube was layered 6b 1mmol (184 mg), corresponding aromatic aldehyde (1mmol), NHC precursor G (10 mol%), K2CO3 (25 mol%), the mixture was stirred under pre-heated 120 °C oil-bath for 10 hours, after finished, the solution was transferred into a 25 mL recovery flask, and concentrated under reduced pressure, the residue was applied on flash silica column chromatograph, which afforded the targeted products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bis[1,2-bis(diphenylphosphine)ethane]ruthenium dichloride; hydrogen at 120℃; for 40h; Green chemistry; | |
72% | With 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene at 70℃; for 24h; | |
33% | With diphenylsilane; C33H36BO6(3-)*Eu(3+)*H2O*2C3H7NO In acetonitrile at 120℃; for 24h; Autoclave; |
With N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride In tetrahydrofuran at 70℃; for 24h; Schlenk technique; Inert atmosphere; Glovebox; | 1.A A-Synthesis of Benzimidazole and Derivatives from Aromatic 1,2-Diamines General procedure: A-Synthesis of Benzimidazole and Derivatives from Aromatic 1,2-DiaminesThe first results presented describe the synthesis of benzimidazole rings and derivatives from aromatic 1,2-diamines. In this case, the amine R1NH2 and the nitrogenous nucleophilic agent R5R6NH are two reactive functional groups of one and the same molecule (diamine) and are thus connected via a covalent bond. This bond is preferably an aromatic ring of benzene, pyridine or pyrimidine type and the ring formed during the reaction is a nitrogenous heterocycle comprising 5 atoms of imidazole type. In the case where the nucleophile is oxygen-based (R7OH), the rings obtained are benzoxazoles. The results presented were produced by preferably using two sources of different reducing agents, polymethylhydrosiloxane (PMHS), sold by Aldrich under the reference 176206, and phenylsilane (PhSiH3), sold by Aldrich. In the case of the PMHS, as a silane is a polymer, the number of equivalents introduced is given with respect to the number of hydrides introduced and thus the number of monomers introduced with respect to the amine. Thus, the introduction of 3 equivalents of PMHS corresponds to the introduction of 3 equivalents of hydride and thus 3 equivalents of monomers of the PMHS with respect to the amine. Different (pre)catalysts were tested for the reaction. | |
48 %Spectr. | With tris(2-diphenylphosphinoethyl)phosphine; hydrogen; cobalt(II) fuoride; cesium fluoride In ethanol at 140℃; for 24h; Glovebox; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 90℃; for 48h;Inert atmosphere; | 5-bromoisophenyldialdehyde (2.11 g, 10 mmol)And N1-phenylbenzene-1,2-diamine (4.41 g, 24 mmol) was added to a solution containing Na2S2O5 (3.32 g 20 mmol) in dimethylformamide (DMF).The reaction was carried out at 90 C under inert gas for 48 h. Distilling off DMF under reduced pressure,The obtained residue was purified by column chromatography to give the intermediate product BPBI (3.7 g, yield 68.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 20h; | To a suspension of <strong>[137178-88-2]5-bromopyridine-2-carbonyl chloride</strong> (10.11 g, 46 mmol), N-phenyl-1,2-diaminobenzene (8.46 g, 46 mmol) in anhydrous dichloromethane (DCM) (100 mE), was added triethylamine (TEA) at 0 C. Then the whole was stirred at room temperature (RT) for about 20 hours. The mixture was poured into water, extracted with dichloromethane (100 mEx2). The organic phase was collected, dried over sodium sulfate (Na2504), and passed through a pad of silica gel (hexanes/ethyl acetate 4:1). After removal of solvent, a brown oil was obtained, which was dissolved in dioxane (150 mE), phosphoryl chloride (POd3) (25 mE) was added at 00 C., and the mixture was then heated at about 1000 C. under argon overnight. Then the whole was poured into ice(200 g) after being cooled to RT, then neutralized by sodium carbonate (Na2CO3), and extracted with dichloromethane (DCM) (200 mLx2). The organic phase was dried over Na2SO4, absorbed on silica gel, and purified by a silica gel colunm (hexanes/ethyl acetate 4:1). The desired fraction wascollected, concentrated, and reprecipitated with hexanes. After filtration and being washed with methanol, an off-white crystalline solid (Compound 1) was obtained, 4.02 g, with an overall 25% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride In methanol at 65℃; for 0.75h; | [1][Cl] To acenaphthoquinone (182 mg, 1.0 mmol) in methanol (50 mL), N-phenyl-o-phenylenediamine (184 mg,1.0 mmol) and few drops of concentrated HCl were added successively and the reaction mixture was refluxed for45 min (at 65 °C). The reaction mixture was cooled at room temperature and filtered. The solution was allowed to evaporate slowly at room temperature (25 °C). After a few days, yellow micro crystals of [1][Cl] separated out, which are collected upon filtration and dried in air. Yield: 310 mg (~85 % with respect to acenaphthoquinone). ESI (positive ion)-MS in CH3CN; m/z: 331.20 for [1]+. Anal. Calcd. for C24H15ClN2:C, 78.58; H, 4.12; N, 7.64; Found: C, 78.35; H, 4.15; N, 7.55.1H NMR (CDCl3, 300 MHz, 25 °C) δ (ppm)=9.44 (t, 1H),8.79 (d, 2H), 8.58 (d, 2H), 8.38 (d, 2H), 8.25 (d, 2H), 7.98 (m,3H), 7.62 (t, 2H), 7.32 (t, 1H). IR (KBr, νmax/cm-1)=3422(s),3020(m), 1600(s), 1438(m), 1421(m), 1320(s), 1111(vs),1040(m), 770(s), 598(m), 552(s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In 1-methyl-pyrrolidin-2-one; water at 445℃; for 0.00277778h; Supercritical conditions; | 6 1.44 g of N- [2- (phenylamino) phenyl] benzamide was dissolved in N-methylpyrrolidone (NMP, manufactured by Wako Pure Chemical Industries, for peptide synthesis) to prepare a raw material solution having a concentration of 0.05 M . Water (purified by an ultra pure water apparatus manufactured by Organo Corporation) was brought into a supercritical state at a temperature of 495 ° C. and a pressure of 45 MPa.A raw material solution mixed in a reaction tube and supercritical water were introduced into a reactor having a volume of 0.88 mL, and the chemical reaction represented by the chemical reaction formula (4) was conducted at a temperature of 445 ° C. and a pressure of 45 MPa to obtain benzazoles 1,2-diphenyl-1H-benzo [d] imidazole was synthesized.The time (reaction time) during which the mixture of raw material solution and supercritical water passed through the reactor, that is, the residence time in the reactor was 10 seconds.Further, the total concentration of the raw materials in the reactor (mass of raw material / sum of mass of water and NMP × 100) was 1.44 mass% In the same manner as in Example 1-1, N-phenyl-1,2-benzenediamine (manufactured by Wako Pure Chemical Industries, Ltd.) and 4-methoxybenzoic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) (9) was carried out in supercritical water. As a result, the reaction time was 10 seconds, and the yield was 90%. |
90 %Chromat. | With water In 1-methyl-pyrrolidin-2-one at 445℃; for 0.001075h; Flow reactor; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 3.5h;Cooling with ice; | 2-aminodiphenylamine 20mmol was placed in a three-necked flask. To this was added 25mL of anhydrous dichloromethane and 5mL triethylamine. it was then placed in an ice bath under stirring. <strong>[5555-00-0]2-methyl-3-furoyl chloride</strong> was slowly added dropwise with a constant pressure funnel for 30min. It was then naturally warmed to room temperature. For 3h completion of the reaction. Resulting salt was removed by suction. The combined organic phases were washed with saturated NaHCO3 solution 3 times respectively and washed with water three times. Liquid was separated. Dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to give crude oily liquid. At atmospheric pressure silica gel column (Eluent: petroleum ether: ethyl acetate = 50: 1 (V / V)) to give Compound 1. | |
With triethylamine; In dichloromethane; at 20℃; for 2h; | To a solution of compounds 4a-j (0.02 mol) in triethylamine (5 mL) and dichloromethane (15 mL)in an ice bath, freshly prepared 3-furoyl chloride was added dropwise and theresulting mixture was stirred at room temperature for 2 hours. The mixture wasthen filtered, successively washed with aqueous sodium hydroxide (5%, 3 x 15mL) and water (2 x 15 mL). The organic phase wasthen dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to remove dichloromethane.Finally, the residue was purified by column chromatography to yield the finaltarget compounds 5a-j.4 2-methyl-N-(2-(phenylamino)phenyl)furan-3-carboxamide(5a).Yield, 62.8 %; white solid; mp, 133.8-134.6 ; 1HNMR (400 MHz, DMSO) delta 9.25 (s, 1H), 7.60 - 7.52 (m, 2H), 7.44 (s, 1H), 7.30 (dd, J =8.1, 1.1 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.04 -6.97 (m, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.87 (d, J = 1.7 Hz, 1H), 6.79(t, J = 7.3 Hz, 1H), 2.53 (d, J = 3.3 Hz, 3H). 13C NMR(400 MHz, DMSO): delta 161.70, 156.40, 143.87, 140.53, 136.28, 128.89, 125.75, 125.54, 121.53,120.01, 119.19, 116.05, 109.23, 13.05. ESI MS: m / z 314.98 [M + Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In aq. phosphate buffer; ethanol; water at 24.84℃; Electrolysis; | 2.2. Electroorganic synthesis of 2ADPA dimer (D6) A mixture of water (phosphate buffer, c = 0.2 M, pH 2.0)/ethanol (60/40, v/v), containing 2ADPA (1.0 mmol) was electrolyzed in an undivided cell under controlled potential condition at 0.50 V versus 3.0M Ag/AgCl or galvanostatic method with current density 0.9 mA cm-1. In controlled potential method, the synthesis was terminated when the decay of the current became more than 95%, and in galvanostatic method the synthesis was finished when the consumed charge was 300 C. The process was interrupted during the electrolysis,and the carbon rod anodes were washed in acetone for reactivation. At the end of electrolysis, the cell was placed in arefrigerator overnight. The precipitated solid was collected by filtration,washed copiously with distilled water and recrystallized from EtOH. Pink solid; mp 162-164 °C; Isolated yield: 95%; FT-IR (KBr) (cm-1): 3363-3370 (medium, stretching N-H); 1H NMR, δ ppm (500 MHz in CDCl3): 5.33 (brs, 3H, NH, disappeared by addition of D2O), 6.54 (s, 2H, Ar-H), 6.75 (s, 2H, Ar-H), 6.89 (s, 1H, Ar-H), 7.13-7.25 (m, 6H, Ar-H), 7.46-7.53 (m, 3H, Ar-H) 7.74 (s, 1H,Ar-H); 13C NMR, δ ppm (125 MHz in CDCl3): 115.9, 118.1, 119.3,120.3, 122.5, 127.7, 129.6, 129.9, 133.2, 134.2, 136.9, 138.3, 142.3,142.9; Anal. Calcd.for C24H18N4 (362.15): C, 79.54; H, 5.01; N, 15.46. Found: C, 79.51; H, 5.11; N, 15.57; MS (EI) m/z (%): 361 [(M-1), 100]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 110℃; for 7h; | General Procedure General procedure: In a 25 mL round bottom flask equipped with a magnetic stir bar, The 2-methylquinoline (80 mg, 0.56 mmol) was dissolved in DMSO (4 mL) and molecular iodine (20 mol%)) was added and heated at 110 °C for 1 h. Next, o-phenylenediamine (0.56 mmol) was added and the resulting solution stirred continuous for 7 h. After this time, the reaction mixture was cooled to room temperature, quenched with saturated solution of Na2S2O3 (20 mL) and the reaction was extracted with ethyl acetate (3x 20 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using Petroleum ether as eluent to provide 3a-u and 5a-g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.8% | Stage #1: 3,5-dibromobenzoic acid With thionyl chloride for 4h; Reflux; Inert atmosphere; Stage #2: N-phenyl-1,2-benzenediamine With triethylamine In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; Stage #3: With acetic acid for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With cyclopentyl methyl ether; dihydrogen peroxide; oxygen In water monomer at 50℃; Sealed tube; | |
94% | With CotA-laccase In aq. phosphate buffer at 20℃; for 2h; Enzymatic reaction; | |
91% | With Eosin In methanol; aq. phosphate buffer at 20℃; for 12h; Irradiation; |
82% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetra-n-butylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 5h; Electrochemical reaction; Green chemistry; | |
With hydrogenchloride; ferric(III) chloride; acetic acid In water monomer | ||
Multi-step reaction with 4 steps 1: triethylamine / ethanol / 3 h / 20 °C 2: triethylamine / tetrahydrofuran / Heating 3: zinc powder; acetic acid / ethanol / 20 °C 4: air / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 140℃; for 10h; | K Synthesis of N-biphenyl-4-yl-N'-phenyl-1,2-benzenediamine To 660 mL of degassed toluene are added 0.35 g (1.58 mmol) of Pd(OAc)2 and 4.8 mL (4.86 mmol) of tri-tert-butylphosphine (1M solution in toluene), and the mixture is stirred for 5 min. Then 37.2 g (160 mmol) of 4-bromobiphenyl, 29.4 g (160 mmol) of N-phenyl-o-phenylenediamine and 22.4 g (233 mmol) of sodium Cert-butoxide are added to the solution, which is then degassed and stirred at 140° C. under a protective gas atmosphere for 10 h. After cooling, 200 mL of NH4Cl solution and 50 mL of ethyl acetate are added to the solution, and the phases are separated, washed with water, dried over MgSO4 and concentrated. The solids are dissolved in toluene and the mixture is filtered through Celite. The crude product is stirred with hot heptane and washed with MeOH. This gives 47 g (140 mmol) of a crystalline solid. The overall yield is 80%. |
80% | With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 140℃; for 10h; Inert atmosphere; | D Example d: Synthesis of N-biphenyl-4-yl-N’-phenyl-l ,2-phenyldiamine 0.35 g (1.58 mmol) of Pd(OAc)2 and 4.8 ml (4.86 mmol) of tri-tertbutylphosphine (1 M solution in toluene) are added to 660 mL of degassed toluene and the mixture is stirred during 5 minutes. Then, the solution istreated with 37.2 g (160 mmol) 4-bromobiphenyl, 29,4g (160 mmol) of Nphenyl-o-phenylenediamine and 22.4 g (233 mmol) of sodium tert-butoxide, the mixture is then degassed and stirred under an inert gas at 140 00 for1 Oh. After cooling, the solution is mixed with 200 ml of a NH4CI solution and50 ml of ethyl acetate, the phases are separated, washed with water, driedover MgSO4 and concentrated. The solid is dissolved in toluene and filtered through Celite. The crude product is stirred with hot heptane and washed with MeOH. This gives 47 g (140 mmol) of a crystalline solid. The yield is 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.8 g | In a three-necked flask equipped with a water separator, a thermometer, a condenser, and a stirring device, 30 g of refined waste oil, 43.5 g of N-phenyl o-phenylenediamine, and 80 ml of xylene were added, and nitrogen was introduced, and the mixture was slowly heated to reflux at 140C. 6.5h, 190 ~ 200mmHg, vacuum distillation 2.5 ~ 3h, then under 20 ~ 25mmHg, vacuum distillation 1 ~ 2h, until no liquid outflow After cooling, add 120ml of 10% NaCl aqueous solution to the mixture and mix well, heat the mixture to 80C and insulate1h, cooling, standing for 1.5h, separating the upper oily substance with a separatory funnel, washing twice with water, separating the aqueous layer, and drying the oil phase in vacuum Dry to give an oil-soluble fat-based N-phenyl benzimidazolide cream solid corrosion inhibitor weighing 49.8 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.5% | With triethylamine; In dichloromethane; at 0℃;Inert atmosphere; | Dissolve <strong>[87700-60-5]6-bromo-2-naphthoyl chloride</strong> (Compound 1) (5.36 g, 19.91 mmol) and o-amino diphenylamine (3.0 g, 16.59 mmol) in a mixed solvent of dichloromethane and triethylamine (50 ml, 4: 1v/v), stirring reaction in ice bath under N2 atmosphere for 10~12 hours,After the reaction is completed, dichloromethane and triethylamine are distilled off under reduced pressure, dissolved in dichloromethane, distilled water is added and extracted with dichloromethane.The resulting organic layer was dried over anhydrous magnesium sulfate and filtered. Dichloromethane was distilled off under reduced pressure, and the resulting crude product was recrystallized from ethanol.The solid was suction-filtered to give 6-bromo-N-(2-(phenylamino)phenyl)-2-naphthalenecarboxamide (Compound 2) as a white solid in 54.5% yield (3.7 g); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium t-butanolate; In toluene; for 5h;Reflux; Inert atmosphere; | 14.3 g of N-phenyl-1,2-diaminobenzene (77.5 mmol), 30.0 g (77.5 mol) of <strong>[58536-46-2]4-(4-bromophenyl)-2,6-diphenylpyrimidine</strong>, 3.2 g (3.9 mmol) of 1,1-bis-(diphenylphosphino)ferrocenepalladium(II) dichloride complex with dichloromethane, and 23 g of sodium tert-butoxide (232 mmol) are heated at the boil for 5 h in 300 ml of toluene under protective atmosphere. The mixture is subsequently partitioned between toluene and water, the organic phase is washed three times with water and dried over Na2SO4 and evaporated in a rotary evaporator. The residue remaining is recrystallised from heptane/toluene. The yield is 27.0 g (71% of theory). 23.6 g (48.0 mmol) of the diaminobenzene derivative are dissolved in 500 ml of toluene, 27.1 ml (192 mmol) of triethylamine are added, and the mixture is subsequently cooled to 0 C. 50 ml of a 1M solution of dibromo-(phenyl)borane (50 mmol) in toluene are slowly added dropwise to the reaction mixture at 0 C. with stirring. The reaction mixture is warmed to room temperature over a period of 30 min. After cooling of the reaction mixture, 600 ml of ethanol are added dropwise. The precipitated solid is recrystallised from toluene and subsequently sublimed. Yield: 20.2 g (73% of theory, purity >99.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride; sodium chloride; In water; at 320℃; for 0.0833333h; | Take 27 mmol (1.6 g) NaCl, 0.275 mmol (57.8 mg) of 2,3-diaminophenazine (10% excess), 0.25 mmo (46.1 mg) of N-phenyl-o-phenylenediamine in a mortar and mix After adding 150 muL of concentrated hydrochloric acid, fully grind to dry; then loadThe small test tube was reacted at 320 C for 5 min; the obtained crude product was dispersed in dilute sulfuric acid, boiled, filtered, washed with water, and dried to obtain 70 mg of a purple-black solid, which was 5-phenyl-12-hydro-5,7,12,14- Tetraaza pentacene, yield 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride; sodium chloride; In water; at 320℃; for 0.08333330000000001h; | Take 27 mmol (1.6 g) NaCl, 0.25 mmol (52.8 mg) of <strong>[4569-77-1]2-amino-3-hydroxyphenazine</strong>, 0.3 mmol (55.3 mg) of N-phenyl-o-phenylenediamine (20% excess) in a milled crucible. After mixing, 150 muL of concentrated hydrochloric acid was added, and the mixture was thoroughly ground to dryness, placed in a small test tube, and reacted at 320 C for 5 minutes. The crude product was dispersed in dilute sulfuric acid, boiled, filtered, and washed with water to obtain 72 mg of a purple-black solid which was 5-phenyl-12-hydro-5,7,12,14-tetraazapentacene in a yield of 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium thiosulfate; In water; N,N-dimethyl-formamide; at 90℃;Cooling with ice; | Phenyl o-phenylenediamine (5.24 g, 48 mmol) p-hydroxypyridinecarboxaldehyde (4.37 g, 40 mmol) was dissolved in DMF, respectively, and an aqueous solution of sodium thiosulfate (7.92 g, 40 mmol) was added in an ice bath, and heated to 90 C in an oil bath. The reaction was overnight. The reaction is over and will be reversedThe product was poured into water to give the product A4 in a yield of 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 130℃; for 15h; Inert atmosphere; | 4 Synthesis of intermediate M70-1 Add 39.6g (100mmol) 9- (3-bromophenyl) -9-phenyl-9H-fluorene and 12.2g (100mmol) o-hydroxybenzaldehyde to a freshly dried 1000mL double-necked bottle under nitrogen protection Add 20.7 g (150 mmol) of anhydrous potassium carbonate and 600 mL of dry N, N-dimethylformamide (DMF), stir at room temperature for 5 hours, then heat to 130 ° C and continue the reaction for 10 h. After the reaction, the temperature was lowered to room temperature, and the solvent of the reaction system was distilled off under reduced pressure. The crude product was dissolved in 500 mL of dichloromethane and washed with a large amount of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. Dichloromethane: petroleum ether = 1: 3 was used as the eluent for column chromatography to obtain 40 g of off-white solid with a yield of 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With ammonium acetate; water at 140℃; for 10h; Inert atmosphere; Schlenk technique; | |
86% | With ammonium acetate In water at 140℃; for 11h; Schlenk technique; Inert atmosphere; | 12 Add N-phenyl o-phenylenediamine (0.2 mmol), dimethyl sulfoxide (2 mL), ammonium acetate (1.2 mmol), and water (80 ul) into the dry Schlenk reaction tube in sequence. After the sample is added After evacuating with an oil pump, nitrogen was injected for gas replacement. After three replacements, the reaction was stopped at 140°C for 11 hours and then cooled to room temperature. The reaction is detected by thin layer chromatography (TLC). After the reaction of the raw materials is completed, the reaction is terminated, and the mixture in the reaction tube is cooled to room temperature. Preliminary treatment of the mixed solution: extraction, collecting the organic layer, spinning powder, and performing column chromatography to obtain the target product with a yield of 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 1,3-dimethylalloxan; oxygen In 2,2,2-trifluoroethanol at 25℃; for 4h; | 5. The general procedure for alloxan-catalyzed intramolecularredox reaction with O2 General procedure: General procedure: Under molecular oxygen (1 atm, balloon), aldehyde (3 or 3'b-3'f:2 equiv, 0.1 mmol; 3'a: 1.2 equiv, 0.06 mmol) and catalyst 1a (20 mol%, 0.01 mmol) were added in turn to o-phenylenediamines (2' or 2) (1 equiv, 0.05 mmol) in TFEA (1mL) at 25 °C. The resulting mixture was stirred intensely at 25 °C for 2 h, then directly purified by preparative TLC or flash column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With acetic acid In ethanol at 20℃; for 2h; | Synthesis of Schiff-base chemosensor, NNP An ethanolic solution (20mL) containing 2-hydroxy-1-naphthaldehyde (0.05mol, 0.344g) was added slowly to a stirring ethanolic solution (20mL) of N-phenyl-o-phenylenediamine (0.05mol, 0.368g) (1:1 ratio). Three drops of acetic acid were added to the resulting mixture followed by refluxing for 2h and then allowed it cool to room temperature. The obtained red colored poly crystals (Fig.S1) were filtered and then washed with ethanol several times. Scheme 1 illustrates the synthetic route for the preparation of NNP.NNP Ligand: Yield: 90%, Color: Red, m.p: 160°C; ESI-MS (m/z): 339; Anal. Calc. for C23H18N2O: C, 81.63; H, 5.36; N, 8.28; Found (%):C, 81.60; H, 5.34; N, 8.25; 1H NMR(CDCl3): δ 14.98 (s, 1H), 8.19 (s, 1H), 9.49 (s, 1H), 6.16 (s, 2H), 7.8 (d, 6H), 7.4 (t, 7H); FT-IR (KBr, cm-1): ν 1602 (-CH=N-), 566 (bend, -NH), 3490 (stretch, -NH), 3449 (stretch-OH), 1384 (bend-OH), 1238 (stretch, -CO), 3042 (stretch-CH), 739 (bend-CH).UV-vis (THF, λmax/nm, ε/M-1cm-1)): 245 (136626), 290(106989) and 415(58942). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic acid; In ethanol; at 50℃; for 3h; | A swirling ethanolic solution (20 mL) of N-phenyl-o-phenylenediamine(0.1 mol, 0.368 g) was added dropwise to an ethanolic solution(20 mL) containing <strong>[2631-77-8]3,5-diiodosalicylaldehyde</strong> (0.1 mol, 0.42 g). Theresulting dark brown solution in which 3 drops of acetic acid were addedwas refluxed for three hours at 50 C. After the completion of reaction,dark red coloured polycrystals were formed, which was filtered andwashed with hot ethanol. The synthetic route for the preparation of thechemosensor ISNP is depicted as shown in Scheme 1.Chemosensor ISNP: Yield: 85%, Colour: Dark red, m.p: 160 C; ESIMS(m/z) (Fig. S1): 540; Anal. Calc. (%) for C19H14I2N2O: C, 42.25; H,2.61; N, 5.19; Found (%):C, 42.20; H, 2.55; N, 5.15; 1H NMR (CDCl3)(Fig. S2): 14.07 (s, 1H), 8.11 (s, 1H), 8.48 (s, 1H), 6.1 (s, 2H), 7.0 (d,4H), 7.3 (t, 5H); FT-IR (KBr, cm 1) (Fig. S3): 1610 (-CH = N-), 590(bend, -NH), 3310 (stretch, -NH), 3540 (stretch-OH), 1340 (bend-OH),1217 (stretch, -CO), 3048 (stretch-CH), 743 (bend-CH), 558 (C-I).UV-vis (THF, max/nm (/M 1cm 1)) (Fig. S4): 245 (65519), 290(54657), 360 (18458) and 415 (19046) [28,29]. |
[ 3213-79-4 ]
N1,N2-Dimethylbenzene-1,2-diamine
Similarity: 0.93
[ 25148-68-9 ]
N-Methyl-1,2-benzenediamine dihydrochloride
Similarity: 0.90
[ 28458-68-6 ]
N1-(tert-Butyl)benzene-1,2-diamine
Similarity: 0.88
[ 3213-79-4 ]
N1,N2-Dimethylbenzene-1,2-diamine
Similarity: 0.93
[ 25148-68-9 ]
N-Methyl-1,2-benzenediamine dihydrochloride
Similarity: 0.90
[ 28458-68-6 ]
N1-(tert-Butyl)benzene-1,2-diamine
Similarity: 0.88
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P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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