* 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.
Step A: 2-Chloro-4-methyl-l -benzo[d]imidazole To 4-methyl-lH-benzo[d]imidazol-2(3H)-one (1.5 g, 10 mmol) was added POCb (19 ml, 200 mmol) and the reaction mixture was heated to 135 °C for 3 hours. The reaction was then cooled to room temperature and the excess POCb was removed in vacuo. The solid residue was diluted carefully with water and then slowly neutralized with saturated NaHCC until the pH was ~7-8. The mixture was extracted with ethyl acetate (2 x 150 mL) and the organics extracts were combined. The organics were dried with MgS04, filtered, and the solvent was removed to yield the crude residue. The crude material was purified by chromatography (Biotage) to yield 2-chloro-7-methyl-lH- benzo[d]imidazole (1.1 g, 6.3 mmol, 62 percent yield) as a slightly yellow powder. MS (LC/MS) R.T. = 2.61 ; [M+]+ = 166.93
Reference：
[1] Patent: WO2016/73407, 2016, A1, . Location in patent: Page/Page column 56
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7188 - 7211
[3] Patent: US5273975, 1993, A,
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5010 - 5014
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
2
[ 19190-68-2 ]
[ 15965-57-8 ]
Yield
Reaction Conditions
Operation in experiment
93%
for 20 h; Heating / reflux
2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 ml of phosphoryl chloride are introduced into a 250 ml two-necked flask under an argon atmosphere, equipped with a magnetic stirrer. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 ml), the mixture is neutralized to pH=8 with 28percent aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 ml). After the usual work-up, the 2-chloro-4-methylbenzimidazole is obtained in a yield of 93percent (6.23 g). 1H NMR (300 MHz, δ ppm) DMSO-d6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
93% (6.23 g)
With ammonium hydroxide; trichlorophosphate In water
1.4.2. 2-Chloro-4-methylbenzimidazole 2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL of phosphoryl chloride are introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 mL), neutralized to pH=8 with 28percent aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 mL). After the usual work-up, the title product is obtained in a yield of 93percent (6.23 g). 1H NMR (300 MHz, δ ppm) DMSO D6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
Rk. mit 1) Phosgen/80grad -> 1-Chlorformyl-4-methyl-benzimidazolon-(2), 2) 175-180grad -> Tolylen-2,3-diisocyanat;
Yield
Reaction Conditions
Operation in experiment
90%
With hydrogen sulfide; 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 40℃; for 12h; Sealed tube;
4 Example 4 Synthesis of benzimidazolone derivatives by reacting o-phenylenediamine with CO2 under the action of hydrogen sulfide
General procedure: Add 2mmol o-phenylenediamine, organic base and 1mL suitable solvent successively in the high pressure reaction kettle of 15mL, tighten the reaction kettle; Feed the required amount of H2S and CO2 gas into the reaction kettle successively;The reaction was continued for 12 hours at a suitable temperature; after the reaction was completed, a certain amount of distilled water was added to the reaction solution to completely precipitate the product, and then the target product was obtained by suction filtration and drying in sequence.
78%
With sodium hydrogen sulphide In 1-methyl-pyrrolidin-2-one at 90℃; for 24h;
22 Synthesis of benzimidazolone compound
General procedure: Add in a 15ml Teflon-lined reactor216 mg (2 mmol) of o-phenylenediamine, 56 mg (1 mmol)NaHS (molar ratio of o-phenylenediamine to NaHS is 1:2),Add 1 mL of NMP as the reaction solvent.Put the magnets and tighten the reactor.Then charge 3MPa of carbon dioxide,The reaction was stirred at 90 ° C for 24 hours.After cooling the reactor to room temperature,Extracted with ethyl acetate,Washed with saturated saline,After drying the organic layer, the solvent is removed under reduced pressure to give a crude material;The crude product is separated by recrystallization or column chromatography (200-300 mesh silica gel,Petroleum ether and ethyl acetate as eluent)99% white powder benzimidazolone 116mg,The yield was 88%.
77%
With caesium fluoride In diethylene glycol dimethyl ether at 100℃; for 20h; Glovebox; Schlenk technique;
5 Example 1. Reaction of o-phenylenediamine with CO2 ring carbonylation to produce 1,3-dihydrobenzimidazol-2-one
General procedure: In a glove box, add o-phenylenediamine (1mmol), CsF (2mol), and diglyme (3mL) to a 10ml Schlenk bottle, and replace the air with CO2; connect the Schlenk bottle with a CO2 balloon, and then PMHS (4.5 mmol) was poured into a reaction bottle using a syringe, and the mixture was placed in an oil bath and stirred at 100 ° C for 20 hours. After the reaction was completed, the temperature was lowered to room temperature, and then poured into 30 mL of H2O to immediately obtain a large amount of precipitate. Then, a large amount of solid powder was obtained by suction filtration. The solid powder was washed with n-hexane (3 × 5 mL) to remove unreacted raw materials, and then ethyl acetate (3 × 10 mL) Wash the solid powder. The ethyl acetate layer was collected, dried over anhydrous magnesium sulfate, and then subjected to vacuum rotary evaporation to obtain a pure product with an isolated yield of 95%.
3-Methyl-o-phenylendiamin (9), Phosgen;
Photolyse von 23;
Aus 1-Hydroxy-4-methylbenzimidazolon(21)-Hydrogenolyse (Pd/C);
75.A Part A.
Part A. 4-Methyl-1H-benzimidazolidinone 1,1-Carbonyldiimidazole (30.5 g, 0.19 mol) was added, with cooling, to a stirred solution of 3-methyl-1,2-benzenediamine (22.98 g, 0.19 mol) in dimethylformamide (200 mL) and the mixture was heated at 100° C. for 1 hour. The solvent was removed under reduced pressure until solid began to appear. Water (200 mL) was slowly added, with stirring, to precipitate the desired product. The precipitate was filtered off and air-dried overnight to give 26.28 g brown solid, mp >280° C., which was used without further purification.
In tetrahydrofuran; dichloromethane at 20℃; for 6.5h;
2.1 Step 1 Synthesis of 4-methyl-1,3-dihydrobenzimidazol-2-one (7)
General procedure: To a solution of 4-methyl-1,2-phenylenediamine (1) (25 g) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1′-carbonyldiimidazole (36.5 g) in dichloromethane (375 mL). After stirring at room temperature for 6.5 hr, diisopropylether (375 mL) was added to the reaction mixture. After stirring at room temperature, the resulting precipitate was collected by filtration. The precipitate was washed with diisopropyl ether, and dried under reduced pressure to give 5-methyl-1,3-dihydrobenzimidazol-2-one (2) (24.6 g). [0101] ESI-HRMS (positive ion, sodium formate): calcd for C8H8N2ONa([M+Na]+) 171.0529. found 171.0529 [0102] NMR (DMSO-d6, δ): 2.27 (3H, s), 6.70-6.81 (3H, m), 10.46 (2H, br s)
5
[ 201230-82-2 ]
[ 601-87-6 ]
[ 19190-68-2 ]
Yield
Reaction Conditions
Operation in experiment
71%
With selenium; 1,8-diazabicyclo[5.4.0]undec-7-ene; triethylamine In toluene at 150℃; for 4h;
With trichlorophosphate; for 20h;Heating / reflux;
2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 ml of phosphoryl chloride are introduced into a 250 ml two-necked flask under an argon atmosphere, equipped with a magnetic stirrer. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 ml), the mixture is neutralized to pH=8 with 28% aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 ml). After the usual work-up, the 2-chloro-4-methylbenzimidazole is obtained in a yield of 93% (6.23 g). 1H NMR (300 MHz, delta ppm) DMSO-d6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
93% (6.23 g)
With ammonium hydroxide; trichlorophosphate; In water;
1.4.2. 2-Chloro-4-methylbenzimidazole 2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL of phosphoryl chloride are introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 mL), neutralized to pH=8 with 28% aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 mL). After the usual work-up, the title product is obtained in a yield of 93% (6.23 g). 1H NMR (300 MHz, delta ppm) DMSO D6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
Step A: 2-Chloro-4-methyl-l -benzo[d]imidazole To 4-methyl-lH-benzo[d]imidazol-2(3H)-one (1.5 g, 10 mmol) was added POCb (19 ml, 200 mmol) and the reaction mixture was heated to 135 C for 3 hours. The reaction was then cooled to room temperature and the excess POCb was removed in vacuo. The solid residue was diluted carefully with water and then slowly neutralized with saturated NaHCC until the pH was ~7-8. The mixture was extracted with ethyl acetate (2 x 150 mL) and the organics extracts were combined. The organics were dried with MgS04, filtered, and the solvent was removed to yield the crude residue. The crude material was purified by chromatography (Biotage) to yield 2-chloro-7-methyl-lH- benzo[d]imidazole (1.1 g, 6.3 mmol, 62 % yield) as a slightly yellow powder. MS (LC/MS) R.T. = 2.61 ; [M+]+ = 166.93
With hydrogenchloride; ammonium hydroxide; In chloroform; water; trichlorophosphate;
Part B. 2-Chloro-4-methyl-1H-benzimidazole Hydrogen chloride gas was bubbled through a stirred mixture of 4-methyl-1H-benzimidazolidone (5 g, 0.034 mol) in phosphorus oxychloride (50 mL) for 1 hour at 120 C. The solvent was removed and the resulting solid was dissolved in water (50 mL). Ammonium hydroxide (20 mL) was carefully added until the mixture was basic. The aqueous phase was then extracted with chloroform, filtered through celite, and evaporated to give 5.2 g, of brown oil. The product was chromatographed on silica gel in chloroform, and was eluted with 1% methanol:chloroform to give 3.96 g of brown oil. Crystallization from ethyl acetate:hexane gave 2.72 g of brown crystals, mp 137.5-139.5 C.
With trichlorophosphate; at 95℃; for 1.5h;
General procedure: A mixture of 5-methyl-1,3-dihydrobenzimidazol-2-one (1.00 g, 6.84 mmol) and phosphorous oxychloride (9.54 mL, 103 mmol) was stirred for 1.5 h at 95 C. After being cooled to ambient temperature, the reaction mixture was carefully added to a mixture of saturated NaHCO3 aq. (60 mL) and ethyl acetate (60 mL). The separated organic layer was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was evaporated in vacuo, The resulting precipitates were collected by filtration, and successfully washed with isopropyl ether to give 2-chloro-5-methyl-benzimidazole (1.74 g, 58.9 %).
In tetrahydrofuran; dichloromethane at 20℃; for 6.5h;
Typical experimental procedure for substituted 1,3-dihydrobenzimidazol-2-one
General procedure: To a solution of 4-methyl-1,2-phenylenediamine (25 g, 0.205 mol) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1'-carbonyldiimidazole (36.5 g, 0.225 mol) in dichloromethane (375 mL). After stirring for 6.5 h at ambient temperature, to the reaction mixture was added diisopropyl ether (375 mL). After stirring at ambient temperature, the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether and dried in vacuo to give 5-methyl-1,3-dihydrobenzimidazol-2-one (24.6 g, 70.1%).
(8-methyl-3H-1'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,3'-bicyclo[2.2.2]octan]-1'-yl-8-ium)trihydroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: trichlorophosphate / 3 h / 135 °C
2.1: n-butyllithium / tetrahydrofuran / 0.75 h / -78 °C
2.2: 2.25 h / -78 - 75 °C
(R)-8-methyl-3H-1’-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,3’-bicyclo[2.2.2]octane][ No CAS ]
(S)-8-methyl-3H-1’-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,3’-bicyclo[2.2.2]octane][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 3 steps
1.1: trichlorophosphate / 3 h / 135 °C
2.1: n-butyllithium / tetrahydrofuran / 0.75 h / -78 °C
2.2: 2.25 h / -78 - 75 °C
3.1: hydrogenchloride / acetone / 0.58 h / 20 °C
1-(4-methyl-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 3 steps
1: trichlorophosphate / 16 h / 100 °C
2: potassium dihydrogenphosphate / butan-1-ol / 17 h / 115 °C
3: potassium carbonate / N,N-dimethyl-formamide / 22 h / 110 °C
General procedure for the synthesis of (un)symmetrical 1,3-disubstituted ureas and 1H-benzimidazol-2(3H)-ones
General procedure: A mixture of amine (4 mmol or 2 mmol), or substituted OPDA (2 mmol), urea (2.4mmol), or N-phenylurea (2 mmol) and sulfated polyborate (10 wt%) was heated at 120°C in an oil bath. The reaction was monitored by thin layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and quenched by water (5 mL); solid precipitated was filtered at vacuum pump, washed with water (3×5 mL), dried under vacuum and recrystallized from ethanol to afford the pure product.
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