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CAS No. : | 934-22-5 | MDL No. : | MFCD00831692 |
Formula : | C7H7N3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WFRXSXUDWCVSPI-UHFFFAOYSA-N |
M.W : | 133.15 | Pubchem ID : | 13623 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 40.5 |
TPSA : | 54.7 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 0.63 |
Log Po/w (XLOGP3) : | 1.13 |
Log Po/w (WLOGP) : | 1.15 |
Log Po/w (MLOGP) : | 0.37 |
Log Po/w (SILICOS-IT) : | 1.36 |
Consensus Log Po/w : | 0.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.04 |
Solubility : | 1.2 mg/ml ; 0.00905 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.87 |
Solubility : | 1.79 mg/ml ; 0.0134 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.52 |
Solubility : | 0.404 mg/ml ; 0.00303 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.33 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P233-P260-P261-P264-P270-P271-P280-P301+P312-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P322-P330-P332+P313-P337+P313-P340-P362-P363-P403-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H312-H315-H319-H332-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 |
---|---|---|
100% | With hydrogen In methanol for 20 h; | Example 10; 1H-Benzimidazol-5-amine A solution of 5-nitrobenzin-ddazole (10. 0 g, 61.3 mmol) in methanol (250 mL) was hydrogenated in the presence of 10percent Pd/C (0. 40 g) at atmospheric pressure for 20h. The mixture was filtered through CeliteNo. and the solvent removed under reduced pressure to afford the pure product () percent). |
92% | With hydrogen In tetrahydrofuran; ethanol at 20℃; for 4 h; | A mixture of 5-nitrobenzoimidazol (2.00 g, 12.3 mmol) and 10percent palladium carbon (200 mg) in ethanol (100 ML) and THF (100 ML) was stirred under hydrogen atmosphere at room temperature for 4 hours.. The insolubles were filtered off, the filtrate was evaporated under reduced pressure, to obtain the titled compound as a solid. 1.50 g (92.0percent) 1H-NMR (CDCl3) δ; 6.67 (1H, dd, J = 2.2, 9.2 Hz), 6.86 (1H, d, J = 2.2 Hz), 7.43 (1H, d, J = 9.2 Hz), 7.84 (1H, s) |
85% | at 20℃; for 16 h; | Intermediate Example 14.Ethyl 1 -(1 H-benzo[d}imidazol-5-yl)- 1 H-i ,2,3-triazole-4-carboxylate‘a) 1H-benzo[djimidazol-5-amineTo a solution of 5-nitro-1H-benzo[d]imidazole (5 g, 44.2 mmol) in methanol (‘100 ml) was added Pd/C and the reaction mixture was stirred at RT for 16 h and filtered. The filtrate was diluted with water and extracted with ethyl acetate (3 x 100ml). The ‘combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by washing with diethyl ether to afford the title product in 85 percent yield (2.5 g). LC-MS (ESI):Calculated rnassi33.06 Observed mass: 134.2 [M+F1J + (rt: 0.175 mm). |
0.163 g | With palladium on activated charcoal; hydrazine hydrate In ethanol for 4 h; Reflux | Next, 5-nitrobenzoimidazole (0.25 g) was dissolved in ethanol (20 mL). The solution was stirred and heated to reflux, and the palladium-on-charcoal catalyst (0.15 g) and hydrazine hydrate (1.6 mL) were added. Then the mixture was stirred for 4 h, and filtered in hot. The filtrate was evaporated, and the residue was recrystallised from ethanol to give rise to the precursor compound 5-aminobenzoimidazole (0.163 g). |
99 %Chromat. | With hydrogen In methanol at 100℃; for 8 h; Autoclave | General procedure: The hydrogenation of nitroarenes was carried out in a Teflon-lined stainless steel autoclave equipped with a pressure gauge anda magnetic stirrer. Typically, a mixture of 0.5 mmol nitroarene, 15molpercent Co/C–N–X catalyst, 100 L n-hexadecane and 2 mL solventwas introduced into the reactor at room temperature. Air in theautoclave was purged several times with H2. Then, the reactionbegan by starting the agitation (600 r/min) when hydrogen was reg-ulated to 1 MPa after the reaction temperature was reached. Afterreaction, the solid was isolated from the solution by centrifuga-tion. The products in the solution were quantified and identifiedby GC–MS analysis (Shimadzu GCMS-QP5050A equipped with a0.25 mm × 30 m DB-WAX capillary column).1H NMR and13C NMRdata were obtained on Bruker Avance III 400 spectrometer usingCDCl3or DMSO-d6 as solvent and tetrmethylsilane (TMS) as aninternal standard. The pure product in the scale-up experimentwas obtained by flash column chromatography (petroleum ether and ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42%; 26% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); for 48h;Heating / reflux; | EXAMPLE 13 1-(6-[(1S)-1-Phenylethyl]amino)pyrazin-2-yl)-1H-benzimidazol-5-amine and 1-(6-[(1S)-1-Phenylethyl]amino)pyrazin-2-yl)-1H-benzimidazol-6-amine To a stirred solution of 5-amino-benzimidazole (290 mg, 2.2 mmol) in anhydrous DMF (10 mL) under N2 was added caesium carbonate (980 mg) The resulting mixture was stirred at 70C for 60 min. To this was added a solution of 6-chloro-N-[(1,S)-1-phenylethyl]pyrazin-2-amine (470 mg) in DMF (5 mL) and the renting mixture was then heated at reflux for 48h. The DMF wws removed under reduced pressure and the residue diluted with chloroform. The organic layer was washed with aqueous Na2CO3, dried (Na2SO4) and the solvent removed under reduced pressure to furnish the crude product. Column chromatography using dichloromethane-methanol (95: 5-92: S) as eluant separated'two fractions from unreacted starting material. The higher Rf fraction was assigned as the 6-isomer (276mg, 42%). <P>1H-n. m. r. (CDCl3) 51. 64 (d, 3H,/= 6. 9Hz, CH3), 2. 90 (br s, 2H, NH2), 5. 05 (m, 1H, CH), 5. 21 (d, 1H, NH), 6.70 (dd, 1H, J = 8. 7,2. 1Hz, ArH), 6. 97 (d, 1H, J = 1.8Hz, ArH), 7. 28-7. 43 (m, 5H, Ph-H), 7.58 (d, 1H, J = 8.4Hz, ArH), 7.84 (s, 1H, pyraz-H), 8.08 (s, 1H, pyraz-H), 8. 21 (s, 1H, ArH). m/z (ES) 331 (M++H). The lower fraction was assigned as the 5-isomer (170mg, 26%). 1H-n.m.r. (CDCl3) No.1.64 (d, 3H, J = 6.9 hz, CH3), 2.85 (br s, 2H, NH2), 5.01 (m, 1H, CH), 5.19 (d, 1H, NH), 6. 70 (dd, 1H, J = 8.7, 2. 1Hz, Arbi), 7.11 (d, 1H, J = 1.8Hz, ArH), 7.29-7. 40 (m, 5H, Ph-H), 7. 51 (d, 1H, J=8.7Hz, ArH), 7.81 (s, 1H, pyraz-H), 8.10 (s, 1H, pyraz-H), 8. 32 (s, 1H, ArH). m/z (ES) 331 (M++H). |
42%; 26% | To a stirred solution of 5-amino-benzimidazole (290mg, 2. 2MMOL) in anhydrous DMF (lOmL) under N2 was added caesium carbonate (980mg) The resulting mixture was stirred at 70C for 60 min. To this was added a solution of 6-CHLORO-N-[(15)-1-PHENYLETHYL] PYRAZIN-2-AMINE (470mg) in DMF (5mL) and the resulting mixture was then heated at reflux for 48h. The DMF was removed under reduced pressure and the residue diluted with chloroform. The organic layer was washed with aqueous NA2CO3, dried (NA2SO4) and the solvent removed under reduced pressure to furnish the crude product. Column chromatography using dichloromethane-methanol (95: 5 No. 92: 8) as eluant separated two fractions from unreacted starting material. The higher Rf fraction was assigned as the 6-isomer (276mg, 42%). 1H-n. m. r. (CDCl3) 81. 64 (d, 3H, J= 6.9Hz, CH3), 2.90 (br s, 2H, NH2), 5.05 (m, 1H, CH), 5.21 (d, 1H, NH), 6.70 (dd, 1H, /= 8.7, 2. 1Hz, benzimid-H), 6.97 (d, 1H, J = 1. 8Hz, benzimid-H), 7.28-7. 43 (m, 5H, Ph-H), 7.58 (d, 1H, J= 8.4Hz, benzimid-H), 7.84 (s, 1H, pyraz-H), 8.08 (s, 1H, pyraz-H), 8.21 (s, 1H, benzimid-H). m/z (ES) 331 (M++H). The lower fraction was assigned as the 5-isomer (170mg, 26%),'H-n. m. r. (CDCl3) 81. 64 (d, 3H, J= 6. 9HZ, CH3), 2.85 (BR S, 2H, NHZ), 5.01 (m, 1H, CH), 5.19 (d, 1H, NH), 6.70 (dd, 1H, J= 8.7, 2. 1Hz, benzimid-H), 7.11 (d, 1H, J= 1. 8Hz, benzimid-H), 7.29-7. 40 (m, 5H, Ph-H), 7.51 (d, 1H, YE8. 7Hz, benzimid-H), 7.81 (s, 1H, pyraz-H), 8.10 (s, 1H, pyraz-H), 8.32 (s, 1H, benzimid-H). m/z (ES) 331 (M++H). | |
42%; 26% | Example 12; 1-(6-([(1S)-1-phenylethyl]amino/pyrazin-2-yl)-1H-benzimidazol-5-amine and 1-(6-([(1S)-1-phenylethyl]amino/pyrazin-2-yl)-1H-benzimidazol-6-amine To a stirred solution of 5-amino-benzimidazole (290mg, 2.2mmol) in anhydrous DMF (lOmL) under Ni was added caesium carbonate (980mg) The resulting mixture was stirred at 70'C for 60 min. To this was added a solution of 6-chloro-N- [ (lS)-l- phenylethyllpyrazin-2-amine (470mg) in DMF (5mL) and the resulting mixture was then heated at reflux for 48h. The DMF was removed under reduced pressure and the residue diluted with chloroform.. The organic layer was washed with aqueous Na2CO3, dried (Na2SO4) and the solvent removed under reduced pressure to furnish the crude product. Column chrumatography using dichloromethane-methanol (95 : 5-92 : 8) as eluant separated two fractions from unreacted starting material. The higher Rf fraction was assigned as the 6-isomer (276mg, 42%). 1H-n.m.r. (CDCl3) No.1. 64 (d, 3H, J=6.9Hz, CH3), 2. 90 (br s, 2H, NH2), 5. 05 (m, 1H, CH), 5.21 (d, 1H, NH), 6.70 (dd, 1H, J=8. 7, 2. 1Hz, benzimid-H), 6. 97 (d, 1H, = l. 8Hz, benzimid-H), 7. 28-7. 43 (m, 5H, Ph-H), 7. 58 (d, 1H, J= 8. 4Hz, benzimid-H), 7. 84 (s, IH, pyraz-H), 8.08 (s, 1 pyraz-H), 8. 21 (s, 1H, benzimid-H). m/z (ES) 331 (M++H). The lower fraction was assigned aa the 5-isomer (170mg, 26%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; sodium acetate; In acetic acid; | A. 5-Amino-4-bromobenzimidazole To a solution of 1.08 g of 5-aminobenzimidazole in 20 mL of glacial acetic acid are added 2.68 g of sodium acetate. To this solution is added dropwise 0.4 mL of bromine. The resulting brown precipitate is stirred at room temperature for 2 hours. The reaction mixture is rotary evaporated and the residue is diluted with water and ethyl acetate. The mixture is basified with 1N sodium hydroxide and decanted. The organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluding with 12.5 to 16.5% methanol/methylene chloride followed by recrystallization from hexanes/ethyl acetate to provide 887 mg of 5-amino-4-bromobenzimidazole as a pale brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Example 98: iV-(lH-Benzoimidazol-5-yl)-2,6-dimorpholin-4-yI-pyrimidine-4-carboxamideA mixture of 2,6-dimorpholin-4-ylpyrimidine-4-carboxylic acid (45 mg5 0.15 mmol), HATU (65 mg, 0.17 mmol) and lH-benzoimidazol-5-amine (23 mg, 0.17 mmol) in DMF (1 mL) and triethylamine (0.054 mL, 0.31 mmol) was stirred at room temperature overnight. Water (4 mL) was added and the mixture extracted with ethyl acetate (3 x 4 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 10 - 45% ethyl acetate in isohexane, to give the desired material as a pale yellow solid (43.6 mg).LCMS Spectrum: MH+ 410, Retention Time 2.05, Method: Monitor AcidNMR Spectrum: 1H NMR (399.9 MHz5 CDCl3) 63.75 (m, 12H), 3.85 - 3.86 (m, 4H)5 5.90(s, IH), 6.93 (m, IH)5 6.96 (m, IH)5 7.32 (m, IH)5 7.34 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.4% | With pyridine; In tetrahydrofuran; at 0 - 20℃; for 1.5h; | Example 133; N-1H-Benzimidazol-5-yl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide; (1) 2,2,2-Trichloroethyl 1H-benzimidazol-5-ylcarbamate; To a solution of 1H-benzimidazol-5-amine (1.00 g, 7.51 mmol) and pyridine (0.73 ml, 9.01 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.01 mmol), and the mixture was stirred at room temperature for 1.5 hour . Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.49 g (64.4%) of the desired product as a solid was separated by filtration. 1H-NMR (CDCl3) delta; 5.22 (2H, s), 7.27 - 7.29 (1H, m), 7.90 - 8.01 (2H, m), 8.06 (1H, br s), 8.56 (1H, s), 10.16 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In ethanol; for 3h;Heating / reflux; | To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-Aminobenzimidazole (1 mmol) in 5 ml EtOH, was added Et3N(1 mmol). The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine in a yield of 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran; for 12h;Heating / reflux; | 1-(1H-benzo[d]imidazol-5-yl)-3-(3,4-dimethoxyphenyl)urea1H-benzo[d]imidazol-5-amine (0.36 g, 2.0 mmol) and 4-isocyanato-1,2-dimethoxybenzene (0.27 g, 2.0 mmol) were dissolved in THF (20 mL) and heated under reflux for 12 h. After the solvent was removed the products were purified by means of flash-chromatography using silica gel and a CHCl3/MeOH-gradient.Yield: 0.61 g (98%). 1H NMR (DMSO-d6): delta 3.70 (s, 3H); 3.74 (s, 3H); 6.84-6.88 (m, 2H); 6.98 (br s, H); 7.21 (s, H); 7.47 (br s, H); 7.88 (br s, H); 8.08 (s, H); 8.41 (s, H); 8.52 (br s, H); 12.21 (br s, H). MS m/z 313.0 (M+H)+. HPLC (lambda=214 nm, [alpha]): rt 9.00 min (99.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 256: 1 -(1 H-Benzoimidazol-5-yl)-4-butyryl-3-hydroxy-5-(5-methyl-furan-2- yl)-1 ,5-dihydro-pyrrol-2-one; EPO <DP n="176"/>1 H-Benzoimidazol-5-ylamine (1 mmol) and 5-Methyl-furan-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 365.39 RT - UV254nm (min): 2.88IC50 hQC (nM): 203 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Compound 421 : 1 -(1 H-Benzoimidazol-5-yl)-5-benzo[c][1 ,2,5]oxadiazol-5-yl-4-butyryl-3- hydroxy-1 ,5-dihydro-pyrrol-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1 ,2,5]oxadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 403.40 RT - UV254nm (min): 2.9IC50 hQC (nM): 246Yield: 0.725g (18 %); mp: 266C, 1H NMR delta 0.75 (t, 3J=7.4 Hz, 3 H, CH3), 1.41-1.49 (m, 2 H, CH2-CH3), 2.74 (t, 3J=7.2 Hz, 2 H, C(O)CH2), 6.35 (s, 1 H, CH-N), 7.36 (dd, 3J=8.2 Hz, 4J=1.2 Hz, 1 H, Benzimid), 7.66 (s, 2 H, Ar), 7.83 (d, 3J=9.4 Hz, 1 H, Benzimid), 8.01 (s, 1 H, Ar), 8.18 EPO <DP n="185"/>(s, 1 H, Benzimid), 8.99 (s, 1 H, Benzimid); MS m/z 404.0 (IVH-H)+, HPLC (254 nm): rt 2.90 min(100 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Compound 387: 1 -(1 H-Benzoimidazol-5-yl)-4-butyryl-3-hydroxy-5-(4-pyridin-2-yl- phenyl)-1 ,5-dihydro-pyrrol-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and 4-Pyridin-2-yl-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 438.49 RT - UV254nm (min): 2.79 IC50 hQC (nM): 1.2Yield: 0.087g (20 %); mp: 294C, 1H NMR delta 0.77 (t, 3J=7.4 Hz, 3 H, CH3), 1.44-1.49 (m, 2 H, CH2-CH3), 2.72 (q, 3J=6.4 Hz, 4J=1.1 Hz, 2 H, C(O)CH2), 6.13 (s, 1 H, CH-N), 7.25-7.28 (m, 1 H, Ar), 7.33 (d, 3J=8.4 Hz, 2 H, Ar), 7.36 (dd, 3J=8.7 Hz, 4J=2.0 Hz, 1 H, Ar), 7.45 (d, 3J=8.7 Hz, 1 H, Ar), 7.76 (dd, 3J=9.6 Hz, 4J=I .7 Hz, 1 H, Benzimid), 7.78-7.81 (m, 2 H, Ar, Benzimid), 7.84 (d, 3J=8.5 Hz, 2 H, Ar), 8.15 (s, 1 H, Benzimid), 8.17 (s, 1 H, Benzimid), 8.56-8.57 (m, 1 H, Benzimid).MS m/z 439.3 (M+H)+, HPLC (254 nm): rt 2.79 min (100 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Compound 471 : 1 -(1 H-benzo[d]imidazol-6-yl)-5-(5-bromo-2-fluorophenyl)-3-hydroxy- 4-methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5ml_ of dry EtOH and 3-bromo-5-fluoro- benzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2-oxal- propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHCIs/MeOH gradient. The purified carboxylic acid ethyl EPO <DP n="192"/>ester derivative was suspended in 1 OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried.Yield: 0.403g (51 %);1H-NMR 400 MHz, CD3OD, 1.78 (s, 3H, CH3), 6.00 (s, 1 H, CH-N), 6.99 -7.10 (m, 1 H, aro), 7.36 - 7.44 (m, 1 H, aro) 7.69 -781 (3H, aro, benzimid), 8.10 (s, 1 H, benzimid),9.28 (s, 1 H, benzimid); MS m/z 404.3 (M+H)+, HPLC (254 nm): purity 97 % molecular weight (g/mol): 402.21Ki hQC (nM): 33.16 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Compound 468: 1 -(1 H-benzo[d]imidazol-5-yl)-5-(2,3-dichlorophenyl)-3-hydroxy-4- methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5mL of dry EtOH and 2,3- diclorobenzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2- oxal-propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash EPO <DP n="190"/>chromatography device and purified by means of a CHCI3/Me0H gradient. The purified carboxylic acid ethyl ester derivative was suspended in 1OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried. Yield: 0.086g (23 %);1H-NMR (500 MHz, DMSO-D6, rotamers): 1.62, 1.66 (d, 3J=0.9 Hz , 3 H, CH3), 6.08, 6.28 (s, 1 H, CH-N), 6.99, 7.69 (dd, 3J=7.9 Hz, 4J=1.5 Hz, 1 H, Ar), 7.22, 7.39 (t, 3J=7.9 Hz, 1 H, Ar), 7.33, 7.44 (dd, 3J=8.9 Hz, 4J=1.8 Hz, 1 H, Benzimid), 7.50, 7.53 (dd, 3J=7.9 Hz, 4J=1.5 Hz, 1 H, Ar), 7.63, 7.66 (d, 3J=8.0 Hz, 1 H, Benzimid), 7.86, 7.91 (d, 4J=1.8 Hz, 1 H, Benzimid), 8.92, 8.96 (s, 1 H, Benzimid), 9.60, 9.72 (s, br., 1 H, NH); MS m/z 374.1 (M+H)+, Fp.: 162-174C; calc: C: 57.77, H: 3.50, N: 1 1.23, found.: C: 50.40, H: 4.90, N: 8.31 corresponds Ci8H13CI2N3O2 + 1.0 H2O + 1.0 HCI., HPLC (254 nm): purity 94 %molecular weight (g/mol): 374.1 Ki hQC (nM): 14.6 |
Yield | Reaction Conditions | Operation in experiment |
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53% | Compound 469: 1 -(1 H-benzo[d]imidazol-5-yl)-5-(2,4,5-trifluorophenyl)-3-hydroxy-4- methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5mL of dry EtOH and 2,4,5- trifluorobenzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2- oxal-propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHCI3/MeOH gradient. The purified carboxylic acid ethyl ester derivative was suspended in 1OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried. Yield: 0.19Og (53 %);1H-NMR (500 MHz, DMSO-D6, rotamers): 1.69 (s, 3 H, CH3), 6.00, 6.04 (s, 1 H, CH-N), 7.48-7.55 (m, 1 H, Ar), 7. 61 (dd, 3J=8.5 Hz, 4J=1.5 Hz, 1 H, Benzimid), 7.75, 7.80 (d, 3J=8.9 Hz, 1 H, Benzimid), 8.02, 8.06 (d, 4J=1.8 Hz, 1 H, Benzimid), 9.40 (s, 1 H, Benzimid), 9.71 (s, br., 1 H, NH); MS m/z 360.3 (M+H)+, Fp.: 184C;calc: C: 60.17, H: 3.37, N: 1 1.69, found.: C: 49.16, H: 4.25, N: 8.69 corresponds to Ci8H12F3N3O2 + 2.0 H2O + 1.0 HCI; HPLC (254 nm): purity 96 % molecular weight (g/mol): 359.30 EPO <DP n="191"/>Ki hQC (nM): 53.6 |
Yield | Reaction Conditions | Operation in experiment |
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28% | Compound 473: 1 -(1 H-benzo[d]imidazol-6-yl)-5-(2,6-difluorophenyl)-3-hydroxy-4- methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5ml_ of dry EtOH and 2,6-difluoro - benzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2-oxal- propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHC^/MeOH gradient. The purified carboxylic acid ethyl ester derivative was suspended in 1OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried.Yield: 0.098g (28 %);1H-NMR 400 MHz, CD3OD11.81 (s, 3H, CH3), 6.17(s, 1 H, CH-N), 6.72 - 6.83 (m, 1 H, aro), 6.93 - 7.08 (m, 1 H, aro) 7.21 -7.37 (m, 1 H, aro), 7.74(m, 2H, benzimid), 8.07 (s, 1 H, benzimid), 9.28 (s, 1 H, benzimid) MS m/z 342.0 (M+H)+, HPLC (254 nm): purity 99 % molecular weight (g/mol): 341.31 Ki: hQC (nM): 29.2 |
Yield | Reaction Conditions | Operation in experiment |
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46% | Compound 467: 1 -(1 H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-hydroxy-4- methyl-1 H-pyrrol-2(5H)-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5ml_ of dry EtOH and 2,3- difluorobenzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2- oxal-propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHC^/MeOH gradient. The purified carboxylic acid ethyl ester derivative was suspended in 1OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried. Yield: 0.15Og (46 %);1H-NMR (400 MHz, CD3OD), 1.78 (s, 3H, CH3), 6.06 (s, 1 H, CH-N), 6.94 - 7.17 (m, 3H, aro), 7.74 (s, 2H, benzimid), 8.08 (s, 1 H, benzimid), 9.27 (s, 1 H, benzimid), MS m/z 342.1 (M+H)+, HPLC (254 nm): purity 100 %molecular weight (g/mol): 341.3 Ki hQC (nM): 1 1.6 |
Yield | Reaction Conditions | Operation in experiment |
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26% | Compound 472: 1 -(1 H-benzo[d]imidazol-6-yl)-5-(2-chloro-3,6-difluorophenyl)-3- hydroxy-4-methyl-1 H-pyrrol-2(5H)-one; 1H-Benzoimidazol-5-ylamine (1 mmol) was dissolved in 5mL of dry EtOH and 2-chloro-3,6- difluoro-benzaldehyd (1 mmol) were added. The solution was stirred overnight and after that 2- oxal-propionsaure diethylester (1 mmol) was added and the solution was stirred for 2Oh at 500C. After that the solvent was evaporated and remaining oil was subjected to a flash chromatography device and purified by means of a CHCI3/MeOH gradient. The purified carboxylic acid ethyl ester derivative was suspended in 1OmL of a 10% aqueous solution of HCI and kept for 3h at reflux. The resulting precipitate was filtered off and dried. Yield: 0.092g (26 %);1H-NMR 400 MHz, CD3OD, ?:1.78 - 1.82 (2 s, 1 H + 2H, CH3), 6.35 (s, 0.4H, CH-N), 6.40 (s, 0.6 H, CH-N), 6.90 - 7.00 (m, 0.6 H, aro), 7.16 - 7.24 (m, 1.6 H, aro) 7.68 - 7.79 (2H, benzimid), 8.04 - 8.08 (2s, 0.6 + 0.4 H, benzimid), 9.28 (s, 1 H, benzimid); MS m/z 376.3 (M+H)+, HPLC (254 nm): purity 98 % molecular weight (g/mol): 375.75 1 Ki: hQC (nM): 55.79 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Compound 403: 4-Acetyl-1 -(1 H-benzoimidazol-5-yl)-5-benzo[c][1 ,2,5]oxadiazol-5-yl-3- hydroxy-1,5-dihydro-pyrrol-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1 ,2,5]oxadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-pentanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 375.35 IC50 hQC (nM): 28.34Yield: 0.06g (16 %); mp: 175C, 1H NMR 5 2.37 (s, 3 H, CH3), 6.36 (s, 1 H, CH-N), 7.39 (dd, 3J=9.5 Hz, 4J=1.4 Hz, 1 H, Benzimid), 7.70 (d, 3J=1.2 Hz, 2 H, Ar), 7.83 (dd, 3J=9.5 Hz, 4J=0.8 Hz, 1 H, Benzimid), 8.06 (t, 4J=I .2 Hz, 1 H, Ar), 8.20 (d, 4J=I .1 Hz, 1 H, Benzimid), 9.11 (s, 1 H, Benzimid).MS m/z 376.2 (M+H)+, HPLC (254 nm): rt 2.49 min (100 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | Compound 440: 1 -(1 H-Benzoimidazol-5-yl)-5-benzo[c][1 ,2,5]oxadiazol-5-yl-4- cyclopropanecarbonyl-S-hydroxy-I .S-dihydro-pyrrol^-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1 ,2,5]oxadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 401.38 IC50 hQC (nM): 1 1.4Yield: 0.032g (8 percent); mp: 1700C, 1H NMR delta 0.73-0.75 (m, 1 H, CH2), 0.83-0.85 (m, 2 H, CH2), 0.94-0.96 (m, 1 H, CH2), 2.92-2.94 (CH-CH2), 6.37 (s, 1 H, CH-N), 7.40 (dd, 3J=9.5 Hz, 4J=1.2 Hz, 1 H, Ar), 7.64-7.66 (m, 2 H, Ar, Benzimid), 7.83 (d, 3J=9.5 Hz, 1 H, Ar), 8.05 (s, 1 H, Benzimid), 8.18 (s, 1 H, Benzimid), 9.10 (s, 1 H, Benzimid); MS m/z 402.2 (M+H)+, HPLC (254 nm): rt 2.75 min (100 percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Compound 446: 1 -(1 H-Benzoimidazol-S-ylJ^-cyclopropanecarbonyl-S-hydroxy-S-tdelta- hydroxy-quinolin-2-yl)-1 ,5-dihydro-pyrrol-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and 8-Hydroxy-quinoline-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 EPO <DP n="188"/>mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 426.44 IC50 hQC (nM): 1.35Yield: 0.174g (41 percent); mp: 155°C, 1H NMR delta 0.67-0.71 (m, 1 H, CH2), 0.77-0.85 (m, 2 H, CH2), 0.88-0.93 (m, 1 H, CH2), 2.85-2.96 (CH-CH2), 6.39 (s, 1 H, CH-N), 6.99 (dd, 3J=6.4 Hz, 4J=1.2 Hz, 1 H, Ar), 7.22 (dd, 3J=7.0 Hz, 4J=1.2 Hz, 1 H, Ar), 7.31 (t, 3J=7.8 Hz, 1 H, Ar), 7.51 (d, 3J=8.6 Hz, 1 H, Ar), 7.60 (d, 3J=9.0 Hz, 1 H, Benzimid), 7.75 (dd, 3J=9.0 Hz, 4J=1.9 Hz, 1 H, Ar), 8.09-8.1 1 (m, 2 H, Benzimid), 9.03 (s, 1 H, Benzimid), 9.53 (s, br., 1 H, NH); MS m/z 427.0 (M+H)+, HPLC (254 nm): rt 2.81 min (100 percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Compound 287: 1 -(1 H-Benzoimidazol-5-yl)-5-benzo[c][1 ,2,5]thiadiazol-5-yl-4- cyclopropanecarbonyl-S-hydroxy-I .S-dihydro-pyrrol^-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1 ,2,5]thiadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 500C and stirred for 24h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 417.45 IC50 hQC (nM): 0.7Yield: 0.05 g (16 percent); mp: 270.000C, decomposed, 1H NMR delta 1 H-NMR (500 MHz, DMSO-D6): 0.66-0.71 (m, 1 H, CH2), 0.77-0.84 (m, 2 H, CH2), 0.89-0.95 (m, 1 H, CH2), 2.91-2.95 (CH-CH2), 6.36 (s, 1 H, CH-N), 7.45-7.50 (m, 3 H, Ar), 7.85-7.87 (m, 2 H, Benzimid), 8.12 (d, 4J=0.9 Hz, 1 H, Benzimid), 9.03 (s, 1 H, Benzimid). MS m/z 418.4 (M+H)+, HPLC (254 nm): rt 2.74 min (100 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Compound 199; 1 -(1 H-Benzoimidazol-5-yl)-5-(4-bromo-phenyl)-4-(cyclohexylimino)- imidazolidin-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and 4-Bromobenzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2ml of a solution of KOCN (KSCN) (2mmol) and Pyridinehydrochloride (2mmol) in MeOH is added was added. Finally 3- Isocyano-cyclohexane EPO <DP n="129"/>(1 mmol) is added. The reaction was stirred at room temperature for 48h. After evaporation of the solvent the residue was purified with chromatographic methods. Yield: 0.290 g (64 %); mp: 2050C, 1H-NMR (500 MHz, DMSO-D6): 1.05-1.12 (m, 3 H, CH2), 1.22-1.28 (m, 3 H, CH2), 1.52- 1.74 (m, 4 H, CH2), 1.86-1.89 (m, 1 H, CH2), 4.40 (s, br., 1 H, NH), 5.98 (s, 1 H, CH-N), 7.24 (d, 3J=8.6 Hz, 2 H, Ar), 7.36 (d, 3J=6.6 Hz, 1 H, Benzimid), 7.48 (d, 3J=8.6 Hz, 2 H, Ar), 7.64 (s, br., 1 H, NH), 8.04 (d, 3J=7.6 Hz, 1 H, imidazole), 8.08 (s, 1 H, imidazole), 12.31 (s, br., 1 H, NH). MS m/z 452.3 (M+H)+, HPLC (254 nm): rt 2.95 min (100 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Compound 216; 1 -(1 H-Benzoimidazol-5-yl)-4-benzylimino-5-(4-bromo-phenyl)- imidazolidin-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and 4-Bromobenzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2ml of a solution of KOCN (KSCN) (2mmol) and Pyridinehydrochloride (2mmol) in MeOH is added was added. Finally 3- Benzylisocyanide (1 mmol) is added. The reaction was stirred at room temperature for 48h. After evaporation of the solvent the residue was purified with chromatographic methods. Yield: 0.230 g (50 %); mp: 244C, 1H-NMR (500 MHz, DMSO-D6): 4.46 (t, 3J=5.1 Hz, 2 H, CH2), 6.18 (s, 1 H, CH-N), 7.17 (m, 8 H, Ar), 7.39 (d, 3J=8.7 Hz, 1 H, Benzimid), 7.48 (dd, 3J=6.6 Hz, 4J=1.9 Hz, 2 H, Ar), 7.67 (s, br., 1 H, NH), 8.08 (s, 1 H, Benzimid), 8.67 (t, 1 H, Ar), 12.36 (s, br., 1 H, NH). . MS m/z 460.3 (M+H)+, HPLC (254 nm): rt 2.86 min (100 %)molecular weight (g/mol): 460.34 IC50 hQC (nM): 22 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 220; 1 -(1 H-Benzoimidazol-5-yl)-5-(3-chloro-2,6-difluoro-phenyl)-4- (cyclohexylimino)-imidazolidin-2-one; EPO <DP n="131"/>1 H-Benzoimidazol-5-ylamine (1 mmol) and <strong>[190011-87-1]3-Chloro-2,6-difluorobenzaldehyde</strong> (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2ml of a solution of KOCN (KSCN) (2mmol) and Pyridinehydrochloride (2mmol) in MeOH is added was added. Finally Isocyano-cyclohexane (1 mmol) is added. The reaction was stirred at room temperature for 48h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 443.89 RT - UV254nm (min): 2.88IC50 hQC (nM): 98.4 |
Yield | Reaction Conditions | Operation in experiment |
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Compound 274; 1 -(1 H-Benzoimidazol-5-yl)-5-(3-chloro-2,6-difluoro-phenyl)-4-(1 ,2,2- trimethyl-propylimino)-imidazolidin-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and <strong>[190011-87-1]3-Chloro-2,6-difluorobenzaldehyde</strong> (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2ml of a solution of KOCN (KSCN) (2mmol) and Pyridinehydrochloride (2mmol) in MeOH is added was added. Finally 3-lsocyano-2,2- dimethyl-butane (1 mmol) is added. The reaction was stirred at room temperature for 48h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 445.90 RT - UV254nm (min): 2.95IC50 hQC (nM): 101 |
Yield | Reaction Conditions | Operation in experiment |
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Compound 183; 1 -(1 H-Benzoimidazol-5-yl)-5-(3-chloro-2,6-difluoro-phenyl)-4-(1 ,2,3,4- tetrahydro-naphthalen-1 -ylimino)-imidazolidin-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and <strong>[190011-87-1]3-Chloro-2,6-difluorobenzaldehyde</strong> (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2ml of a solution of KOCN (KSCN) (2mmol) and Pyridinehydrochloride (2mmol) in MeOH is added was added. Finally 1 -lsocyano-1 , 2,3,4- tetrahydro-naphthalene (1 mmol) is added. The reaction was stirred at room temperature for 48h. After evaporation of the solvent the residue was purified with chromatographic methods.molecular weight (g/mol): 491.93 RT - UV254nm (min): 3.00IC50 hQC (nM): 80.8 |
Yield | Reaction Conditions | Operation in experiment |
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27% | Compound 226:; 1 -(1 H-Benzoimidazol-5-yl)-4-(cyclopentylimino)-5-(1 H-indol-5-yl)- imidazolidin-2-one; 1 H-Benzoimidazol-5-ylamine (1 mmol) and 1 H-lndole-5-carbaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2ml of a solution of KOCN (KSCN) (2mmol) and Pyridinehydrochloride (2mmol) in MeOH is added was added. Finally Isocyano-cyclopentane (1 mmol) is added. The reaction was stirred at room temperature for 48h. After evaporation of the solvent the residue was purified with chromatographic methods. Yield: 0.107 g (27 %); mp: 2100C, 1H-NMR (400 MHz, DMSO-D6): 1.20-1.25 (m, 1 H, CH2), 1.38-1.56 (m, 5 H, CH2), 1.70- 1.79 (m, 1 H, CH2), 1.82-1.90 (m, 1 H, CH2), 4.08-4.14 (m, 1 H, CH2-CH), 5.91 (s, 1 H, CH-N), 6.33-6.36 (m, 1 H, Ar), 6.85 (dd, 3J=8.3 Hz, 4J=1.7 Hz, 1 H, Ar), 7.24-7.33 (m, 4 H, 3 H Ar, 1 H Benzimid), 7.52 (s, 1 H, Benzimid), 7.63 (s, 1 H, Benzimid), 7.86 (m, 1 H, NH), 8.06 (s, 1 H, Benzimid), 11.05 (s, 1 H, NH), MS m/z 399.4 (M+H)+, HPLC (254 nm): rt 2.56 min (100 %), calc: C: 69.33, H: 5.57, N: 21.09, found.: C: 63.34, H: 6.16, N: 19.04 corresponds to C23H22N6O + 2.0 H2Omolecular weight (g/mol): 398.47 EPO <DP n="132"/>RT - UV254nm (min): 2.56IC50 hQC (nM): 34.5 |
Yield | Reaction Conditions | Operation in experiment |
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97% | In ethanol; at 75℃; for 20h; | EXAMPLE 1; The preparation of 3-(1H-benzimidazol-5-ylamino)-4-(3-hydroxybenzylamino)cyclobut-3-ene-1,2-dione (?A1?) is carried out analogously to the following scheme 1.1 6.2 g (35.7 mmol) of 3,4-diethoxy-3-cyclobutene-1,2-dione 1 are dissolved in 50 ml of ethanol, 5.0 g (35.7 mmol) of 3H-benzimidazol-5-ylamine 2 are added, and the mixture is stirred at 75 C. for 20 h. The mixture is then subjected to conventional work-up, giving 8.93 g (97%) of 3-(1H-benzimidazol-5-ylamino)-4-ethoxycyclobut-3-ene-1,2-dione 3; MS-FAB (M+H+)=358, m.p. 243-244. |
Yield | Reaction Conditions | Operation in experiment |
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42.2% | With potassium carbonate; In dichloromethane; water; at 0℃; for 3h; | 5-isothiocyanato-1 H-benzo[d]imidazole (14)To a suspension of thiophosgene (10 mmol, 1 eq.), potassium carbonate (10 mmol, 1 eq.), 5 ml_ of dichloromethane and 10 ml. of water was added slowly a suspension of 1 H-benzo[d]imidazol- 5-amine in 17.5 ml. of dichloromethane. The mixture was stirred at 00C for 3 hours. The organic layer was separated and washed with 10 ml. of water three times. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to result in a yellow solid. Yield: 0.74 g (42.2 %). 1H NMR: (DMSOd6, 400 Mhz) delta 7.25-7.27 (dd, H, 3J=8.3 Hz, 4J=I .7 Hz); 7.61-7.63 (d, H, J=8.3 Hz); 7.69 (d, H, 4J=1.7 Hz); 8.32 (s, H); 12.69 (bs, H) |
Yield | Reaction Conditions | Operation in experiment |
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Sodium hydride (7.2 g, 60% in mineral oil, 0.18 mol) was added in portions over 30 min to a stirred solution of 5-aminobenzimidazole (15.0 g, 0.105 mol) in dry DMF (100 mL) and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0 C. and a solution of di-tert-butyl dicarbonate (24.0 g, 0.110 mol) in dry DMF (25 mL) was added over 10 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (200 mL) and diethyl ether (200 mL). The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water and brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration through a pad of silica gel and the filtrate evaporated to give a mixture of 5- and 6-amino-1-tert-butoxycarbonylbenzimidazole, 21.5 g (84%). H1 NMR (DMSO-d6): delta 8.40 (s, 1H), 8.23 (s, 1H), 7.55 (d, 1H, J=8.8 Hz), 7.34 (d, 1H, J=8.4 Hz), 7.13 (d, 1H, J=1.6 Hz), 6.83 (d, 1H, J=2 Hz), 6.68 (dd, 1H, J=8.8, 1.6 Hz), 6.60 (dd, 1H, J=8.4, 2 Hz), 1.61 (s, 9H), 1.60 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; for 15h; | Example 17 N-(4-(4-(1H-benzo[D]imidazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide To a solution of 2,4-dichloro-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.28 mmol) in n-butyl alcohol (1 mL) was added 6-aminoindazole (0.043 g, 0.32 mmol) and DIPEA (0.057 mL, 0.32 mmol) at room temperature. After heating at 80 C. for 15 h, the mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with 1N HCl, Sat NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to give crude N-(1H-benzo[d]imidazol-6-yl)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.105 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.7% | To a solution (6 ML) of 1-[5-amino-2-(benzhydryloxy)phenyl]-2-methylpropan-1-one (190 mg, 0.550 mmol) in acetonitrile were added diisopropylethyl amine (0.110 ML, 0.660 mmol) and N,N'-disuccinimidyl carbonate (169 mg, 0.660 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour.. To the reaction solution were added diisopropylethyl amine (0.110 ML, 0.660 mmol) and 1H-benzoimidazol-5-amine (87.8 mg, 0.6605 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours.. The reaction solution was poured into water and was extracted with ethyl acetate.. The extracted solution was washed with water, and was dried with anhydrous magnesium sulfate.. The solvent was distilled off under reduced pressure, and the residue was purified by silicagel column chromatography (ethyl acetate:methanol = 10:1).. The fractions containing the titled compound were collected, which was washed with water, was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain the titled compound as a solid. 102 mg (36.7%) 1H-NMR (CDCl3) delta; 0.96 (6H, d, J = 7.0 Hz), 3.39 to 3.46 (1H, m), 6.07 (1H, s), 6.63 to 6.77 (2H, m), 7.18 to 7.46 (15H, m), 8.16 (2H, bs) |
Yield | Reaction Conditions | Operation in experiment |
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6.2% | 1 equivalent of the aldehyde was dissolved in AcOH (5 mL in case of 4 mmol starting material) and 1.1 equivalents of the amine were added. 1 equivalent of TMSCN was then added to the mixture. The mixture was stirred for 1.5 h at r.t.The mixture was then poured on ice/ammonia (containing 12 mL of a 25% NH3 solution in case of 4 mmol starting material). The aqueous layer was extracted 3 times by means of CH2Cl2 the organic phases were combined, dried, filtrated and the solvent was removed. The remains were re-dissolved in concentrated HCl and kept at 40 C. overnight. Water was added and the solution was neutralized by adding NaOH. The aqueous phase was extracted three times by means of CH2Cl2, thereafter the organic phases were combined and dried. The solvent was removed and the remains were taken up in triethyl-ortho formate. The mixture was kept under reflux for 1 h. The orthoester was removed and the remaining oil was dissolved in MeOH and NaBH4 (1.5 equivalents) were added. The mixture was kept at ambient temperature for 1 h, followed by 60 C. for 1 h and the reaction was quenched by addition of an aqueous solution of ammonia (12%). The aqueous layer was extracted three times by means of CH2Cl2, thereafter the organic phases were combined and dried. The solvent was removed and the remaining mixture was subjected to preparative HPLC. Example 631-(1H-benzo[d]imidazol-5-yl)-5-phenylimidazolidin-4-oneThe compound was synthesized starting from <strong>[934-22-5]5-aminobenzimidazole</strong> (0.75 g, 5.61 mmol), benzaldehyde (0.52 mL, 5.1 mmol), TMSCN (0.64 mL, 5.1 mmol), conc. aqueous HCl (10 mL), triethyl orthoformate (13 mL, excess), NaBH4 (0.227 g, 6 mmol) as described in method 4. Yield: 0.088 g (6.2%); MS m/z 279.3 (M+H)+; 1H NMR (400 MHz, DMSO-D6): delta 4.78-4.80 (m, H); 5.04-5.05 (m, H); 5.17-5.19 (m, H); 6.23 (d, H, J=2.1 Hz); 6.79 (dd, H, 3J=9.1 Hz, 4J=2.1 Hz); 7.24-7.27 (m, H); 7.30-7.36 (m, 4H); 7.59 (d, H, J=9.1 Hz); 8.89 (s, H); 9.16 (s, H), HPLC (lambda=214 nm), [B]: rt 6.43 min (97.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.3% | The compound was synthesized as hydrochloride salt by the following procedure.Phenyl chloroformate (0.98 mL, 7.8 mmol) was dissolved in CH2Cl2, cooled down to 0 C. and <strong>[934-22-5]5-aminobenzimidazole</strong> (0.865 g, 6.5 mmol) was added slowly. The mixture was kept at 0 C. for 30 min and then the mixture was allowed to adapt ambient temperature. The mixture was stirred at ambient temperature for 2 h. The resulting solid was withdrawn by suction, dried and taken up in a small amount of DMF. To the solution, 1-amino-3,3-dimethylbutan-2-one (0.986, 6.5 mmol) and TEA (2.73 mL, 19.5 mmol) were added. The mixture was kept at 40 C. for 2 h. The solvent was removed and purified by means of preparative HPLC. The remains were re-dissolved in MeOH and a small amount of HCl was added (1-2%). The solution was subjected to hydrogenation (PdC, 10% on charcoal, 4 bar, 60 C.) for 4 h. The catalyst was removed by filtration through a pad of CELITE and the residue was washed with water. The organic layer was dried, filtrated and the solvent was removed to result in the final product. Yield: 0.087 g (6.3%); MS m/z 259.4 (M+H)+; 1H NMR (DMSO, 400 MHz): delta 0.72 (s, 9H); 3.23-3.27 (m, H); 3.46-3.50 (m, H); 4.37-4.41 (m, H); 6.84 (bs, H); 7.56 (dd, H, 3J=9.1 Hz, 4J=1.7 Hz); 7.70 (d, H, J=9.1 Hz); 7.81 (d, H, 4J=1.7 Hz); 9.27 (s, H), HPLC (lambda=214 nm, [B]: rt 6.83 min (99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The respective 4-oxo-butanoic acid (1 eq.) was dissolved in dichlormethane (10 ml). Carbonyldiimidazole (1 eq.) was added and the mixture was stirred at room temperature for 1 h. After the addition of benzimidazol-5(6)-amine (1 eq.) the mixture was stirred overnight. The precipitated solid was collected by filtration and washed with dichlormethane to give the title compounds that were used without further purification. Step A4-(4-Fluorophenyl)-4-oxobutanoic acid (196 mg; 1 mmol; 1 eq.), carbonyldiimidazol (162 mg; 1 mmol; 1 eq.) and benzimidazol-5(6)-amine (133 mg; 1 mmol; 1 eq.); yield: 0.189 g (60.8%); MS m/z: 312.2 [M+H]+; HPLC ([A]): rt 10.45 min (81.9%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.1% | The respective 2-oxo benzoic acid (1 eq.) was dissolved in THF (5 ml in case of 1 mmol) and DCC (1 eq.) was added. After stirring at r.t. for 1 h, benzimidazol-5(6)-amine (1 eq.) was added and stirring at r.t. was continued for 24 h. The mixture was put into the fridge for 2 h and afterwards the precipitated solid was filtered off. The filtrate was concentrated in vacuo, re-dissolved in a mixture of AcOH and toluol (3 ml and 7 ml in case of 1 mmol batch) and refluxed over night. After cooling the solvents were evaporated. The resulting residue was dissolved in CH2Cl2 (10 ml in case of 1 mmol batch), cooled to 0 C. and treated with TFA (1 ml (4 ml) per mmol). After stirring at r.t. for 10 min, triethylsilane (2 eq. (4 eq.)) was added. The reaction was allowed to warm up to room temperature and stirred for 3 h. After that time, the mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×25 ml). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the remaining residue was purified by flash-chromatography using silica gel and a CHCl3/MeOH gradient. Example 1262-(1H-benzo[d]imidazol-5-yl)-3-(4-biphenyl)isoindolin-1-oneThe compound was synthesized according to method 11.2-(4-Phenylbenzoyl)benzoic acid (1.0 g; 3.3 mmol), DCC (680 mg; 3.3 mmol), benzimidazol-5(6)-amine (440 mg; 3.3 mmol), TFA (3.92 ml) and triethylsilane (0.624 ml; 3.92 mmol; 4 eq.) and was additional purified by semi-preparative HPLC; yield: 0.120 g (9.1%); MS m/z: 402.1 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): delta 6.79 (s, 1H); 7.28-7.32 (m, 1H); 7.36-7.40 (m, 5H); 7.53-7.60 (m, 5H); 7.63-7.66 (m, 1H); 7.72-7.74 (d, 1H, 3J=8.7 Hz); 7.76-7.79 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.89-7.91 (m, 1H); 8.17-8.18 (d, 1H, 4J=1.7 Hz); 9.06 (s, 1H); HPLC (Gradient 3): rt 15.20 min (97.0%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.045 g (15.4%) | With potassium carbonate; | Example 40 N-(2,5-Dichlorobenzyl)-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), <strong>[85482-13-9]2,5-dichlorobenzylbromide</strong> (528 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5. Yield: 0.045 g (15.4%); MS m/z: 292.2/294.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 4.32 (d, 2H, 3J=6.1 Hz); 6.20 (br s, 1H); 6.43 (br s, 1H); 6.60 (dd, 1H, 4J=1.6 Hz, 3J=8.8 Hz); 7.30-7.33 (m, 2H); 7.40 (d, 1H, 4J=2.6 Hz); 7.49 (d, 1H, 3J=8.5 Hz); 7.86 (s, 1H), 11.83 (br s, 1H); HPLC (METHOD [A]): rt 12.97 min (100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.067 g (15.1%) | With potassium carbonate; | Example 37 N,N-Bis((2-methylquinolin-6-yl)methyl)-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), <strong>[141848-60-4](2-methylquinolin-6-yl)methylbromide</strong> (519 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.067 g (15.1%); MS m/z: 444.5 [M+H]+, 222.8 [M+2H]2+; 1H-NMR (500 MHz, DMSO d6): delta 2.60 (s, 6H); 4.92 (s, 4H); 6.77-6.82 (m, 2H); 7.33-7.35 (m, 3H); 7.67 (dd, 2H, 4J=2.1 Hz, 3J=8.5 Hz); 7.77 (br s, 2H); 7.85-7.87 (m, 3H); 8.14 (d, 2H, 3J=8.5 Hz); 11.81 (br s, 1H); HPLC (METHOD [A]): doublepeak rt 6.61 min (61.2%), 6.84 min (38.8%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.187 g (37.9%) | With potassium carbonate; | Example 36 N,N-Bis((5-chlorobenzo[b]thiophen-3-yl)methyl)-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), <strong>[1198-51-2](5-chlorobenzo[b]thiophen-3-yl)methylbromide</strong> (576 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.187 g (37.9%); MS m/z: 494.4/496.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 4.84 (s, 4H); 6.90-6.92 (m, 2H); 7.37-7.39 (m, 3H); 7.51 (s, 2H); 7.88 (d, 2H); 7.94-7.96 (m, 2H); 7.98 (s, 1H); 12.00 (br s, 1H); HPLC (METHOD [A]): rt 19.77 min (100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-(1H-Benzo[d]imidazol-5-yl)-5-(4-butoxyphenyl)-pyrrolidine-2,4-dione The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.798 g, 6 mmol), 4-butoxybenzaldehyde (1.0 g, 6 mmol), 2-(ethoxycarbonyl)acetic acid (0.79 g, 6 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.943 g, 6 mmol) and sodium tert.-butoxide (0.572 g, 5 mmol) according to method 3. Yield: 0.50 g (22.9%); MS m/z 364.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | General procedure: A solution of 1 H-benzo[d]imidazol-5-amine (1 eq.) and the respective aldehyde (1 eq.) in dry methanol (3 ml in case of 1 mmol) was stirred at room temperature for 3 hours. After addition of 2-(ethoxycarbonyl)acetic acid (1 eq.) and 1-isocyano-2-methylpropan-2-yl methyl carbonate (1 eq.) stirring was continued for 16 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using a CHCl3/MeOH gradient. | |
Ethyl 2-[(1H-benzo[d]imidazol-5-yl)([4-(morpholin-4-yl)phenyl]({2-[(methoxy-carbonyl) oxy]-2-methylpropyl}carbamoyl)methyl})carbamoyl]acetate The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.134 g, 1 mmol), 4-morpholinobenzaldehyde (0.191 g, 1 mmol), 2-(ethoxycarbonyl)acetic acid (119 mul, 0.133 g, 1 mmol) and 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.157 g, 1 mmol) according to the method described in step 1. Yield: 0.38 g (63.8%); MS m/z 349.3, 596.6 [M+H]+; HPLC (lambda=214 nm, [A]): rt 11.24 min (81%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | General procedure: A mixture of compound II-1, II-2 or II-3 (2 mmol),SnCl2·2H2O (10 mmol) in EtOAc (15 mL) was refluxed for12 h. When the reaction was complete according to TLCanalysis, the resulting reaction mixture was cooled to room temperature. Subsequently, the reaction mixture wasadjusted to pH 8-9 with saturated aq. NaHCO3 (50 mL).Then the mixture was extracted with EtOAc (2 × 150 mL).The combined organic phase was washed with brine (200mL), dried over anhydrous Na2SO4, and concentrated toafford compounds III-1, III-2 or III-3, which were useddirectly for the next step without further purification. To amixture of 5-amino-1H-benzimidazole (III-1, III-2 or III-3,2 mmol), water (5 mL) and concentrated HCl (12 mol/L,0.51 mL) at 0C, a solution of sodium nitrite (NaNO2, 2.1mmol) in water (10 mL) was added dropwise whilemaintaining the temperature below 5C. After stirring for 20min, a solution of diazonium chloride was prepared.Subsequently, a solution of diazonium chloride was addedgradually to a mixture of phenols (IV-1-IV-10, 2 mmol),sodium hydroxide (NaOH, 2 mmol), ethanol (15 mL) andwater (25 mL) at 0-5C. After the addition of the abovediazonium solution, the mixture was continued to stir for 3-6h until a lot of precipitate was produced. The solid wascollected, washed with water (3×10 mL), dried and purifiedby PTLC to give the target products V-1~V-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | b) 5-Azido-1H-benzo[djimidazoleTo a solution of the compound of Intermediate Example 14(a) (2 g, 15 mmol) in concentrated HC1 (8 ml) at 0 C?was added aqueous solution of NaNO2 (1.3 g, 18.7 mmol, 1.25 eq) dropwise and the mixture was stirred at 0 C for 30 ruin. Then NaN3(1.13g. 18.7 mmol, 1.25 eq)was added at 0 C and the mixture was stirred for 15mm. The? mixture was quenched and extracted as in Intermediate Example 1(a). The solvent was distilled off to afford the product in 75 % yield (1.8 g). LC-MS (ESI): Calculated mass: 159.05; Observed mass: 160.0 [M+H] (rt: 0.136 ruin). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.4% | With acetic acid; In i-Amyl alcohol;Reflux; Inert atmosphere; | 2,3-Dibromo-6-hydroxy-5-methoxybenzaldehyde (0.1 g, 0.32 mmol), 5-Aminobenzimidazole (0.03 g, 0.21 mmol), and isoamyl alcohol (2 mL) were stirred at room temperature under N2. Acetic acid (0.07 mL) was added drop-wise, and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH2Cl2, MeOH, and dried to yield 26 (0.06 g, 0.14 mmol, 65.4%) as an orange powder. 1H NMR (DMSO, 300 MHz) delta 15.54 (s, 1H), 9.20 (s, 1H), 8.34 (s, 1H), 7.76-7.68 (m, 2H), 7.43 (s, 1H), 7.38 (s, 1H), 3.86 (s, 3H); 13C NMR (DMSO, 700 MHz) delta 162.30, 154.74, 149.45, 144.27, 140.84, 120.42, 118.82, 118.46, 117.60, 117.43, 117.10, 113.95, 112.87, 56.78. Rf=0.48 (CH2Cl2/MeOH 9:1) |
65.4% | With acetic acid; In i-Amyl alcohol;Inert atmosphere; Reflux; | 2,3-di-bromo-6-hydroxy-5-methoxybenzaldehyde (0.1g, 0.32 mmol), 5-amino-benzimidazole (0.03g, 0.21 mmol) and isoamyl alcohol (2 mL) and N2It was stirred at room temperature.It was added dropwise acetic acid (0.07 mL) and the mixture was refluxed overnight.Filtering the reaction mixture, CH2Cl2and dried and then washed with MeOH, the orange powder obtained in26to give a (0.06g, 0.14mmol, 65.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.4% | With acetic acid; In i-Amyl alcohol;Reflux; Inert atmosphere; | 2,3-Dibromo-5-ethoxy-6-hydroxybenzaldehyde (0.1 g, 0.31 mmol), 5-Aminobenzimidazole (0.03 g, 0.20 mmol), and isoamyl alcohol (2 mL) were stirred at room temperature under N2. Acetic acid (0.07 mL) was added drop-wise, and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH2Cl2, MeOH, and dried to yield 29 (0.06 g, 0.13 mmol, 65.4%) as an orange powder. 1H NMR (DMSO, 300 MHz) delta 15.57 (s, 1H), 12.50 (bs, 1H), 9.20 (s, 1H), 8.31 (s, 1H), 7.81-7.68 (m, 2H), 7.38 (s, 1H), 7.35 (s, 1H), 4.10 (q, 2H, J=6.9 Hz), 1.36 (t, 3H, J=6.9 Hz); 13C NMR (DMSO, 700 MHz) delta 162.36, 154.82, 148.63, 144.23, 140.92, 120.40, 119.77, 117.69, 117.42, 117.30, 116.15, 113.00, 111.88, 104.91, 65.01, 15.00. Rf=0.48 (CH2Cl2/MeOH 9:1) |
65.4% | With acetic acid; In i-Amyl alcohol;Inert atmosphere; Reflux; | 2,3-di-bromo-5-ethoxy-6-hydroxybenzaldehyde (0.1g, 0.31 mmol), 5- amino-benzimidazole (0.03g, 0.20 mmol) and isoamyl alcohol (2 mL) and N2It was stirred at room temperature.It was added dropwise acetic acid (0.07 L) and the mixture was refluxed overnight.Filtering the reaction mixture, CH2Cl2and dried and then washed with MeOH, the compound as an orange powder29to give a (0.06g, 0.13mmol, 65.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With toluene-4-sulfonic acid; In butan-1-ol; at 110℃; for 18h; | 5-Aminobenzimidazole (47 mg, 0.36 mmol) and compound 5 (50 mg, 0.12 mmol) were dissolved in n-butanol (0.5 mL), p-toluene sulfonic acid monohydrate (43 mg, 0.24 mmol) was added. The mixture was heated to 110 C. and stirred for 18 hours, then cooled to room temperature. The mixture was treated with saturated aqueous NaHCO3 solution (10 mL), extracted with dichloromethane (5 mL×3). The organic layers were combined, washed with water (5 mL×3) and saturated brine (5 mL), dried over anhydrous sodium sulfate, then filtrated. The residue was purified by preparation HPLC (mobile phase:methanol, water (0.05% trifluoroacetic acid); gradient: 50%-80%-10%) to give yellow solid T-58 (20 mg, yield: 33%). LC-MS (ESI): m/z=520 [M+H]+. (0376) 1H-NMR (500 MHz, DMSO-d6) delta: 10.11 (s, 1H), 9.45 (s, 1H), 8.88 (s, 1H), 8.76 (d, J=1.5 Hz, 1H), 8.52 (s, 2H), 8.47 (d, J=1.5 Hz, 1H), 7.85 (dd, J=10 Hz, J=1.5 Hz, 1H), 7.44 (d, J=5.5 Hz, 1H), 4.59 (d, J=9 Hz, 2H), 4.29 (d, J=9 Hz, 2H), 3.75 (s, 2H), 3.25 (q, J=7 Hz, 2H), 1.26 (t, J=7 Hz, 3H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In tetrahydrofuran; at 70℃; for 4h; | General procedure: 2-Chloro-4,6-dimethoxy-1,3,5-triazine (1 mmol) (2), substituted aniline (1 mmol)/heterocyclic amines (3) (1 mmol), anhydrous K2CO3 (2 mmol) were added in dry THF (5 mL) taken in a round bottom flask. The reaction mixture was refluxed at 70 C for 4 h. After completion of the reaction the product is confirmed on thin-layer chromatography (TLC) using eluent (2:8 mL,ethyl acetate-hexane). The reaction mixture was quenched with water and the crude product was extracted with ethyl acetate (3 times) and organic layer was separated and dried over anhydrous Na2SO4. The solvent evaporated on rotavapour. The Crude material was purified by column chromatography (ethylacetate-n-hexane) and product 4(a-x) with good yield (70-75 %) were obtained (Scheme-II). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.0% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; | General procedure: [0205] A solution of benzimidazol-5-amine (1 eq.) in DMF (5 ml) was treated with K2CO3 (2.2 eq.) and the respectivealkylhalide (2.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted by meansof ethyl acetate (3x25 ml). The combined organic layers were dried over Na2SO4, evaporated and the residue waspurified by flash chromatography on silica using a CHCl3/MeOH gradient; Example 20 N,N-Bis((4-methylbenzyl)-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-methylbenzylbromide (407 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.109 g (32.0%); MS m/z: 342.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 2.23 (s, 6H); 4.57 (s, 4H); 6.66 (br s, 1 H); 6.71 (dd, 1 H, 4J=2.1 Hz, 3J=8.9 Hz); 7.09 (d, 4H, 3J=7.9 Hz); 7.14 (d, 4H, 3J=7.9 Hz); 7.30 (d, 1 H, 3J=8.5 Hz); 7.88 (s, 1 H); 11.88 (br s, 1 H); HPLC (METHOD [A]): rt 17.36 min (98.1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of 1 H-benzo[d]imidazol-5-amine (1 eq.) and the respective aldehyde (1 eq.) in dry methanol (2-5 ml per mmoll) was stirred at room temperature for 3 hours. After addition of 2-(ethoxycarbonyl)acetic acid (1 eq.) and 1-isocyano-2-methylpropan-2-yl methyl carbonate (1 eq.) stirring was continued for 16-24 hours. The solvent was evaporated and the residue was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14 mg | Example 297: Preparation of N2-(lH-benzo[d]imidazol-6-yl)-N4-(5-cyclobutyl-lH-pyrazol- 3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.087 g, 0.401 mmol), 5-cyclobutyl-lH- pyrazol-3-amine (0.055 g, 0.401 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.077 ml,0.441 mmol) were mixed in acetonitrile (2 ml). The mixture was microwaved at 80 C for 20 min and then concentrated. lH-benzo[d]imidazol-6-amine (0.053 g, 0.401 mmol) and acetic acid (0.024 g, 0.401 mmol) were added. The mixture was microwaved at 110 C for 20 min and then concentrated. 14 mg of product was recovered after automated reverse phase chromatography (water-MeCN). MS calcd for [Ci9Hi7F3N8+H]+: 415.16, found 415.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | To a solution of (4,S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-l,4- methanopyrido[2,3-£][l,4]diazepine (300 mg, 0.983 mmol) in THF (20 mL) at RT was added Et3N (0.822 mL, 5.90 mmol), tri-phosgene (292 mg, 0.983 mmol) and stirred for 1 h. then lH-benzo[d]imidazol-5-amine (393 mg, 2.95 mmol) was added and the reaction was heated at 65 C for 15 h. (TLC eluent: 100% EtOAc: R/-0.2; UV active). The reaction mixture was cooled to RT, concentrated in vacuo and the residue was partitioned between water (30 mL) and DCM (50 mL). Organic layer was separated and dried over anhydrous sodium sulphate, filtered and filtrate was evaporated to get crude compound. The crude product was purified by flash column chromatography (neutral alumina, eluent: 70% ethyl acetate in hexane) to afford the desired product (4,S)-N-(lH-benzo[<i]imidazol-5-yl)-7-(3- (trifluoromethyl)phenyl)-3,4-dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)- carboxamide (215 mg, 0.461 mmol, 47.0 % yield) as an off-white solid. LCMS (m/z): 465.09 [M+H]+, Rt = 1.77 min1H NMR (400 MHz, DMS0 ): 5ppm 13.02 - 12.63 (m, 1 H), 12.34 (br s, 1 H), 8.30 - 8.20 (m, 2 H), 8.16 - 8.10 (m, 1 H), 8.06 (s, 1 H), 7.92 - 7.77 (m, 2 H), 7.73 - 7.67 (m, 1 H), 7.67 - 7.60 (m, 1 H), 7.52 - 7.37 (m, 1 H), 7.18 - 6.91 (m, 1 H), 5.53 (dd, J=5.70, 3.07 Hz, 1 H), 3.22 (br t, 7=9.21 Hz, 1 H), 3.16 - 3.05 (m, 2 H), 2.97 (dd, 7=12.06, 3.29 Hz, 1 H), 2.35 - 2.19 (m, 1 H), 1.95 (dt, 7=13.37, 6.69 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 14h; | To 185 mg 2-bromobenzaldehyde (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine(1.0 mmol), 213 mg <strong>[845267-78-9]ter<strong>[845267-78-9]t-butyl 2,4-dioxopiperidine-1-carboxylate</strong></strong>(1.0 mmol), 10 mg CuI (0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for14 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 350 mg (85 %) 5a as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M.p.:[300 C; 1H NMR (CDCl3, 400 MHz): d = 1.67 (s, 9H,3CH3), 3.50-3.53 (m, 2H, CH2), 4.30 (t, J = 6.0 Hz, 2H,CH2), 7.58 (t, J = 7.6 Hz, 1H, ArH), 7.83 (t, J = 7.6 Hz,1H, ArH), 8.05 (d, J = 8.8 Hz, 1H, ArH), 8.18 (d,J = 8.0 Hz, 1H, ArH), 8.44 (d, J = 8.8 Hz, 1H, ArH),8.83 (d, J = 7.6 Hz, 1H, ArH), 9.05 (s, 1H, ArH) ppm; 13CNMR (CDCl3, 100 MHz): d = 28.2, 34.4, 43.3, 83.8,116.0, 121.9, 125.6, 126.3, 128.7, 132.1, 132.4, 133.9,134.8, 137.5, 140.1, 141.7, 146.5, 151.8, 159.0, 160.6,164.9 ppm; IR (KBr): v = 3097, 2976, 2915, 1706, 1651,1610, 1595, 1563, 1545, 1513, 1469, 1409, 1343, 1314,1282, 1246, 1152, 1102, 1091, 827, 806, 775, 761 cm-1;HRMS (ESI): m/z calcd for C24H21N4O3 [M ? H]?413.1614, found 413.1608. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 17h; | To 203 mg 2-bromo-4-fluorobenzaldehyde (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg <strong>[845267-78-9]ter<strong>[845267-78-9]t-butyl 2,4-dioxopiperidine-1-carboxylate</strong></strong> (1.0 mmol), 10 mg CuI(0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 17 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 327 mg(76 %) 5d as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M.p.: [300 C; 1HNMR (CDCl3, 400 MHz): d = 1.67 (s, 9H, 3CH3), 3.51 (t,J = 6.0 Hz, 2H, CH2), 4.30 (t, J = 6.0 Hz, 2H, CH2),7.28-7.31 (m, 1H, ArH), 7.80-7.83 (m, 1H, ArH), 8.05 (d,J = 9.2 Hz, 1H, ArH), 8.43 (d, J = 8.8 Hz, 1H, ArH),8.84-8.87 (m, 1H, ArH), 8.95 (s, 1H, ArH) ppm; 13C NMR(CDCl3, 100 MHz): d = 28.2, 34.4, 43.3, 83.9, 103.0 (d,JF-C = 25.7 Hz), 112.8, 113.6 (d, JF-C = 21.7 Hz), 116.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 17h; | To 219 mg <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg tert-butyl 2,4-dioxopiperidine-1-carboxylate (1.0 mmol), 10 mg CuI(0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 17 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 371 mg(83 %) 5c as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M. p.: [300 C; 1HNMR (CDCl3, 400 MHz): d = 1.59 (s, 9H, 3CH3), 3.51 (t,J = 6.0 Hz, 2H, CH2), 4.28-4.31 (m, 2H, CH2), 7.51-7.53(m, 1H, ArH), 8.06 (d, J = 9.2 Hz, 1H, ArH), 8.14-8.15(m, 1H, ArH), 8.44 (d, J = 8.8 Hz, 1H, ArH), 8.76 (d,J = 8.8 Hz, 1H, ArH), 9.00 (s, 1H, ArH) ppm; 13C NMR(CDCl3, 100 MHz): d = 28.2, 34.4, 43.2, 83.9, 116.1,117.5, 119.0, 121.0, 122.2, 125.9, 126.4, 129.2, 133.3,134.1, 134.3, 138.5, 146.5, 151.7, 156.7, 159.2, 164.8,165.0 ppm; IR (KBr): v = 3098, 2981, 2935, 1716, 1697,1656, 1606, 1592, 1557, 1510, 1472, 1391, 1369, 1340,1320, 1308, 1279, 1249, 1187, 1147, 1096, 963, 873, 851,820, 767 cm-1; HRMS (ESI): m/z calcd for C24H20ClN4O3[M ? H]? 447.1224, found 447.1215. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 18h; | To 219 mg 2-bromo-5-chlorobenzaldehyde (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg <strong>[845267-78-9]ter<strong>[845267-78-9]t-butyl 2,4-dioxopiperidine-1-carboxylate</strong></strong> (1.0 mmol), 10 mg CuI(0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 18 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 348 mg(78 %) 5e as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M.p.: [300 C; 1HNMR (CDCl3, 400 MHz): d = 1.70 (s, 9H, 3CH3), 3.51 (t,J = 6.0 Hz, 2H, CH2), 4.30 (t, J = 6.0 Hz, 2H, CH2),7.74-7.76 (m, 1H, ArH), 8.02-8.07 (m, 2H, ArH), 8.41 (d,J = 8.8 Hz, 1H, ArH), 8.77-8.78 (m, 1H, ArH), 8.97 (s,1H, ArH) ppm; 13C NMR (CDCl3, 100 MHz): d = 28.2,34.3, 42.9, 84.1, 113.1, 117.1, 118.0, 121.9, 122.2, 126.4,131.2, 131.7, 132.0, 132.3, 133.1, 134.9, 146.5, 152.3,159.1, 161.8, 164.6 ppm; IR (KBr): v = 3088, 2988, 2977,1762, 1727, 1687, 1668, 1543, 1480, 1470, 1393, 1370,1306, 1291, 1253, 1202, 1149, 1095, 1046, 1032, 988, 974,958, 844, 830, 822, 799, 768 cm-1; HRMS (ESI): m/zcalcd for C24H20ClN4O3 [M ? H]? 447.1224, found447.1207. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 11h; | To 191 mg 3-bromothiophene-2-carbaldehyde (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg <strong>[845267-78-9]ter<strong>[845267-78-9]t-butyl 2,4-dioxopiperidine-1-carboxylate</strong></strong> (1.0 mmol), 10 mg CuI(0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 11 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 335 mg(80 %) 5i as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M.p.: [300 C; 1HNMR (CDCl3, 400 MHz): d = 1.69 (s, 9H, 3CH3), 3.55 (t,J = 6.0 Hz, 2H, CH2), 4.21 (t, J = 6.0 Hz, 2H, CH2), 7.83(d, J = 5.6 Hz, 1H, ArH), 8.03 (d, J = 5.6 Hz, 1H, ArH),8.08 (d, J = 8.8 Hz, 1H, ArH), 8.47 (d, J = 8.8 Hz, 1H,ArH), 8.92 (s, 1H, ArH) ppm; 13C NMR (CDCl3,100 MHz): d = 28.2, 34.3, 43.3, 83.6, 111.3, 112.2,114.7, 121.6, 122.3, 126.0, 133.1, 133.4, 134.0, 135.1,136.2, 146.6, 151.7, 158.6, 164.7 ppm; IR (KBr):v = 3097, 3071, 2985, 1695, 1659, 1592, 1531, 1509,1488, 1460, 1397, 1386, 1370, 1329, 1313, 1274, 1253,1226, 1169, 1149, 1108, 1084, 1038, 1023, 976, 961, 869,848, 828, 775 cm-1; HRMS (ESI): m/z calcd for C22H19-N4O3S [M ? H]? 419.1178, found 419.1176. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h; | To 229 mg 6-bromopiperonylaldehyde (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg <strong>[845267-78-9]ter<strong>[845267-78-9]t-butyl 2,4-dioxopiperidine-1-carboxylate</strong></strong> (1.0 mmol), 10 mg CuI (0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 12 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 406 mg (89 %) 5g as pale yellow powder using ethyl acetate and petroleum ether (1:2) as aneluent. M.p.: [300 C; 1H NMR (CDCl3, 400 MHz):d = 1.67 (s, 9H, 3CH3), 3.49 (t, J = 6.0 Hz, 2H, CH2),4.28 (t, J = 6.0 Hz, 2H, CH2), 6.20 (s, 2H, OCH2O), 7.52(s, 1H, ArH), 7.03 (d, J = 8.8 Hz, 1H, ArH), 8.10 (s, 1H,ArH), 8.42 (d, J = 9.2 Hz, 1H, ArH), 8.90 (s, 1H, ArH)ppm; 13C NMR (CDCl3, 100 MHz): d = 28.2, 34.4, 43.1,83.8, 96.1, 100.0, 102.9, 109.8, 111.9, 112.5, 114.8, 117.0,121.8, 126.1, 130.3, 132.7, 134.6, 146.0, 146.4, 151.7,152.1, 159.0 ppm; IR (KBr): v = 3050, 2979, 2928, 2915,1756, 1719, 1634, 1593, 1545, 1514, 1468, 1415, 1389,1370, 1320, 1261, 1244, 1190, 1145, 1105, 1037, 964, 933,894, 849, 827, 772 cm-1; HRMS (ESI): m/z calcd forC25H21N4O5 [M ? H]? 457.1512, found 457.1512. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 11h; | To 185 mg 2-chloro-5-nitrobenzaldehyde (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg <strong>[845267-78-9]ter<strong>[845267-78-9]t-butyl 2,4-dioxopiperidine-1-carboxylate</strong></strong> (1.0 mmol), 10 mg CuI (0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 11 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 379 mg (83 %) 5h as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M.p.: [300 C; 1H NMR (CDCl3, 400 MHz):d = 1.73 (s, 9H, 3CH3), 3.51 (t, J = 6.0 Hz, 2H, CH2),4.37 (t, J = 6.0 Hz, 2H, CH2), 8.14 (d, J = 9.2 Hz, 1H,ArH), 8.30 (d, J = 8.8 Hz, 1H, ArH), 8.49 (d, J = 8.8 Hz,1H, ArH), 8.67-8.70 (m, 1H, ArH), 9.09 (s, 1H, ArH),9.82-9.83 (m, 1H, ArH) ppm; 13C NMR (CDCl3,100 MHz): d = 28.1, 34.4, 43.0, 84.7, 100.0, 113.3,116.8, 118.4, 121.2, 122.9, 126.66, 126.71, 128.3, 133.4,133.5, 137.3, 144.3, 146.7, 152.4, 159.7, 164.0 ppm; IR(KBr): v = 3099, 2979, 1758, 1724, 1692, 1617, 1591,1575, 1548, 1526, 1481, 1394, 1371, 1339, 1305, 1280,1255, 1212, 1155, 1123, 1097, 1049, 990, 971, 857, 835,814, 794 cm-1; HRMS (ESI): m/z calcd for C24H19N5O5-Na [M ? Na]? 480.1284, found 480.1265. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 15h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 16h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 16h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 18h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 18h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 18h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 14h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 10h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 10h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 16h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 16h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 18h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To the solution of 1H-benzimidazol-5-amine 121 (0.68 g, 5.11 mmol) in acetic acid (20 mL), the Compound 120a (1.06 g, 5.62 mmol) was added and stirred at room temperature for 20 minutes. TMSCN (1 mL) was added dropwise to the reaction mixture and continuously stirred for 2 hours. After reaction completing, the reaction mixture was concentrated under reduced pressure to yield a viscous liquid. The viscous liquid was diluted with ethyl acetate (10 mL) and water. The diluted solution was adjusted to the pH 6-7 with ammonia at an ice-bath. The neutralized solution was extracted with ethyl acetate (20 mL x 4), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a viscous dark-yellow solid. The solid was dissolved in ethyl acetate (15 mL) and brine (15 mL). The mixture was stirred at room temperature for 2 minutes to form the pale-yellow precipitates. The pale-yellow precipitates was filtered and washed with water. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to obtain the pale- yellow solid. Those pale-yellow solids were combined as the desired product 122a at a yield of 96%. | |
(1H-benzimidazol-5-ylamino)[4-(1,3-thiazol-2-yl)phenyl]acetonitrile (Compound 122a) To the solution of 1H-benzimidazol-5-amine 121 (0.68 g, 5.11 mmol) in acetic acid (20 mL), the Compound 120a (1.06 g, 5.62 mmol) was added and stirred at room temperature for 20 minutes. TMSCN (1 mL) was added dropwise to the reaction mixture and continuously stirred for 2 hours. After reaction completing, the reaction mixture was concentrated under reduced pressure to yield a viscous liquid. The viscous liquid was diluted with ethyl acetate (10 mL) and water. The diluted solution was adjusted to the pH 6-7 with ammonia at an ice-bath. The neutralized solution was extracted with ethyl acetate (20 mL*4), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a viscous dark-yellow solid. The solid was dissolved in ethyl acetate (15 mL) and brine (15 mL). The mixture was stirred at room temperature for 2 minutes to form the pale-yellow precipitates. The pale-yellow precipitates was filtered and washed with water. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to obtain the pale-yellow solid. Those pale-yellow solids were combined as the desired product 122a at a yield of 96%. |
Tags: 934-22-5 synthesis path| 934-22-5 SDS| 934-22-5 COA| 934-22-5 purity| 934-22-5 application| 934-22-5 NMR| 934-22-5 COA| 934-22-5 structure
[ 90000-54-7 ]
1H-Benzo[d]imidazole-5,6-diamine dihydrochloride
Similarity: 0.93
[ 26530-93-8 ]
1-Methyl-1H-benzo[d]imidazol-6-amine
Similarity: 0.91
[ 90000-54-7 ]
1H-Benzo[d]imidazole-5,6-diamine dihydrochloride
Similarity: 0.93
[ 26530-93-8 ]
1-Methyl-1H-benzo[d]imidazol-6-amine
Similarity: 0.91
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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 |
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