* 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.
General procedure: o-Phenylenediamine (0.54 g, 5 mmol) and required amino acid or anthranilic acid (7 mmol) was added sequentially to 10 ml of toluene in a quickfit flask. The reacting mixture was heated under reflux at carefully controlled temperature of 85 – 95 oC for 9 h under the influence of a magnetic stirrer to obtain coloured solution which was allowed to cool overnight. The crystals formed was filtered and air-dried to afford (1H-benzo[d]imidazol-2-yl)methanamine, 10a in 97.3percent yield. Due to high efficiency observed in Method B for the synthesis of 10a,it was therefore adopted as the viable method for the synthesis of the rest of the compounds 10b-i. Synthesis of (1H-benzo[d] imidazol- 2- yl) methanamine, 10aTreatment ofo-phenylenediamine (0.54 g, 5 mmol) with L-glycine (0.53 g, 7 mmol) afforded(1H-benzo[d]imidazol-2-yl)methanamine, 10a.1HNMR (400 MHz, DMSO-d6) δ: 7.95 (s, 1H, NH), 7.82-7.80 (d, J= 8.03 Hz, 2H, Ar-H), 7.17-7.13 (m, 2H, Ar-H), 6.44-6.42 (t, J= 5.78 Hz, 2H, NH2-CH2), 3.55-3.53 (t, J= 5.78 Hz, 2H, CH2-NH2). 13C-NMR (100 MHz, DMSO-d6) δ: 142.6, 139.3, 138.9, 125.3, 125.3, 119.2, 119.2, 41.7 ppm. lmax in nm (log εmax): 236 (1.7782), 290 (1.324), 407 (0.8541). IR (KBr): 3384, 3363 (N-H of NH2, two bands), 3245 (N-H), 3021 (C-H aromatic), 2930 (C-H aliphatic), 1605 (C=C), 1580 (C=N), 741 (Ar-H) cm-1. MS: in m/z (rel. percent): 295.04 (2M + 1, 10.5percent), 148.01 (MH, 24.5percent), 147.03 (M+, 20percent), 132.04 (M – NH, 100percent), 118.07 (M – CH2=NH, 35.3percent), 76.11 (68.3percent).
87%
With hydrogenchloride In water for 2 h; Reflux
A solution of 1,2-phenylenediamine (13 g, 0.12 mol) and glycine (18 g, 0.24 mol) in 4 N hydrochloric acid (40 mL) was heated to reflux with stirring for 2 h. The progress of the reaction was monitored by TLC. On completion of the reaction, the reaction mixture was cooled to room temperature and the pH was adjusted to 7.2 using 1 N sodium hydroxide solution to obtain buff colored product 1. The product was recrystallized using rectified sprit as solvent.Yield: 87 percent, mp 261−263 °C, Rf: 0.72, IR (KBr) 3371 (NH2), 3053 (=C−H), 1591 (C=N) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H, NH), 7.2−6.9 (m, 4H), 5.2 (s,2H, NH2), 2.3 (d, J = 12.7 Hz, 2H, CH2).
61%
With hydrogenchloride In water for 5 h; Reflux
General procedure: General procedure for the synthesis of (1H-benzimidazole-2-yl)alkylamines was adapted from the Phillips procedure.18 L-Amino acid was added to a stirred solution of 4-nitro-o-phenylendiamine and aqueous HCl (5.5 M). The mixture was heated under reflux for 5 h. The blue reaction mixture was cooled to room temperature. The mixture was allowed to stand for overnight where upon the desired (1H-benzimidazole-2-yl)alkylamine was crystallized in its HCl salt form. The free base was obtained by neutralization of the reaction mixture with 1M K2CO3 solution followed by extraction with ethyl acetate. The extract was evaporated to dryness and recrystallized from an ethanol.
Reference：
[1] Oriental Journal of Chemistry, 2016, vol. 32, # 1, p. 109 - 120
[2] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[3] Journal of the Korean Chemical Society, 2014, vol. 58, # 5, p. 450 - 455
[4] Asian Journal of Chemistry, 2014, vol. 26, # 3, p. 926 - 932
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 550 - 558
[6] Die Pharmazie, 1980, vol. 35, # 2, p. 73 - 75
[7] Journal of the Indian Chemical Society, 1988, vol. 65, # 12, p. 853 - 854
[8] Bulletin de la Societe Chimique de France, 1991, p. 255 - 259
[9] Organic Letters, 2009, vol. 11, # 4, p. 907 - 910
[10] European Journal of Medicinal Chemistry, 2003, vol. 38, # 5, p. 473 - 480
[11] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1800 - 1807
[12] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3437 - 3446
[13] Bangladesh Journal of Pharmacology, 2016, vol. 11, # 1, p. 67 - 74
[14] Tetrahedron, 2016, vol. 72, # 27-28, p. 3980 - 3985
Reference：
[1] Journal and Proceedings of the Royal Society of New South Wales, 1937, vol. 71, p. 209,221
[2] Chemische Berichte, 1959, vol. 92, p. 977,980
[3] Chemische Berichte, 1959, vol. 92, p. 977,980
[4] Supramolecular Chemistry, 2011, vol. 23, # 6, p. 435 - 440
[5] Supramolecular Chemistry, 2012, vol. 24, # 10, p. 748 - 754,7
[6] Inorganic Chemistry, 2017, vol. 56, # 15, p. 8889 - 8899
General procedure: o-Phenylenediamine (0.54 g, 5 mmol) and required amino acid or anthranilic acid (7 mmol) was added sequentially to 10 ml of toluene in a quickfit flask. The reacting mixture was heated under reflux at carefully controlled temperature of 85 - 95 oC for 9 h under the influence of a magnetic stirrer to obtain coloured solution which was allowed to cool overnight. The crystals formed was filtered and air-dried to afford (1H-benzo[d]imidazol-2-yl)methanamine, 10a in 97.3% yield. Due to high efficiency observed in Method B for the synthesis of 10a,it was therefore adopted as the viable method for the synthesis of the rest of the compounds 10b-i. Synthesis of (1H-benzo[d] imidazol- 2- yl) methanamine, 10aTreatment ofo-phenylenediamine (0.54 g, 5 mmol) with L-glycine (0.53 g, 7 mmol) afforded(1H-benzo[d]imidazol-2-yl)methanamine, 10a.1HNMR (400 MHz, DMSO-d6) delta: 7.95 (s, 1H, NH), 7.82-7.80 (d, J= 8.03 Hz, 2H, Ar-H), 7.17-7.13 (m, 2H, Ar-H), 6.44-6.42 (t, J= 5.78 Hz, 2H, NH2-CH2), 3.55-3.53 (t, J= 5.78 Hz, 2H, CH2-NH2). 13C-NMR (100 MHz, DMSO-d6) delta: 142.6, 139.3, 138.9, 125.3, 125.3, 119.2, 119.2, 41.7 ppm. lmax in nm (log epsilonmax): 236 (1.7782), 290 (1.324), 407 (0.8541). IR (KBr): 3384, 3363 (N-H of NH2, two bands), 3245 (N-H), 3021 (C-H aromatic), 2930 (C-H aliphatic), 1605 (C=C), 1580 (C=N), 741 (Ar-H) cm-1. MS: in m/z (rel. %): 295.04 (2M + 1, 10.5%), 148.01 (MH, 24.5%), 147.03 (M+, 20%), 132.04 (M - NH, 100%), 118.07 (M - CH2=NH, 35.3%), 76.11 (68.3%).
87%
With hydrogenchloride; In water; for 2h;Reflux;
A solution of 1,2-phenylenediamine (13 g, 0.12 mol) and glycine (18 g, 0.24 mol) in 4 N hydrochloric acid (40 mL) was heated to reflux with stirring for 2 h. The progress of the reaction was monitored by TLC. On completion of the reaction, the reaction mixture was cooled to room temperature and the pH was adjusted to 7.2 using 1 N sodium hydroxide solution to obtain buff colored product 1. The product was recrystallized using rectified sprit as solvent.Yield: 87 %, mp 261-263 C, Rf: 0.72, IR (KBr) 3371 (NH2), 3053 (=C-H), 1591 (C=N) cm-1; 1H NMR (400 MHz, DMSO-d6) delta 12.1 (s, 1H, NH), 7.2-6.9 (m, 4H), 5.2 (s,2H, NH2), 2.3 (d, J = 12.7 Hz, 2H, CH2).
61%
With hydrogenchloride; In water; for 5h;Reflux;
General procedure: General procedure for the synthesis of (1H-benzimidazole-2-yl)alkylamines was adapted from the Phillips procedure.18 L-Amino acid was added to a stirred solution of 4-nitro-o-phenylendiamine and aqueous HCl (5.5 M). The mixture was heated under reflux for 5 h. The blue reaction mixture was cooled to room temperature. The mixture was allowed to stand for overnight where upon the desired (1H-benzimidazole-2-yl)alkylamine was crystallized in its HCl salt form. The free base was obtained by neutralization of the reaction mixture with 1M K2CO3 solution followed by extraction with ethyl acetate. The extract was evaporated to dryness and recrystallized from an ethanol.
3,4,5-Trihydroxy-cyclohex-1-enecarboxylic acid ((2R,3R,4S,5R)-2-{6-[(1H-benzoimidazol-2-ylmethyl)-amino]-purin-9-yl}-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multistep reaction.;
Stage #1: 2-Aminomethylbenzimidazole; 9-[2'-deoxy-2'-trifluoroacetamido-3',5'-O-(diacetyl)]-(1-β-D-ribofuranosyl)-6-chloropurine With triethylamine In ethanol at 60℃; for 18h;
Stage #2: With ammonium hydroxide In ethanol at 80℃; for 24h;
Stage #3: shikimic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Further stages.;
(E)-N-((2R,3R,4S,5R)-2-{6-[(1H-Benzoimidazol-2-ylmethyl)-amino]-purin-9-yl}-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yl)-3-(3,5-dimethoxy-phenyl)-acrylamide[ No CAS ]
(3S,5R,8R,9R,10R,13R,14R,17S)-17-{1-[(1H-Benzoimidazol-2-ylmethyl)-amino]-ethyl}-4,4,8,10,14-pentamethyl-hexadecahydro-cyclopenta[a]phenanthren-3-ol[ No CAS ]
(2R,3S,4R,5R,6R)-5-Amino-2-aminomethyl-6-((1R,2R,3S,4R,6S)-4,6-diamino-2-{2-[(1H-benzoimidazol-2-ylmethyl)-amino]-ethoxy}-3-hydroxy-cyclohexyloxy)-tetrahydro-pyran-3,4-diol[ No CAS ]
(1R,3S,4R,5R,6S)-4-((2R,3R,4R,5R,6R)-3-Amino-6-aminomethyl-4,5-bis-benzyloxy-tetrahydro-pyran-2-yloxy)-5-{2-[(1H-benzoimidazol-2-ylmethyl)-amino]-ethoxy}-6-benzyloxy-cyclohexane-1,3-diamine[ No CAS ]
activated carbonate of hydroxymethyl polystyrene[ No CAS ]
(2R,3S,4R,5R,6R)-5-Amino-2-aminomethyl-6-((1R,2R,3S,4R,6S)-4,6-diamino-2-{2-[(1H-benzoimidazol-2-ylmethyl)-amino]-ethoxy}-3-hydroxy-cyclohexyloxy)-tetrahydro-pyran-3,4-diol[ No CAS ]
activated carbonate of hydroxymethyl polystyrene[ No CAS ]
(1R,3S,4R,5R,6S)-4-((2R,3R,4R,5R,6R)-3-Amino-6-aminomethyl-4,5-bis-benzyloxy-tetrahydro-pyran-2-yloxy)-5-{2-[(1H-benzoimidazol-2-ylmethyl)-amino]-ethoxy}-6-benzyloxy-cyclohexane-1,3-diamine[ No CAS ]
EXAMPLE 51 N-(1H-benzimidazol-2-yl-methyl)-3-(4'-trifluoromethyl-biphenyl-2-carbonylamino)-benzoic acid amide Prepared analogously to Example 7 from 3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid and 2-(aminomethyl)-benzimidazole in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield:19% of theory Rf value:0.58 (silica gel; dichloromethane/ethanol=9:1)
With potassium hydroxide; In methanol; at 20℃; for 0.5h;
Preparation 1 2-(Aminomethyl)benzimidazole; Add 2-(aminomethyl)bcnzimidazole, dihydrochloride, hydrate (18.50 g) to a solution of potassium hydroxide (9.50 g) in methanol (400 mL). Stir the resulting mixture at room temperature for 30 minutes, filter, and concentrate the filtrate in vacuo. Extract the residue with EtOAc (5 x 500 mL) and filter. Concentrate the filtrate in vacuo to give the title compound as a white solid (9.60 g).
EXAMPLE 2 2-[N-(3-Aminopropyl)-N-thien-2-ylmethylamino]pyridine (1.5 g) in methanol (30 ml) was added dropwise to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.98 g) in methanol (70 ml) at 5°-10° C. over 0.5 hr. After 2 hr. a solution of 2-aminomethylbenzimidazole (from 1.7 g of its dihydrochloride salt and 0.34 g of sodium) in methanol (20 ml) was added and after a further 3 hr. at 5°-10° C. The mixture was allowed to stand for 3 days at room temperature. The solvent was evaporated and the residue chromatographed (silica gel, chloroform/methanol 20:1) to give, after crystallisation from ethanol, 3-[3-(N-thien-2-ylmethyl-N-pyrid-2-ylamino) propylamino]-4-benzimidazol-2-ylmethylamino-1,2,5-thiadiazole-1-oxide (0.86 g; 31percent) m.p. 211.5°-212° C. (decomp.). C23 H24 N8 OS2: Found: C 56.36, H 4.95, N 22.93. Requires: C 56.08, H 4.91, N 22.75.
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of C-(1 H-benzoimidazol-2-yl)- methylamine (200 mg, 1 .0 mmol) and triethylamine (139 muIota_, 1 mmol) in CH2CI2 (5 ml_) (Boc)20 (420 mg, 2 mmol) is added, and the reaction mixture is stirred at r.t. for 1 h. After solvent evaporation, the crude product is purified by flash chromatography (1 :1 EtOAc-Et.petr., Rf = 0.5), to give 2-(tert- butoxycarbonylamino-methyl)-benzoimidazole-1 -carboxylic acid t-butyl ester as a yellow oil (246 mg, 0.71 mmol) in 71 .percent yield. 1H NMR (CDCI3, 200 MHz) delta 7.96- 7.91 (m, 1 H), 7.72-7.67 (m, 1 H), 7.35-7.26 (m, 2H), 5.85 (br, 1 H), 4.80 (d, 2H), 1 .71 (s, 9H), 1 .48 (s, 9H) ppm
71%
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of C-(1H-benzoimidazol-2-yl)-methylamine (200 mg, 1.0 mmol) and triethylamine (139 muL, 1 mmol) in CH2Cl2 (5 mL) (Boc)2O (420 mg, 2 mmol) is added, and the reaction mixture is stirred at r.t. for 1 h. After solvent evaporation, the crude product is purified by flash chromatography (1:1 EtOAc-Et.petr., Rf=0.5), to give 2-(tert-butoxycarbonylamino-methyl)-benzoimidazole-1-carboxylic acid t-butyl ester as a yellow oil (246 mg, 0.71 mmol) in 71.percent yield. 1H NMR (CDCl3, 200 MHz) epsilon 7.96-7.91 (m, 1H), 7.72-7.67 (m, 1H), 7.35-7.26 (m, 2H), 5.85 (br, 1H), 4.80 (d, 2H), 1.71 (s, 9H), 1.48 (s, 9H) ppm. This intermediate (175 mg, 0.5 mmol) is dissolved in anhydrous THF (10 mL) and PPh3 (330 mg, 0.5 mmol) and 4-pentynol (46 muL, 0.5 mmol) are added. Then, after cooling to 0° C., DIAD (100 muL, 0.5 mmol) is slowly added, and after 15 min at 0° C., the mixture is heated under microwave irradiation at 110° C. for 1 h. Following flash chromatography purification (5:1 EtOAc-petr. et.), compound 10 is obtained in 64percent yield. 1H NMR (CDCl3, 200 MHz) delta 7.95-7.90 (m, 1H), 7.71-7.67 (m, 1H), 7.34-7.26 (m, 2H), 5.79 (d, 2H), 2.30-2.20 (m, 2H), 2.03 (s, 1H), 1.95-1.92 (m, 2H), 1.80 (t, 2H), 1.71 (s, 9H), 1.47 (s, 9H) ppm.
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; for 1h;
(R/5)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- l,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H- benzo[d]imidazol-2-yl)methanamine (10.24 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge CI 8, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 methanohwater with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient: 45-100percent B over 25 minutes, then a 5-minute hold at 100percent B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/5)-N- ((lH-benzo[d]imidazol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)acetamide (12.8 mg, 0.023 mmol, 49.3 percent yield): LCMS = 561.1 [M+H]+; 'H NMR (400 MHz, methanol- cU) 5 ppm 8.19 (2 H, d, J=8.58 Hz), 7.51-7.79 (10 H, m), 7.34 (2 H, dd, J=6.05, 3.19 Hz), 5.27 (1 H, s), 4.76-4.94 (2 H, m); HPLC peak RT = 2.6 min (Method E).
In a round bottom flask a mixture of (1H-benzo[d]imidazol-2-yl)methanamine (58; 720 mg, 3.8 mmol), 4,7-dichloroquinoline (1.07 g, 5.39 mmol) and phenol (2.33 g, 24.74 mmol) was heated for 3.5 h at 130 °C, stirring under N2. After cooling, the mixture was dissolved in a solution of CH2Cl2/MeOH (95:5) and surplus of phenol was extracted with 2 N NaOH. The organic layers were washed with water, brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude solid was purified by CC on silica gel (CH2Cl2/MeOH; 93:7). The resulting product was rinsed with diethyl ether.
General procedure: A mixture of hetero/aromatic aniline (20 mmol) and 3-5 drops of conc. hydrochloric acid was added to a solution of compound 3 (20 mmol) in ethanol (50 mL). This mixture was refluxed for 7 h. The reaction mixture was then allowed to cool at room temperature. The precipitate was collected by filtration, dried and recrystallizedfrom appropriate solvent.
[Cu(2-(aminomethyl)benzimidazole)(thiocyanate)2]n[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
In methanol; water; at 20℃; for 12h;
General procedure: NH4SCN (0.092 g, 1.2 mmol) was dissolved in water (5 ml) and slowly added to the methanolic solution of CuCl2·2H2O (0.1 g; 0.59 mmol) and suitable N-donor ligand, and stirred at room temperature for 12 h. Green crystalline precipitates were filtered off and dried in air. The crystals suitable for X-ray structure determination were obtained by slow recrystallization from methanol.
With triethylamine; In tetrahydrofuran; for 3h;Reflux;
General procedure: Starting amino compound (0.238 mmol) was dissolved in THF (25 mL) and triethylamine (10 drops) was added to the stirred solution. Acyl halide (0.149 mmol) was added dropwise to the stirred solution, which was then heated under reflux for 3h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with aq. K2CO3 solution followed by brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 1?5 methanol/DCM v/v.
With triethylamine; In tetrahydrofuran; for 3h;Reflux;
General procedure: Starting amino compound (0.238 mmol) was dissolved in THF (25 mL) and triethylamine (10 drops) was added to the stirred solution. Acyl halide (0.149 mmol) was added dropwise to the stirred solution, which was then heated under reflux for 3h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with aq. K2CO3 solution followed by brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 1?5 methanol/DCM v/v.
With triethylamine; In tetrahydrofuran; for 3h;Reflux;
General procedure: Starting amino compound (0.238 mmol) was dissolved in THF (25 mL) and triethylamine (10 drops) was added to the stirred solution. Acyl halide (0.149 mmol) was added dropwise to the stirred solution, which was then heated under reflux for 3h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with aq. K2CO3 solution followed by brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 1?5 methanol/DCM v/v.
General procedure: To a stirred solution of parthenolide (50 mg,0.201 mmol) in methanol (2 mL), was added the appropriate heterocyclicamino compound (16.53 mg, 0.201 mmol). The reaction mixture was stirred at ambient temperature for 15 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the crude compound, water (5 mL) was added to the crude compound and extracted with dichloromethane (2 5 mL). The organic layer was dried over Na2SO4 and concentrated to afford pure compound (6b) as white solid.
8-(benzyloxy)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate[ No CAS ]
5-(((1H-benzimidazol-2-yl)methyl)amino)-8-(benzyloxy)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6 mg
With triethylamine; In 1,4-dioxane; at 60 - 70℃; for 3.75h;
To 8-(benzyloxy)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (128 mg) and 2-(aminomethyl)benzimidazole (131 mg), triethylamine (86 muL) and dioxane (12 mL) were added, and the mixture was heated with stirring at 60 to 70°C for 3 hours and 45 minutes. After cooling of the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-80percent chloroform/methanol] and then suspended in a mixed solvent of 2-propanol and diisopropyl ether, and the deposit was collected by filtration to obtain a pale yellow solid of 5-(((1H-benzimidazol-2-yl)methyl)amino)-8-(benzyloxy)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (6 mg). 1H-NMR (DMSO-d6) delta value: 3.10 (s, 3H), 4.68-4.76 (m, 2H), 5.07 (s, 2H), 5.56 (s, 1H), 7.00-7.80 (m, 10H), 8.93 (s, 1H).
N-((1H-benzo[d]imidazol-2-yl)methyl)acridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-methoxyacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-methylacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2,3-difluoroacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methoxyacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-4-methylacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-4-methoxyacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-chloroacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methylacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-indol-2-yl)methyl)-3-fluoroacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-ethylacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-butylacridin-9-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
General procedure: 9-Chloroacridine or its derivatives (1.0 mmol) and phenol (10.0 mmol) were added into a 100 ml round-bottom flask and the mixture was stirred for 1 h at 60 C under argon atmosphere. Then benzimidazole derivatives (8a?8n, 8p?8q, 1.2 mmol) were added. The mixture was stirred under 120 °C for 2 h. Then the mixture was poured into a mixture of ethyl acetate (50 mL) and N-methyl morpholine (1 ml) to get the crude product as yellow precipitation. The crude product was recrystallized from ethylacetate.
ethyl 2-[(1H-benzo[d]imidazol-2-yl)methylamino]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With potassium carbonate; In acetone; for 8h;Reflux;
A solution of compound 1 (15 g, 0.10 mol), ethyl 2-chloroacetate (30 mL, 0.24 mol) and activated anhydrous potassium carbonate (12 g) in acetone (30 mL) were heated to reflux with stirring for 8 h. The progress of the reaction was monitored by TLC. On completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and poured into the crushed ice to obtain the solid product 2. The product was recrystallized using rectified sprit as solvent. Yield: 69 percent, mp 143?144 °C, Rf: 0.68, IR (KBr) 3384 (NH), 3030 (C=C),1737 (C=O), 1633 (C=N) cm?1; 1H NMR (400 MHz, DMSO-d6) delta 12.5 (s, 1H, NH), 7.6?7.2 (m, 4H), 5.1 (s, 1H, CH2NH), 3.4 (d, J = 11.3 Hz, 2H, CH2COO), 3.2 (q, J = 6.4 Hz, 2H, COOCH2), 2.4 (d, J = 16.6 Hz, 2H, CH2NH), 1.3 (t, J =14.8 Hz, 3H, CH3).
4-((1H-benzo[d]imidazol-2-yl)methylamino)-3-bromo-5-ethoxyfuran-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium fluoride; In tetrahydrofuran; at 20℃; for 36h;
General procedure: A flame-dried 25-mL round-bottomed flask was chargedwith aminomethyl benzimidazoles 1 (0.12 mmol, 1a: 18 mg;1b: 19 mg; 1c: 22 mg; 1d: 21 mg; 1e: 21 mg; 1f: 19 mg; 1g:21 mg; 1h: 19 mg; 1i: 27 mg; 1j: 19 mg) and KF (0.3 mmol,17 mg) in THF (5 mL). The mixture was stirred at roomtemperature. A solution of 5-alkoxy-3,4-dihalo-2(5H)-furanones 2 (0.1 mmol, 2a: 27 mg; 2b: 29 mg; 2c: 35 mg; 2d:18 mg) in THF (5 mL) was added in dropwise. Then, thereaction proceeded at room temperature for 36 h. When thereaction completed, the reaction mixture was diluted with asaturated aqueous solution of NaCl (10 mL) and extractedwith ethyl acetate (310 mL). The organic layer was driedover anhydrous MgSO4, filtered, and concentrated in vacuo.The residue was purified by flash chromatography on silicagel to afford compounds 3a-3u (Table 2) for analysis.
4-((1H-benzo[d]imidazol-2-yl)methylamino)-5-(benzyloxy)-3-bromofuran-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium fluoride; In tetrahydrofuran; at 20℃; for 36h;
General procedure: A flame-dried 25-mL round-bottomed flask was chargedwith aminomethyl benzimidazoles 1 (0.12 mmol, 1a: 18 mg;1b: 19 mg; 1c: 22 mg; 1d: 21 mg; 1e: 21 mg; 1f: 19 mg; 1g:21 mg; 1h: 19 mg; 1i: 27 mg; 1j: 19 mg) and KF (0.3 mmol,17 mg) in THF (5 mL). The mixture was stirred at roomtemperature. A solution of 5-alkoxy-3,4-dihalo-2(5H)-furanones 2 (0.1 mmol, 2a: 27 mg; 2b: 29 mg; 2c: 35 mg; 2d:18 mg) in THF (5 mL) was added in dropwise. Then, thereaction proceeded at room temperature for 36 h. When thereaction completed, the reaction mixture was diluted with asaturated aqueous solution of NaCl (10 mL) and extractedwith ethyl acetate (310 mL). The organic layer was driedover anhydrous MgSO4, filtered, and concentrated in vacuo.The residue was purified by flash chromatography on silicagel to afford compounds 3a-3u (Table 2) for analysis.
4-((1H-benzo[d]imidazol-2-yl)methylamino)-3-chloro-5-methoxyfuran-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium fluoride; In tetrahydrofuran; at 20℃; for 36h;
General procedure: A flame-dried 25-mL round-bottomed flask was chargedwith aminomethyl benzimidazoles 1 (0.12 mmol, 1a: 18 mg;1b: 19 mg; 1c: 22 mg; 1d: 21 mg; 1e: 21 mg; 1f: 19 mg; 1g:21 mg; 1h: 19 mg; 1i: 27 mg; 1j: 19 mg) and KF (0.3 mmol,17 mg) in THF (5 mL). The mixture was stirred at roomtemperature. A solution of 5-alkoxy-3,4-dihalo-2(5H)-furanones 2 (0.1 mmol, 2a: 27 mg; 2b: 29 mg; 2c: 35 mg; 2d:18 mg) in THF (5 mL) was added in dropwise. Then, thereaction proceeded at room temperature for 36 h. When thereaction completed, the reaction mixture was diluted with asaturated aqueous solution of NaCl (10 mL) and extractedwith ethyl acetate (310 mL). The organic layer was driedover anhydrous MgSO4, filtered, and concentrated in vacuo.The residue was purified by flash chromatography on silicagel to afford compounds 3a-3u (Table 2) for analysis.
4-((1H-benzo[d]imidazol-2-yl)methylamino)-3-bromo-5-methoxyfuran-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium fluoride; In tetrahydrofuran; at 20℃; for 36h;
General procedure: A flame-dried 25-mL round-bottomed flask was chargedwith aminomethyl benzimidazoles 1 (0.12 mmol, 1a: 18 mg;1b: 19 mg; 1c: 22 mg; 1d: 21 mg; 1e: 21 mg; 1f: 19 mg; 1g:21 mg; 1h: 19 mg; 1i: 27 mg; 1j: 19 mg) and KF (0.3 mmol,17 mg) in THF (5 mL). The mixture was stirred at roomtemperature. A solution of 5-alkoxy-3,4-dihalo-2(5H)-furanones 2 (0.1 mmol, 2a: 27 mg; 2b: 29 mg; 2c: 35 mg; 2d:18 mg) in THF (5 mL) was added in dropwise. Then, thereaction proceeded at room temperature for 36 h. When thereaction completed, the reaction mixture was diluted with asaturated aqueous solution of NaCl (10 mL) and extractedwith ethyl acetate (310 mL). The organic layer was driedover anhydrous MgSO4, filtered, and concentrated in vacuo.The residue was purified by flash chromatography on silicagel to afford compounds 3a-3u (Table 2) for analysis.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1.25h;
General procedure: To a stirring solution of appropriately substituted 11 or 12 (0.76 mmol) in DMF at RT, HATU (0.83 mmol) and diisopropylethylamine (2.29 mmol) were added. Appropriately, substituted amine (0.76 mmol) was added after 15 min and stirring continued for another 1 h at rt. The reaction was monitored by TLC and then poured into ice water with stirring. On complete consumption of reactants, the reaction mixture was cooled to room temperature. The so-formed precipitate was filtered off and chromatographed on a silica gel (Hexane/EtOAc) on silica gel (100?200 mesh).
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-(5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yloxy)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1.25h;
General procedure: To a stirring solution of appropriately substituted 11 or 12 (0.76 mmol) in DMF at RT, HATU (0.83 mmol) and diisopropylethylamine (2.29 mmol) were added. Appropriately, substituted amine (0.76 mmol) was added after 15 min and stirring continued for another 1 h at rt. The reaction was monitored by TLC and then poured into ice water with stirring. On complete consumption of reactants, the reaction mixture was cooled to room temperature. The so-formed precipitate was filtered off and chromatographed on a silica gel (Hexane/EtOAc) on silica gel (100?200 mesh).
(S)-2-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propanoic acid[ No CAS ]
[ 5805-57-2 ]
tert-butyl (S)-1-((1H-benzo[d]imidazol-2-yl)methylcarbamoyl)-2-(2,4-dichlorophenyl)ethylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
The solution of (S)-Boc-2-amino-3-(2,4-dichlorophenyl)propionic acid (203 mg , 0.608 mmoi, 1.0 equiv), DIPEA (3 equiv), EDC HCi ( 1.5 equiv) and DMAP (1.0 equiv) in DCM (20 mL) was stirred for l Omin. To this reaction mixture (lH~benzo[d]imidazoJ-2~ yi)methanamine (1.0 equiv) was added. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with aq aHC03 and brine. It was then dried over anhydrous sodium sulphaie and evaporated under vacuum io afford iert-butyi (S)- l-('( lH- benzo[d]imidazoi-2-yl)methylcarbamoyl)-2-(2,4-dichiorophenyl)ethy
(S)-methyl 2-(3-((1H-benzo[d]imidazol-2-yl)methyl)ureido)-3-(2,4-dichlorophenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of (S)-methyl 2~amino-3~(2,4~ dichiorophenylipropanoate (103 mg, 0.415 mmol) in DCM (10 mL) was added DIPEA ( 1.5 equiv) and cooled to 0 °C. A solution of triphosgene (0.33 equiv) in DCM (2 mL) was added dropwise to the reaction mixture and stirred at room temperature for 2 h. The solution was 106 back to 0 °C and ( lH-benzo[d]imidazol-2-yl)niethanamine (1.5 equiv) in DCM (2 nil) was added. The reaction mixture was stirred at 0 °C for 30niin. The solution washed with brine, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to give (S)-methyi 2-(3-(( lH-benzo[dJimidazol-2- yl)methyl)ureido)-3-(2,4-dich{orophenyl)propanoate.
(E)-4-(4-chloro-2-hydroxyphenyl)but-3-enoic acid[ No CAS ]
4-(4-chloro-2-hydroxyphenyl)but-3-enoic acid (1H-benzoimidazol-2-ylmethyl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
The solution of (E)-4-(4-Chloro-2-hydroxy-phenyl)- but-3-enoic acid (20 mg , 0,094 mmoL 1.0 equiv), DIPEA ( 3 equiv), EDC HCI ( 1.5 equiv) and DMAP (1.0 equiv) in DCM (20 mL) was stirred for lOmin. To this reaction mixture (1H- benzoid]imidazol-2-yl)methanamine (1.0 equiv) was added. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with sat. NailCC and brine. It was then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to afford 4-(4-Chloro-2-hydroxy-phenyl)-but- 3- enoic acid (lH-benzoimidazol-2-ylmethyl)-amide (1737). LC/MS: (ESI) (M +H)?- 342.3.
(S)-3-(2,4-dichlorophenoxy)-2-(tritylamino)propanoic acid[ No CAS ]
(S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(2,4-dichlorophenoxy)-2-aminopropanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The solution of (S)-3-(2,4-dichlorophenoxy)-2-(tritylatnino)propanoic acid (60 nig , 0.12 mmol, 1.0 equiv), DIPEA (3 equiv), EDC HC1 ( 1.5 equiv) and DMAP (1.0 equiv) in DCM (20 ml.) was stirred for 10mm, To this reaction mixture (1H- berizo[d]imidazol-2-yl)methanarnine (1.0 equiv) was added. The reaction mixtitre was stirred at room temperature overnight. The organic layer was washed with aq NaHCCO and brine. It was then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was treated with TFA (1ml) and DCM (3ml) for 4h. After the solvents was removed, the residue was dissolved in methanol and purified by preparative HPLC to give (S)-N-((1H- benzo[d]imidazol-2-yl)methyl)-3-(2,4-dichloropheiioxy)-2-aniinopropanarnide (1807).
(Z)-N-((1H-benzo[d]imidazol-2-yl)methyl)-3-(2,4-dichlorophenoxy)acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
The solution of (Z)- 3- (2,4-Dichloro-phenoxy)-acrylic acid (20 mg , 0.086 mmoi), D1PEA (0.26mmoi), EDC HCi (Q, 13mmoi) and DMAP (0.086mmol) in DCM (20 mL) was stirred for lOmin. To this reaction mixture ( 1 H-benzo [d]imidazol-2-y l)methanamine (0.086mmo1) was added. The reaction mixture was stirred ai room temperature overnight. The organic layer was washed with sat. aHCOi and brine. It was then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to afford (Z)-N- ((lH-benzo[d]imidazol-2-yl)methyl)-3-(2,4-dicWorophenoxy)aorylamide (1730). LC/MS: (ESI) (M - Pi ) 363.4.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-(5,7-dichlorobenzofuran-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
The residue was dissolved in DMF and EDC (0.5 mmol), HOBt (0.5 mmol), DIPEA (1.0 mmol), (lH-benzo[d]imidazol-2-yl)methanamine (0.5 mmol) were added. The solution was stirred at room temperature overnight and then removed under vacuum. The residue was dissolved in EtOAc (25 mL). The organic layer was washed with water, brine (25 mL), dried and concentrated under vacuum. The residue was chromatographed to give N-((1H- be^o[d]irmdazol-2-yl)methyl)-2-(5,7-dichlorobenzofuran-2-yl)acetamide (1756). LC/MS: (ESI) (M +H)+= 375.6.
N-((1H-benzo[d]imidazol-2-yl)methyl)-2-(5,7-dichloro-1H-benzo[d]imidazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
The residue was dissolved in DMF and EDC (0.15 rnmol), HOBt (0.1 rnmol), DIPEA (0.25 rnmol), ( lH-benzo[d]imidazol-2- yl)methanamine (0.1 rnmol) were added. The solution was stirred at room temperature overnight and then removed under vacuum. 'T'he residue was dissolved in EtOAc (25 mL). The organic layer was washed with water, brine (25 mL), dried and concentrated under vacuum. The residue was chromatographed to give N-((lH-benzo[d]iniidazoi-2-yl)ineihyi)-2- (5,7-dichloro- 1 H-benzo[d]imidazol-2-yl)acetamide (1764). LC/MS: (EST) (M +H)+= 375.6.
N1-((1H-benzo[d]imidazol-2-yl)methyl)-N2-(2,4-dichlorobenzyl)oxalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
The residue was dissolved in DMF and EDC (0.5 mmol), HOBt (0.5 mmol), DIPEA (1 .0 mmol), (l H-benzo[d]imidazol-2-yl)methanamine (0.5 mmol) were added. The solution was stirred at room temperature overnight and then removed under vacuum. The residue was dissolved in EtOAc (25 mL). The organic layer was washed with water, brine (25 mL), dried and concentrated under vacuum. The residue was chromatographed to give N1-((1H- benzo[d]imidazol-2-yl)methyl)-N2-(2,4-dichlorobenzyl)oxalamide (1802). LC/MS: (ESI) (M - i ) 378.6.
N1-((1H-benzo[d]imidazol-2-yl)methyl)-N3-(2,4-dichlorophenyl)malonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
The residue was dissolved in DMF and EDC (0,5 mmol), HOBt (0.5 mmol), DIPEA (1.0 mmol), (lH-benzo[d]imidazol-2-yl)methanamine (0.5 mmol) were added. The solution was stirred at room temperature overnight and then removed under vacuum. The residue was dissolved in EtOAc (25 mL). The organic layer was washed with water, brine (25 mL), dried and concentrated under vacuum. The residue was chromatographed to give N1-((1H- benzo[d]imidazol-2-yl)methyl)-N3-(2,4-dichlorophei yl)maionamide (1803). LC/MS: (ESI) (M +H)' = 378.6.
N-(1H-benzoimidazol-2-ylmethyl)-3-(2,4-dichlorophenylamino)propionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
The solution of (3-(2,4-dichlorophenylamino)propanoic acid (20 mg , 0.089 mmoL 1.0 equiv), DIPEA ( 3 equiv), EDC HCI ( 1.5 equiv) and DMAP (1 ,0 equiv) in DCM (2.0 mL) was stirred for lOmin, To this reaction mixture (IH- 1 14 benzo[d]imidazol-2-yl)methanamine (1.0 equiv) was added. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with aq NaHC03 and brine. It was then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to afford N-(lH-Benzoimidazol-2-ylmethyl)- 3-(2,4-dichloro-phenylamino)-propionamide (1763). LC/MS: (ESI) (M · ) 364.3.
(3R)-3-[[(tert-butoxy)carbonyl]amino]-4-(2,4-dichlorophenyl)butanoic acid[ No CAS ]
(R)-N-((1H-benzo[d]imidazol-2-yl)methyl)-3-Boc-amino-4-(2,4-dichlorophenyl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
The solution of (R)-3-Boc-ammo-4-(2,4-dichlorophenyl)butanoic acid (30 mg , 0,086 mmol), DIPEA (0.25mmol), EDC HCl (0.13mmol) and DMAP (0.086mmol) in DMF (20 mL) was stirred for lOmin. To this reaction mixture (lH-benzo[d]imidazol-2- yljmethanamine (0.086mmol) was added. The reaction mixture was stirred at room teinperaatre overnight. The organic layer was washed with sat. NaHC< and brine. It was then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography to afford (R)-N-((lH~benzo[d]imidazoi-2~ yl)methyl)-3-Boc-amino-4-(2,4-dichlorophenyl)butanamide.
(3R)-3-[[(tert-butoxy)carbonyl]amino]-4-(2,4-dichlorophenyl)butanoic acid[ No CAS ]
(R)-N-((1H-benzo[d]imidazol-2-yl)methyl)-3-amino-4-(2,4-dichlorophenyl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The solution of Boc-( )-3-amino-4-(2,4-dichlorphenyl)butyric acid (30 mg , 0,086 mmoL 1 ,0 equiv), DIPEA ( 3 equiv), EDC HCi ( 1.5 equiv) and DMAP (1.0 equiv) in DCM (20 mL) was stirred for 1 Grain. To this reaction mixture ( 1 H-benzo[d]imidazol-2- yljmethanamine (1 .0 equiv) was added. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with aq NaHC03 and brine. It was then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash column chromatography. The above purified compound was dissolved in 3 ml of DCM, To the solution, 1 ml of TFA was added dropwise. The solution was stirred for 40 min at room temperature. The reaction mixture was evaporated under vacuum, neutralized with aq aHC03 and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concen (M - i i , 378.3.
N-((1H-benzo[d]imidazol-2-yl)methyl)quinoline-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.42 g
With trimethylamine; In dichloromethane; at 0 - 20℃; for 4.5h;
As shown in Scheme 1, L was synthesized via a simple procedure.(1H-benzo[d]imidazol-2-yl)methanamine was obtained via themethod reported in our previous paper.37 2-Quinolinecarboxylic acid (0.38 g, 2 mmol) was refluxed in oxalyl dichloride (20 mL) for2 h, and then the solvent was removed. The crude quinoline-2-carbonyl chloride was obtained, which was added into (1H-benzo[d]imidazol-2-yl)methanamine (0.29 g, 2 mmol) dichloromethane solution containing 0.3 mL trimethylamine at 0 C in a 0.5 h timescale.The reaction mixture was gradually returned to room temperatureand maintained for 4 h, which was evaporated and separated via column chromatography. Pale yellow solid was obtained.Yield: 0.42 g, 70percent. Mp, 212 C; HRMS (ESI): Calcd for [MH]303.1246; found: 303.1236. 1H NMR (400 MHz, CD3OD, ppm): 8.49(d, 1H, J8.40 Hz), 8.20e8.25 (m, 2H), 8.02 (d, 1H, J8.40 Hz), 7.85(m,1H), 7.71 (m,1H), 7.53 (m, 2H), 7.21e7.23 (m, 2H), 4.97 (s, 2H). 13CNMR (100MHz, CD3OD, ppm): 166.08,158.58,151.92,149.36,146.68,137.55, 130.11, 129.50, 129.45, 129.39, 128.01, 127.62, 122.13, 118.33,115.12. Anal. Calcd for C18H14N4O: C, 71.51; H, 4.69; N, 18.53; Found:C, 71.39; H, 4.75; N, 18.19.
General procedure: Compounds were synthesized in solution phase using Boc-protected amino acids on 100?200mg scale. Firstly, the amino acid (1.2?1.5equiv) was activated with HBTU (1.5equiv) and DIPEA (1.5equiv) as 0.2?0.5M solution in DMF for 10min. Then the solution was added to an amino group bearing C-terminal moiety (R1R2NH) and the mixture was stirred for a minimum of 1h at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 (2×). The organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude product was then treated with 20percent TFA in DCM and stirred for 1?2h to remove the Boc group. TFA was removed by evaporating the reaction mixture under a stream of N2. The residue was dissolved in DCM and washed with saturated NaHCO3 (2×). DCM phase was dried with MgSO4, filtered and evaporated in vacuo. Subsequent N-Boc-amino acids and amines were sequentially coupled under the same conditions. Each coupling reaction was monitored by ESMS, with most reactions going to completion overnight. All final compounds were purified on rpHPLC (97percent by analytical HPLC) and fully characterized by NMR and HRMS (yields between 30percent and 40percent).
The synthesis of C1was carried out in accordancewith the previouslyreported method [29]. An aqueous solution of 0.25 g (0.6 mmol) ofK2PtCl4 was heated to 50-60 °C. An equivalent amount of thedihydrochloride form of the ligand ambim was neutralized withNaHCO3 for optimal yield. The resultant ligand solution was addeddropwise into the K2PtCl4 solution with continuous stirring. The mixturewas further stirred for 24 h at 50 °C. The product was obtained asa gray precipitate and the solution gradually turned colorless. The productwas filtered off and washed sequentially with water, acetone anddiethyl ether and dried under vacuum (yield 0.221 g; 89percent).Microanalysis (atom percent) of C1 (C8H9N3Cl2Pt, 413.164) gave; C, 22.98;H, 2.41; N, 9.90 (calc. C, 23.24; H, 2.20; N, 10.17). lambdamax(DMF): 282 nm.Molar conductance, LambdaM (1 × 10?3 M, DMSO): 28.6 Omega?1 cm2 mol?1. IRdata (cm?1): nu(?NH2) 3205, nu(imC_N) 1618(Sup. Fig. S1). 1H NMR(200 MHz, DMSO d6) delta(ppm): 13.79 (s, 1Hd), 8.55 (d, J = 6.0 Hz, 1Hk),7.66 (d, J = 8.0 Hz, 1Hf), 7.55?7.20 (m, 2Hg,h), 6.12 (brt, 2Ha), 4.04 (t, J= 6.0 Hz, 2Hb) (Sup. Fig. S2). ESI MS (DMSO): m/z 413.06 and 455.02(Sup. Fig. S3).
(4-(((1H-benzimidazol-2-yl)methyl)amino)-6-methylpyrimidin-2-yl)sulfamoyl chloride[ No CAS ]
N-(1H-benzimidazol-2-ylmethyl)-N'-4-[(1H-benzimidazol-2-ylmethyl)amino]-6-methyl-2-pyrimidinylsulfamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With methanesulfonic acid; In ethanol;Reflux;
General procedure: A mixture of 6a/6b/6c/7a/7b/7c (1 mmol),benzoxazol-2-amine (2a)/benzothiazol-2-amine (2b)/1Hbenzimidazol-2-amine (2c)/(benzoxazol-2-yl)methanamine(3a)/(benzothiazol-2-yl) methanamine (3b)/(1H-benzimidazol-2-yl)methanamine (3c) (1.1 mmol), dry ethanol (4 ml)and a catalytic amount of methanesulfonic acid (0.2 ml) wasrefluxed for 6?7 h. The contents of the flask were cooledand diluted with water (15 ml). The separated solid wasfiltered, washed with water, dried and recrystallized from 2-propanol.
(4-chloro-6-methylpyrimidin-2-yl)sulfamoyl chloride[ No CAS ]
N-(1H-benzimidazol-2-ylmethyl)-N'-4-[(1H-benzimidazol-2-ylmethyl)amino]-6-methyl-2-pyrimidinylsulfamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With methanesulfonic acid; In ethanol;Reflux;
General procedure: A mixture of (4-chloro-6-methylpyrimidin-2-yl)aminosulfonyl chloride (8) (1 mmol), benzoxazol-2-amine (2a)/benzothiazol-2-amine (2b)/1H-benzimidazol-2-amine (2c)/(benzoxazol-2-yl) methanamine (3a)/(benzothiazol-2-yl)methanamine (3b)/(1H-benzimidazol-2-yl)methanamine (3c), (2.2 mmol), dry ethanol (8 ml) and acatalytic amount of methanesulfonic acid (0.4 ml) wererefluxed for 3?5 h. The contents of the flask were cooledand diluted with water (25 ml). The separated solid wasfiltered, washed with water, dried and recrystallized from 2-propanol.
N<SUP>4</SUP>-(1H-benzimidazol-2-ylmethyl)-6-methyl-2,4-pyrimidinediamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With methanesulfonic acid; In ethanol;Reflux;
General procedure: The 4-chloro-6-methylpyrimidin-2-amine (1) (1 mmol)was dissolved in dry ethanol (5 ml). To this, (benzoxazol-2-yl)methanamine (3a)/(benzothiazol-2-yl)methanamine (3b)/(1H-benzimidazol-2-yl)methanamine (3c) (1.1 mmol) and acatalytic amount of methanesulfonic acid (0.2 ml) wereadded and refluxed for 4?6 h. After completion of thereaction, the reaction mixture was cooled and diluted withwater (15 ml). The separated solid was filtered, washed withwater, dried and recrystallized from 2-propanol.
N-((1H-benzo[d]imidazol-2-yl)methyl)-6-chloro-4-hydroxy-3-methylquinoline-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: A mixture of 6-chloro-4-hydroxy-3-methylquinoline-2-carboxylic acid (14) (1.05 mmol), BOP (0.6 g, 1.37 mmol), andDIPEA (0.37 mL, 2.10 mmol) in DCM (30 mL) was stirred for10 min at rt before addition of an appropriate primary or secondaryamine (1.26 mmol) dissolved in DCM (5 mL) and the resulting reactionmixture was stirred overnight at rt. The formed precipitatewas filtered, washed with Et2O and dried to afford pure desiredquinoline-2-carboxamides (15-28).
((1aR,7aS,10aS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methyl ((1H-benzo[d]imidazol-2-yl)methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
In dichloromethane; at 20℃; for 4h;
General procedure: To the triazole carbamate ester of MMB (7) (0.167 mmol) indichloromethane (2 mL) was added the appropriate imidazole orbenzimidazole amine (0.167 mmol) at ambient temperature, andthe reaction mixture was stirred for 4?16 h. After completion ofthe reaction (monitored by TLC), water was added and the resultingmixture extracted with dichloromethane. The organic liquorswere separated, washed with water, followed by brine solution,dried over anhydrous Na2SO4, filtered, and the solvent removedto afford the crude reaction product. The crude product was purifiedby column chromatography (silica gel, 2?5percent methanol indichloromethane) to afford the appropriate carbamate derivativeof MMB as a white solid (yield: 65?75percent).
A mixture of 6,9-dichloro-2-methoyl-anzacridine (278 mg,1 mmol) and benzimidazoles (220 mg, 1 mmol) was heated in phenolunder 120 C for 2 h with nitrogen protection. Then the mixturewas poured into ethyl acetate to give yellow precipitates,which were purified by washing with ethyl acetate twice.
2-amino-5-[2-(4-bromophenyl)ethyl]-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one[ No CAS ]
[ 15226-74-1 ]
N-[(1H-benzimidazol-2-yl)methyl]-4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 90℃; for 5h;Autoclave;
General procedure: To a suspension of 6(0.1 mol) in 1,4-dioxane (5 mL), amine nucleophiles R(a?l) (0.2 mol), Pd(OAc)2(5 molpercent) and Xantphos (5 molpercent) were added in an autoclave at about 25 °C. To this, Co2(CO)8(0.25 mol for primary and secondary amine nucleophiles, 0.7 mol for aryl amine nucleophiles) was added and the resultant reaction mixture was heated to about 90 °C for 5 h in the autoclave. On reaction completion, the reaction mixture was quenched using water and the solid obtained was stirred for 30 min and collected by filtration. The crude material was further purified by hot methanol to afford the desired benzamides 7a?l.
To a solution of intermediate 3 (500 mg, 1.754 mmol) in n-BuOH (5.0 mL) was added benzothiazolemethylamine (345 mg, 2.104 mmol) and triethylamine (733 mu, 5.262 mmol) in a pressure tube. The reaction mixture was heated at 100 °C for 30 min, and the reaction progress was monitored by TLC (5percent MeOH in DCM). Upon completion of the reaction, the mixture was diluted with DCM (50 mL), washed with water (3 x 50 mL) and brine (50 mL), and the combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give crude residue that was purified by silica gel column chromatography (0-5percent MeOH in DCM) to give 570 mg of intermediate 5 as a solid.
With triethylamine; In butan-1-ol; at 100 - 110℃; for 2h;
To a solution of intermediate 15 (100 mg, 0.369 mmol) in n-BuOH (1.0 mL) was added benzothiazolemethylamine (73 mg, 0.442 mmol) and triethylamine (few drops) in a pressure tube, and the reaction mixture was heated at 100 °C for 2 h and monitored by TLC (5percent MeOH in DCM). The reaction mixture was then diluted with DCM (25 mL) and washed with water (3 x 20 mL) and brine (20 mL), and the combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to give a crude residue, that was purified by silica gel column chromatography (60percent EtOAc in DCM) to give 70 mg of pure intermediate 16 as white solid.
(2S,4R)-1-(tert-butoxycarbonyl)-4-((4-(oct-1-yn-1-yl)benzyl)oxy)pyrrolidine-2-carboxylic acid[ No CAS ]
C33H42N4O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Compound 7 (0.5mmol) and DIPEA (0.7mmol) were mixed in anhydrous DMF (4mL) at 0°C. After 45min, HBTU (0.6mmol) followed by the amine partner (8a-s; 0.55mmol) were added and stirring was continued at room temperature for 10?13h. After completion, the reaction mixture was diluted with EtOAc and washed with cold water and followed by brain solution. Then, the organic layer was dried over Na2SO4 and concentrated under the vacuum to obtain the crude product. Then, the residue was purified on flash chromatography using EtOAc/hexane or MeOH/DCM as eluent to obtain the title compounds 9a-s.
In dichloromethane; at 20℃; for 0.5h;Alkaline conditions; Sonication;
General procedure: The receptors were prepared as follows: Tom-phthaloyl chloride (4 mmol) solution indichloromethane, was added benzimidazolederivatives (8.1 mmol) with catalytic amount oftrimethylamine under ultrasonication irradiation andstirred for 20-30 min at room temperature. Thereaction progress was examined by thin filmchromatography using solvent system, (8:2) pet ether:ethyl acetate. After completion of reaction, asmonitored by TLC, the reaction mixture was pouredinto a saturated sodium bicarbonate solution, filteredand washed with water (3x50 mL) to afford thedesired dipodal products (RA-RD). N,N'-Bis-(IH-benzoimidazol-2-ylmethyl)-isophthalamide(RA): M. pt.: 188 °C. Yield: 88.1percent. FTIR (KBr,v cm-1): 3259 (N-H), 3010 (aliphatic C-H), 1645(C-O). IH NMR (DMSO-d6, 400 MHz, ppm) d 4.70(2H, s, CH2), 7.12-7.47 (m, IlH, aromatic C-H), 8.06(s, IH, phenyl C-H), 8.50 (s, 2H, amide N-H), 11.28(s, 2H, benzimidazole N-H). 13C NMR (DMSO-d6,100 MHz, ppm) 115.17, 122.61, 127.46, 128.92,129.01, 130.88, 134.51, 138.06, 152.78, 166.49,166.79, 167.42. MS (ESI) m/z: 425.1874 [M+H]+calcd. for C24H2oN602: 424.1648.
(1R,2S)-2-[2-(benzimidazolylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of 241 (97 mg, 0.25 mmol), (1H-benzimidazol-2-yl)methanamine3 (108 mg, 0.737 mmol), NaBH(OAc)3 (58 mg, 0.27 mmol), and MS4A (80 mg) in CH2Cl2 (8.2 mL) was stirred at room temperature for 10 h. After addition of MeOH, the reaction mixture was partitioned between AcOEt and sat. aq. NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by NH silica gel column chromatography (hexane/CH2Cl2, 1:1?0:1) to give the corresponding amine as pale red oil. To a solution of the amine in EtOH (1.0 mL) was added aq. HCl (2 M, 2.0 mL) and the mixture was heated under reflux for 4 h. The solvent was evaporated, and the residue was partitioned between CH2Cl2 and aq. HCl (1 M). The aqueous layer was basified with aq. NaOH and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (CHCl3/MeOH, 99:1) to give 13 as a free amine. The amine was dissolved in methanolic HCl (2 M) and the solvent was evaporated. The residue was triturated with Et2O to give 13?3HCl (45 mg, 0.12 mmol, 47percent for 2 steps) as a pale-brown amorphous solid. 1H NMR (500 MHz, CD3OD) delta 8.76 (1 H, s, imidazole-2), 7.89 (2 H, dd, J = 6.3, 2.9 Hz, aromatic), 7.65 (2 H, dd, J = 6.3, 2.9 Hz, aromatic), 7.32 (1 H, s, imidazole-5), 4.89 (2 H, s, -NCH2Ar), 3.49 (2 H, brs, -CH2CH2N-), 2.04?1.85 (3 H, m, H-1, -CH2CH2N-), 1.34 (1 H, brs, H-2), 1.13 (1 H, brs, H-3a), 1.08 (1 H, brs, H-3b); 13C NMR (125 MHz, CD3OD) delta 144.36, 136.72, 134.40, 133.25, 128.17, 115.99, 115.68, 49.85, 42.96, 30.98, 19.43, 14.37, 13.33; HRMS (EI) calcd for C16H20N5 282.1713, found 282.1715 [(M + H)+]; Anal. Calcd for C16H19N5?3HCl?1H2O: C, 47.02; H, 5.92; N, 17.13. Found: C, 47.15; H, 5.91; N, 17.05.
4-N,N-Diamino-2-hydroxybenzaldehyde (2.0 g, 0.01 mol) and 2-cyanogen methyl benzimidazole (1,67 g, 0.01 mol) were dissolved in ethanol (0.07 g, 0.001 mol), and pyridine was added as the catalystinto the reaction system at room temperature (25 C). The mixturewas stirred for 24 h, and the productwas filtered,washed with ethanol,and dried. 3-(2-Benzimidazole)-7-diamine coumarin (2.0 g, 0.006mol),malononitrile (0.6 g, 0.009 mol), and ethylene glycol monomethyl ether(20mL) were further added. The mixture was refluxed for 5 h to obtainDisperse Red 277 (1.9 g, 0.004 mol, yield 82%), which was used in thesubsequent step without any purification. In the ice water bath,chlorosulfonic acid (30 mL) was added to Disperse Red 277 (2.0 g,0.005 mol), and the mixture was refluxed at 130 C for 3.5 h. After themixture was cooled to room temperature and poured into ice water,an orange-red solid was precipitated. The precipitate was washedusing cold water until the pH was adjusted to approximately 5. TheDR-SO2Cl compound was obtained after being dried and grinded.Next, sodium azide (0.124 g, 0.002 mol) dissolved in water/ethanol(3 mL:3 mL) was added to a solution of DR-SO2Cl (0.5 g, 0.001 mol)in ethanol (50 mL), and the mixture was stirred at 80 C for 24 h. Further,the solvents were evaporated under vacuum, and DR-SO2N3(0.38 g, 0.0008mol, yield 80%) was obtained as a dark red solid powder(Rf = 0.35; 5% CH3OH in dichloromethane).
2-(1H-benzimidazol-2-ylmethyl)-4-methoxy-1H-isoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
In toluene Molecular sieve; Reflux;
3.1.2. General Procedure for Synthesis of the Final Series of Compounds (3-23)
General procedure: Procedure B (6-8,10,11,13-15,17-23): an amount of 4-methoxy-2-benzofuran-1,3-dione (0.178 g, 1.0 mmol), along with specific amounts of an appropriate amine (1.2 mmol), trimethylamine (0.28 mL, 2 mmol), and 4 Å molecular sieves were added in anhydrous toluene (4 mL) and the mixture was refluxed and stirred overnight. The reaction mixture was then filtered and the solvent was evaporated in vacuum [40]. All the final compounds (3-23) were purified by column chromatography using dichloromethane (9)/methanol (0.7) as eluent.
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