* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4713 - 4726
[2] Monatshefte fur Chemie, 2016, vol. 147, # 12, p. 2209 - 2220
[3] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1272 - 1274
[4] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1724 - 1730
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 933 - 936
[6] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 584 - 600
[7] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 608 - 621
[8] Molecules, 2016, vol. 21, # 11,
2
[ 1632-83-3 ]
[ 20461-86-3 ]
[ 3012-80-4 ]
Yield
Reaction Conditions
Operation in experiment
40%
With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 24 h; Inert atmosphere; Irradiation; Green chemistry
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 87 - 90[2] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 1, p. 98 - 101
10
[ 13109-82-5 ]
[ 3012-80-4 ]
Reference：
[1] Patent: US2018/44324, 2018, A1,
11
[ 87-69-4 ]
[ 4760-34-3 ]
[ 3012-80-4 ]
Reference：
[1] Liebigs Annalen der Chemie, 1980, # 4, p. 542 - 556
12
[ 85510-65-2 ]
[ 1632-83-3 ]
[ 3012-80-4 ]
[ 3878-69-1 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1987, vol. 23, # 2, p. 284 - 287[2] Khimiya Geterotsiklicheskikh Soedinenii, 1987, vol. 23, # 2, p. 339 - 342
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1987, vol. 23, # 2, p. 284 - 287[4] Khimiya Geterotsiklicheskikh Soedinenii, 1987, vol. 23, # 2, p. 339 - 342
[5] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1987, vol. 23, # 2, p. 284 - 287[6] Khimiya Geterotsiklicheskikh Soedinenii, 1987, vol. 23, # 2, p. 339 - 342
13
[ 2876-08-6 ]
[ 3012-80-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1959, p. 343,347[2] Rev. textile-Tiba, 1958, vol. 57, p. 164,166
14
[ 615-15-6 ]
[ 3012-80-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1959, p. 343,347[2] Rev. textile-Tiba, 1958, vol. 57, p. 164,166
With diisobutylaluminium hydride In tetrahydrofuran at 0℃; for 1.5h;
88%
With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 1h;
50.4%
Stage #1: 1-Methyl-1H-benzoimidazole-2-carbaldehyde With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 24h;
Stage #2: With water monomer In tetrahydrofuran
49
2- hydroxymethyl-l -methyl-1 H-benzimidazole (Compound 49a)A suspension of l -methyl-2-formyl-l H-benzimidazole (500 mg, 3.12 mmol) and NaBH4 (134 mg, 3.43 mmol) in anhydrous THF (25 ml) was stirred for 24 hours at r.t.. The reaction mixture was quenched with water, extracted with EtOAc, dried over Na2S04 and evaporated to dryness in vacuo. The crude was purified by automated flash chromatography (HorizonTM - Biotage) eluting with CHC13 - 1.7M NH3 sol. in MeOH 100:2 giving the title product as white solid. Yield: 50.4 %. MS: [ +H]+ = 163.5
Stage #1: 1-Methyl-1H-benzoimidazole-2-carbaldehyde With lithium naphthalenide In tetrahydrofuran at 0℃;
Stage #2: With water monomer In tetrahydrofuran
Stage #1: 1-Methyl-1H-benzoimidazole-2-carbaldehyde With sodium tetrahydridoborate; ethanol at 20℃;
Stage #2: With water monomer In ethyl acetate
12
Example 12; (1-Methyl-1H-benzoimidazol-2-yl)-methanol; Sodium borohydride (472 mg, 12.48 mmol) was added to the solution of 1-methyl-1H-benzoimidazole-2-carbaldehyde (1 g, 6.24 mmol) in ethanol (50 mL). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was condensed, the residue was diluted with ethyl acetate; water was added. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and condensed to give off-white solid as product (953 mg, 94%). This product was used in the later steps without further purification.1HNMR (300 MHz, CDCl3): (ppm) 7.63 (m, 1H), 7.21 (m, 3H), 4.84 (s, 2H), 3.75 (s, 3H)
With methanol; sodium tetrahydridoborate at 0 - 20℃; for 5h;
47
To a 0°C solution of 1 -methyl- lH-benzimidazole-2-carbaldehyde (1.1 g, 6.8 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (350 mg, 9.3 mmol). The reaction mixture was stirred at room temperature for 5 hours. Saturated ammonium chloride solution (20 mL) was added. Methanol was evaporated. The resultant mixture was extracted with EtOAc (3 x 50 mL) and CH2Cl2 (1 x 50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. (1 -methyl- lH-benzimidazol-2-yl)methanol was obtained (1.1 g, 99% yield). The product was used without further purification.
With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;
(1-methyl-1H-benzo[d]imidazol-2-yl)methanol (5-5b).
To a solution of 1-methyl- 1H-benzo[d]imidazole-2-carbaldehyde (5-5a, 150 mg, 936.49 umol, 1 eq) in THF (3 mL) was added NaBH4 (38.97 mg, 1.03 mmol, 1.1 eq) at 20°C under N2. The mixture was stirred at 20°C for 1 hour. LCMS showed 5-5a was comsumed completely and desired mass was detected. The reaction mixture was quenched by addition water (30 mL) at 20°C. The aqueous phase was extracted with ethyl acetate (25 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (ethyl acetate: methanol = 20:1) to give 5-5b as a white solid.1H NMR (400MHz, CDCl3-d) 7.77-7.67 (m, 1H), 7.34-7.28 (m, 2H), 7.27- 7.23 (m, 1H), 4.91 (s, 2H), 3.83 (s, 3H).
A solution of 1-methyl-2-formylbenzimidazole (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 eq.) and NaCNBH3 (0.85 g, 2 eq.) at 25 C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic phase layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was chromatographed on silica gel, eluting with 8% methanol/dichloromethane to give the title compound (1.2 g 64% yield).
64%
With sodium cyanoborohydride; In methanol; acetic acid; at 25℃; for 1h;
A solution of 1-methyl-2-formylbenzimidazole (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25 C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was chromatographed on silica gel, eluting with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
64%
With sodium cyanoborohydride; acetic acid; In methanol; at 25℃; for 1h;
EXAMPLE 64A 2,2-dimethoxy-N-[(1-methyl-1H-benzimidazol-2-yl)methyl]ethanamine A solution of 1-methyl-2-formylbenzimidazole (1 g) in methanol (27 mL) and acetic acid (0.54 mL) was treated with aminoacetaldehyde diethylacetal (0.9 g, 1 equivalent) and NaCNBH3 (0.85 g, 2 equivalents) at 25 C., stirred for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed sequentially with saturated NaHCO3 and brine, and concentrated. The residue was purified by eluding with 8% methanol/dichloromethane to give 1.2 g (64%) of the title compound.
With Dess-Martin periodane In dichloromethane at 4℃; for 1h;
79%
With selenium(IV) oxide In toluene at 80 - 90℃; for 2h;
67%
With Dess-Martin periodane In dichloromethane at 0℃; for 6h;
33%
With Dess-Martin periodane In dichloromethane at 0 - 20℃;
30%
With Dess-Martin periodane In dichloromethane at 4℃; for 1h;
Procedures for the synthesis of 2-carbonylbenzimidazoles 1-2.
General procedure: Dess-Martin reagent (1.1 mmol) was added to a solution of benzimidazol-2-ylmethanol 4 or 7(1 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at 4 °C for 1 h prior tobeing quenched with saturated aqueous sodium thiosulfate solution (3 mL). The subsequent mixturewas extracted with methylene chloride (3 × 10 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and concentrated in vacuo to provide a crude product, which wascrystallized from methanol to give corresponding product.1-Methyl-1H-benzimidazole-2-carboxaldehyde (1) [3] was obtained as beige solid in 30%yield. M.p. 134-136°C from methanol. 1H NMR (500 MHz, CDCl3) δ 4.12 (s, NMe), 7.35-7.39 (m,1Harom.), 7.43-7.48 (m, 2Harom.), 7.90 (d, 1Harom., J = 10.3 Hz), 10.09 (s, 1H, CHO). 13C NMR (125MHz, CDCl3) δ 31.2, 110.5, 122.3, 124.0, 126.8, 136.9, 142.7, 146.1, 185.0.
With manganese(IV) oxide In dichloromethane at 20℃; for 72h;
With Dess-Martin periodane In dichloromethane at 0℃; for 6h;
With Dess-Martin periodane In dichloromethane at 0 - 20℃;
With manganese(IV) oxide In ethyl acetate at 65℃; for 1h;
3.2.2. Synthesis and Purification of Compound 3a-3d
General procedure: A solution of 2a-2d (2 mmol), MnO2 (3.48 g, 40 mmol) was added to EtOAc (120 mL), then refluxedat 65 C for 1 h (monitored by TLC). Afterwards the solution was filtered, and concentrated in vacuoto give pure compounds 3a-3d (in 60%-76% yield) [17].
Stage #1: 1-methyl-2-formyl-1H-benzimidazole; 2-piperazinobenzothiazole With acetic acid In dichloromethane at 20℃; for 0.25h;
Stage #2: In dichloromethane at 110℃; for 0.166667h; Microwave irradiation;
1-butyryl-5-fluoro-1'-[(1-methyl-1H-benzimidazol-2-yl)methyl]-1,2-dihydrospiro[indole-3,4'-piperidine][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A 2.0 M solution of triethylamine solution in DCE was prepared. 2.0 M stock solutions of amine (XLVII) in this mixture were prepared and sonicated for 10 min. A 0.25 M tetramethylammonium triacetoxyborohydride solution in DCE was prepared and sonicated for 10 min. 0.25 M solutions of aldehyde (III) in DCE were prepared. 1 mL of the solution of amine (XLVII) was dispensed into 2-dram vials. To each vial was added 0.8 mL of the solution of aldehyde (III), and 2.4 mL of the tetramethylammonium triacetoxyborohydride solution. The vials were capped and shaken at room temperature for 16 h. 1.5 mL of 15percent NH4OH aqueous solution was added to each vial. The vials were initially slowly then more <n="87"/>vigorously vortexed, centrifuged, and allowed to stand for 2 h. The aqueous layer was discarded and the organic layers were evaporated. 1 mL of DCM and 0.25 mL of TFA was added to each vial. The vials were capped and shaken at room temperature for 16 h. The solvent was evaporated and 1 mL of toluene was added to each vial. The samples were evaporated to dryness. 2 M solution of Et3N and 0.25 M solutions of various acid chlorides in anhydrous DMA were prepared. 1 mL of the Et3N solution was added to each vial and the vials were vortexed until the solutions became clear. 0.96 of the acid chloride solution was added to the corresponding vial and the vials were capped and shaken at room temperature for 16 h. The solvent was evaporated. To each vial was added 3 mL of DCE and 2 mL of water. The vials were vortexed and centrifuged. The orranic layers were transferred into collections vial. The samples were evaporated, dissolved in 1 mL of DMSO, filtered and submitted to HPLC purification.
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In dichloromethane; 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20℃; for 32h; Inert atmosphere;
2-((4-(2-chlorophenyl)piperidin-1-yl)methyl)-1-methyl-1H-benzo-[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In dichloromethane; 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20℃; for 32h; Inert atmosphere;
(E)-2-((2-(3-fluorophenyl)hydrazono)methyl)-1-methyl-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.6%
In methanol; at 20℃; for 2h;
General procedure: The equimolar aldehyde 3a-3d (1 mmol) and substituted phenylhydrazine 5a-5s (1 mmol) weremixed in CH3OH (10 mL) and stirred at room temperature [18]. After about 2 h, the reaction wascompleted (monitored by TLC). The residual crude was purified via silica gel column chromatogramusing a gradient mixture of petroleum ether and ethyl acetate to obtain the pure target compounds6a-6ai (in 45-80% yield).
(E)-2-((2-(4-chlorophenyl)hydrazineylidene)methyl)-1-methyl-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In ethanol at 20℃; for 4h;
2.2 General procedure for the synthesis of (benz)imidazole-hydrazone derivatives 1-10
General procedure: The hydrazones 1-10 were prepared by a condensation reaction between phenylhydrazine derivatives and imidazole or benzimidazole carbaldehydes [45-47]. In a 25-mL Erlenmeyer flask, 1mmol of 1-methylbenzimidazole-2-carbaldehyde or 1-methylimidazole-2-carbaldehyde and 1mmol of phenylhydrazine derivative (phenylhydrazine, 4-methoxyphenylhydrazine, 3,4-dimethylphenylhydrazine, 4-chlorophenylhydrazine and (4-benzylphenyl)hydrazine) were dissolved in 3ml of ethanol. The reaction mixture was stirred at room temperature for 4h, and then filtered and air-dried. The resulting residue was then purified by recrystallization in a mixture of ethanol/DMSO to give the pure product.
67.5%
In methanol at 20℃; for 2h;
3.2.4. Synthesis and Purification of Compound 6a-6ai
General procedure: The equimolar aldehyde 3a-3d (1 mmol) and substituted phenylhydrazine 5a-5s (1 mmol) weremixed in CH3OH (10 mL) and stirred at room temperature [18]. After about 2 h, the reaction wascompleted (monitored by TLC). The residual crude was purified via silica gel column chromatogramusing a gradient mixture of petroleum ether and ethyl acetate to obtain the pure target compounds6a-6ai (in 45-80% yield).
(E)-4-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)methylene)hydrazinyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.8%
In methanol; at 20℃; for 2h;
General procedure: The equimolar aldehyde 3a-3d (1 mmol) and substituted phenylhydrazine 5a-5s (1 mmol) weremixed in CH3OH (10 mL) and stirred at room temperature [18]. After about 2 h, the reaction wascompleted (monitored by TLC). The residual crude was purified via silica gel column chromatogramusing a gradient mixture of petroleum ether and ethyl acetate to obtain the pure target compounds6a-6ai (in 45-80% yield).
With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; Irradiation; Green chemistry; regioselective reaction;
Procedure A for compounds (3a-3p) in Schemes 2
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
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