CN109020895B - Synthesis method of metal-catalyzed 1-benzylamino-substituted benzimidazole - Google Patents
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Abstract
The invention provides a synthesis method of metal-catalyzed 1-benzylamino-substituted benzimidazole, which takes o-halogenated aryl-N, N-dimethyl formamidine or derivatives thereof and derivatives of aromatic primary amine as raw materials, greatly improves the reaction activity by adding a metal catalyst, can use various halogen atoms in the initial raw materials, has wider raw material range and higher application value.
Description
Technical Field
The invention belongs to the field of synthesis of benzimidazole compounds, and particularly relates to a synthesis method of metal-catalyzed 1-benzylamino-substituted benzimidazole.
Background
The compound containing benzimidazole skeleton has special structure, physiological activity, reaction activity and the like, has wide application, and is a basic structural unit of various medicines. Such as antitumor drugs, anticancer drugs, antiviral drugs, antibacterial drugs, anti-inflammatory drugs, antiparasitic drugs and the like, and has important medical value. Meanwhile, the compound with the benzimidazole structure has important significance in the fields of simulating the biological activity and chemiluminescence of natural superoxide dismutase (SOD).
The synthesis method of the benzimidazole compound is reported by the review of Cheng Zheng, Zhang Geng, etc. in Chin.J.org.chem.2015,35, 1189-one 1203, and mainly comprises the following steps: 1) the reaction of o-phenylenediamine and carboxylic acid derivative in strong acid condition needs high temperature or long reaction time, and has low yield and harsh conditions. 2) The compound is prepared by oxidizing o-phenylenediamine and aldehyde compounds, and has the advantages of simple reaction conditions, more byproducts and difficult purification. 3) The benzimidazole compound is synthesized by a specific catalyst, such as Lewis acid, transition metal complex and the like, through catalytic reaction, and the yield is better.
Most of the existing synthetic methods obtain 2-substituted or 1, 2-substituted benzimidazole compounds, while the methods for simply obtaining 1-substituted benzimidazole derivatives have few reports, and the following two methods are mainly used:
the method comprises the following steps: the 1-substituted benzimidazole derivative is prepared by directly carrying out N-alkylation on the benzimidazole. This method has poor selectivity, difficult separation, and is time-consuming and labor-intensive.
Synthetic route to method 1
The method 2 comprises the following steps: is prepared from mono-substituted o-phenylenediamine through reaction with formic acid for cyclization. The method needs to prepare different mono-substituted o-phenylenediamine, the reaction steps are complicated, and the reaction conditions are harsh.
Synthetic route to method 2
Liuxue Jing et al (CN 107445899A, CN 106946862A)]Disclosed is a compound prepared from o-fluoro aryl-N, N-dimethyl formamidine and primary amine through SN2The fluorine atom is replaced and then dimethylamine is eliminated to cyclize to form the product. Although the method has simple reaction, the synthetic raw materials are only limited to aniline substituted by fluorine atoms as raw materials, the expansibility degree is low, and the further application of the method is limited. Meanwhile, the yield of the target product is not high.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a method for synthesizing 1-benzylamino-substituted benzimidazole through metal catalysis, the activity of the reaction is greatly improved by adding Cu or Pd metal catalysts, and meanwhile, various halogen atoms can be applied to the starting raw materials, so that the raw materials are wider in range and have higher application value.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing 1-benzylamino substituted benzimidazole by metal catalysis takes a compound (I) and a compound (II) as raw materials to synthesize the 1-benzylamino substituted benzimidazole under the condition of the presence of a metal catalyst, an organic ligand and alkali;
the reaction route is as follows:
wherein, X ═ Cl, Br, I;
R1＝-F,-Cl,-Br,-I,-CH3,-CH2CH3,-OCH3,-CF3,-CO2CH3,-CO2CH2CH3；
R2＝-H,-CH3,-CH2CH3,-CH(CH3)2；
the metal catalyst cat is CuCl, CuBr, CuI, Pd (OAc)2，PdCl2，Pd(PPh3)4Or Pd (dppf)2。
In order to solve the problems of single raw material source and low yield of target products in the existing synthesis method of 1-benzylamino substituted benzimidazole, the application discovers through large-scale experiments that: the use of the Cu or Pd-based metal catalyst can effectively improve the activity of the reaction (1), broaden the atom substitution pattern of the compound (i), and obtain a target product with high yield and high purity, which may be caused by attack of C ═ N double bonds after the Cu or Pd-based metal catalyst forms a salt with a halogen compound.
In some embodiments, the organic ligand is 1,10-Phenanthroline (1,10-Phenanthroline), 1,2-Diaminocyclohexane (1,2-Diaminocyclohexane), (±) -2,2' -bis- (diphenylphosphino) -1,1' -Binaphthyl (BINAP), triphenylphosphine (PPh3),1,1' -bis (diphenylphosphino) ferrocene (DPPF).
In some embodiments, the base is LiOH, NaOH, KOH, NaOEt, t-BuOK, t-BuONa, K2CO3，Cs2CO3Or NaH.
In some embodiments, the above reaction is carried out in an organic solvent, which is DMSO, DMF, Toluene, Benzene, THF, Dioxane or NMP.
In some embodiments, the molar ratio of compound (i) to compound (ii) is 1: 1.1.
in some embodiments, the metal catalyst is added in an amount of 1 to 10% based on the molar amount of the compound (I).
In some embodiments, the compound (i), organic ligand, is present in a molar ratio of 1: 0.1 to 0.5.
In some embodiments, the compound (i), base are present in a molar ratio of 1: 5.
the present invention also provides a 1-benzylamino-substituted benzimidazole prepared by any of the above-described methods.
The invention also provides the application of the 1-benzylamino substituted benzimidazole in preparing antitumor drugs, anticancer drugs, antiviral drugs, antibacterial drugs, anti-inflammatory drugs and antiparasitic drugs, and simulating the biological activity and chemiluminescence of natural superoxide dismutase (SOD).
The invention has the advantages of
(1) The invention provides a synthesis method of metal-catalyzed 1-benzylamino-substituted benzimidazole, which greatly improves the reaction activity by adding a metal catalyst, can use various halogen atoms in the initial raw materials, has wider raw material range and higher application value.
(2) The synthesis method is simple, high in yield, strong in practicability and easy to popularize.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application.
FIG. 1 is a 1H-NMR chart and a 13C-NMR chart of example 1.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
Reaction scheme of the present application:
X＝Cl,Br,I.
R1＝-F,-Cl,-Br,-I,-CH3,-CH2CH3,-OCH3,-CF3,-CO2CH3,-CO2CH2CH3
R2＝-H,-CH3,-CH2CH3,-CH(CH3)2
cat.＝CuCl,CuBr,CuI,Pd(OAc)2,PdCl2,Pd(PPh3)4,Pd(dppf)2
Ligand＝1,10-Phenanthroline,1,2-Diaminocyclohexane,BINAP,PPh3,DPPF
Base＝LiOH,NaOH,KOH,NaOEt,t-BuOK,t-BuONa,K2CO3,Cs2CO3,NaH
solvent＝DMSO,DMF,Toluene,Benzene,THF,Dioxane,NMP
example 1:
a35 mL thick-walled sealed tube was charged with a magnetic stirrer, (E) -N- (2-chlorophenyl) -N, N-dimethylformamidine 0.183g (1.0mmol), p-methoxybenzylamine 0.151g (1.1mmol)，Pd(PPh3)411.6mg(0.01mmol)，PPh326.2mg (0.1mmol), KOH 0.281g (5mmol), toluene 10 mL. After the addition, argon gas was evacuated by a vacuum pump, and the reaction flask was put in an oil bath and heated to 90 ℃ for 12 hours. After the reaction was stopped, the sealed tube was naturally cooled to room temperature, the reaction mixture was poured into a separatory funnel containing 50mL of water, extracted with 3X 30mL of ethyl acetate, the organic phases were combined, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Removing ethyl acetate by rotary evaporation, and separating with silica gel column chromatography to obtain product 1- (4-methoxybenzyl) -1-benzimidazole [1- (4-methoxybenzyl) -1H-benzol [ d]imidazole]0.216g, yield 90.7%.
1H-NMR(CDCl3,400MHz):δ(ppm)＝7.94(s,1H),7.76(d,1H,J＝1.2Hz),7.25(m,3H),7.08(d,2H,J＝6.8Hz),6.79(d,2H,J＝6.8Hz),5.21(s,2H),3.70(s,3H)；13C-NMR(CDCl3,100MHz):δ(ppm)＝159.59,143.30,142.92,133.74,128.73,127.17,123.21,122.49,120.15,114.43,110.21,55.33,48.57.ESI-MS(m/z),Calcd.for C15H14N2O(M)238.1,Found 239.1[M+H+]。
Example 2:
a35 mL thick-walled sealed tube was charged with a magnetic stirrer, (E) -N- (2-iodo-4-carbomethoxyphenyl) -N, N-dimethylformamidine 0.285g (1.0mmol), p-methoxybenzylamine 0.151g (1.1mmol), cuprous iodide 19.1mg (0.1mmol), 1,2-Diaminocyclohexane 57.1mg (0.5mmol), t-BuOK 0.561g (5mmol), and DMSO 10 mL.
After the addition was complete, argon was evacuated by a vacuum pump, and the reaction flask was placed in an oil bath and heated to 110 ℃ for 12 hours. The reaction was stopped, the sealed tube was naturally cooled to room temperature, and then poured into a separatory funnel containing 50mL of water, extracted with 3X 30mL of dichloromethane, the organic phases were combined, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Removing dichloromethane by rotary evaporation, and separating by silica gel column chromatography to obtain the product 1- (4-methoxybenzyl) -1-4-carbomethoxy benzimidazole.
[1-(4-methoxybenzyl)-1H-4-methoxycarbonylbenzo[d]imidazole]0.265g, 89.5% yield.1H-NMR(CDCl3,400MHz):δ(ppm)＝8.12(s,1H),8.04(s,1H),8.01(d,1H,J＝8.5Hz),7.84(d,1H,J＝8.5Hz),7.18(d,2H,J＝8.6Hz),6.89(d,2H,J＝8.6Hz),5.34(s,2H),3.93(s,3H),3.79(s,3H)；13C-NMR(CDCl3,100MHz):δ(ppm)＝167.54,159.83,147.40,145.60,133.76,128.89,126.89,125.13,123.83,120.16,114.66,112.49,55.46,52.33,48.70.ESI-MS(m/z),Calcd.for C17H16N2O3(M)296.1,Found 297.1[M+H+]。
Example 3:
a35 mL thick-walled sealed tube was charged with a magnetic stirrer, (E) -N- (2-iodophenyl) -N, N-dimethylformamidine 0.274g (1.0mmol), 1-phenylethylamine 0.134g (1.1mmol), PdCl28.87mg(0.05mmol)，PPh30.131g(0.5mmol)，Cs2CO31.63g (5mmol), toluene 10 mL.
After the addition, argon gas was evacuated by a vacuum pump, and the reaction flask was put in an oil bath and heated to 90 ℃ for 12 hours. The reaction was stopped, the sealed tube was naturally cooled to room temperature, and then poured into a separatory funnel containing 50mL of water, extracted with 3X 30mL of ethyl acetate, the organic phases were combined, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Ethyl acetate is removed by rotary evaporation, and the product 1- (1-phenethyl) -1-benzimidazole [1- (1-phenylethyl) -1H-benzimidazole [ d ] imidazole ] is obtained by silica gel column chromatography separation in 0.203g with 91.3 percent of yield.
1H-NMR(CDCl3,400MHz):δ(ppm)＝8.10(s,1H),7.76(d,2H,J＝8.0Hz),7.28(m,4H),7.13(m,4H),5.59(q,1H,J＝7.1Hz),1.94(d,2H,J＝7.1Hz)；13C-NMR(CDCl3,100MHz):δ(ppm)＝143.41,140.95,140.58,133.57,129.16,128.31,126.11,123.20,122.67,120.22,110.88,55.53,21.71.ESI-MS(m/z),Calcd.for C15H14N2(M)222.1,Found 223.1[M+H+]。
Example 4:
a35 mL thick-walled sealed tube was charged with magnetic stir bar, (E) -N- (2-chlorophenyl) -N, N-dimethylformamidine 0.092g (0.5mmol), p-methoxybenzylamine 0.076g (0.6mmol), Ru (PPh)3)3Cl24.8mg(0.005mmol)，PPh313.1mg (0.05mmol), NaOEt 0.171g (2.5mmol), and 6mL of toluene. After the addition, argon gas was evacuated by a vacuum pump, and the reaction flask was put in an oil bath and heated to 90 ℃ for 12 hours. After the reaction was stopped, the sealed tube was naturally cooled to room temperature, the reaction mixture was poured into a separatory funnel containing 50mL of water, extracted with 3X 30mL of ethyl acetate, the organic phases were combined, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Removing ethyl acetate by rotary evaporation, and separating with silica gel column chromatography to obtain product 1- (4-methoxybenzyl) -1-benzimidazole [1- (4-methoxybenzyl) -1H-benzol [ d]imidazole]0.029g, yield 12.2%.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (1)
1. A method for synthesizing 1-benzylamino substituted benzimidazole through metal catalysis, which is characterized in that,
a35 mL thick-walled sealed tube was charged with magnetic stirrer, (E) -N- (2-chlorophenyl) -N, N-dimethylformamidine 1.0mmol, p-methoxybenzylamine 1.1mmol, Pd (PPh)3)40.01mmol, 0.1mmol of triphenylphosphine, 5mmol of KOH and 10mL of toluene, after the addition, the argon is pumped by a vacuum pump, the reaction bottle is put into an oil bath and heated to 90 ℃ and kept for 12 hours, after the reaction is stopped, a sealed tube is naturally cooled to room temperature, the reaction mixture is poured into a separating funnel filled with 50mL of water, 3X 30mL of ethyl acetate is used for extraction, the organic phases are combined, water and saturated water are used in sequence, and the mixture is sequentially addedWashing the organic phase with salt solution, drying with anhydrous sodium sulfate, removing ethyl acetate by rotary evaporation, and separating with silica gel column chromatography to obtain 1- (4-methoxybenzyl) -1-benzimidazole;
or: a35 mL thick-walled sealed tube was charged with a magnetic stirrer, (E) -N- (2-iodo-4-carbomethoxyphenyl) -N, N-dimethylformamidine 1.0mmol, p-methoxybenzylamine 1.1mmol, cuprous iodide 0.1mmol, 1,2-diaminocyclohexane 0.5mmol, t-BuOK 5mmol, DMSO 10mL,
after the feeding is finished, vacuumizing and changing argon, putting a reaction bottle into an oil bath, heating to 110 ℃, keeping for 12 hours, stopping the reaction, naturally cooling a sealing tube to room temperature, pouring the cooled sealing tube into a separating funnel filled with 50mL of water, extracting with 3X 30mL of dichloromethane, combining organic phases, washing the organic phases with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, removing the dichloromethane by rotary evaporation, and separating by silica gel column chromatography to obtain a product 1- (4-methoxybenzyl) -1-4-carbomethoxybenzimidazole;
or: a35 mL thick-walled sealed tube was charged with a magnetic stirrer, (E) -N- (2-iodophenyl) -N, N-dimethylformamidine 1.0mmol, 1.1mmol of 1-phenylethylamine, PdCl20.05mmol, 0.5mmol of triphenylphosphine, Cs2CO35mmol of toluene and 10mL of toluene,
and after the addition is finished, vacuumizing and replacing argon, putting the reaction bottle into an oil bath, heating to 90 ℃ and keeping for 12 hours, stopping the reaction, naturally cooling the sealed tube to room temperature, pouring the cooled sealed tube into a separating funnel filled with 50mL of water, extracting with 3X 30mL of ethyl acetate, combining organic phases, washing the organic phases with water and saturated saline water in sequence, drying with anhydrous sodium sulfate, removing the ethyl acetate by rotary evaporation, and separating by silica gel column chromatography to obtain the product 1- (1-phenethyl) -1-benzimidazole.
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