CN113429349B - Preparation method of heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound - Google Patents
Preparation method of heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound Download PDFInfo
- Publication number
- CN113429349B CN113429349B CN202110820929.9A CN202110820929A CN113429349B CN 113429349 B CN113429349 B CN 113429349B CN 202110820929 A CN202110820929 A CN 202110820929A CN 113429349 B CN113429349 B CN 113429349B
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- benzimidazole compound
- substituted benzimidazole
- carbon nitride
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/10—Radicals substituted by halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound, which comprises the following steps: adding copper-doped carbon nitride, potassium carbonate, trifluoroethylimidoyl chloride and amine into an organic solvent, reacting for 18-30 hours at 70-90 ℃, and after the reaction is completed, performing post-treatment to obtain the 2-trifluoromethyl-substituted benzimidazole compound. The preparation method has the advantages of mild conditions, simple operation, cheap and easily-obtained starting raw materials and high reaction efficiency, the copper heterogeneous catalyst can be recycled, and the benzimidazole compound with the trifluoromethyl substituted by different functional groups can be synthesized through substrate design, so that the method is convenient to operate and widens the applicability of the method.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound.
Background
Benzimidazole compounds are a very important nitrogen-containing heterocycle widely present in the molecular backbone of many natural products and functional materials (bioorg. Med. Chem. Lett.2005,15, 805-807). Benzimidazoles are also commonly used in many areas such as dyes, polymers, fluorescent molecules, and corrosion science. Introduction of trifluoromethyl into the parent molecule can significantly improve its physicochemical properties such as electronegativity, bioavailability, metabolic stability, lipophilicity, etc. (j.med.chem.2015, 58, 8315-8359). Therefore, the method for constructing the trifluoromethyl substituted benzimidazole compound has important theoretical research significance and practical application value.
The traditional methods for synthesizing trifluoromethyl substituted benzimidazoles mainly include: 1) Condensation reaction of o-amino aniline with trifluoroacetic acid or trifluoroacetic aldehyde; 2) Reductive cyclization reaction of o-nitroaniline and trifluoroacetic acid; 3) Direct trifluoromethylation reaction of benzimidazole and trifluoromethyl reagent; 4) Electrochemical or periodicium compounds promote the cyclization of fluoroamidines. However, the above synthetic methods generally have the disadvantages of difficulty in obtaining starting materials, narrow substrate range, severe reaction conditions, and the like. In 2009, two subject groups reported the synthesis of trifluoromethyl-substituted benzimidazole compounds by homogeneous copper-catalyzed cascade cyclization of trifluoroacetimide chloride and amine, respectively. However, no report has been made on the synthesis of trifluoromethyl substituted benzimidazoles using a recyclable heterogeneous catalyst. Therefore, a method for simply and efficiently synthesizing 2-trifluoromethyl substituted benzimidazole by using cheap and easily-obtained trifluoroethylimidoyl chloride and amine as starting materials and through a copper-doped carbon nitride-catalyzed serial cyclization reaction is developed.
Disclosure of Invention
The invention provides a preparation method of a 2-trifluoromethyl substituted benzimidazole compound, which has the advantages of simple reaction steps, cheap and easily-obtained starting raw materials and heterogeneous catalysts, high reaction efficiency and convenient operation and application; the heterogeneous catalyst can be recycled, and the catalytic efficiency of the heterogeneous catalyst which is recycled for three times is only partially reduced.
A method for preparing a 2-trifluoromethyl-substituted benzimidazole compound, comprising the steps of: adding copper-doped carbon nitride, potassium carbonate, trifluoroethylimidoyl chloride and amine into an organic solvent, reacting for 18-30 hours at 70-90 ℃, and after the reaction is completed, performing post-treatment to obtain the 2-trifluoromethyl-substituted benzimidazole compound;
the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):
the structure of the amine is shown as the formula (III):
R 2 -NH 2 (III)
the structure of the 2-trifluoromethyl substituted benzimidazole compound is shown as the formula (I):
in formulae (I) to (III), R 1 Is H, C 1 ～C 4 Alkyl, halogen or trifluoromethyl; r 2 Is C 3 ～C 6 Alkyl, phenyl or benzyl.
The reaction formula is as follows:
during the reaction, trifluoroethylimidoyl chloride and amine undergo nucleophilic addition-elimination reaction to obtain amidine compounds, then a copper catalyst is inserted into a carbon-iodine bond on aryl to form a copper complex, one molecule of hydrogen iodide is removed under the action of alkali to form a bivalent or trivalent ring copper intermediate, and then reduction elimination reaction is performed to obtain the 2-trifluoromethyl-substituted benzimidazole compound.
In the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally performing column chromatography purification to obtain the corresponding 2-trifluoromethyl substituted benzimidazole compound, wherein the column chromatography purification is a technical means commonly used in the field.
Preferably, R 1 Is H, methyl, cl, br or trifluoromethyl; r 2 I-propyl, n-butyl, n-pentyl, n-hexyl, phenyl or benzyl, the trifluoroethylimidoyl chloride and the amine are readily available and the reaction yields are high.
The amine is relatively inexpensive and is used in excess of the amount of p-trifluoroethylimidoyl chloride, preferably, the molar ratio of trifluoroethylimidoyl chloride: amine: copper-doped carbon nitride: potassium carbonate =1 to 2; as a further preference, the molar amount of trifluoroethylimidoyl chloride: amine: copper-doped carbon nitride: potassium carbonate = 1.5.
In the present invention, the organic solvent capable of sufficiently dissolving the raw materials can cause the reaction, but the difference in reaction efficiency is large, and the organic solvent is preferably an aprotic solvent which can effectively promote the reaction; preferably, the organic solvent is acetonitrile, DMF or THF; further preferably, the organic solvent is DMF, in which case the various starting materials can be converted into the product with high conversion.
The dosage of the organic solvent can be enough to better dissolve the raw material, and the dosage of the organic solvent used by 1mmol of trifluoroethyl imidoyl chloride is about 5-10 mL.
Preferably, the catalyst is copper-doped carbon nitride, copper sulfate pentahydrate and carbon nitride used for preparing the heterogeneous catalyst are relatively cheap, and the reaction efficiency is higher when the copper-doped carbon nitride is used as the catalyst.
Preferably, the alkali is potassium carbonate, the price of the potassium carbonate is relatively cheap, and the reaction efficiency is higher when the potassium carbonate is used as an accelerator.
As a further preference, the 2-trifluoromethyl-substituted benzimidazole compound is one of compounds shown in a formula (I-1) and a formula (I-5):
in the preparation method, the aromatic amine and the aliphatic amine, the copper sulfate pentahydrate, the carbon nitride and the potassium carbonate are generally commercially available products and can be conveniently obtained from the market, and the trifluoroethylimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid. Copper-doped carbon nitride can be conveniently synthesized from copper sulfate pentahydrate, carbon nitride, isonicotinic acid chloride and triethylamine.
Compared with the prior art, the invention has the beneficial effects that: the preparation method has mild reaction conditions, easy operation and simple and convenient post-treatment; the reaction starting raw materials and the catalyst are cheap and easy to obtain, designability of a reaction substrate is strong, the tolerance range of a substrate functional group is wide, reaction efficiency is high, the heterogeneous catalyst can be recycled (experiments show that the catalytic efficiency of the catalyst which is recycled for three times is respectively 92%, 80% and 69%), different substituted benzimidazole compounds with trifluoromethyl can be designed and synthesized according to actual needs, and the practicability is strong.
Detailed Description
The invention is further described with reference to specific examples.
Preparation of the catalyst:
carbon nitride (g-C) 3 N 4 ) Dispersed in DMF and sonicated for three hours, then the sonicated carbon nitride, isonicotinic acid chloride hydrochloride and a few drops of triethylamine were mixed in DMF and reacted at 60 ℃ for 6 hours. Centrifuging, washing and freeze-drying the reaction solution to obtain a compound (g-C) of carbon nitride and isonicotinic acid chloride 3 N 4 -INCH). G to C 3 N 4 -INCH and blue vitriol are mixed in the water solution, and triethylamine is added dropwise to react for 3 hours at 60 ℃. Washing the product after the reaction is completed for a plurality of times by DMF and ultrapure water, and freeze-drying to obtain the copper-doped carbon nitride catalyst (Cu/g-C) 3 N 4 )。
Testing of Cu/g-C Using inductively coupled plasma emission Spectroscopy (ICP-OES) 3 N 4 The copper content in the alloy is 16%, and the Cu/g-C content is tested by a Transmission Electron Microscope (TEM) 3 N 4 The nano-rod particles with the morphology of 10-20nm are loaded on carbon nitride. X-ray photoelectron spectroscopy (XPS) for Cu/g-C 3 N 4 The valence of the copper is zero valence and one valence.
Examples 1 to 10
Adding copper-doped carbon nitride, potassium carbonate, trifluoroethylimidoyl chloride (II), amine (III) and 2mL of organic solvent into a 35mL Schlenk tube according to the raw material ratio of Table 1, uniformly mixing and stirring, reacting for 18-30 hours according to the reaction condition of Table 2, filtering, mixing with silica gel, and purifying by column chromatography to obtain a corresponding 2-trifluoromethyl-substituted benzimidazole compound (I), wherein the reaction process is shown as the following formula:
TABLE 1 raw material addition amounts of examples 1 to 10
TABLE 2
In tables 1 and 2, T is the reaction temperature, T is the reaction time, ph is phenyl, me is methyl, i-Pr is isopropyl, n-Bu is n-butyl, n-Amyl is n-pentyl, bn is benzyl, CF 3 Is trifluoromethyl, and DMF is N, N-dimethylformamide.
Structure confirmation data of the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of 2-trifluoromethyl-substituted benzimidazole Compound (I-1) prepared in example 1: ( 1 H NMR、 13 C NMR and 19 f NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )δ7.88(d,J＝8.1Hz,1H),7.47–7.39(m,2H), 7.39–7.33(m,1H),4.37–4.24(m,2H),1.94–1.81(m,2H),1.51–1.38(m, 2H),0.98(t,J＝7.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ141.3,140.6(q,J (C-F) ＝38.3Hz),135.5,125.3, 123.7,121.8,119.4(q,J (C-F) ＝271.3Hz),110.7,45.1,32.3,20.2,13.7.
19 F NMR(377MHz,CDCl 3 )δ-61.89.
nuclear magnetic resonance of 2-trifluoromethyl-substituted benzimidazole Compound (I-2) prepared in example 2: ( 1 H NMR、 13 C NMR and 19 f NMR) the data were:
1 H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.40–7.33(m,2H),4.27(t,2H), 1.84(dd,J＝16.3Hz,6.9Hz,2H),1.48–1.35(m,2H),0.97(t,J＝7.4Hz, 3H).
13 C NMR(101MHz,CDCl 3 )δ141.9,141.6(q,J (C-F) ＝38.8Hz),134.1,129.4, 126.0,121.4,119.0(q,J (C-F) ＝271.5Hz),111.6,45.3,32.1,20.1,13.7.
19 F NMR(377MHz,CDCl 3 )δ-62.08.
HRMS(ESI):[M+H] + calcd.for C 12 H 13 ClF 3 N 2 + 277.0714,found 277.0724.
nuclear magnetic resonance of 2-trifluoromethyl-substituted benzimidazole Compound (I-3) prepared in example 3: ( 1 H NMR、 13 C NMR and 19 f NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )δ7.88(d,J＝7.3Hz,1H),7.68(d,J＝7.4Hz, 1H),7.41–7.28(m,2H),4.48–4.39(m,1H),2.35–2.19(m,2H),2.04– 1.95(m,4H),1.83(d,J＝12.9Hz,1H),1.56–1.42(m,2H),1.40–1.27(m, 1H).
13 C NMR(101MHz,CDCl 3 )δ142.1,140.5(q,J (C-F) ＝38.0Hz),134.2,124.8, 123.3,122.1,119.4(q,J (C-F) ＝271.3Hz),113.6,57.9,31.4,26.0,25.3.
19 F NMR(377MHz,CDCl 3 )δ-61.70.
nuclear magnetic resonance of 2-trifluoromethyl-substituted benzimidazole Compound (I-4) prepared in example 4: ( 1 H NMR、 13 C NMR and 19 f NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝6.7Hz,1H),7.42–7.23(m,6H), 7.11(d,J＝7.7Hz,2H),5.54(s,2H).
13 C NMR(101MHz,CDCl 3 )δ141.3,141.0(q,J (C-F) ＝38.5Hz),135.7,135.0, 129.1,128.4,126.4,125.7,123.9,121.8,119.3(q,J (C-F) ＝271.6Hz),111.3, 48.6.
19 F NMR(377MHz,CDCl 3 )δ-61.49.
nuclear magnetic resonance of 2-trifluoromethyl-substituted benzimidazole Compound (I-5) prepared in example 5 (II) 1 H NMR、 13 C NMR and 19 f NMR) the data were:
1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝7.1Hz,1H),7.61–7.56(m,3H), 7.46–7.34(m,4H),7.16(d,J＝6.9Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ141.0(d,J (C-F) ＝38.6Hz),140.8,137.3,134.5, 130.0,129.9,127.5,125.9,124.2,121.5,119.0(q,J (C-F) ＝271.8Hz),111.3.
19 F NMR(377MHz,CDCl 3 )δ-60.46。
Claims (4)
1. a heterogeneously catalyzed process for the preparation of a 2-trifluoromethyl-substituted benzimidazole compound, characterized by comprising the steps of: adding copper-doped carbon nitride, alkali, trifluoroethylimidoyl chloride and amine into an organic solvent, reacting for 18 to 30 hours at the temperature of 70 to 90 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 2-trifluoromethyl-substituted benzimidazole compound;
the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):
the structure of the amine is shown as the formula (III):
the structure of the 2-trifluoromethyl substituted benzimidazole compound is shown as the formula (I):
in the formulae (I) to (III), R 1 Is H, C 1 ~C 4 Alkyl, cl, br or trifluoromethyl; r 2 Is C 3 ~C 6 Alkyl, phenyl or benzyl;
the organic solvent is DMF;
the alkali is potassium carbonate;
dispersing carbon nitride in DMF, ultrasonic treating for three hours, mixing the carbon nitride, isonicotinic acid chloride hydrochloride and several drops of triethylamine in DMF, reacting at 60 deg.C for 6 hours, centrifuging, washing and freeze drying the reaction solution to obtain the compound of carbon nitride and isonicotinic acid chloride, and mixing g-C 3 N 4 mixing-INCH and blue vitriol in water solution, dripping triethylamine to react for 3 hours at 60 ℃, washing the product for a plurality of times by DMF and ultrapure water after the reaction is completed, and freeze-drying to obtain the copper-doped carbon nitride.
2. The method for preparing 2-trifluoromethyl-substituted benzimidazole compound according to claim 1, wherein R is 1 Is H, methyl, cl, br or trifluoromethyl; r 2 Is isopropyl, n-butyl, n-pentyl, n-hexyl, phenyl or benzyl.
3. The method for producing a 2-trifluoromethyl-substituted benzimidazole compound according to claim 1, wherein the molar ratio of trifluoroethylimidoyl chloride: amine: copper-doped carbon nitride: the alkali =1, 1 to 2, 0.02 to 0.08, 1 to 3.
4. The method for preparing a 2-trifluoromethyl-substituted benzimidazole compound according to claim 1, wherein the 2-trifluoromethyl-substituted benzimidazole compound is one of the compounds represented by formula (I-1) to formula (I-5):
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110820929.9A CN113429349B (en) | 2021-07-20 | 2021-07-20 | Preparation method of heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110820929.9A CN113429349B (en) | 2021-07-20 | 2021-07-20 | Preparation method of heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113429349A CN113429349A (en) | 2021-09-24 |
| CN113429349B true CN113429349B (en) | 2022-12-20 |
Family
ID=77761073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110820929.9A Active CN113429349B (en) | 2021-07-20 | 2021-07-20 | Preparation method of heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113429349B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105056895B (en) * | 2015-08-17 | 2017-07-28 | 中国科学院上海高等研究院 | A kind of preparation method and applications of metal organic framework mesopore silicon oxide composite |
| CN109065873B (en) * | 2018-08-17 | 2021-10-22 | 广东凯金新能源科技股份有限公司 | Preparation method and material of supported nano-copper mesoporous graphite carbon nitride negative electrode material |
| CN110538485A (en) * | 2019-08-27 | 2019-12-06 | 河南大学 | Nano carbon nitride/copper oxide composite material, nano carbon nitride/copper oxide composite solid phase micro-extractor and preparation method and application thereof |
| CN111423381B (en) * | 2020-01-17 | 2021-09-07 | 浙江理工大学 | Preparation method of 2-trifluoromethyl substituted imidazole compound |
| CN111905796A (en) * | 2020-09-02 | 2020-11-10 | 江苏理工学院 | Preparation method of superfine metal nanoparticle/carbon nitride nanosheet composite material |
-
2021
- 2021-07-20 CN CN202110820929.9A patent/CN113429349B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113429349A (en) | 2021-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111675662B (en) | Preparation method of 2-trifluoromethyl substituted quinazolinone compound | |
| CN111978265B (en) | Preparation method of 5-trifluoromethyl substituted 1,2, 4-triazole derivative | |
| Guo et al. | Photoinduced, copper-catalyzed three components cyanofluoroalkylation of alkenes with fluoroalkyl iodides as fluoroalkylation reagents | |
| CN113105402B (en) | Preparation method of 3,4, 5-trisubstituted 1,2, 4-triazole compound | |
| CN113307790B (en) | Preparation method of 3-quinolyl-5-trifluoromethyl substituted 1,2, 4-triazole compound | |
| CN111423381B (en) | Preparation method of 2-trifluoromethyl substituted imidazole compound | |
| CN110467579B (en) | Preparation method of 5-trifluoromethyl substituted 1,2, 4-triazole compound | |
| CN113121462B (en) | Preparation method of 5-trifluoromethyl substituted 1,2,3-triazole compound | |
| CN113307778A (en) | Preparation method of 3-trifluoromethyl substituted 1,2, 4-triazole compound | |
| CN112125856A (en) | Preparation method of 2-trifluoromethyl substituted quinazolinone derivative | |
| CN113045503B (en) | Preparation method of 2-trifluoromethyl substituted quinazolinone compound and application of compound in synthesis of drug molecules | |
| CN112480015B (en) | Method for synthesizing 2-trifluoromethyl substituted quinazolinone by multi-component one-pot method | |
| CN113735778B (en) | Preparation method of 5-trifluoromethyl substituted imidazole compound | |
| CN107935925B (en) | Preparation method of polysubstituted phenanthridine compound | |
| CN113429349B (en) | Preparation method of heterogeneous catalytic 2-trifluoromethyl substituted benzimidazole compound | |
| CN111393384A (en) | Application of cuprous complex containing ortho-carborane Schiff base ligand | |
| CN115160312B (en) | Viridigdine key intermediate and preparation method thereof | |
| CN113880781B (en) | Method for synthesizing 3-trifluoromethyl substituted 1,2, 4-triazole compound by taking glucose as carbon source | |
| CN115286578A (en) | Preparation method of pyrazole compound containing trifluoromethyl | |
| CN110627823B (en) | Method for catalyzing arylamine to generate deamination boric acid esterification or halogenation | |
| CN115215810B (en) | Preparation method of heating-promoted 5-trifluoromethyl-substituted 1,2, 4-triazole compound | |
| CN112778351A (en) | Preparation method of beta-dimethylphenyl silicon substituted aromatic nitro compound | |
| CN114195726B (en) | Preparation method of 1,2, 4-triazole substituted arylamine compound | |
| CN114920707B (en) | Preparation method of 3-trifluoromethyl substituted 1,2,4-triazole compound | |
| CN115353482B (en) | Preparation method of trifluoromethyl and selenium substituted azaspiro [4,5] -tetraenone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |