CN111423381A - Preparation method of 2-trifluoromethyl substituted imidazole compound - Google Patents
Preparation method of 2-trifluoromethyl substituted imidazole compound Download PDFInfo
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- CN111423381A CN111423381A CN202010055490.0A CN202010055490A CN111423381A CN 111423381 A CN111423381 A CN 111423381A CN 202010055490 A CN202010055490 A CN 202010055490A CN 111423381 A CN111423381 A CN 111423381A
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- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
The invention discloses a preparation method of a 2-trifluoromethyl substituted imidazole compound, which comprises the following steps: adding a palladium catalyst, a ligand, a carbon monoxide substitute, an additive, trifluoroethylimidoyl chloride, propargylamine and diaryl iodide into an organic solvent, reacting for 18-20 hours at 30 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 2-trifluoromethyl-substituted imidazole compound. The preparation method is simple to operate, the initial raw materials are cheap and easy to obtain, the reaction efficiency is high, the substrate compatibility is good, and diversified substituted imidazole compounds with trifluoromethyl can be synthesized through substrate design, so that the practicability of the method is widened while the operation is convenient.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 2-trifluoromethyl substituted imidazole compound.
Background
Imidazole compounds are important nitrogen-containing five-membered heterocycles and are widely present in various molecular backbones with important biological activities (Med. Res. Rev.2014,34, 340-one 437). Many drugs and functional material molecules contain imidazole molecular structures. Imidazole compounds can also be used as ionic liquids and ligands for coordination to metals, and are often used in the field of coordination catalysis (chem.Soc.Rev.2017,46, 4845-one 4854). The introduction of trifluoromethyl into a heterocyclic molecule has many advantages, such as significantly improved electronegativity, bioavailability, metabolic stability, lipophilicity, etc. of the parent molecule (j.med. chem.2015,58, 8315-.
The literature reports now that the method for synthesizing nitrogen-containing heterocycles with trifluoromethyl functional groups is mainly to directly obtain trifluoromethyl-substituted nitrogen-containing heterocycles by reacting a synthon with a trifluoromethyl group with a suitable substrate (Angew. chem. int. Ed.2018,57, 6633-containing 6637; chem. Commun.2015,51, 8789-containing 8792). Among them, the more commonly used trifluoromethyl synthons are trifluorodiazoethane and trifluoroethylimidoyl halide, which are relatively not widely used at present, but have a great application potential and need to be studied deeply.
Based on the method, cheap and easily-obtained trifluoroethyliminato chloride, propargylamine and diaryl iodide are used as starting materials, and carbonylation series reaction catalyzed by transition metal palladium is used for efficiently synthesizing the 2-trifluoromethyl substituted imidazole.
Disclosure of Invention
The invention provides a preparation method of a 2-trifluoromethyl substituted imidazole compound, which has the advantages of simple steps, cheap and easily obtained reaction raw materials, compatibility with various functional groups and good reaction applicability, can be expanded to gram level, and provides possibility for industrial large-scale production and application.
A method for preparing a 2-trifluoromethyl-substituted imidazole compound, comprising the steps of: adding a mixture of palladium chloride, triphenylphosphine, sodium bicarbonate, acetic anhydride and formic acid, trifluoroethylimidoyl chloride, propargylamine and diaryl iodide into an organic solvent, reacting at 30 ℃ for 16-24 hours, and after the reaction is completed, performing post-treatment to obtain the 2-trifluoromethyl-substituted imidazole compound;
the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):
the propargylamine has a structure shown in a formula (III):
the structure of the diaryl iodonium salt is shown as the formula (IV):
the 2-trifluoromethyl substituted imidazole compound has a structure shown in a formula (I):
in the formulas (I) to (IV), R is substituted or unsubstituted aryl;
ar is a substituted or unsubstituted aryl group;
the substituent on the aryl is selected from C1～C5Alkyl, halogen, trifluoromethyl or nitro.
The molar ratio of the palladium chloride to the triphenylphosphine to the sodium bicarbonate is 0.05:0.1: 2;
the substitution position on the aryl of R and Ar can be ortho, para or meta.
The reaction formula is as follows:
during the reaction, an intermolecular carbon-nitrogen bond promoted by alkali may be formed to obtain a trifluoroacetamidine compound, then isomerization is carried out, palladium-catalyzed alkyne amine is subjected to palladation to obtain an alkenyl palladium intermediate, then isomerization is carried out to obtain an alkyl palladium intermediate, then carbonylation reaction is carried out under the action of carbon monoxide released from formic acid acetic anhydride to obtain an acyl palladium intermediate, diaryl iodonium salt is subjected to oxidation addition to obtain a tetravalent palladium intermediate, and finally reduction elimination is carried out to obtain the final 2-trifluoromethyl-substituted imidazole 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 imidazole compound, wherein the column chromatography purification is a technical means commonly used in the field.
Preferably, R is a substituted or unsubstituted aryl group, and the substituent on the aryl group is selected from methyl, tert-butyl, chlorine, bromine, trifluoromethyl or nitro, in which case the trifluoroethylimidoyl chloride is readily available and the yield of the reaction is high.
Preferably, Ar is a substituted or unsubstituted aryl group, in which case the diaryliodonium salt is readily available and the yield of the reaction is high.
The aromatic amine used to prepare the trifluoroethylimidoyl chloride is relatively inexpensive, widely available in nature, in excess relative to the propargylamine, preferably, in molar amounts, trifluoroethylimidoyl chloride: propargylamine: diaryl iodonium salts: palladium chloride is 1-3: 1: 1-3: 0.02-0.1; as a further preference, the molar amount of trifluoroethylimidoyl chloride: propargylamine: diaryl iodonium salts: palladium chloride ═ 1.5:1:1.5: 0.05.
Preferably, the reaction time is 16-24 hours, and if the reaction time is too long, the reaction cost is increased, and on the contrary, the completeness of the reaction is difficult to ensure.
In the present invention, the organic solvent capable of sufficiently dissolving the raw material can cause the reaction, but the difference in reaction efficiency is large, and the aprotic solvent is preferably an aprotic solvent which can effectively promote the reaction; preferably, the organic solvent is tetrahydrofuran, acetonitrile or dioxane; further preferably, the organic solvent is tetrahydrofuran, in which case various starting materials can be converted into products with high conversion.
The amount of the organic solvent can be used for better dissolving the raw materials, and the amount of the organic solvent used for 1mmol of trifluoroethylimidoyl chloride is about 5-10 m L.
Preferably, the catalyst is palladium chloride, which is relatively inexpensive among many palladium catalysts, and the reaction efficiency is high when palladium chloride is used as the catalyst.
As a further preference, the 2-trifluoromethyl-substituted imidazole compound is one of compounds represented by the formulae (I-1) to (I-5):
in the preparation method, the aromatic amine, the alkynylamine, the formic acid, the acetic anhydride, the palladium chloride and the triphenylphosphine are generally commercially available products and can be conveniently obtained from the market, the trifluoroethyliminecarbonyl chloride can be quickly synthesized from the corresponding aromatic amine, the triphenylphosphine, the carbon tetrachloride and the trifluoroacetic acid, and the diaryl iodide salt can be simply and quickly prepared from the corresponding aryl phenylboronic acid and the aryl iodide.
Compared with the prior art, the invention has the beneficial effects that: the preparation method is easy to operate, and the post-treatment is simple and convenient; the initial raw materials for the reaction are cheap and easy to obtain, the designability of the substrate is strong, the tolerance range of the functional group of the substrate is wide, the reaction efficiency is high, the imidazole compounds with trifluoromethyl and different substitutions at the 1 and 5 positions 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.
According to the raw material ratio of table 1, palladium chloride, triphenylphosphine, acetic anhydride and formic acid mixture, sodium bicarbonate, trifluoroethylimidoyl chloride (II), propargylamine (III), diaryl Iodide (IV) and organic solvent 2m L are added into a Schlenk tube of 35m L, the mixture is uniformly mixed and stirred, the mixture reacts for 16 to 24 hours according to the reaction conditions of table 2, the mixture is filtered, silica gel is stirred, and the corresponding 2-trifluoromethyl substituted imidazole compound (I) is obtained through column chromatography purification, wherein the reaction process is shown as the following formula:
TABLE 1 raw material addition amounts of examples 1 to 15
TABLE 2
In tables 1 and 2, T is the reaction temperature, T is the reaction time, Ph is phenyl, Me is methyl, OMe is methoxy, T-Bu is T-butyl, NO2Is nitro, CF3Is trifluoromethyl and THF is tetrahydrofuran.
Structure confirmation data of the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of 2-trifluoromethyl-substituted imidazole Compound (I-1) prepared in example 1 ((II-1))1H NMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)7.79(d,J＝7.3Hz,2H),7.56(t,J＝7.4Hz,1H),7.42(t,J＝7.8Hz,2H),7.22(d,J＝8.4Hz,2H),7.16(d,J＝8.3Hz,2H),7.13(s,1H),4.07(s,2H),2.37(s,3H).
13C NMR(101MHz,CDCl3)194.5,140.4,136.9(q,J＝38.6Hz),136.0,133.7,131.6,130.6,130.1,128.8,128.4,128.2,127.7,118.8(q,J＝270.0Hz),34.1,21.3.
19F NMR(377MHz,CDCl3)-60.3.
HRMS(ESI):[M+H]+calcd.for C19H15F3N2O 345.1209,found 345.1227.
nuclear magnetic resonance of 2-trifluoromethyl-substituted imidazole Compound (I-2) prepared in example 2 ((II-2))1HNMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)7.76(d,J＝7.2Hz,2H),7.55(t,J＝7.4Hz,1H),7.42(d,J＝8.4Hz,4H),7.19(d,J＝8.5Hz,2H),7.13(s,1H),4.05(s,2H),1.30(s,9H).
13C NMR(101MHz,CDCl3)194.8,153.5,137.0(q,J＝37.2Hz),136.2,133.7,131.6,130.7,128.8,128.4,128.2,127.5,126.4,118.8(q,J＝270.0Hz),35.0,34.1,31.3.
19F NMR(377MHz,CDCl3)-60.3(s).
HRMS(ESI):[M+H]+calcd.for C22H21F3N2O 387.1679,found 387.1693.
nuclear magnetic resonance of 2-trifluoromethyl-substituted imidazole Compound (I-3) prepared in example 3 ((II-3))1HNMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)7.93(dd,J＝16.5,7.9Hz,2H),7.57(dd,J＝14.5,4.3Hz,3H),7.53–7.50(m,2H),7.47(dd,J＝7.2,6.1Hz,2H),7.30(dd,J＝10.6,4.9Hz,3H),7.12(d,J＝8.3Hz,1H),3.90(dd,J＝137.1,17.6Hz,2H).
13C NMR(101MHz,CDCl3)194.3,137.5(q,J＝39.1Hz),135.8,134.0,133.6,131.4,130.9,130.4,130.3,128.8,128.7,128.5,128.3,128.1,127.2,127.1,125.1,122.7,118.7(q,J＝270.1Hz),33.9.
19F NMR(377MHz,CDCl3)-61.1.
HRMS(ESI):[M+H]+calcd.for C22H15F3N2O 381.1209,found 381.1227.
nuclear magnetic resonance of 2-trifluoromethyl-substituted imidazole Compound (I-4) prepared in example 4 ((II-4))1HNMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)7.77(d,J＝8.9Hz,2H),7.48–7.40(m,3H),7.29(dd,J＝6.7,4.7Hz,2H),7.13(s,1H),6.88(d,J＝8.9Hz,2H),4.02(s,2H),3.85(s,3H).
13C NMR(101MHz,CDCl3)192.9,164.0,136.7(q,J＝39.0Hz),134.3,130.9,130.6,130.2,129.5,128.9,128.4,128.0,118.8(q,J＝269.9Hz),114.0,55.6,33.8.
19F NMR(377MHz,CDCl3)-60.3.
HRMS(ESI):[M+H]+calcd.for C19H15F3N2O2361.1158,found 361.1174.
nuclear magnetic resonance of 2-trifluoromethyl-substituted imidazole Compound (I-5) prepared in example 5 ((II-5))1HNMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)7.72(d,J＝8.6Hz,2H),7.48–7.41(m,3H),7.41–7.36(m,2H),7.28(d,J＝5.7Hz,2H),7.15(s,1H),4.05(s,2H).
13C NMR(101MHz,CDCl3)193.3,140.3,136.9(q,J＝39.0Hz),134.2,130.3,130.1,129.6,129.6,129.2,128.6,128.0,118.7(q,J＝270.2Hz),34.1.
19F NMR(377MHz,CDCl3)-60.3.
HRMS(ESI):[M+H]+calcd.for C18H12ClF3N2O 365.0663,found 365.0678.
Claims (10)
1. a method for preparing a 2-trifluoromethyl-substituted imidazole compound, comprising the steps of: adding a palladium catalyst, a ligand, a carbon monoxide substitute, an additive, trifluoroethylimidoyl chloride, propargylamine and diaryl iodide into an organic solvent, reacting for 16-24 hours at 20-40 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 2-trifluoromethyl-substituted imidazole compound;
the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):
the propargylamine has a structure shown in a formula (III):
the structure of the diaryl iodonium salt is shown as the formula (IV):
the 2-trifluoromethyl substituted imidazole compound has a structure shown in a formula (I):
in the formulas (I) to (IV), R is substituted or unsubstituted aryl;
ar is a substituted or unsubstituted aryl group;
the substituent on the aryl is selected from C1～C5Alkyl, halogen, trifluoromethyl or nitro.
2. The method for producing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein R is a substituted or unsubstituted aryl group;
the substituent on the aryl is selected from methyl, tert-butyl, chlorine, bromine, trifluoromethyl or nitro.
3. The method for producing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein Ar is a substituted or unsubstituted phenyl group;
the substituent on the phenyl is selected from methoxy, methyl, chlorine or bromine.
4. The method for producing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein, in terms of molar amount, the ratio of trifluoroethylimidoyl chloride: propargylamine: diaryl iodonium salts: additive: palladium catalyst: ligand: the carbon monoxide substitute is 1-2: 1: 1-2: 8-10: 0.05:0.1: 2-4.
5. The method for preparing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein the organic solvent is tetrahydrofuran.
6. The method for preparing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein the palladium catalyst is palladium chloride.
7. The method for producing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein the ligand is triphenylphosphine.
8. The method for preparing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein the additive is a mixture of acetic anhydride and formic acid.
9. The method of claim 1, wherein the carbon monoxide substitute is sodium bicarbonate.
10. The method for preparing a 2-trifluoromethyl-substituted imidazole compound according to claim 1, wherein the 2-trifluoromethyl-substituted imidazole compound is one of compounds represented by formula (I-1) to formula (I-5):
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