CN110818639A - Synthesis method of N-imido imidazole compound - Google Patents

Synthesis method of N-imido imidazole compound Download PDF

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CN110818639A
CN110818639A CN201911179332.XA CN201911179332A CN110818639A CN 110818639 A CN110818639 A CN 110818639A CN 201911179332 A CN201911179332 A CN 201911179332A CN 110818639 A CN110818639 A CN 110818639A
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iminoimidazole
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CN110818639B (en
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祝志强
季久健
乐长高
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East China Institute of Technology
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    • 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
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—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
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Abstract

The invention discloses a method for synthesizing an N-imido imidazole compound, which comprises the step of carrying out oxidative dehydrogenation cross-coupling reaction on α -aminoketone and an imidazole compound under the action of a cuprous salt catalyst and di-tert-butyl peroxide in an air atmosphere to obtain the N-imido imidazole compound.

Description

Synthesis method of N-imido imidazole compound
Technical Field
The invention relates to a synthesis method of an N-imido imidazole compound, in particular to a method for directly carrying out oxidative dehydrogenation cross-coupling reaction on α -aminoketone and an imidazole compound under the action of a cuprous salt catalyst and di-tert-butyl peroxide to obtain the N-imido imidazole compound, belonging to the field of organic synthesis.
Background
Imidazole rings are important five-membered nitrogen-containing heterocycles with aromaticity, widely exist in natural products, drugs and functional materials, imidazoles and derivatives with unique electronic-rich characteristics are easy to combine with various enzymes through various interactions, and good biological activity is shown, wherein some medicaments containing imidazole skeleton structures, particularly N-substituted imidazole derivatives, are widely used for treating various diseases such as cancer, malaria and the like in clinic, at present, substitution or coupling reaction on nitrogen atoms of imidazole compounds is required, a traditional method needs pretreatment, a synthesis process is relatively complex, the atom utilization rate is low, reaction conditions are harsh, and the like, in recent years, amination reaction directly utilizing C-H bonds in reaction substrates is a very effective and attractive synthesis strategy, α -aminocarbonyl is an important structural component, a plurality of natural products, biomolecules and drugs with biological activity exist in nature, and a plurality of atmosphere containing carbon-hydrogen bonds are constructed in natural world, a series of amino-H functional groups and a series of indole-carbonyl compounds with C-H bonds, NH-carbonyl bonds, NH-O-NH-C-H bonds are constructed through a series of aromatic carbonyl-carbonyl compounds with aromatic carbonyl bonds, NH-H bonds, NH-carbonyl bonds, N-carbonyl bonds are constructed through a series of aromatic amine-carbonyl compounds with a very important research significance, a series of aromatic carbonyl-carbonyl compounds, a series of aromatic amine-carbonyl compounds with a single bond-carbonyl bond catalysis, a single-carbonyl bond synthesis strategy is constructed through a single-carbonyl bond synthesis strategy, a single-carbonyl amine-.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a method for synthesizing an N-imido imidazole compound by direct oxidative dehydrogenation coupling of α -aminoketone and an imidazole compound, which adopts a cheap cuprous salt catalyst, has lower cost, is realized through one-pot reaction, greatly simplifies a synthetic route, improves reaction efficiency, reduces energy loss, has good reaction chemical selectivity, high atom economy, less byproducts and high product purity, and is suitable for large-scale synthetic conversion.
In order to realize the technical purpose, the invention provides a synthesis method of an N-imido imidazole compound, which comprises the steps of carrying out oxidative dehydrogenation cross-coupling reaction on α -aminoketone and an imidazole compound under the action of a cuprous salt catalyst and di-tert-butyl peroxide in an air atmosphere to obtain the N-imido imidazole compound;
the α -aminoketone has the structure of formula 1:
Figure BDA0002290827300000021
the imidazole compound has the structure of formula 2:
Figure BDA0002290827300000022
the N-imidoimidazole compound has the structure of formula 3:
Figure BDA0002290827300000023
wherein the content of the first and second substances,
R1is hydrogen, an electron donating group or an electron withdrawing group;
R2is alkoxy or aryl;
R3is hydrogen, an electron donating group or an electron withdrawing group;
R4is hydrogen or alkyl.
α -amino ketones of the invention1Is a substituent on the benzene ring, which can be hydrogen, an electron-donating group or an electron-withdrawing group, R1When it is an electron-donating group, it may be selected from C1～C5Alkyl or C1～C5Alkoxy radicals, e.g. C1～C5The alkyl group may be a straight-chain alkyl group or a branched-chain alkyl group, such as methyl, propyl, isopropyl, butyl, etc., C1～C5Alkoxy groups such as methoxy, ethoxy, isobutoxy, and the like. R1When the group is an electron-withdrawing group, it is selected from fluorine, chlorine, bromine, iodine, cyano or trifluoromethyl. R1The position on the benzene ring is not limited and may be ortho, meta or para. R2Is a group attached to a carbonyl group, which may be alkoxy or aryl, R2When it is an alkoxy group, it is selected from C1～C5Alkoxy groups, such as specifically methoxy, ethoxy, isobutoxy, and the like. R2When the aryl is selected from phenyl, naphthyl or phenyl containing substituent, the substituent on the phenyl is selected from C1～C5Alkyl radical, C1～C5Alkoxy or halogen, the number of the substituent can be 1 or more, preferably 1, the position of the substituent is not limited, and the substituent can be any position of a benzene ring; c1～C5The alkyl group may be a straight-chain alkyl group or a branched-chain alkyl group, such as methyl, propyl, isopropyl, butyl, etc., C1～C5Alkoxy such as methoxy, ethoxy, isobutoxy, and the like, halogen such as fluorine, chlorine, bromine, iodine, and the like. The choice of substituents has an influence on the efficiency of the oxidative dehydrogenation cross-coupling reaction, e.g. R1Yield was 83% when R is hydrogen1When the compound is used as an electron-donating group, the yield is up to more than 90 percent, and the reaction is facilitated; when R is1When the compound is an electron-withdrawing group, the yield is slightly lower than that of the electron-withdrawing group and is more than 80 percent. R2When the aryl is adopted, the yield is up to more than 90 percent; r2In the case of ethoxy, the yield drops sharply to 33% relative to the aryl radical.
R in the imidazole Compounds of the present invention3Is a substituent at position 4 or 5 on the imidazole ring, orThese are aromatic ring structures formed at the 4-position and 5-position, such as benzene ring, substituted benzene ring, etc. R3When it is an electron-donating group, it may be selected from C1～C5Alkyl, which may be straight-chain alkyl or branched, such as methyl, propyl, isopropyl, butyl, and the like; or from aryl groups containing electron-donating groups, e.g. from C1～C5Phenyl of alkyl or containing C1～C5Phenyl of alkoxy. R3When it is an electron-withdrawing group, it is selected from halogens such as fluorine, chlorine, bromine, iodine, etc.; r4Is a substituent at the 2-position on the imidazole ring, which may be hydrogen, or C1～C5The alkyl group may be a straight-chain alkyl group or a branched-chain alkyl group, specifically, methyl, propyl, isopropyl, butyl, etc. R3When the compound is an electron-donating group, the yield is better than that of an electron-withdrawing group at the same position; r3When the aromatic ring is used, good yield can be obtained no matter the aromatic ring is connected with an electron-withdrawing group or an electron-supplying group. R4The yields are significantly better than alkyl substituted imidazoles when hydrogen is present.
Compared with a copper salt catalyst or other transition metal catalysts, the yield of the oxidative dehydrogenation cross-coupling reaction between α -aminoketone and the imidazole compound by the cuprous salt is obviously high, and the cuprous salt catalyst has obvious advantages.
In a preferable scheme, the dosage of the cuprous salt catalyst is 5-20% of the molar weight of the imidazole compound. The dosage of the cuprous salt catalyst is too small, the impurity content in the product is obviously increased, and the dosage of the cuprous salt catalyst is too large, so that the product yield is reduced.
In a preferable scheme, the molar ratio of α -aminoketone to imidazole compound is 1-2: 1, in the ratio range, the α -aminoketone content is increased, the product yield can be obviously increased, but when the α -aminoketone ratio is higher than 2, the atom utilization rate is reduced.
In a preferable scheme, the dosage of the di-tert-butyl peroxide is 1-3 times of the molar weight of α -aminoketone, the dosage of the oxidant is preferably about 2 times of the molar weight of α -aminoketone, and the reaction yield is reduced due to too high or too low condition.
In a preferred embodiment, the oxidative dehydrogenation cross-coupling reaction is carried out in at least one solvent system selected from acetonitrile, dimethylsulfoxide, toluene and chlorobenzene. Most preferred is a chlorobenzene solvent system.
In a preferred embodiment, the oxidative dehydrogenation cross-coupling reaction conditions are as follows: reacting for 1-4 hours at the temperature of 80-130 ℃, and preferably, the oxidative dehydrogenation cross-coupling reaction conditions are as follows: reacting for 2-3 hours at the temperature of 100-110 ℃. The optimum temperature is 110 ℃, the product yield can be obviously improved by increasing the temperature, and the product yield can be reduced by increasing the temperature when the temperature is higher than 110 ℃.
According to the synthesis method of the N-imido imidazole compound, α -aminoketone and the imidazole compound are used as reaction substrates in an organic solvent system in the presence of a cuprous salt catalyst and di-tert-butyl peroxide under the air environment, the reaction substrates are stirred until the reaction is completely detected by TLC (thin layer chromatography), and the N-imido imidazole can be efficiently prepared by column chromatography separation after concentration, wherein the reaction general formula is as follows:
Figure BDA0002290827300000041
the reaction mechanism is that α -aminoketone forms an imine intermediate under the action of a CuCl/DTBP catalytic system, then nitrogen atoms on an electron-rich imidazole ring perform nucleophilic addition on the imine intermediate, and then the N-imino substituted imidazole compound is obtained through further oxidative dehydrogenation.
Compared with the prior art, the technical scheme of the invention has the following advantages and beneficial effects:
the synthesis method of the N-imido imidazole compound provided by the invention is realized through one-pot reaction, can be used for reaction in air atmosphere, has the advantages of short synthesis route, high reaction efficiency, simple operation and the like, and is suitable for large-scale preparation.
The synthesis method of the N-imido imidazole compound provided by the invention adopts cheap and easily available cuprous salt as a catalyst and di-tert-butyl peroxide as an oxidant, so that the raw materials are easily available and the cost is low.
The synthesis method of the N-imido imidazole compound provided by the invention has the advantages of good reaction chemical selectivity, high atom economy, less by-products and high product purity.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the product prepared in example 1;
FIG. 2 is a nuclear magnetic carbon spectrum of the product prepared in example 1.
Detailed Description
The present invention will be described in further detail below with reference to specific examples, but the embodiments of the present invention are not limited thereto.
Condition optimization experiment:
the following examples take the oxidative dehydrogenation cross-coupling reaction between 2- (4-toluidino) acetophenone and benzimidazole as an example to perform optimization experiments of catalyst, oxidant, solvent and reaction conditions:
adding 2- (4-toluidine amino) acetophenone, a benzimidazole compound, a catalyst and an oxidant into a reaction tube provided with a stirring magneton, then adding a solvent into a test tube, putting a reaction mixed solution into an oil bath kettle, stirring and reacting under a heating condition, removing the solvent by reduced pressure distillation by using a rotary evaporator after TLC detection reaction is finished, and separating and purifying residues by column chromatography.
The specific reaction formula is as follows:
TABLE 1 catalyst selection optimization experiment
Entry Catalyst Oxidant Solvent Yield(％)
1 CoCO3 DTBP PhCl 26
2 CuBr DTBP PhCl 78
3 Cu(OAc)2 DTBP PhCl 75
4b FeCl3 DTBP PhCl 13
5 CuBr2 DTBP PhCl 73
6 Cu2O DTBP PhCl 72
7 CuCl DTBP PhCl 82
8 CuI DTBP PhCl 80
9 Cu(OAc)2·H2O DTBP PhCl 73
10 Cu(OTf)2 DTBP PhCl 62
11 CuCl2 DTBP PhCl 80
12 CuO DTBP PhCl 62
13 Co(OAc)2 DTBP PhCl 29
14 Co(ClO4)2·6H2O DTBP PhCl 19
Reaction conditions are as follows: s10.20mmol, S20.15mmol, Catalyst 10 mol%, oxidantan 2eq, solvent (2.0mL), reaction time 2h at 120 ℃,bthe reaction time is 2 h.
As can be seen from table 1, among the various transition metal catalysts, the copper-based catalyst has a better catalytic effect, and among the copper-based catalysts, the cuprous salt has the most prominent catalytic effect, particularly cuprous chloride, which has the best catalytic effect.
TABLE 2 catalyst optimization experiment
Figure BDA0002290827300000061
Figure BDA0002290827300000071
Reaction conditions are as follows: s10.20mmol, S20.15mmol, catalyst CuCl, oxidant 2eq, solvent (2.0mL), and the reaction time is 2 hours at 120 ℃.
As can be seen from Table 2, the cuprous chloride catalyst has a good catalytic effect when used in an amount of 5 mol% to 30 mol%, but the product yield is significantly reduced when the amount of the cuprous chloride catalyst exceeds 10 mol%, and when the cuprous chloride catalyst is not used, a large amount of reaction byproducts is produced.
TABLE 3 Oxidation agent selection optimization experiment
Figure BDA0002290827300000072
Figure BDA0002290827300000081
Reaction conditions are as follows: s10.20mmol, S20.15mmol, oxidantan CuCl 5 mol%, oxidantan 2eq, PhCl 2mL, reaction time 2h at 120 ℃,bthe reaction time is 4h, and no catalyst or oxidant is added.
As can be seen from Table 3, DTBP exhibited the best oxidation among the various oxidizing agents.
TABLE 4 temperature optimization experiment
Entry Temperature(℃) Yield(％)
1b 30 37
2c 60 53
3 80 82
4 90 85
5 100 86
6 110 89
7 120 82
8 130 79
9 150 73
Reaction conditions are as follows: s10.20mmol, S20.15mmol, oxidantan CuCl 5 mol%, Oxidant DTBP2eq, PhCl 2mL, reaction time of 2h,bthe reaction time is 4 hours,cthe reaction time is 3 h.
As can be seen from table 4, the reaction temperature was in the range of 30 ℃ to 150 ℃, and the product yield peaked as the temperature increased to 110 ℃, but the product yield decreased significantly beyond 110 ℃.
TABLE 5 optimization experiment of material ratio
Figure BDA0002290827300000082
Figure BDA0002290827300000091
Reaction conditions are as follows: s20.15mmol, catalyst CuCl 5 mol%, oxidant DTBP2eq, PhCl (2mL), 110 ℃, reaction time 2 h.
As can be seen from Table 5, a suitable increase in the amount of S1 substrate significantly increased the product yield.
Through the optimized experimental conditions, the final determination conditions are as follows: 2- (4-toluidino) acetophenone (2equiv,0.3mmol), benzimidazole (1.0equiv, 0.15mmol), CuCl (5 mmol%), DTBP (2equiv,3mmol), chlorobenzene (2mL) were reacted at 110 ℃ for 2 h.
The specific examples are as follows:
example 1
2- (4-toluidino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), di-t-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and stirred at 110 ℃ for 2 hours. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, the residue is separated and purified by column chromatography to obtain pure yellow solid with the yield of 93 percent (control experiment: if other conditions are not changed in the reaction, the reaction atmosphere is changed into nitrogen atmosphere, the product yield is only 30 percent), and the structural characterization data are as follows:
Yellow solid；mp 132.7-133.2℃；1H NMR(400MHz,CDCl3)δ8.48-8.33(m,1H),8.06(s,1H),7.84(t,J＝6.8Hz,3H),7.56(t,J＝7.4Hz,1H),7.46-7.32(m,4H),6.97(d,J＝8.1Hz,2H),6.86(d,J＝8.2Hz,2H),2.19(s,3H)；13C NMR(100MHz,CDCl3)δ190.7,148.4,144.3,142.8,141.4,135.5,134.9,133.5,131.6,129.6,129.6,129.3,125.3,124.8,121.2,120.6,115.9,20.8；HRMS(ESI)calcd for C22H18N3O(M+H)+340.1444,found340.1447.
example 2
2- (m-tolylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), di-t-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, chlorobenzene (2mL) solvent was then added to the test tube and the reaction mixture was placed in an oil bath, and the reaction was stopped with stirring at 110 ℃ for 2 hours. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 94%, and the structural characterization data is as follows:
Figure BDA0002290827300000101
Yellow oil；1H NMR(400MHz,CDCl3)δ8.46-8.36(m,1H),8.07(s,1H),7.84(dd,J＝12.4,5.6Hz,3H),7.56(t,J＝7.4Hz,1H),7.47-7.35(m,4H),7.04(t,J＝7.8Hz,1H),6.77(dd,J＝18.0,7.2Hz,3H),2.21(s,3H)；13C NMR(100MHz,CDCl3)δ190.3,148.5,145.3,144.3,141.4,138.9,135.5,133.6,131.6,129.6,129.2,128.8,126.0,125.3,124.9,122.0,120.6,118.2,115.9,21.2；HRMS(ESI)calcd for C22H18N3O(M+H)+340.1444,found340.1444.
example 3
2- (o-tolylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), di-t-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with continuous stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 94%, and the structural characterization data is as follows:
Figure BDA0002290827300000111
Yellow oil；1H NMR(400MHz,CDCl3)δ8.59-8.45(m,1H),8.09(s,1H),7.92-7.83(m,1H),7.79(d,J＝7.6Hz,2H),7.56(t,J＝7.2Hz,1H),7.48-7.35(m,4H),7.06(d,J＝7.2Hz,1H),6.92(dt,J＝20.8,7.2Hz,2H),6.74(d,J＝7.6Hz,1H),2.33(s,3H)；13C NNMR(100MHz,CDCl3)δ190.3,148.2,144.3,143.9,141.5,135.5,133.8,131.7,130.5,129.9,129.2,129.2,126.2,125.4,124.9,120.7,120.0,115.9,18.4；HRMS(ESI)calcd forC22H18N3O(M+H+)340.1444,found 340.1446.
example 4
2- [ (4-phenyl) amino ] acetophenone (0.3mmol), benzimidazole (0.15mmol), cuprous chloride (5 mmol%), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, chlorobenzene (2mL) solvent was then added to the tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with constant stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 83%, and the structural characterization data is as follows:
Figure BDA0002290827300000112
Yellow solid；mp 114.4-115.9℃；1H NMR(400MHz,CDCl3)δ8.49-8.38(m,1H),8.08(s,1H),7.89-7.76(m,3H),7.55(t,J＝7.4Hz,1H),7.46-7.34(m,4H),7.17(t,J＝7.7Hz,2H),6.97(dd,J＝13.3,7.5Hz,3H)；13C NMR(100MHz,CDCl3)δ190.3,148.8,145.4,144.3,141.4,135.6,133.5,131.6,129.6,129.3,129.0,125.4,125.2,124.9,121.2,120.7,116.0；HRMS(ESI)calcd for C21H16N3O(M+H)+326.1288,found 326.1291
example 5
2- (4-Fluorophenylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with constant stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow solid, wherein the yield is 85%, and the structural characterization data is as follows:
Figure BDA0002290827300000121
Yellow solid；mp 133.4-135.7℃；1H NMR(400MHz,CDCl3)δ8.47-8.35(m,1H),8.07(s,1H),7.90-7.77(m,3H),7.58(t,J＝7.4Hz,1H),7.47-7.37(m,4H),7.02-6.77(m,4H)；13C NMR(100MHz,CDCl3)δ190.3,161.5,159.1,149.3,144.4,141.5(d,J＝2.9Hz),141.4,135.8,133.3,131.5,129.5(d,J＝18.4Hz),125.4,125.01,122.7(q,J＝8.3Hz),120.7,115.9(q,J＝2.3Hz),115.7；HRMS(ESI)calcd for C21H15FN3O(M+H)+344.1194,found344.1196.
example 6
2- (4-chlorophenylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with continuous stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain a pure yellow solid, wherein the yield is 94%, and the structural characterization data is as follows:
Yellow solid；mp 124.8-126.6℃；1H NMR(400MHz，CDCl3)δ8.40(dd，J＝7.63.6Hz,1H),8.05(s,1H),7.91-7.75(m,3H),7.60(t,J＝7.4Hz,1H),7.49-7.36(m,4H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H)；13C NMR(100MHz,CDCl3)δ189.9,149.3,144.4,144.0,141.3,135.9,133.3,131.5,130.7,129.6,129.5,129.1,125.5,125.1,122.6,120.7,115.9；HRMS(ESI)calcd for C21H15ClN3O(M+H)+360.0898,found 360.0896.
example 7
2- (4-bromophenylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with continuous stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain a pure yellow solid, wherein the yield is 95%, and the structural characterization data is as follows:
Figure BDA0002290827300000131
Yellow solid；mp 135.1-136.9℃；1H NMR(400MHz,CDCl3)δ8.45-8.35(m,1H),8.05(s,1H),7.89-7.79(m,3H),7.59(t,J＝7.4Hz,1H),7.42(dd,J＝10.0,3.6Hz,4H),7.28(t,J＝6.8Hz,2H),6.83(d,J＝8.8Hz,2H)；13C NMR(100MHz,CDCl3)δ189.8,149.3,144.5,144.3,141.3,135.9,133.3,132.1,131.5,129.6,129.5,125.5,125.1,122.9,120.7,118.4,115.9；HRMS(ESI)calcd for C21H15BrN3O(M+H)+404.0393,found 404.0395.
example 8
2- (4-iodophenylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with constant stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation through a rotary evaporator, and the residue is separated and purified by column chromatography to obtain a pure yellow solid, wherein the yield is 93%, and the structural characterization data is as follows:
Figure BDA0002290827300000141
Yellow solid；mp 144.8-145.1℃；1H NMR(400MHz,CDCl3)δ8.43-8.34(m,1H),8.04(s,1H),7.89-7.78(m,3H),7.60(t,J＝7.4Hz,1H),7.52-7.37(m,6H),6.71(d,J＝8.4Hz,2H)；13C NMR(100MHz,CDCl3)δ189.8,149.2,145.1,144.3,141.3,138.0,135.9,133.3,131.5,129.6,129.5,125.5,125.1,123.2,120.8,115.9,89.3；HRMS(ESI)calcd forC21H15IN3O(M+H)+452.0254,found 452.0257.
example 9
2- (4-Cyanophenylamino) acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with continuous stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow solid, wherein the yield is 85%, and the structural characterization data is as follows:
Figure BDA0002290827300000142
Yellow solid；1H NMR(400MHz,CDCl3)δ8.37(dd,J＝6.0,3.2Hz,1H),8.05(s,1H),7.90-7.77(m,3H),7.63(t,J＝7.4Hz,1H),7.49-7.43(m,6H),7.01(d,J＝8.4Hz,2H)；13CNMR(100MHz,CDCl3)δ188.8,149.8,149.6,144.3,141.3,136.2,133.1,133.1,131.3,129.6,125.8,125.5,121.8,120.9,118.6,115.9,114.4,108.5；HRMS(ESI)calcd forC22H15N4O(M+H)+351.1240,found 351.1241.
example 10
2- [ (4- (trifluoromethyl) phenyl) amino ] acetophenone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), and di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted at 110 ℃ for 2 hours with continuous stirring. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow solid with the yield of 80 percent and the structural characterization data as follows:
Figure BDA0002290827300000151
Yellow solid；mp 132.0-132.7℃；1H NMR(400MHz,CDCl3)δ8.40(dd,J＝6.4,3.2Hz,1H),8.06(s,1H),7.90-7.78(m,3H),7.60(t,J＝7.4Hz,1H),7.44(q,J＝6.8Hz,6H),7.03(d,J＝8.0Hz,2H)；13C NMR(100MHz,CDCl3)δ189.2,149.7,148.6,144.4,141.3,136.0,133.3,131.3,129.6,129.5,127.2,126.9,126.2(q,J＝3.5Hz),125.3,124.0(q,J＝270.3Hz),121.3,120.8,115.9；HRMS(ESI)calcd for C22H15F3N3O(M+H)+394.1162,found394.1158.
example 11
1- (4-tolyl) -2- (4-toluylamino) ethanone (0.3mmol), a benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), and di-t-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the tube and the reaction mixture was placed in an oil bath and stirred at 110 ℃ for 2 hours. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain a pure yellow solid, wherein the yield is 94%, and the structural characterization data is as follows:
Figure BDA0002290827300000152
Yellow solid；mp 131.9-132.9℃；1H NMR(400MHz,CDCl3)δ8.48-8.30(m,1H),8.06(s,1H),7.88-7.78(m,1H),7.73(d,J＝8.0Hz,2H),7.47-7.35(m,2H),7.18(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.88(d,J＝8.0Hz,2H),2.34(s,3H),2.20(s,3H)；13CNMR(100MHz,CDCl3)δ190.1,148.6,147.1,144.3,142.9,141.5,134.8,131.6,131.1,130.1,129.8,129.6,125.3,124.8,121.2,120.6,115.9,21.9,20.8；HRMS(ESI)calcd forC23H20N3O(M+H)+354.1601,found 354.1600.
example 12
1- (4-methoxyphenyl) -2- (p-toluidino) ethanone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, chlorobenzene (2mL) solvent was then added to the tube and the reaction mixture was placed in an oil bath and allowed to react for 2 hours with constant stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow solid, wherein the yield is 99%, and the structural characterization data is as follows:
Figure BDA0002290827300000161
Yellow solid；mp 135.9-136.8℃；1H NMR(400MHz,CDCl3)δ8.33(d,J＝9.2Hz,1H),8.06–7.96(m,2H),7.91(s,1H),7.83(d,J＝7.6Hz,4H),7.71(d,J＝8.8Hz,1H),7.56(t,J＝7.4Hz,2H),7.39(td,J＝7.6,2.4Hz,4H),7.32(d,J＝2.4Hz,1H),7.09-7.00(m,2H),6.96(t,J＝6.6Hz,4H),6.86(dd,J＝8.0,5.2Hz,4H),3.88(d,J＝6.4Hz,6H),2.19(d,J＝2.8Hz,6H).；13C NMR(100MHz,CDCl3)δ188.62,165.48,148.74,144.29,142.96,141.58,134.76,132.31,131.65,129.58,126.51,125.22,124.72,121.16,120.52,115.96,114.70,77.37,77.05,76.73,55.66,20.84；HRMS(ESI)calcd for C23H20N3O2(M+H)+370.1550,found370.1554.
example 13
2-naphthyl-2- (p-toluidino) ethanone (0.3mmol), benzimidazole (0.15mmol), cuprous chloride (5 mmol%), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with continuous stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 98 percent, and the structural characterization data is as follows:
Figure BDA0002290827300000171
Yellow solid；mp 144.8-145.9℃；1H NMR(400MHz,CDCl3)δ8.48-8.41(m,1H),8.33(s,1H),8.13(s,1H),8.00-7.73(m,5H),7.60(t,J＝7.4Hz,1H),7.51(t,J＝7.6Hz,1H),7.47-7.37(m,2H),6.92(s,4H),2.12(s,3H)；13C NMR(100MHz,CDCl3)δ190.6,148.5,144.4,142.9,141.5,136.6,134.9,133.3,132.3,131.7,130.8,130.0,129.7,129.6,128.0,127.4,125.3,124.9,123.3,121.2,120.6,116.0,20.8；HRMS(ESI)calcd forC26H20N3O(M+H)+390.1601,found 390.1598.
example 14
1- (4-fluorophenyl) -2- (p-toluidino) ethanone (0.3mmol), benzimidazole compound (0.15mmol), cuprous chloride (5 mmol%), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the test tube and the reaction mixture was placed in an oil bath and stirred for 2 hours at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 90%, and the structural characterization data is as follows:
Figure BDA0002290827300000172
Yellow oil；1H NMR(400MHz,CDCl3)δ8.49-8.29(m,1H),8.07(s,1H),7.93-7.78(m,3H),7.50-7.35(m,2H),7.06(t,J＝8.4Hz,2H),6.98(d,J＝8.0Hz,2H),6.85(d,J＝8.4Hz,2H),2.21(s,3H)；13C NMR(100MHz,CDCl3)δ189.1,167.0(d,J＝260.9Hz),148.0,144.3,142.7,141.3,135.1,132.5(d,J＝10.1Hz),131.6,129.9(d,J＝2.6Hz),129.7,125.4,124.9,121.1,120.7,116.8(d,J＝22.4Hz),115.89,20.82；HRMS(ESI)calcd forC22H17FN3O(M+H)+358.1350,found 358.1353.
example 15
2- (4-toluidino) acetophenone (0.3mmol), 5, 6-dimethylbenzimidazole (0.15mmol), cuprous chloride (5 mmol%), and di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, and then chlorobenzene (2mL) solvent was added to the tube and the reaction mixture was placed in an oil bath and reacted for 2 hours with continuous stirring at 110 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 77%, and the structural characterization data is as follows:
Yellow solid；mp 122.2-123.9℃；1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.91(s,1H),7.82(d,J＝8.0Hz,2H),7.63-7.50(m,2H),7.38(t,J＝7.6Hz,2H),6.97(d,J＝8.0Hz,2H),6.86(d,J＝8.0Hz,2H),2.41(d,J＝4.8Hz,6H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ190.7,148.6,143.0,142.8,140.7,135.4,134.7,134.6,133.9,133.6,130.0,129.6,129.6,129.2,121.2,120.6,116.1,20.8,20.6,20.3；HRMS(ESI)calcd for C24H22N3O(M+H)+368.1757,found 368.1757.
example 16
2- (4-toluidino) acetophenone (0.3mmol), 2-methyl-1H-imidazole (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, then chlorobenzene (2mL) solvent was added to the tube and the reaction mixture was placed in an oil bath and reacted for 3 hours with constant stirring at 55 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 71%, and the structural characterization data is as follows:
Yellow oil；1H NMR(400MHz,CDCl3)δ7.82-7.71(m,2H),7.56(t,J＝7.4Hz,1H),7.40(t,J＝7.8Hz,2H),7.08(d,J＝1.6Hz,1H),6.99-6.87(m,3H),6.77(d,J＝8.0Hz,2H),2.71(s,3H),2.18(s,3H)；13C NMR(100MHz,CDCl3)δ190.5,148.6,146.6,142.6,135.3,135.0,133.4,129.5,129.4,129.2,128.2,120.8,117.9,20.8,17.3；HRMS(ESI)calcd forC19H18N3O(M+H)+304.1444,found 304.1442.
example 17
2- (4-toluidino) acetophenone (0.3mmol), 4-methyl-1H-imidazole (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, then chlorobenzene (2mL) solvent was added to the tube and the reaction mixture was placed in an oil bath and reacted for 3 hours with constant stirring at 55 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 63 percent, and the structural characterization data is as follows:
Figure BDA0002290827300000192
Yellow oil；1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.77(dd,J＝8.0,0.8Hz,2H),7.55(t,J＝7.4Hz,1H),7.39(t,J＝7.8Hz,2H),7.28(s,1H),6.93(d,J＝8.4Hz,2H),6.79(d,J＝8.0Hz,2H),2.26(s,3H),2.17(s,3H)；13C NMR(100MHz,CDCl3)δ190.8,147.0,142.5,140.3,135.5,135.4,135.1,133.3,129.6,129.5,129.2,121.1,112.5,20.8,13.6；HRMS(ESI)calcd for C19H18N3O(M+H)+304.1444,found 304.1442.
example 18
2- (4-toluidino) acetophenone (0.3mmol), 4-iodo-1H-imidazole (0.15mmol), cuprous chloride (5 mmol), di-tert-butyl peroxide (DTBP,0.6mmol) were added to a reaction tube equipped with a stirring magneton, then chlorobenzene (2mL) solvent was added to the tube and the reaction mixture was placed in an oil bath and reacted for 3 hours with constant stirring at 55 ℃. After TLC detection reaction is finished, the solvent is removed by reduced pressure distillation of a rotary evaporator, and the residue is separated and purified by column chromatography to obtain pure yellow liquid, wherein the yield is 43 percent, and the structural characterization data is as follows:
Figure BDA0002290827300000201
Yellow solid；mp 109.6-111.3℃；1H NMR(400MHz,CDCl3)δ7.84(d,J＝1.6Hz,1H),7.78-7.72(m,2H),7.69(d,J＝1.6Hz,1H),7.62-7.52(m,1H),7.40(t,J＝8.0Hz,2H),6.95(d,J＝8.4Hz,2H),6.80(d,J＝8.4Hz,2H),2.19(s,3H)；13C NMR(100MHz,CDCl3)δ190.2,145.3,141.8,137.2,135.8,135.7,132.9,129.7,129.6,129.3,122.0,121.1,85.2,20.8；HRMS(ESI)calcd for C18H15IN3O(M+H)+416.0254,found 461.0255.

Claims (10)

1. a synthesis method of an N-imido imidazole compound is characterized in that α -aminoketone and an imidazole compound are subjected to oxidative dehydrogenation cross-coupling reaction under the action of a cuprous salt catalyst and di-tert-butyl peroxide in an air atmosphere to obtain the N-imido imidazole compound;
the α -aminoketone has the structure of formula 1:
Figure FDA0002290827290000011
the imidazole compound has the structure of formula 2:
Figure FDA0002290827290000012
the N-imidoimidazole compound has the structure of formula 3:
Figure FDA0002290827290000013
wherein the content of the first and second substances,
R1is hydrogen, an electron donating group or an electron withdrawing group,
R2is alkoxy or aryl;
R3is hydrogen, an electron donating group or an electron withdrawing group;
R4is hydrogen or alkyl.
2. The method of claim 1, wherein the step of synthesizing the N-iminoimidazole compound comprises:
R1when it is an electron donating group, it is selected from C1～C5Alkyl or C1～C5An alkoxy group;
R1when the group is an electron-withdrawing group, the group is selected from fluorine, chlorine, bromine, iodine, cyano or trifluoromethyl;
R2when it is an alkoxy group, it is selected from C1～C5An alkoxy group;
R2when the aryl is selected from phenyl, naphthyl or phenyl containing substituent, the substituent on the phenyl is selected from C1～C5Alkyl radical, C1～C5Alkoxy or halogen;
R3when it is an electron donating group, it is selected from C1～C5Alkyl or selected from C-containing1～C5Phenyl of alkyl or containing C1～C5Phenyl of alkoxy;
R3when an electron withdrawing group, is selected from halogen;
R4when it is an alkyl group, it is selected from C1～C5An alkyl group.
3. The method of claim 1, wherein the step of synthesizing the N-iminoimidazole compound comprises: the cuprous salt catalyst comprises at least one of CuCl, CuBr and CuI.
4. The method of claim 1 or 3, wherein the step of synthesizing the N-iminoimidazole compound comprises: the dosage of the cuprous salt catalyst is 5-20% of the molar weight of the imidazole compound.
5. The method for synthesizing an N-imidoimidazole compound according to claim 1, wherein the molar ratio of α -aminoketone to imidazole compound is 1-2: 1.
6. The method for synthesizing an N-imidoimidazole compound according to claim 1, wherein the amount of the di-tert-butyl peroxide is 1 to 3 times the molar amount of α -aminoketone.
7. The method of claim 1, wherein the step of synthesizing the N-iminoimidazole compound comprises: the oxidative dehydrogenation cross-coupling reaction is carried out in at least one solvent system of acetonitrile, dimethyl sulfoxide, toluene and chlorobenzene.
8. The method of claim 7, wherein the step of synthesizing the N-iminoimidazole compound comprises: the oxidative dehydrogenation cross-coupling reaction is carried out in a chlorobenzene solvent system.
9. The method for synthesizing an N-iminoimidazole compound according to any one of claims 1 to 8, comprising: the oxidative dehydrogenation cross-coupling reaction conditions are as follows: reacting for 1-4 hours at 80-130 ℃.
10. The method of claim 9, wherein the step of synthesizing an N-iminoimidazole compound comprises: the oxidative dehydrogenation cross-coupling reaction conditions are as follows: reacting for 2-3 hours at the temperature of 100-110 ℃.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5775903A (en) * 1980-10-27 1982-05-12 Nippon Soda Co Ltd Agricultural and horticultural germicidal composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5775903A (en) * 1980-10-27 1982-05-12 Nippon Soda Co Ltd Agricultural and horticultural germicidal composition

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHUANG CHEN，ET AL.: "Copper-catalyzed oxidative cross-coupling of α-aminocarbonyl compounds with primary amines toward 2-oxo-acetamidines", 《ORG. BIOMOL. CHEM.》 *
GUILLERMO MARTINEZ-ARIZA，ET AL.: "One-Pot Two-Step Multicomponent Process of Indole and Other Nitrogenous Heterocycles or Amines toward α‑Oxo-acetamidines", 《ORG. LETT.》 *
XING-XING LIU，ET AL.: "Copper-Catalyzed C¢N Bond Formation via Oxidative Cross-Coupling of Amines with α-Aminocarbonyl Compounds", 《ADV.SYNTH.CATAL.》 *

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