CN110818639B - Synthesis method of N-imido imidazole compound - Google Patents

Synthesis method of N-imido imidazole compound Download PDF

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CN110818639B
CN110818639B CN201911179332.XA CN201911179332A CN110818639B CN 110818639 B CN110818639 B CN 110818639B CN 201911179332 A CN201911179332 A CN 201911179332A CN 110818639 B CN110818639 B CN 110818639B
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imidoimidazole
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imidazole compound
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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
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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 steps of carrying out oxidative dehydrogenation cross-coupling reaction on alpha-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 method has the advantages of simple reaction conditions, simple operation, high reaction efficiency, wide substrate application range, good reaction chemical selectivity, high atom economy, few byproducts and high product purity, and is suitable for large-scale synthesis and conversion.

Description

Synthesis method of N-imido imidazole compound
Technical Field
The invention relates to a method for synthesizing an N-imido imidazole compound, in particular to a method for directly carrying out oxidative dehydrogenation cross-coupling reaction on alpha-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, and are widely present in natural products, medicaments and functional materials. Imidazole and derivatives with unique electron-rich characteristics are easy to combine with various enzymes through various interactions, and show good biological activity. Among them, some of the drugs containing imidazole skeleton structures, especially N-substituted imidazole derivatives, have been widely used clinically for the treatment of various diseases such as cancer, malaria, and the like. At present, the traditional method of substitution or coupling reaction on nitrogen atoms of imidazole compounds needs pretreatment, the synthetic process is relatively complex, the atom utilization rate is low, the reaction conditions are harsh, and the like. In recent years, amination directly using the C-H bond in the reaction substrate is a very efficient and attractive synthetic strategy. Alpha-aminocarbonyl is an important structural component in a number of biologically active natural products, biomolecules and drugs found in nature. Therefore, the C-H functionalization of alpha-aminocarbonyl compounds is of great research interest. In recent years, the direct functionalization of the α -C-H bond of α -aminocarbonyl compounds has attracted great interest to organic and bio-organic chemists, and many different types of coupling reagents can be efficiently introduced into α -aminocarbonyl compounds. However, reports of one-step construction of C-N single and double bonds are rare through the strategy of α -C-H bond activation of α -aminocarbonyl compounds. In recent years, the coupling of alpha-aminocarbonyl compounds with indole, diphenylphosphine oxide, alcohols, amines via alpha-C-H bond activation has been reported. In 2012, the Li jin Heng subject group takes CuBr/TBHP as a catalytic system, and alpha-aminocarbonyl compounds and indole carbon-carbon bond coupling are realized in an argon atmosphere to synthesize a series of C3 imino-substituted indole derivatives. In 2016, professor of Huang nationality adopts copper salt to catalyze alpha-aminocarbonyl compound and secondary alkyl amine to perform oxidation cross coupling in air atmosphere at room temperature, so that various alpha-aminated alpha-aminocarbonyl compounds are effectively constructed. However, this synthetic method is limited to secondary amines, primary aliphatic amines and primary aromatic amines only, and fails to achieve the construction of a C — N bond. In 2017, a copper salt and tert-butyl hydroperoxide (TBHP) catalytic system is adopted by professor Jiannan and the like, and oxidation cross coupling of secondary amine, aliphatic primary amine and aromatic primary amine and alpha-aminocarbonyl compounds is realized in a nitrogen atmosphere to construct a series of 2-amino-2-imine carbonyl compounds. However, so far, no report is found for constructing an N-imidoimidazole compound containing a C-N single bond and a double bond by introducing an imidazole-based nitrogen-containing heterocyclic compound into an alpha-aminocarbonyl compound through dehydrogenation cross-coupling.
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 directly oxidative dehydrogenation coupling of alpha-aminoketone and an imidazole compound, which adopts a cheap cuprous salt catalyst, has lower cost, is realized through one-pot reaction, greatly simplifies the synthetic route, improves the reaction efficiency, reduces the 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 method for synthesizing an N-imido imidazole compound, which comprises the steps of carrying out oxidative dehydrogenation cross-coupling reaction on alpha-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 alpha-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.
R in the alpha-aminoketones 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 aryl, it is selected from phenyl, naphthyl, or substituted phenylThe substituents on the phenyl group being 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 on the 4-position or the 5-position of the imidazole ring, or an aromatic ring structure formed on the 4-position and the 5-position, such as a benzene ring, a benzene ring containing a substituent and the like. 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.
In a preferred embodiment, the cuprous salt catalyst comprises at least one of CuCl, CuBr, and CuI. Compared with a copper salt catalyst or other transition metal catalysts, the cuprous salt has obvious high yield and obvious advantages on the oxidative dehydrogenation cross-coupling reaction between the alpha-aminoketone and the imidazole compound. Cuprous chloride in the cuprous salt catalyst is the best catalyst.
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 preferred embodiment, the molar ratio of the alpha-aminoketone to the imidazole compound is 1-2: 1. Within this ratio range, the amount of alpha-aminoketone increases, which can significantly increase the product yield, but when the alpha-aminoketone ratio is higher than 2, the atom utilization rate decreases.
In a preferable scheme, the dosage of the di-tert-butyl peroxide is 1-3 times of the molar weight of the alpha-aminoketone. The amount of the oxidizing agent is preferably about 2 times the molar amount of the alpha-aminoketone, and the reaction yield is lowered when the amount is too high or too low.
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, provided by the invention, in an air environment and in an organic solvent system in the presence of a cuprous salt catalyst and di-tert-butyl peroxide, alpha-aminoketone and the imidazole compound are used as reaction substrates, are stirred until the reaction is completely detected by TLC (thin layer chromatography), are concentrated and then are subjected to column chromatography separation, so that the N-imido imidazole can be efficiently prepared, and the reaction general formula is as follows:
Figure BDA0002290827300000041
the reaction mechanism is as follows: the alpha-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:
Figure BDA0002290827300000051
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)2·6H2 O 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 DTBP 2eq, 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 DTBP 2eq, 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:
Figure BDA0002290827300000092
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,found 340.1447.
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,found 340.1444.
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 for C22H18N3O(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,found 344.1196.
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:
Figure BDA0002290827300000122
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 for C21H15IN3O(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)；13C NMR(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 for C22H15N4O(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,found 394.1158.
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)；13C NMR(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 for C23H20N3O(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,found 370.1554.
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 for C26H20N3O(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 for C22H17FN3O(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:
Figure BDA0002290827300000181
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:
Figure BDA0002290827300000191
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 for C19H18N3O(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 (6)

1. a kind ofN-a process for the synthesis of an imidoimidazole compound, characterized in that: in the air atmosphere, the alpha-aminoketone and the imidazole compound are subjected to oxidative dehydrogenation cross-coupling reaction under the action of a cuprous salt catalyst and di-tert-butyl peroxide to obtainN-an imidoimidazole compound;
the alpha-aminoketone has the structure of formula 1:
Figure DEST_PATH_IMAGE002
formula 1
The imidazole compound has the structure of formula 2:
Figure DEST_PATH_IMAGE004
formula 2
The above-mentionedNThe imidoimidazole compound has the structure of formula 3:
Figure DEST_PATH_IMAGE006
formula 3
Wherein the content of the first and second substances,
R1is hydrogen, C1~C5Alkyl radical, C1~C5Alkoxy, fluoro, chloro, bromo, iodo, cyano or trifluoromethyl;
R2is C1~C5Alkoxy, phenyl or naphthyl, or phenyl containing substituent, wherein the substituent on the phenyl is selected from C1~C5Alkyl radical, C1~C5Alkoxy or halogen;
R3is hydrogen, C1~C5Alkyl radical, containing C1~C5Phenyl of alkyl or containing C1~C5Phenyl for alkoxy, or halogen;
R4is hydrogen or C1~C5An alkyl group;
the cuprous salt catalyst comprises at least one of CuCl, CuBr and CuI;
the molar ratio of the alpha-aminoketone to the imidazole compound is 1-2: 1;
the oxidative dehydrogenation cross-coupling reaction conditions are as follows: reacting for 1-4 hours at 80-130 ℃.
2. A method as claimed in claim 1N-a process for the synthesis of an imidoimidazole compound, characterized in that: the dosage of the cuprous salt catalyst is 5-20% of the molar weight of the imidazole compound.
3. A method as claimed in claim 1N-a process for the synthesis of an imidoimidazole compound, characterized in that: the dosage of the di-tert-butyl peroxide is 1-3 times of the molar weight of the alpha-aminoketone.
4. A method as claimed in claim 1N-a process for the synthesis of an imidoimidazole compound, characterized in that: the oxidative dehydrogenation cross-coupling reaction is carried out in at least one solvent system of acetonitrile, dimethyl sulfoxide, toluene and chlorobenzene.
5. A process according to claim 4N-a process for the synthesis of an imidoimidazole compound, characterized in that: the oxidative dehydrogenation crossThe coupling reaction was carried out in a chlorobenzene solvent system.
6. A method as claimed in claim 1N-a process for the synthesis of an imidoimidazole compound, characterized in that: 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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