CN111732546A - Fused ring compound containing imidazole skeleton and preparation method thereof - Google Patents
Fused ring compound containing imidazole skeleton and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a fused ring compound containing an imidazole skeleton and a preparation method thereof, wherein the fused ring compound containing the imidazole skeleton has a structure shown as a structural formula (I) or (II). The condensed ring compound containing imidazole skeleton provided by the invention is a novel condensed heterocyclic lead compound containing indene [1,2-d ] imidazole skeleton and having potential bioactivity, which is obtained by taking carbon atoms as a nucleophilic reagent and inserting isonitrile into the carbon atoms on the fourth position of imidazole through a functionalization reaction.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a fused ring compound containing an imidazole skeleton and a preparation method thereof.
Background
Imidazole derivatives are multifunctional scaffold modules, present in many important branches of natural science, and have important applications in many fields including pharmaceutical research, functional materials and synthetic chemistry. The compounds show wide range of biological activities, including anticancer, anti-inflammatory, antibacterial and antihypertensive activities, and can also be used in the fields of corrosion inhibitors, surface active treatment agents, chemiluminescent materials and the like. Because of the many uses of imidazole compounds, the development of strategies for the efficient synthesis of imidazole has been receiving attention in the field of synthetic chemistry.
The isonitrile compounds are important organic molecules, have wide application in MCRs, insertion reactions and other one-pot series reactions, and can effectively generate a series of C-N, C-S, C-O and C-C bonds. Transition metal (including Pd, Cu, Co, Ni, etc.) catalyzed isonitrile insertion reactions have been widely reported in the synthesis of heterocyclic compounds over the past several decades. Such reactions typically involve the formation of C (sp2) -M metal species, followed by oxidative addition of a metal catalyst to an aryl or alkenyl/halide, followed by coupling with different nucleophiles under basic conditions to produce the target compound. However, in comprehensive literature research, most nucleophilic functional groups are concentrated on O, N and S atoms, and reports of capturing active C (sp2) -M substances by using carbon atoms as a nucleophilic reagent are rare in the literature, mainly because the carbon atoms have relatively poor nucleophilicity, so that the synthesis process is complex and the synthesis efficiency is low.
Disclosure of Invention
The invention mainly aims to provide a fused ring compound containing an imidazole skeleton and a preparation method thereof, and aims to provide a fused ring compound containing an imidazole skeleton, wherein nucleophilic functional groups are concentrated on carbon atoms.
In order to achieve the above object, the present invention provides a fused ring compound containing an imidazole skeleton, which has a structure represented by the following structural formula (i):
wherein R is1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of (1), R7Including any one of tert-butyl, cyclohexyl, adamantyl and 1, 3-dimethylphenyl.
The invention also provides a fused ring compound containing an imidazole skeleton, which has a structure shown in the following structural formula (II):
wherein R is1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of them.
In order to achieve the above object, the present invention also provides a method for preparing a fused ring compound having an imidazole skeleton, comprising the steps of:
step S10, adding the first reactant and the second reactant into absolute methanol, stirring and mixing, then adding TosMIC reagent, and adding K2CO3Reacting for 6-8 hours at 55-65 ℃ by using alkali, and purifying a reaction product by column chromatography to obtain an intermediate A with a structure shown in a structural formula (III);
step S20, adding the intermediate A, the third reactant, the catalyst, the ligand and the alkali into an organic solvent, reacting at 95-105 ℃ for 8-24 h, and carrying out column chromatography purification on a reaction product to obtain a target compound B, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (I);
the first reactant is a compound with a structure shown in a structural formula (IV), the second reactant is a compound with a structure shown in a structural formula (V), and the structural general formula of the third reactant is R7-NC：
In the structural formulas (III), (IV) and (V), X is Br or I, R1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of the above;
r in the structural general formula of the third reactant7Including any one of tert-butyl, cyclohexyl, adamantyl and 1, 3-dimethylphenyl.
Alternatively, in step S10: the molar ratio of the first reactant to the second reactant to the TosMIC reagent is 1:1 (1-2).
Optionally, the catalyst comprises PdCl2、Pd(dba)2、Pd(OAc)2And Pd (TFA)2Any one of the above; and/or the presence of a gas in the gas,
the ligand comprises PPh3、DPPF、DPPB、DPEPhos、PCy3Any one of tris (o-methylphenyl) phosphorus and phenanthroline; and/or the presence of a gas in the gas,
the base comprises K2CO3、DABCO、t-BuONa、t-BuOK、DBU、Cs2CO3And cesium pivalate; and/or the presence of a gas in the gas,
the organic solvent comprises toluene, 1,4-dioxane and CH3CN, DCE, DMF and DMSO.
Optionally, in step S20: the molar ratio of the intermediate A to the third reactant is 1: (1-2); and/or the presence of a gas in the gas,
the molar ratio of the alkali to the intermediate A is (0.75-2): 1; and/or the presence of a gas in the gas,
the molar ratio of the catalyst to the intermediate A is (0.025-0.1): 1; and/or the presence of a gas in the gas,
the molar ratio of the ligand to the intermediate A is (0.025-0.2): 1.
optionally, in step S10, the eluent used in the column chromatography purification of the reaction product is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1: (8-10).
Optionally, in step S20, the eluent used in the column chromatography purification of the reaction product is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1: (20-30).
Optionally, after step S20, the method further includes:
and step S30, adding the target compound B into tetrahydrofuran, then adding a hydrochloric acid solution, reacting for 3.5-4.5 h at 55-65 ℃, and extracting and purifying by column chromatography to obtain the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (II).
Optionally, the eluent used in the step S30 for performing column chromatography purification on the reaction product is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1: (14-16).
The condensed ring compound containing the imidazole skeleton provided by the invention is a novel condensed heterocyclic compound containing the indene [1,2-d ] imidazole skeleton, which is obtained by taking a carbon atom as a nucleophilic reagent and inserting isonitrile into the carbon atom on the fourth position of imidazole through a functionalization reaction.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. In addition, the meaning of "and/or" appearing throughout includes three juxtapositions, exemplified by "A and/or B" including either A or B or both A and B. In addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The isonitrile compounds are important organic molecules, have wide application in MCRs, insertion reactions and other one-pot series reactions, and can effectively generate a series of C-N, C-S, C-O and C-C bonds. Transition metal (including Pd, Cu, Co, Ni, etc.) catalyzed isonitrile insertion reactions have been widely reported in the synthesis of heterocyclic compounds over the past several decades. Such reactions typically involve the formation of C (sp2) -M metal species, followed by oxidative addition of a metal catalyst to an aryl or alkenyl/halide, followed by coupling with different nucleophiles under basic conditions to produce the target compound. However, a large portion of the nucleophilic functional groups are concentrated on the O, N and S atoms as a result of extensive literature studies. The reports of capturing active C (sp2) -M substances by using carbon atoms as nucleophilic reagents are rare in the literature, and the main reason is that the synthesis process is complex and the synthesis efficiency is low because the nucleophilicity of the carbon atoms is relatively poor.
In view of the above, the invention provides a fused ring compound containing an imidazole skeleton, which aims to research the carbon atom at the fourth position of imidazole, promote the application of the carbon atom as a nucleophilic reagent in an isonitrile insertion reaction through the functionalization reaction of C (sp2) -H, and synthesize a novel fused heterocyclic compound containing an indene [1,2-d ] imidazole skeleton. Specifically, in one embodiment of the fused ring compound having an imidazole skeleton provided by the present invention, the fused ring compound having an imidazole skeleton has a structure represented by the following structural formula (i):
wherein R is1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of (1), R7Including any one of tert-butyl, cyclohexyl, adamantyl and 1, 3-dimethylphenyl.
In another embodiment of the fused ring compound having an imidazole skeleton provided by the present invention, the fused ring compound having an imidazole skeleton has a structure represented by the following structural formula (ii):
wherein R is1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of them.
The condensed ring compound containing the imidazole skeleton provided by the invention is a novel condensed heterocyclic compound containing the indene [1,2-d ] imidazole skeleton, which is obtained by taking a carbon atom as a nucleophilic reagent and inserting isonitrile into the carbon atom on the fourth position of imidazole through a functionalization reaction.
Further, the invention also provides a preparation method of the fused ring compound containing the imidazole skeleton, which takes o-bromine or o-iodine aryl aldehyde, aromatic amine and TosMIC reagent as raw materials, obtains an imidazole heterocyclic intermediate through van Leusen reaction under a mild condition, obtains a heterocycle shown as a structural formula (I) by further insertion reaction of a C-H bond at the 4 th position of imidazole and an isonitrile compound under the action of a palladium metal catalyst, a ligand, alkali and heating, and comprises the following steps:
step S10, adding the first reactant and the second reactant into absolute methanol, stirring and mixing, then adding TosMIC (p-toluenesulfonyl isonitrile) reagent, and reacting with K2CO3Reacting for 6-8 hours at 55-65 ℃ by using alkali, and purifying a reaction product by column chromatography to obtain an intermediate A with a structure shown in a structural formula (III);
step S20, adding the intermediate A, the third reactant, the catalyst, the ligand and the alkali into an organic solvent, reacting at 95-105 ℃ for 8-24 h, and carrying out column chromatography purification on a reaction product to obtain a target compound B, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (I);
wherein the first reactant is a compound (namely o-bromine or o-iodine aryl aldehyde) with a structure shown in a structural formula (IV), the second reactant is a compound (namely aromatic amine) with a structure shown in a structural formula (V), and the structural general formula of the third reactant is R7-NC (i.e. isonitrile compound):
in the structural formulas (III), (IV) and (V), X is Br or I, R1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of the above; r in the structural general formula of the third reactant7Including any one of tert-butyl, cyclohexyl, adamantyl and 1, 3-dimethylphenyl. It should be noted that the aldehyde and amine in the reaction raw material should not have electron-donating functional groups, such as methyl, methoxy, etc., and in addition, the aldehyde and amine should not have ortho-position groups at the same time, so as to avoid the problem that the steric hindrance of the compound structure is too large and synthesis is not easy.
The preparation method of the fused ring compound containing the imidazole skeleton provided by the invention has the advantages that the fused ring compound containing the indene [1,2-d ] imidazole skeleton is simply, conveniently and efficiently synthesized by using the carbon atom at the fourth position of the imidazole heterocycle as a nucleophilic reagent and selecting o-bromine or o-iodine aryl aldehyde, aromatic amine and isonitrile as raw materials, the application range of the nucleophilic reagent is effectively expanded, the raw materials are easy to obtain, the substrate range is wide, the atom economy and the step economy are higher, and a new method is provided for the fused ring compound containing the indene [1,2-d ] imidazole skeleton.
In this embodiment, the feeding amounts of the reaction raw materials in step S10 are: the first reactant, the second reactant, the TosMIC reagent and the base K2CO3The molar ratio of (1: 1), (1-2), (1-up)2) The first reactant and the second reactant are reacted in a molar ratio of 1:1, so that raw materials can sufficiently participate in the reaction, the utilization rate of the raw materials can reach over 90 percent, unnecessary waste is avoided, and the feeding amount of the TosMIC reagent and the alkali can be properly excessive, so that the utilization rate of the raw materials of the first reactant and the second reactant is ensured.
The feeding amount of each reaction raw material, the catalyst and the like in the step S20 is as follows: the molar ratio of the intermediate A to the third reactant is 1: (1-2) enabling the intermediate A to fully participate in the reaction by enabling the third reactant to be excessive relative to the intermediate A, and improving the conversion rate of the intermediate A into the target product. Further, based on the intermediate A, the charge amounts of the catalyst, the base and the ligand are as follows: the molar ratio of the alkali to the intermediate A is (0.75-2): 1; and/or the molar ratio of the catalyst to the intermediate A is (0.025-0.1): 1; and/or the molar ratio of the ligand to the intermediate A is (0.025-0.2): 1. in this embodiment, the feeding amounts of the raw materials in step S20 are preferably limited at the same time, so that unnecessary waste caused by excessive feeding amount can be avoided on the premise that the reaction is efficiently performed and the raw materials sufficiently participate in the reaction.
Further, in this embodiment, the catalyst comprises PdCl2(Palladium chloride), Pd (dba)2(bis-dibenzylideneacetone palladium), Pd (OAc)2(Palladium acetate) and Pd (TFA)2Any one of (palladium trifluoroacetate); and/or, the ligand comprises PPh3(triphenylphosphine), DPPF (1,1' -bis (diphenylphosphino) ferrocene), DPPB (1, 4-bis (diphenylphosphino) butane), DPPPhos (bis (2-diphenylphosphino) phenyl ether), PCy3Any one of (tricyclohexylphosphine), tris (o-methylphenyl) phosphorus and phenanthroline; and/or, the base comprises K2CO3(Potassium carbonate), DABCO (1, 4-diazabicyclo [ 2.2.2)]Octane), t-BuONa (sodium tert-butoxide), t-BuOK (potassium tert-butoxide), DBU (1, 8-diazabicycloundec-7-ene), Cs2CO3Any one of cesium (carbonate) and cesium pivalate; and/or, the organic solvent comprises toluene, 1,4-dioxane (1, 4-dioxane), CH3CN (acetonitrile), DCE (dichloroethane), DMF (N, N-dimethylformamide) and DMSO (dimethyl sulfoxide). The condensed ring compound containing the imidazole skeleton, the structural formula of which is shown as the formula (I), can be prepared by selecting any matching combination, and when different combination modes are selected, the yield of a target product fluctuates between 27% and 83%. In addition, it should be noted that, when different substances are selected for the catalyst, the ligand and the organic solvent, the yield of the product is not greatly influenced, and when different types of bases are selected and the addition amount of the bases is different, the yield of the product is greatly influenced, wherein Cs is used2CO3As the alkali in the step S20, the yield of the product is relatively high, therefore, in the examples that follow herein, Cs is used as the alkali in the step S202CO3The fused ring compound having an imidazole skeleton was prepared as an example.
In addition, in this embodiment, the eluents used in the column chromatography purification of the intermediate a and the target compound B are all mixed solvents of ethyl acetate and petroleum ether, wherein, in the column chromatography purification of the intermediate a in step S10, the volume ratio of ethyl acetate to petroleum ether is 1: (8-10); when the target product is purified by column chromatography in step S20, the volume ratio of ethyl acetate to petroleum ether is 1: (20-30). The following will explain in detail the preparation method of the fused ring compound having an imidazole skeleton provided in the embodiments of the present invention, taking laboratory operations as examples:
firstly, adding the first reactant and the second reactant into a flask filled with anhydrous methanol, stirring for 1 hour at normal temperature, and then adding a TosMIC reagent and K2CO3Reacting for 6-8 h under the condition of oil bath at the temperature of 55-65 ℃; after the reaction is finished, removing the solvent by reduced pressure distillation, and purifying the residue by column chromatography to obtain the intermediate A with the yield of 48-83%; then, respectively adding the intermediate A, the third reactant, the catalyst, the ligand and the alkali into an organic solvent in a Schlenk tube filled with the organic solvent, putting the mixture into an oil bath kettle, heating to 95-105 ℃, and reacting for 8-24 hours; after the reaction is monitored by a point plate, the solvent is removed by distillation under reduced pressure, and the residue is subjected to the reactionAnd (3) performing column chromatography purification on the product to obtain a target compound B, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (I), wherein the yield is 66-80%.
The heterocyclic ring shown in the structural formula (I) prepared by the method can be further hydrolyzed under an acidic condition to obtain the heterocyclic ring shown in the structural formula (II), and the fused ring compound containing the imidazole skeleton provided by the invention can be used as a lead compound with biological activity. Therefore, based on the first embodiment provided above, in the second embodiment of the method for producing a fused ring compound having an imidazole skeleton provided by the present invention, after step S20, the method further includes:
and step S30, adding the target compound B into tetrahydrofuran, then adding a hydrochloric acid solution, reacting for 3.5-4.5 h at 55-65 ℃, and extracting and purifying by column chromatography to obtain a target product, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (II).
In this embodiment, the eluent used for the column chromatography purification of the target product is also a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1: (14-16). The method can be operated according to the following steps in specific implementation: adding the target compound B into a round-bottom flask filled with tetrahydrofuran, dropwise adding a hydrochloric acid solution into the round-bottom flask at room temperature within 5 minutes, heating to 55-65 ℃ in an oil bath kettle, reacting for 3.5-4.5 hours, and monitoring by Thin Layer Chromatography (TLC); after the reaction is complete, the mixture obtained is diluted with water and then with CH2Cl2And (3) extracting, namely washing the extracted organic layer with saline water, drying the organic layer with anhydrous sodium sulfate, then concentrating the organic layer under reduced pressure, and purifying the organic layer by using column chromatography to obtain a hydrolysate of the target compound B, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (II), wherein the yield is 88-91%.
The technical solutions of the present invention are further described in detail with reference to the following specific examples, which should be understood as merely illustrative and not limitative.
Example 1
(1) Synthesis of intermediate a:
firstly, a synthetic route:
② Synthesis method comprises adding o-bromine or o-iodobenzaldehyde (2mmol) and amine (2mmol) into a 50mL flask containing anhydrous methanol (10mL), stirring at room temperature for 1h, and adding K2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, the solvent is removed by reduced pressure distillation, and then column chromatography purification is carried out (eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 9), so as to obtain an intermediate A which is a white solid.
The synthesis yields of some of the intermediates A (intermediates A-1 to A-12) are shown in Table 1.
Table 1 synthetic yields of partial intermediate a
(2) Synthesis of a fused ring compound containing an imidazole skeleton having a structure represented by the structural formula (i):
firstly, a synthetic route:
② Synthesis method to a 25mL Schlenk tube containing toluene (5mL), were added the intermediate A (1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (OAc)2(11mg, 0.05mmol), phosphorus ligand DPPB (21mg, 0.05mmol) and inorganic base Cs2CO3(326mg, 1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 16 h; after the point plate monitoring reaction is finished, the solvent is removed by reduced pressure distillation, and then column chromatography purification is carried out (eluent is mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain the target compoundAnd B, the compound is yellow solid, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (I).
Wherein the structural formulas of some of the target compounds B (target compounds B-1 to B-13) are shown below, and the corresponding synthesis yields are shown in Table 2.
TABLE 2 Synthesis yields of part of the target Compound B
Example 2
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 9) to obtain an intermediate A-1 which is a white solid, the yield is 0.418g, the yield is 63%, the melting point is 121-122 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.76(s,1H),7.55(d,J＝8.0Hz,1H),7.30-7.05(m,8H)；13C{1H}NMR(CDCl3,100MHz)(ppm)137.6,134.9,133.6,133.0,132.7,131.2,130.5,130.4,130.2,129.4,127.2,125.9,124.9；HRMS(ESI-TOF)m/z:[M+H]+Calcd forC15H11BrClN2332.9789；Found 332.9797。
(2) into a 25mL Schlenk tube containing toluene (5mL), the intermediate A-1(1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (OAc) were added2(11mg, 0.05mmol), phosphorus ligand DPPB (21mg,0.05mmol) and an inorganic base Cs2CO3(326mg, 1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 16 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-1 which is a yellow solid, the yield is 0.248g, the yield is 74%, the melting point is 152-153 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.76-7.47(m,6H),7.16(t,J＝4.0Hz,2H),6.89(d,J＝6.0Hz,1H),1.66(s,9H)；13C{1H}NMR(CDCl3,100MHz)(ppm)152.3,144.6,142.1,140.7,140.1,134.8,134.5,130.2,130.0,129.5,127.4,125.2,122.9,116.6,56.8,29.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H19ClN3336.1262；Found 336.1277。
example 3
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (2mmol) in an oil bath at 55 ℃ for 8 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 8) to obtain an intermediate A-2 which is a white solid, the yield is 0.527g, the yield is 72%, the melting point is 134-135 ℃, and the detection result of the structure of the compound is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.79(s,1H),7.48(d,J＝8.4Hz,1H),7.33-6.96(m,7H)；13C{1H}NMR(CDCl3,100MHz)(ppm)138.0,137.7,135.0,134.1,133.3,132.4,132.1,130.9,130.4,130.3,130.0,128.2,124.7,122.8,122.7；HRMS(ESI-TOF)m/z:[M+H]+Calcdfor C15H10BrCl2N2366.9399；Found 366.9387。
(2) a25 mL Schlenk tube containing toluene (5mL) was charged with the intermediate A-2(1mmol) synthesized in step (1), the isonitrile compound (1.0mmol), and,Catalyst Pd (OAc)2(5.5mg, 0.025mmol), phosphorus ligand DPPB (10.5mg, 0.025mmol) and inorganic base Cs2CO3(244.5mg, 0.75mmol), then putting the mixed system into an oil bath kettle, heating to 95 ℃, and reacting for 24 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 20) to obtain a target compound B-2 which is a yellow solid, the yield is 0.269g, the yield is 73%, the melting point is 150-151 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.69-7.42(m,6H),7.15(t,J＝8.0Hz,1H),6.86(s,1H),1.64(s,9H)；13C{1H}NMR(CDCl3,100MHz)(ppm)151.3,143.0,141.5,140.6,140.2,136.8,135.9,135.3,131.4,131.2,129.3,127.0,124.1,123.9,122.0,117.0,57.1,29.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H18Cl2N3370.0872；Found 370.0878。
example 4
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (4mmol) in an oil bath at 65 ℃ for 6 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 8-10) to obtain an intermediate A-3 which is a white solid, the yield is 0.490g, the yield is 70%, the melting point is 131-132 ℃, and the detection result of the structure of the compound is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.75(s,1H),7.32-7.00(m,8H)；13C{1H}NMR(CDCl3,100MHz)(ppm)163.6,161.1,137.8,134.8,133.9,133.8,133.7,130.7,130.3,129.6,126.9,126.8,126.0,125.5,125.4,120.6,120.3,114.8,114.6；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C15H10BrClFN2350.9694；Found 350.9691。
(2) in 25mL Schlen with toluene (5mL)The intermediate A-3(1mmol) synthesized in the step (1), the isonitrile compound (2.0mmol) and the catalyst Pd (OAc) were added to the k-tube respectively2(22mg, 0.1mmol), phosphorus ligand DPPB (82mg, 0.2mmol) and inorganic base Cs2CO3(652mg, 2.0mmol), then putting the mixed system into an oil bath pan, heating to 105 ℃, and reacting for 8 hours; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 30) to obtain a target compound B-3 which is a yellow solid, the yield is 0.233g, the yield is 66%, the melting point is 183-185 ℃, and the detection result of the compound structure is as follows:
1H NMR(DMSO-d6,600MHz)(ppm)8.12(s,1H),7.73-6.91(m,7H),1.56(s,9H)；13C{1H}NMR(DMSO-d6,150MHz)(ppm)162.5,160.8,150.9,144.4,143.5,142.0,139.9,134.3,133.3,130.0,126.3,125.8,118.3,115.8,115.6,110.4,110.2,56.6,29.4；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H18ClFN3354.1168；Found 354.1172。
example 5
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 9) to obtain an intermediate A-4 which is a white solid, the yield is 0.640g, the yield is 63%, the melting point is 114-115 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.79(s,1H),7.50(d,J＝8.4Hz,1H),7.33-7.04(m,6H)；13C{1H}NMR(CDCl3,100MHz)(ppm)137.9,137.8,135.7,134.2,133.5,132.4,131.7,131.2,130.7,130.0,128.2,123.0,122.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd forC15H9BrCl3N2400.9009；Found 400.9011。
(2) a25 mL Schlenk tube containing DMF (5mL) was charged with the intermediate A-4(1mmol) synthesized in step (1), the isonitrile compound (1.5mmol) and the catalyst PdCl2(0.05mmol), phosphorus ligand PPh3(0.05mmol) and an inorganic base Cs2CO3(1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 20 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-4 which is a yellow solid, the yield is 0.282g, the yield is 70%, the melting point is 205-206 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,600MHz)(ppm)7.68-7.18(m,6H),6.87(s,1H),1.63(s,9H)；13C{1H}NMR(CDCl3,150MHz)(ppm)151.1,142.9,141.6,140.4,140.1,137.4,136.7,135.5,131.1,129.4,127.2,124.0,122.5,117.0,57.2,29.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd forC20H17Cl3N3404.0483；Found 404.0489。
example 6
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 9) to obtain an intermediate A-5 which is a white solid, the yield is 0.599g, the yield is 78%, the melting point is 122-123 ℃, and the detection result of the structure of the compound is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.79(s,1H),7.36-7.02(m,7H)；13C{1H}NMR(CDCl3,100MHz)(ppm)163.8,161.3,138.0,137.6,135.6,133.8,133.7,130.9,130.2,128.2,126.3,126.2,125.4,125.3,123.2,120.7,120.5,115.0,114.8；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C15H9BrCl2FN2384.9305；Found 384.9312。
(2) into a 25mL Schlenk tube containing DCE (5mL), the intermediate A-5(1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (dba) were added2(0.05mmol), phosphorus ligand DPPF (0.05mmol) and inorganic base Cs2CO3(1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 12 hours; after the reaction is monitored by a dot plate, the solvent is removed by reduced pressure distillation, and then column chromatography purification is carried out (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-5 which is yellow solid, the yield is 0.344g, the yield is 74%, the melting point is more than 265 ℃, and the detection result of the structure of the compound is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.61-7.43(m,5H),6.87(t,J＝5.6Hz,2H),2.28-1.73(m,15H)；13C{1H}NMR(CDCl3,100MHz)(ppm)163.9,161.5,150.5,145.3,145.2,143.6,141.5,141.4,139.5,137.7,136.5,129.0,125.7,122.4,117.4,117.3,115.5,115.3,111.7,111.5,57.8,41.8,36.4,30.0；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C26H23Cl2FN3466.1248；Found 466.1262。
example 7
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 9) to obtain an intermediate A-6 which is a white solid, the yield is 0.549g, the yield is 75%, the melting point is 125-126 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.78(s,1H),7.58(d,J＝8.0Hz,1H),7.37-7.02(m,7H)；13C{1H}NMR(CDCl3,100MHz)(ppm)138.1,137.4,135.4,133.2,132.7,131.1,130.7,130.6,130.1,127.9,127.5,124.8,123.1；HRMS(ESI-TOF)m/z:[M+H]+Calcd forC15H10BrCl2N2366.9399；Found 366.9404。
(2) in the presence of CH3CN (5mL) in a 25mL Schlenk tube, the intermediate A-6(1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (TFA) were added2(0.05mmol), phosphorus ligand DPEPhos (0.05mmol) and inorganic base Cs2CO3(1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 16 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-6 which is a yellow solid, the yield is 0.273g, the yield is 74%, the melting point is 168-169 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,600MHz)(ppm)7.77-7.47(m,4H),7.21(t,J＝3.6Hz,2H),6.93(d,J＝5.4Hz,1H),1.65(s,9H)；13C{1H}NMR(CDCl3,150MHz)(ppm)152.1,144.2,142.0,140.9,139.8,137.7,136.5,129.7,129.0,127.7,123.0,122.4,116.6,56.9,29.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C20H18Cl2N3370.0872；Found 370.0875。
example 8
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, distilling under reduced pressure to remove the solvent, and then purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 9) to obtain an intermediate A-7 which is a white solid, the yield is 0.664g, the yield is 83%, the melting point is 154-155 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.83(s,1H),7.64-7.21(m,8H)；13C{1H}NMR(CDCl3,100MHz)(ppm)139.2,138.0,134.2,133.4,132.4,132.1,131.2,130.5,130.2,130.1,129.9,126.7,124.8,124.6,122.8,122.1；HRMS(ESI-TOF)m/z:[M+H]+Calcd forC16H10BrClF3N2400.9662；Found 400.9670。
(2) into a 25mL Schlenk tube containing DMSO (5mL), the intermediate A-7(1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (OAc) were added2(0.05mmol), phosphorus ligand PCy3(0.05mmol) and an inorganic base Cs2CO3(1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 16 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-7 which is a yellow solid, the yield is 0.274g, the yield is 68%, the melting point is 187-188 ℃, and the detection result of the compound structure is as follows:
1H NMR(CDCl3,600MHz)(ppm)7.92-7.66(m,6H),7.17(d,J＝7.8Hz,1H),6.87(s,1H),1.65(s,9H)；13C{1H}NMR(CDCl3,150MHz)(ppm)151.2,142.9,141.8,140.6,140.2,138.7,135.4,131.4,131.3,131.1,127.6,127.1,124.0,117.0,57.2,29.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C21H18ClF3N3404.1136；Found 404.1150。
example 9
(1) The procedure was the same as in example 1;
(2) the procedure was the same as in example 1;
(3) synthesis of a fused ring compound containing an imidazole skeleton having a structure represented by the structural formula (ii):
firstly, a synthetic route:
② Synthesis method, comprises adding the target compound B (0.5mmol) synthesized in step (2) into a 25mL round-bottomed flask containing tetrahydrofuran (5mL), dropwise adding hydrochloric acid solution (4M, 1.0mL) into the round-bottomed flask at room temperature for about 5min, heating to 60 deg.C in oil bath, reacting for 4h, and reacting with thin layerMonitoring the chromatogram; after completion of the reaction, the reaction mixture was diluted with water (80mL) and then CH2Cl2(3 × 40mL), washing the organic layer obtained by extraction with saline water, drying the organic layer with anhydrous sodium sulfate, then concentrating the organic layer under reduced pressure, and purifying the organic layer by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 15) to obtain a target product C which is a yellow solid, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (II).
Wherein, the structural formulas of part of the target products (target products C-1 to C-2) are shown in the following table 3, and the corresponding synthesis yields are shown in the table.
Table 3 Synthesis yields of the target products
| Compound (I) | C-1 | C-2 |
| Yield (%) | 91 | 88 |
Example 10
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol) and TosMIC isonitrile reagent (3mmol) in an oil bath at 60 ℃ for 7 h; after the reaction is finished, the solvent is removed by reduced pressure distillation, and then column chromatography purification is carried out (the eluent is ethyl acetate and petroleum ether)The volume ratio of the mixed solvent, ethyl acetate and petroleum ether is 1: 9) to obtain an intermediate A-1;
(2) into a 25mL Schlenk tube containing toluene (5mL), the intermediate A-1(1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (OAc) were added2(11mg, 0.05mmol), phosphorus ligand DPPB (21mg, 0.05mmol) and inorganic base Cs2CO3(326mg, 1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 16 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-1;
(3) adding the target compound B-1(0.5mmol) synthesized in the step (2) into a 25mL round-bottom flask containing tetrahydrofuran (5mL), dropwise adding a hydrochloric acid solution (4M, 1.0mL) into the round-bottom flask at room temperature, after dropwise adding for about 5min, heating to 55 ℃ in an oil bath, reacting for 4.5h, and monitoring by thin-layer chromatography; after completion of the reaction, the reaction mixture was diluted with water (80mL) and then CH2Cl2(3 × 40mL), washing an organic layer obtained by extraction with saline water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of ethyl acetate to petroleum ether is 1: 14) to obtain a target product C-1, the melting point is 166-167 ℃, and the detection result of the structure of the compound is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.63-7.45(m,6H),7.19(t,J＝4.4Hz,2H),6.81(d,J＝7.6Hz,1H)；13C{1H}NMR(CDCl3,100MHz)(ppm)183.4,151.1,142.5,137.5,135.4,133.9,132.9,132.3,130.4,129.4,125.0,124.4,117.7；HRMS(ESI-TOF)m/z:[M+H]+Calcd forC16H10ClN2O 281.0476；Found 281.0479。
example 11
(1) To a 50mL flask containing anhydrous methanol (10mL) were added o-bromo or o-iodo benzaldehyde (2mmol) and amine (2mmol), stirred at room temperature for 1h, then K was added2CO3(3mmol), TosMIC isonitrile reagent (3 mm)ol), reacting for 7h in an oil bath at 60 ℃; after the reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 9) to obtain an intermediate A-10;
(2) into a 25mL Schlenk tube containing toluene (5mL), the intermediate A-10(1mmol) synthesized in step (1), the isonitrile compound (1.2mmol), the catalyst Pd (OAc) were added2(11mg, 0.05mmol), phosphorus ligand DPPB (21mg, 0.05mmol) and inorganic base Cs2CO3(326mg, 1.0mmol), then putting the mixed system into an oil bath kettle, heating to 100 ℃, and reacting for 16 h; after the point plate monitoring reaction is finished, carrying out reduced pressure distillation to remove the solvent, and then carrying out column chromatography purification (eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 25) to obtain a target compound B-10;
(3) adding the target compound B-10(0.5mmol) synthesized in the step (2) into a 25mL round-bottom flask containing tetrahydrofuran (5mL), dropwise adding a hydrochloric acid solution (4M, 1.0mL) into the round-bottom flask at room temperature, after dropwise adding for about 5min, heating to 65 ℃ in an oil bath, reacting for 3.5h, and monitoring by thin-layer chromatography; after completion of the reaction, the reaction mixture was diluted with water (80mL) and then CH2Cl2(3 × 40mL), washing an organic layer obtained by extraction with saline water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (eluent is a mixed solvent of ethyl acetate and petroleum ether, the volume ratio of ethyl acetate to petroleum ether is 1: 16) to obtain a target product C-2, the melting point is 166-167 ℃, and the detection result of the structure of the compound is as follows:
1H NMR(CDCl3,400MHz)(ppm)7.58(t,J＝7.2Hz,2H),7.44-7.22(m,5H),6.80(d,J＝7.2Hz,1H),2.51(s,3H)；13C{1H}NMR(CDCl3,100MHz)(ppm)183.5,151.1,143.2,142.6,138.6,137.5,135.4,133.8,132.9,132.4,130.6,129.2,125.9,124.2,122.3,117.7,20.2；HRMS(ESI-TOF)m/z:[M+H]+Calcd for C17H12ClN2O 295.0633；Found 295.0637。
in conclusion, according to the preparation method provided by the invention, through Pd-catalyzed isonitrile insertion reaction, the carbon atom at the fourth position of the imidazole heterocycle is used as a nucleophilic reagent, and o-bromine or o-iodine aryl aldehyde, aromatic amine and isonitrile are used as raw materials, so that the fused ring compound containing the imidazole skeleton and having the structures shown in structural formulas (I) and (II) is successfully and efficiently prepared.
The above is only a preferred embodiment of the present invention, and it is not intended to limit the scope of the invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall be included in the scope of the present invention.
Claims (10)
1. A fused ring compound containing an imidazole skeleton, characterized in that the fused ring compound containing an imidazole skeleton has a structure represented by the following structural formula (I):
wherein R is1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of (1), R7Including any one of tert-butyl, cyclohexyl, adamantyl and 1, 3-dimethylphenyl.
2. A fused ring compound containing an imidazole skeleton, characterized in that the fused ring compound containing an imidazole skeleton has a structure represented by the following structural formula (II):
wherein R is1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of them.
3. A method for preparing a fused ring compound containing an imidazole skeleton is characterized by comprising the following steps:
step S10, adding the first reactant and the second reactant into absolute methanol, stirring and mixing, then adding TosMIC reagent, and adding K2CO3Reacting for 6-8 hours at 55-65 ℃ by using alkali, and purifying a reaction product by column chromatography to obtain an intermediate A with a structure shown in a structural formula (III);
step S20, adding the intermediate A, the third reactant, the catalyst, the ligand and the alkali into an organic solvent, reacting at 95-105 ℃ for 8-24 h, and carrying out column chromatography purification on a reaction product to obtain a target compound B, namely the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (I);
the first reactant is a compound with a structure shown in a structural formula (IV), the second reactant is a compound with a structure shown in a structural formula (V), and the structural general formula of the third reactant is R7-NC：
In the structural formulas (III), (IV) and (V), X is Br or I, R1、R2、R3、R4、R5And R6Each independently selected from H, F, Cl, Br, CF3、CN、CH3、COOCH3、COOC2H5Any one of the above;
the third reactionR in the structural general formula of the compound7Including any one of tert-butyl, cyclohexyl, adamantyl and 1, 3-dimethylphenyl.
4. The method for producing a fused ring compound having an imidazole skeleton according to claim 3, wherein in step S10: the molar ratio of the first reactant to the second reactant to the TosMIC reagent is 1:1 (1-2).
5. The method for producing a fused ring compound having an imidazole skeleton according to claim 3, wherein the catalyst comprises PdCl2、Pd(dba)2、Pd(OAc)2And Pd (TFA)2Any one of the above; and/or the presence of a gas in the gas,
the ligand comprises PPh3、DPPF、DPPB、DPEPhos、PCy3Any one of tris (o-methylphenyl) phosphorus and phenanthroline; and/or the presence of a gas in the gas,
the base comprises K2CO3、DABCO、t-BuONa、t-BuOK、DBU、Cs2CO3And cesium pivalate; and/or the presence of a gas in the gas,
the organic solvent comprises toluene, 1,4-dioxane and CH3CN, DCE, DMF and DMSO.
6. The method for producing a fused ring compound having an imidazole skeleton according to claim 3, wherein in step S20: the molar ratio of the intermediate A to the third reactant is 1: (1-2); and/or the presence of a gas in the gas,
the molar ratio of the alkali to the intermediate A is (0.75-2): 1; and/or the presence of a gas in the gas,
the molar ratio of the catalyst to the intermediate A is (0.025-0.1): 1; and/or the presence of a gas in the gas,
the molar ratio of the ligand to the intermediate A is (0.025-0.2): 1.
7. the method for preparing a fused ring compound having an imidazole skeleton according to claim 3, wherein in step S10, the eluent used for the column chromatography purification of the reaction product is a mixed solvent of ethyl acetate and petroleum ether at a volume ratio of 1: (8-10).
8. The method for preparing a fused ring compound having an imidazole skeleton according to claim 3, wherein in step S20, the eluent used for the column chromatography purification of the reaction product is a mixed solvent of ethyl acetate and petroleum ether at a volume ratio of 1: (20-30).
9. The method for producing a fused ring compound having an imidazole skeleton according to claim 3, further comprising, after step S20:
and step S30, adding the target compound B into tetrahydrofuran, then adding a hydrochloric acid solution, reacting for 3.5-4.5 h at 55-65 ℃, and extracting and purifying by column chromatography to obtain the fused ring compound containing the imidazole skeleton and having the structure shown in the structural formula (II).
10. The method for preparing a fused ring compound having an imidazole skeleton according to claim 9, wherein an eluent used in the step S30 of purifying the reaction product by column chromatography is a mixed solvent of ethyl acetate and petroleum ether at a volume ratio of 1: (14-16).
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