CN110204481B

CN110204481B - Polysubstituted nitrogen-containing aromatic heterocyclic compound and preparation method and application thereof

Info

Publication number: CN110204481B
Application number: CN201810166022.3A
Authority: CN
Inventors: 张振华; 李宗洋; 逄森; 霍童雨; 丰硕
Original assignee: China Agricultural University
Current assignee: China Agricultural University
Priority date: 2018-02-28
Filing date: 2018-02-28
Publication date: 2021-01-19
Anticipated expiration: 2038-02-28
Also published as: CN110204481A

Abstract

The invention relates to a preparation method of a polysubstituted nitrogen-containing aromatic heterocyclic compound, wherein the polysubstituted nitrogen-containing aromatic heterocyclic compound has a structure shown as a general formula (I) or (II); the method comprises the following specific steps: adding a transition metal catalyst, a 2, 2' -bipyridyl ligand and a solvent into a reaction vessel, uniformly mixing, adding a raw material A and a raw material B, fully reacting at room temperature, then adding a raw material C or a raw material D or a precursor of the raw material D, and fully reacting at-10-150 ℃ to obtain the catalyst. The method provided by the invention is to prepare the nitrogen-containing aromatic heterocyclic compound by taking alkenyl azide, isonitrile and alkyne compounds as raw materials and adopting a one-pot method under the action of a transition metal catalyst. The reaction related to the method has very good tolerance and universality on functional groups, can be used for synthesizing various different polysubstituted aminopyridine and amino isoquinoline compounds, does not need strict anhydrous and anaerobic conditions, and is very simple to operate.

Description

Polysubstituted nitrogen-containing aromatic heterocyclic compound and preparation method and application thereof

Technical Field

The invention relates to the field of organic synthesis, in particular to a polysubstituted nitrogen-containing aromatic heterocyclic compound and a preparation method and application thereof.

Background

The fluorescent molecular marker detection technology is an efficient and rapid detection means in biological detection and small molecule detection, and because the fluorescence emission wavelength of each marker can be different to simultaneously mark different substances and different sites, high-throughput detection is realized, so that the development of more fluorescent marker molecules and the development of a synthetic method are particularly important. The aminopyridine has the advantages of high fluorescence conversion rate (═ 0.6) and simple and stable molecular structure, and the light conversion rate can be further improved by modifying the structure of the aminopyridine through functional groups, and the absorption and emission wavelengths of the aminopyridine can be adjusted to meet the requirements of different markers.

In recent years, studies on methods for synthesizing structural molecules of a multi-substituted aminopyridine core have been ongoing. The synthesis methods of the compounds mainly comprise the following methods: starting from aminopyridine, modifying a pyridine ring by using traditional electrophilic/nucleophilic reaction, and then modifying an amino group by using coupling reaction (see Chemistry A European Journal 2017,23, 1-8); method II, amination is carried out on the 2-position of pyridine by using substituted pyridine oxide under equivalent phosphorus catalyst to prepare pyridylamine (see Organic Letters 2010,12, 5254-5257.); method III, preparing pyridylamine by utilizing 1, 3-dicarbonyl compounds, aromatic aldehyde, aromatic amines and virulent malononitrile compounds under Fe (III) catalysis in a multi-component manner (see The Journal of Organic Chemistry 2014,79, 8882-8888.).

The following disadvantages mainly exist for the above-mentioned methods: 1) the pyridine amine can not be constructed once due to the need of multiple reactions, such as the method I and the method II; 2) poor atomic economy, equivalent phosphorus catalyst usage, and production of a large number of by-products while producing the product, such as method two; 3) and the use of highly toxic nitrile compounds is required, as described in method three above; 4) and the substrate universality is insufficient, and the fluorescence property of the obtained compound is still insufficient (see heterocyles 2012,85, 2713-2721). Today, environmental protection and resource protection are more strict, and it is very important to develop a method with high atom economy/step economy and high raw material safety.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a preparation method of a polysubstituted nitrogen-containing aromatic heterocyclic compound. The method provided by the invention has very wide substrate adaptability, and different polysubstituted nitrogen-containing aromatic heterocyclic compounds can be synthesized by the method; the method is used as a one-pot method, the target compound can be prepared at one time, the whole reaction has high atom economy, and nitrogen is the only byproduct of the reaction.

The method provided by the invention is characterized in that a nitrogen-containing aromatic heterocyclic compound is prepared by taking a raw material A (alkenyl azide), a raw material B (isonitrile) and a raw material C (acetylene compound) as raw materials and adopting a one-pot method under the action of a transition metal catalyst. The target product of the invention is preferably an aminopyridine compound or an aminoisoquinoline compound.

Specifically, the invention provides a method for preparing a polysubstituted nitrogen-containing aromatic heterocyclic compound, wherein the polysubstituted nitrogen-containing aromatic heterocyclic compound has a structure shown as a general formula (I) or (II):

in the general formula (I) or (II), R¹～R⁶Each independently selected from the group consisting of a hydrogen atom, a disubstituted amine group, an amide group, an ester group, a ketocarbonyl group, a siloxy group, a halogen, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclic group, an alkyl group, an alkenyl group, an alkynyl group, an arylalkyl group, a heteroaryl groupAn arylalkyl, cycloalkylalkyl, heterocyclylalkyl or aryl-alkoxy-alkyl group; and said R is¹～R⁶In (b), at least two groups are not hydrogen atoms;

the reaction process of the method is as follows:

or

The method comprises the following specific steps: adding a transition metal catalyst, a 2, 2' -bipyridyl ligand and an organic solvent into a reaction vessel, uniformly mixing, adding a raw material A and a raw material B, fully reacting at room temperature, then adding a raw material C or a raw material D or a precursor of the raw material D, and fully reacting at-10-150 ℃ to obtain the catalyst. The reaction only needs to ensure that all raw materials are fully reacted; in the actual production process, the molar ratio of the raw material a, the raw material B, and the raw material C/the raw material D/the precursor of the raw material D may be controlled within a range of 1:1.0:1.2 to 1:1.2: 2.0.

The aryl group of the present invention may be a substituted or unsubstituted aryl group. The aryl group may have one or more substituents, and the position of the substituent is not particularly limited, and may be ortho-position, meta-position, or para-position; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogens and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The aryl group of the present invention is preferably a monocyclic or bicyclic aryl group, more preferably an aryl group of 6 to 14 carbon atoms, such as a phenyl group or a naphthyl group. The substituents on the aryl group are preferably an alkyl group, an alkoxy group, a nitro group, a cyano group, an ester group, an aldehyde group, a ketocarbonyl group, and a halogen atom, and more preferably a haloalkyl group such as a trifluoromethyl group.

The heteroaryl groups of the present invention can be substituted or unsubstituted aryl groups bearing at least one nitrogen, oxygen, or sulfur; the heteroaryl group may have one or more substituents, and the position of the substituent is not particularly limited, and may be ortho-position, meta-position, or para-position; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogens and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The heteroatoms in the heteroaryl groups of the present invention can be one, two, three or four. The heteroaryl group preferably has 5 to 30 atoms, more preferably 6 to 20 atoms, and is, for example, thiophene, furan, pyrrole, pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, oxazoline, thiazoline, pyridine, pyran, thiopyran, pyrimidine, pyridazine, pyrazine, piperazine, azepine, oxepin, thioazepine, indole, benzimidazole, benzothiophene, benzofuran, benzothiazole, benzoxazole, benzisoxazole, benzisothiazole, quinoline, isoquinoline, quinazoline, carbazole, pteridine, purine, azaphenanthrene, acridine, phenazine, phenothiazine, or the like. The substituent on the heteroaryl group is preferably an alkyl group, an alkoxy group, a nitro group, a cyano group, an ester group, an aldehyde group, a ketocarbonyl group or a halogen atom, and more preferably a haloalkyl group such as a trifluoromethyl group.

The cycloalkyl group of the present invention may be a substituted or unsubstituted cycloalkyl group; the cycloalkyl group may have one or more substituents, and the position of the substituent is not particularly limited, and may be ortho-position, meta-position, or para-position; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The cycloalkyl groups described herein are preferably saturated or unsaturated monocyclic or polycyclic carbocyclic groups, preferably containing from 3 to 20 atoms, more preferably from 3 to 10 atoms, such as cyclohexane.

The heterocyclic group of the present invention may be a substituted or unsubstituted heterocyclic group; the heterocyclic group may have one or more substituents, and the position of the substituent is not particularly limited, and may be ortho-position, meta-position, or para-position; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The heterocyclic group of the present invention is preferably a saturated or unsaturated monocyclic or polycyclic heterocyclic group having 1 to 4 heteroatoms selected from N, S, O, wherein the heteroatoms may be one, two, three or four. The heterocyclic group preferably contains 5 to 30 atoms, more preferably 6 to 20 atoms, such as nitrogen heterocyclic group, nitrogen, oxygen heterocyclic group, and representative heterocyclic groups include: tetrahydropyrrolyl, tetrahydropyridinyl, piperazinyl, morpholinyl and the like.

The alkyl groups described herein may be substituted or unsubstituted primary, secondary or tertiary alkyl groups; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The alkyl is preferably a straight chain or branched chain alkyl with 1-10 carbon atoms; the substituent on the alkyl group is preferably an alkoxy group, a siloxy group, a nitro group, a cyano group, an ester group, an aldehyde group, a ketocarbonyl group, or a halogen atom, and more preferably a halogen atom such as fluorine, chlorine, bromine. The alkyl group according to the present invention may specifically be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a pentyl group, a neopentyl group or a halogeno C group_1-10An alkyl group. As a preferred embodiment, the alkyl group may be trifluoromethyl.

The alkoxy group in the present invention is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and sec-butoxy.

The alkenyl group in the present invention may be a substituted or unsubstituted alkenyl group, and the position and number of the substituent are not particularly limited, and may be one, two, three, or both cis and trans. The substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The alkenyl group in the present invention is preferably a straight or branched alkenyl group having 2 to 10 carbon atoms, and the substituent on the alkenyl group is preferably an alkoxy group, a siloxy group, a nitro group, a cyano group, an ester group, an aldehyde group, a ketocarbonyl group or a halogen atom, more preferably a halogen atom such as fluorine, chlorine, bromine. The alkenyl group of the present invention may specifically be a vinyl group, propenyl group, butenyl group, isobutenyl group, pentenyl group, hexenyl group or halogeno group C_2-10An alkenyl group.

The alkynyl group of the present invention may be a substituted or unsubstituted alkynyl group; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, siloxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two substituents adjacent or close to each other may be independent of each other or form a ring. The alkynyl group of the present invention is preferably a straight or branched chain alkynyl group having 2 to 10 carbon atoms; the substituent on the alkynyl group is preferably an alkoxy group, a siloxy group, a nitro group, a cyano group, an ester group, an aldehyde group, a ketocarbonyl group or a halogen atom, more preferably a halogen atom such as fluorine, chlorine, bromine. The alkynyl can be particularly ethynyl, propynyl, butynyl, pentynyl, isopentynyl, hexynyl or halogenated C_2-10Alkynyl.

The substituents of the disubstituted amino groups of the present invention may be the same or different and are independently selected from alkyl or aryl groups, such as N, N-dimethylamino, N-diphenylamino, N-methyl-N-phenylamino, and the like.

The amido is-NH-CO-R⁴Wherein R is⁴Is H, C_1-10Alkyl, aryl, e.g.Acetylamino, propionylamino and butyrylamino, and the like.

The ester group of the invention is-COO-R⁵Wherein R is⁵Is H, C_1-10Alkyl, aryl, e.g. R⁵Can be methyl, ethyl, propyl, butyl; formate, acetate, propionate, butyrate, and the like.

The ketone carbonyl of the invention is-CO-R⁶Wherein R is⁶Is H, C_1-10Alkyl, aryl, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, and the like.

The siloxy group is-O-Si (R)⁷)₃Wherein R is⁷The same or different, are independently selected from H, C_1-10Alkyl radicals, such as trimethylsiloxane, dimethylethylsiloxane, dimethylbutylsiloxane.

The halogen atom in the invention refers to fluorine, chlorine, bromine or iodine atom and the like.

In the preparation method provided by the invention, besides reaction substrates, a catalyst and a solvent are also used. Wherein:

the palladium catalyst can be a commercial reagent, and can be palladium, palladium salt, a complex of palladium and a ligand such as a phosphine-containing ligand, a nitrogen-containing ligand, an oxygen-containing ligand, a sulfur-containing ligand or an alkenyl ligand, or supported palladium (the carrier can be titanium dioxide, a silicon-containing material, barium sulfate, calcium carbonate, a high molecular material, etc.), preferably but not limited to one of the following groups: palladium on carbon, palladium oxide, palladium hydroxide, palladium/titanium dioxide, Pd/Ph-SBA-15, Pd-BTP/SiO₂Pd, SiO supported by silicon-containing material₂Pd, Lindla catalyst, Pd/BaSO Supported₄，Pd/CaCO₃And Pd is loaded on the high polymer material. The catalytic amount thereof is preferably in the range of 0.001 to 5% equivalent, more preferably in the range of 0.01 to 2.5% equivalent, still more preferably in the range of 0.05 to 0.1% equivalent, based on the compound of formula (II).

The rhodium catalyst can be a commercial reagent, and can be a complex or load rhodium (the carrier can be titanium dioxide) composed of rhodium, rhodium salt, rhodium and ligands such as phosphorus-containing ligand, nitrogen-containing ligand, oxygen-containing ligand, phosphorus-containing ligand, sulfur-containing ligand or alkenyl ligandSilicon-containing materials, barium sulfate, calcium carbonate, polymeric materials, etc.). Preferably but not limited to one of the following sets: rhodium on carbon, { Rh (COD) Cl }triphenylphosphine rhodium chloride₂,{Rh(COD)OH}₂,Rh(COD)(acac),{Rh(NBD)Cl}₂. The catalytic amount thereof is preferably in the range of 0.001 to 5% equivalent, more preferably in the range of 0.01 to 2.5% equivalent, still more preferably in the range of 0.05 to 0.1% equivalent, based on the compound of formula (II).

The solvent is an organic solvent, preferably but not limited to one or a mixture of several of the following groups: water, dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl n-butyl ether, methanol, ethanol, isopropanol, benzene, toluene, acetonitrile, nitromethane, pentane, hexane, and the like. These solvents are readily available in commercial reagents without special handling.

In the preparation method provided by the invention, the reaction temperature and the reaction time are slightly different according to different raw materials, the reaction temperature is usually-10 ℃ to 150 ℃, preferably 120 ℃ to 130 ℃, and the reaction time is usually 2-24 hours. If heating is required, an oil bath (e.g., silicone oil, paraffin oil, etc.) or other heating means may be employed.

The process of the invention may also comprise a concentration step in order to obtain a product of high purity. Preferably, the concentration process can adopt methods of atmospheric distillation, reduced pressure distillation and the like. After concentration, purification of the product may also be included. The purification preferably adopts column chromatography, reduced pressure distillation and/or recrystallization to obtain a pure product. Preferably, the purification is performed by column chromatography and then reduced pressure distillation or recrystallization to obtain a purified product.

The method provided by the invention realizes that the corresponding polysubstituted nitrogen-containing aromatic heterocyclic compound (namely polysubstituted aminopyridine or amino isoquinoline compound) is obtained by a one-pot method from an alkenyl azide compound and directly using isonitrile and an alkyne/benzyne precursor as raw materials, and the method is high in reaction efficiency, low in reaction cost and high in substrate universality.

Because the reaction related to the method provided by the invention has very good tolerance and universality to functional groups, the invention also provides a brand-new polysubstituted nitrogen-containing aromatic heterocyclic compound, and the compound can be simply, conveniently and efficiently prepared by adopting the scheme provided by the invention.

Specifically, the invention provides a polysubstituted nitrogen-containing aromatic heterocyclic compound, which has a structure shown as a general formula (I) or (II):

in the general formula (I) or (II), R²And R⁶Are each a hydrogen atom, R¹、R³、R⁴、R⁵Each independently selected from ester group, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl or aryl-alkoxy-alkyl.

In the present invention, R is preferably as described above³、R⁴Are all ester groups.

Preferred radicals R according to the invention¹Selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl or aryl-alkoxy-alkyl.

In the present invention, R is preferably as described above⁵Selected from alkyl, cycloalkyl, unsubstituted aryl (e.g., phenyl) or substituted aryl (e.g., p-methoxyphenyl).

As a preferable mode of the invention, the polysubstituted nitrogen-containing aromatic heterocyclic compound is selected from one or more of the following compounds:

the compound prepared by the method provided by the invention has fluorescence characteristics, can be applied to preparation of a fluorescent marker, and is preferably used for preparing a fluorescent marker for biomacromolecules.

Compared with the prior art, the reaction environment is friendly, the reaction itself or the conditions in the synthesis process of the raw materials are mild, the atom economy is high, the reaction starts from alkenyl azide, and the corresponding p-substituted aminopyridine/amino isoquinoline compounds are obtained by a one-pot method. The reaction involved in the method has good tolerance and universality on functional groups, can be aryl, heteroaryl, cycloalkyl, heterocyclic group, alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclic alkyl and aryl-alkoxy-alkyl, and the substituent can be alkyl, alkoxy, siloxy, disubstituted amino, nitro, cyano, ester group, aldehyde group, ketone carbonyl, halogen atom (F, Cl, Br, I) and the like, and can be used for synthesizing various polysubstituted aminopyridine and amino isoquinoline compounds. The reaction involved in the invention does not need strict anhydrous and anaerobic conditions, and the operation is very simple.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example 1

This example provides a novel compound, ethyl 2-tert-butylamino-6-phenylpyridine-3, 4-dicarboxylate, of the formula: c₂₁H₂₆N₂O₄The structural formula is as follows:

the compound is synthesized by adopting the following specific steps:

to a 5ml reaction tube were added { Rh (COD) Cl }2(2mg,0.0038mmol), 2' -bipyridine (1mg,0.0075mmol) and 1, 4-dioxane (2ml) in this order, and after stirring for 5min, (1-vinyl azide) phenylbenzene (22mg,0.15mmol) and tert-butyl isonitrile (13mg,17uL,0.2mmol) were added via syringe and reacted at room temperature for 5 h. After the reaction was complete, diethyl butynoate (51mg,48uL,0.3mmol) was added with a syringe, heated to 120 ℃ for 5h, and checked by TLC for complete reaction. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate 50:1) to give 40mg of a yellow-green solid in 71% yield.

Characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.08–8.03(m,2H),7.97(s,1H),7.50–7.42(m,3H),6.98(s,1H),4.36(q,J＝7.2Hz,2H),4.30(q,J＝7.1Hz,2H),1.57(s,9H),1.38(t,J＝7.2Hz,3H),1.34(t,J＝7.2Hz,3H).

¹³C NMR(101MHz,cdcl3)δ169.05,167.06,159.24,157.85,145.95,138.51,130.00,128.76,127.36,105.81,101.13,61.82,61.42,51.85,29.31,14.27,14.14.

IR(neat)2920.62,1737.53,1687.46,1558.94,1370.21,1290.03,1186.35,1128.80.

HRMS(ESI+)calcd for C₂₁H₂₇N₂O₄:371.1971,found:371.1959.

by using the method provided in example 1 above, only the substituent groups of the starting materials were adjusted accordingly, and the compounds shown in examples 2 to 22 below were obtained.

Example 2

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₈N₂O₄The yield of the product is 60%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ7.99–7.91(m,3H),7.32–7.21(m,2H),6.94(s,1H),4.42–4.23(m,4H),2.41(s,3H),1.56(s,9H),1.42–1.30(m,6H).

¹³C NMR(101MHz,cdcl3)δ169.17,167.10,159.30,157.88,145.90,140.25,135.79,129.51,127.32,105.53,100.73,61.80,61.36,51.82,29.32,21.52,14.27,14.16.

IR(neat)2954.64,1737.67,1686.74,1558.48,1369.89,1289.68,1182.11,1044.46.

HRMS(ESI+)calcd for C₂₂H₂₉N₂O₄:385.2127,found:385.2108.

example 3

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₈N₂O₄The product yield was 68%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ7.97(s,1H),7.89–7.83(m,2H),7.39–7.33(m,1H),7.25(d,J＝6.4Hz,1H),6.96(s,1H),4.36(q,J＝7.2Hz,2H),4.30(q,J＝7.2Hz,2H),2.43(s,3H),1.56(s,9H),1.38(t,J＝7.2Hz,3H),1.34(t,3H).

¹³C NMR(75MHz,CDCl3)δ169.12,167.09,159.45,157.85,145.89,138.52,138.28,130.77,128.68,128.05,124.59,105.88,101.00,61.80,61.39,51.82,29.31,21.74,14.26,14.13.

IR(neat)2917.53,1737.76,1686.83,1559.92,1369.89,1255.88,1229.12,1178.37.

HRMS(ESI+)calcd for C₂₂H₂₉N₂O₄:385.2127,found:385.2112.

example 4

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₈N₂O₄The product yield was 52%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ7.94(s,1H),7.43–7.40(m,1H),7.31–7.28(m,1H),7.27–7.24(m,2H),6.58(s,1H),4.37–4.27(m,4H),2.41(s,3H),1.47(s,9H),1.39–1.31(m,6H).

¹³C NMR(101MHz,cdcl3)δ168.89,167.20,162.79,157.71,145.06,140.33,135.82,130.79,129.57,128.63,125.80,109.94,100.71,61.81,61.48,51.87,29.46,20.72,14.26,14.14.

IR(neat)2929.90,1738.12,1688.51,1587.00,1460.82,1370.40,1286.77,1135.14.

HRMS(ESI+)calcd for C₂₂H₂₉N₂O₄:385.2127,found:385.2114.

example 5

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₅F₃N₂O₄The product yield was 52%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.14(d,J＝8.6Hz,2H),7.96(s,1H),7.72(d,J＝8.6Hz,2H),6.99(s,1H),4.37(dd,J＝14.4,7.2Hz,2H),4.31(dd,J＝7.1Hz,2H),1.56(s,9H),1.39(t,J＝7.2Hz,3H),1.35(t,J＝7.1Hz,3H).

¹³C NMR(101MHz,cdcl3)δ168.71,166.70,158.17,158.12,146.12,141.68,131.67(q,J＝32.5Hz),127.65,125.68(q,J＝3.8Hz),124.21(q,J＝544.5,272.2Hz),106.43,101.87,62.02,61.61,41.11,31.64,20.46,14.27,14.14,14.07.

IR(neat)2929.90,1737.52,1690.32,1585.18,1561.09,1463.92,1325.29,1128.62.

HRMS(ESI+)calcd for C₂₂H₂₆F₃N₂O₄:489.1845,found:489.1824.

example 6

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₅FN₂O₄The product yield is 58%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.06–8.01(m,2H),7.99(s,1H),7.17–7.11(m,2H),6.91(s,1H),4.39–4.26(m,4H),1.55(s,9H),1.41–1.31(m,6H).

¹³C NMR(75MHz,DMSO)δ168.92,167.02,164.16(d,J＝249.9Hz),158.18,157.84,146.09,134.73,129.28(d,J＝8.5Hz),115.73(d,J＝21.7Hz),105.51,101.30,61.83,61.45,51.86,29.30,14.25,14.12.

IR(neat)2979.38,1738.76,1687.27,1560.07,1508.00,1370.21,1289.91,1256.39.

HRMS(ESI+)calcd for C₂₁H₂₆FN₂O₄:389.1877,found:389.1869.

example 7

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₅ClN₂O₄The yield of the product is 60%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.01–7.95(m,3H),7.46–7.40(m,2H),6.93(s,1H),4.36(q,J＝7.2Hz,2H),4.30(q,J＝7.2Hz,2H),1.55(s,9H),1.38(t,J＝7.2Hz,3H),1.34(t,J＝7.2Hz,3H).

¹³C NMR(75MHz,CDCl3)δ168.83,166.98,158.02,157.82,146.10,137.05,136.14,129.00,128.64,105.65,101.71,61.87,61.50,51.89,29.29,14.25,14.12.

IR(neat)2954.64,1736.96,1687.68,1590.99,1556.50,1370.06,1255.51,1129.11.

HRMS(ESI+)calcd for C₂₁H₂₆ClN₂O₄:405.1581,found:405.1555.

example 8

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₅BrN₂O₄The product yield was 53%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ7.97(s,1H),7.93–7.89(m,2H),7.61–7.57(m,2H),6.93(s,1H),4.36(q,J＝7.3Hz,2H),4.30(q,J＝7.3Hz,2H),1.55(s,9H),1.38(t,J＝7.2Hz,3H),1.34(t,J＝7.1Hz,3H).

¹³C NMR(75MHz,CDCl3)δ168.82,166.98,158.09,157.82,146.11,137.52,131.98,128.91,124.56,105.63,101.79,61.88,61.51,51.90,29.29,14.26,14.12.

IR(neat)2923.71,1738.42,1689.52,1591.05,1371.13,1292.35,1185.15,1129.17.

HRMS(ESI+)calcd for C₂₁H₂₆BrN₂O₄:449.1076,found:449.1051.

example 9

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₈N₂O₅The product yield is 58%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.02(d,J＝9.0Hz,2H),7.99(s,1H),6.98(d,J＝9.0Hz,2H),6.91(s,1H),4.35(q,J＝7.2Hz,2H),4.29(q,J＝7.1Hz,2H),3.87(s,3H),1.56(s,9H),1.38(t,J＝7.2Hz,3H),1.33(t,J＝7.1Hz,3H).

¹³C NMR(101MHz,cdcl3)δ169.22,167.11,161.34,158.90,157.89,145.92,131.13,128.87,114.13,105.07,100.25,61.76,61.30,55.50,51.78,29.33,14.27,14.16.

IR(neat)2948.45,1736.53,1685.63,1589.89,1555.73,1509.79,1257.86,1136.07.

HRMS(ESI+)calcd for C₂₂H₂₉N₂O₅:401.2076,found:401.2064.

example 10

Preparation of novel Compound C according to the procedure described in example 1₂₃H₃₀N₂O₆The product yield was 64%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ7.95(s,1H),7.24(d,J＝2.3Hz,2H),6.94(s,1H),6.55(t,J＝2.3Hz,1H),4.36(q,J＝7.2Hz,2H),4.30(q,J＝7.2Hz,2H),4.29–4.29(m,1H),3.86(s,6H),1.56(s,9H),1.38(t,J＝7.2Hz,3H),1.34(t,J＝7.2Hz,3H).

¹³C NMR(101MHz,cdcl3)δ169.03,166.98,161.04,158.73,157.65,145.93,140.50,105.89,105.31,102.38,101.38,61.87,61.46,55.57,51.81,29.25,14.26,14.14.

IR(neat)2951.55,1751.55,1687.20,1560.80,1457.73,1231.50,1290.96,1177.70.

HRMS(ESI+)calcd for C₂₃H₃₁N₂O₆:431.2182,found:431.2173.

example 11

Preparation of novel Compound C according to the procedure described in example 1₂₁H₂₆N₂O₄The yield of the product is 80%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.11–8.02(m,2H),7.90(s,1H),7.50–7.38(m,3H),6.97(s,1H),4.41–4.26(m,4H),3.68–3.59(m,2H),1.73–1.63(m,2H),1.51–1.42(m,2H),1.42–1.30(m,6H),0.98(t,J＝7.3Hz,3H).

¹³C NMR(101MHz,cdcl3)δ169.02,166.85,159.85,158.18,145.93,138.35,130.11,128.71,127.37,106.14,100.74,61.85,61.39,41.03,31.71,20.46,14.26,14.15,14.08.

IR(neat)2957.73,1736.78,1686,45,1559.53,1251.02,1192.48,1128.46,1021.65.

HRMS(ESI+)calcd for C₂₁H₂₇N₂O₄:371.1971,found:371.1962.

example 12

Preparation of novel Compound C according to the procedure described in example 1₂₂H₂₈N₂O₄The yield of the product is 66%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ7.87(s,1H),7.45(d,J＝7.8Hz,1H),7.31–7.23(m,3H),6.63(s,1H),4.39–4.28(m,4H),3.54(dd,J＝12.4,7.0Hz,2H),2.46(s,3H),1.65–1.57(m,2H),1.46–1.32(m,8H),0.94(t,J＝7.3Hz,3H).

¹³C NMR(101MHz,cdcl3)δ168.86,166.94,163.56,157.83,145.31,139.60,136.51,131.17,129.57,128.92,125.93,109.98,100.21,61.84,61.43,41.04,31.87,20.94,20.41,14.26,14.15,14.04.

IR(neat)2957.73,1736.64,1687.33,1559.94,1368.04,1286.50,1187.17,1130.33.

HRMS(ESI+)calcd for C₂₂H₂₉N₂O₄:385.2127,found:385.2121.

example 13

The novel compounds were prepared as described in example 1C₂₂H₂₅F₃N₂O₄The product yield was 57%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.16(d,J＝8.2Hz,2H),7.90(s,1H),7.71(d,J＝8.1Hz,2H),6.99(s,1H),4.42–4.29(m,4H),3.63(q,J＝6.7Hz,2H),1.72–1.63(m,2H),1.52–1.43(m,2H),1.43–1.32(m,6H),0.98(t,J＝7.3Hz,3H).

IR(neat)2954.64,1739.18,1683.51,1560.95,1324.27,1292.98,1252.08,1107.90.

HRMS(ESI+)calcd for C₂₂H₂₆F₃N₂O₄:439.1845,found:439.1826.

example 14

Preparation of novel Compound C according to the procedure described in example 1₂₁H₂₅ClN₂O₄The product yield was 52%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.04–7.97(m,2H),7.90(s,1H),7.45–7.40(m,2H),6.92(s,1H),4.40–4.28(m,4H),3.62(dd,J＝12.4,7.0Hz,2H),1.71–1.62(m,2H),1.50–1.42(m,2H),1.39(t,J＝7.2Hz,3H),1.34(t,J＝7.1Hz,3H),0.98(t,J＝7.3Hz,3H).

¹³C NMR(101MHz,cdcl3)δ168.87,166.76,158.55,158.13,146.06,136.79,136.24,128.94,128.66,105.88,101.10,61.94,61.49,41.06,31.66,20.47,14.27,14.15,14.08.

IR(neat)2967.01,1736.46,1687.40,1558.29,1374.23,1279.48,1250.32,1129.89.

HRMS(ESI+)calcd for C₂₁H₂₆ClN₂O₄:405.1581,found:405.1563.

example 15

Preparation of novel Compound C according to the procedure described in example 1₂₃H₂₈N₂O₄The product yield was 65%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.08–8.00(m,2H),7.89(d,J＝7.3Hz,1H),7.50–7.41(m,3H),6.95(s,1H),4.37(q,J＝7.2Hz,2H),4.31(q,J＝7.2Hz,2H),2.13–2.03(m,2H),1.82–1.73(m,2H),1.69–1.59(m,1H),1.52–1.45(m,2H),1.44–1.21(m,10H).

¹³C NMR(101MHz,cdcl3)δ169.07,166.81,159.84,157.44,146.05,138.38,130.08,128.73,127.33,105.98,100.48,61.84,61.35,49.42,32.99,26.08,24.94,14.26,14.16.

IR(neat)2926.80,1736.92,1686.34,1557.79,1291.40,1252.96,1128.22,1132.99.

HRMS(ESI+)calcd for C₂₃H₂₉N₂O₄:397.2127,found:397.2112.

example 16

Preparation of novel Compound C according to the procedure described in example 1₂₄H₂₄N₂O₄The yield of the product is 30%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.02–7.97(m,2H),7.46–7.37(m,5H),7.36–7.30(m,2H),7.28–7.23(m,1H),7.02(s,1H),4.87(d,J＝5.6Hz,2H),4.38(q,J＝7.2Hz,2H),4.31(q,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H),1.33(t,J＝7.1Hz,3H).

¹³C NMR(101MHz,cdcl3)δ168.88,166.73,159.86,157.83,145.99,139.79,138.15,130.17,128.71,128.64,127.65,127.42,127.12,106.86,101.20,61.92,61.51,45.28,14.26,14.12.

IR(neat)2957.73,1735.82,1686.32,1557.79,1289.04,1251.75,1131.77,1028.66.

HRMS(ESI+)calcd for C₂₄H₂₅N₂O₄:405.1814,found:405.1797.

example 17

Preparation of novel Compound C according to the procedure described in example 1₂₄H₂₄N₂O₅The product yield was 27%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ9.85(s,1H),8.02(M,2H),7.61(M,2H),7.45(M,3H),7.15(s,1H),6.93(M,2H),4.38(M,4H),3.83(s,3H),1.39(M,6H).

¹³C NMR(101MHz,cdcl3)δ168.62,166.87,159.78,155.79,155.68,146.10,137.94,132.77,130.32,128.85,127.48,123.13,114.02,108.30,102.00,62.05,61.90,55.66,14.29,14.13.

IR(neat)2920.62,1736.39,1687.37,1579.82,1510.09,1370.47,1302.32,1184.16.

HRMS(ESI+)calcd for C₂₄H₂₅N₂O₅:421.1763,found:421.1743.

example 18

Preparation of novel Compound C according to the procedure described in example 1₁₉H₂₂N₂O₄The product yield was 65%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.10–8.01(m,2H),7.92(s,1H),7.54–7.39(m,3H),7.00(s,1H),3.90(s,3H),3.84(s,3H),1.57(s,9H).

¹³C NMR(101MHz,cdcl3)δ169.50,167.42,159.41,157.79,145.55,138.37,130.08,128.77,127.35,105.76,101.06,52.79,52.36,51.90,29.29.

IR(neat)2958.10,1737.77,1693.33,1588.12,1559.40,1356.05,1256.64,1129.43.

HRMS(ESI+)calcd for C₁₉H₂₃N₂O₄:343.1658,found:343.1639.

example 19

Preparation of novel Compound C according to the procedure described in example 1₁₉H₂₂N₂O₄The product yield was 57%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.13–7.97(m,2H),7.83(s,1H),7.51–7.37(m,3H),6.99(s,1H),3.91(s,3H),3.84(s,3H),3.65(td,J＝7.0,5.6Hz,2H),1.75–1.59(m,2H),1.47(dd,J＝15.1,7.4Hz,2H),0.98(t,J＝7.3Hz,3H).

¹³C NMR(101MHz,cdcl3)δ169.48,167.19,160.04,158.11,145.60,138.25,130.20,128.74,127.38,106.12,100.70,52.80,52.35,41.07,31.72,20.46,14.07.

IR(neat)2960.82,1740.85,1693.22,1560.00,1350.58,1251.33,1128.84,1080.45.

HRMS(ESI+)calcd for C₁₉H₂₃N₂O:343.1658,found:343.1640.

example 20

Preparation of novel Compound C according to the procedure described in example 1₂₁H₂₄N₂O₄The product yield was 67%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.12–7.97(m,2H),7.82(d,J＝7.2Hz,1H),7.57–7.37(m,3H),6.97(s,1H),4.33–4.15(m,1H),3.91(s,3H),3.84(s,3H),2.13–2.02(m,2H),1.88–1.70(m,2H),1.54–1.30(m,6H).

¹³C NMR(101MHz,cdcl3)δ169.52,167.16,160.02,157.38,145.70,138.28,130.17,128.76,127.34,105.95,100.43,52.79,52.32,49.48,32.98,26.07,24.94.

IR(neat)2932.99,1740.59,1692.87 1557.69,1350.64,1294.93,1253.68,1129.83.

HRMS(ESI+)calcd for C₂₁H₂₅N₂O₄:369.1814,found:369.1799.

example 21

Preparation of novel Compound C according to the procedure described in example 1₂₈H₃₇N₃O₆The yield of the product is 60%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ7.99(dd,J＝8.6,1.4Hz,2H),7.89(d,J＝7.2Hz,1H),7.45(d,J＝7.8Hz,2H),6.90(s,1H),6.65(s,1H),4.36(q,J＝7.2Hz,2H),4.30(q,J＝7.1Hz,2H),4.25–4.16(m,1H),2.15–2.03(m,2H),1.84–1.70(m,2H),1.71–1.60(m,2H),1.54(s,8H),1.45–1.29(m,10H).

¹³C NMR(101MHz,cdcl3)δ169.93,169.21,166.83,159.20,157.42,152.56,146.02,140.28,132.87,128.23,118.19,105.33,61.83,61.27,49.48,32.98,28.45,27.04,26.10,24.97,14.26,14.18.

IR(neat)2957.73,1736.08,1560.60,1527.00,1371.55,1324.94,1296.36,1180.65.

HRMS(ESI+)calcd for C₂₈H₃₈N₃O₆:512.27551,found:512.27502.

example 22

Preparation of novel Compound C according to the procedure described in example 1₂₆H₃₁N₅O₅The product yield was 65%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.20(d,J＝7.2Hz,2H),8.05(s,1H),7.91(d,J＝7.1Hz,1H),7.84(d,J＝7.2Hz,2H),6.98(s,1H),4.92(s,2H),4.44–4.29(m,4H),4.27–4.20(m,1H),2.17–2.02(m,2H),1.86–1.65(m,4H),1.56–1.42(m,8H),1.44–1.30(m,8H).

¹³C NMR(101MHz,cdcl3)δ168.84,166.68,158.01,157.40,146.27,138.83,137.97,128.79,120.57,105.94,101.32,62.01,61.55,56.88,49.57,32.93,26.06,24.93,14.28,14.16.

IR(neat)2953.77,296.11,1737.11,1687.28,1559.70,1347.24,1254.83,1131.59.

HRMS(ESI+)calcd for C₂₆H₃₂N₅O₅:494.23980,found:494.23917.

example 23

This example provides a known compound, 2-tert-butylamino-3-phenylisoquinoline, of the formula: c₁₉H₂₀N₂The structural formula is as follows:

the compound is synthesized by adopting the following specific steps:

to a 5ml reaction tube were added { Rh (COD) Cl } in order₂(2mg,0.0038mmol) and 2, 2' -bipyridine (1mg,0.0075mmol), 1, 4-dioxane (2ml), stirred for 5min, then added with (1-azidoethenyl) benzene (22mg,0.15mmol) and tert-butylisonitrile (13mg,17uL,0.2mmol) using a syringe and reacted at room temperature for 5 h. After the reaction is completed, adding trifluoromethanesulfonic acid (2-trimethylsilyl) phenyl ester (89mg,0.3mmol), KF (17mg,0.3mmol) and 18-crown-6-ether (79mg,0.3mmol) by a syringe, continuing the reaction at room temperature for 24h, and detecting by TLC to complete the reaction. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate: 100:1) to give 30mg of a yellow-green liquid in 74% yield.

Characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.17(d,J＝8.6Hz,2H),7.69(t,J＝7.6Hz,2H),7.56–7.51(m,1H),7.47(t,J＝7.6Hz,2H),7.42–7.33(m,3H),5.18(s,1H),1.67(s,9H).

¹³C NMR(101MHz,cdcl3)δ154.11,148.84,140.56,138.11,129.48,128.56,128.06,127.95,126.75,125.57,121.44,117.94,106.11,51.93,29.38.

by using the method provided in example 23 above, the following compounds of examples 24 to 34 can be obtained by only adjusting the substituent groups of the starting materials accordingly.

Example 24

Preparation of novel Compound C as described in example 23₂₀H₂₂N₂O, product yield 31%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.11(d,J＝8.7Hz,2H),7.67(d,J＝8.2Hz,2H),7.55–7.49(m,1H),7.37(t,J＝7.6Hz,1H),7.32(s,1H),7.05–6.98(m,2H),3.87(s,4H),1.66(s,11H).

¹³C NMR(101MHz,cdcl3)δ159.82,154.05,148.63,138.26,133.31,129.43,127.96,127.75,125.18,121.43,117.59,113.95,104.98,55.48,51.89,29.39.

IR(neat)2957.77,1620.46,1607.44,1569.15,1288.81,1248.53,1275.59,1180.15.

HRMS(ESI+)calcd for C₂₀H₂₃N₂O:307.18049,found:307.17987.

example 25

Preparation of novel Compound C as described in example 23₂₀H₁₉F₃N₂The product yield was 51%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.26(d,J＝8.7Hz,2H),7.76–7.66(m,4H),7.58(t,J＝8.1Hz,1H),7.49–7.41(m,2H),5.24(s,1H),1.67(s,9H).

¹³C NMR(101MHz,cdcl3)δ154.25,147.35,144.02,137.86,129.76,129.73(q,J＝32.2Hz),128.66,126.89,126.23,125.51(q,J＝3.7Hz),124.60(q,J＝272.0Hz),121.48,118.32,107.06,52.02,29.32.

IR(neat)2957.73,1521.17,1414.50,1163.01,1123.06,1070.50,1063.47.

HRMS(ESI+)calcd for C₂₀H₂₀F₃N₂:345.15731,found:345.15662.

example 26

Preparation of novel Compound C as described in example 23₂₀H₂₂N₂The product yield was 54%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.06(d,J＝8.1Hz,2H),7.71–7.64(m,2H),7.57–7.47(m,1H),7.42–7.36(m,2H),7.27(d,J＝7.9Hz,2H),5.17(s,1H),2.41(s,3H),1.66(s,9H).

¹³C NMR(101MHz,cdcl3)δ154.07,148.95,138.18,137.88,129.42,129.31,127.86,126.67,125.35,121.43,117.81,105.62,51.91,29.39,21.42.

IR(neat)2957.11,1621.21,1594.66,1519.92,1445.03,1412.39,1233.44,1215.01.

HRMS(ESI+)calcd for C₂₀H₂₃N₂:291.18558,found:291.18475.

example 27

Preparation of novel Compound C as described in example 23₂₀H₂₂N₂The product yield was 67%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ7.98(d,J＝11.6Hz,2H),7.68(t,J＝7.7Hz,2H),7.53(t,J＝7.6Hz,1H),7.45–7.29(m,3H),7.18(d,J＝7.5Hz,1H),5.17(s,1H),2.45(s,3H),1.67(s,9H).

¹³C NMR(101MHz,cdcl3)δ154.08,149.04,140.59,138.13,137.94,129.44,128.83,128.49,127.92,127.50,125.49,124.02,121.43,117.91,106.13,51.92,29.39,21.89.

IR(neat)2917.53,1621.61,1568.89,1520.89,1417.70,1359.35,1234.89,1215.54.

HRMS(ESI+)calcd for C₂₀H₂₃N₂:291.18558,found:291.18481.

example 28

Preparation of all by the method of example 23New compounds C₂₀H₂₂N₂The yield of the product is 40%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ7.70(d,J＝8.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.57–7.52(m,2H),7.46–7.38(m,1H),7.29–7.22(m,3H),6.98(s,1H),5.16(s,1H),2.47(s,3H),1.58(s,9H).

¹³C NMR(101MHz,cdcl3)δ153.86,151.84,142.21,137.63,136.09,130.53,130.14,129.38,127.66,127.42,125.60,125.54,121.39,117.27,110.28,51.92,29.55,21.01.

IR(neat)2960.82,1622.13,1567.58,1520.82,1420.67,1376.56,1231.52,1241.77.

HRMS(ESI+)calcd for C₂₀H₂₃N₂:291.18558,found:291.18488.

example 29

Preparation of novel Compound C as described in example 23₁₉H₁₉FN₂The product yield was 53%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,cdcl3)δ8.17–8.08(m,2H),7.68(d,J＝8.2Hz,2H),7.57–7.50(m,1H),7.44–7.36(m,1H),7.33(s,1H),7.18–7.11(m,2H),5.20(s,1H),1.66(s,9H).

¹³C NMR(101MHz,cdcl3)δ163.03(d,J＝246.7Hz),154.13,147.91,138.07,136.70,129.58,128.36(d,J＝8.1Hz),127.86,125.61,121.44,117.81,115.34(d,J＝21.3Hz),105.71,51.92,29.34.

IR(neat)2967.01,1602.67,1569.90,1512.27,1444.90,1433.74,1412.95,1230.77.

HRMS(ESI+)calcd for C₁₉H₂₀FN₂:295.16050,found:295.16003.

example 30

Preparation of novel Compound C as described in example 23₁₉H₁₉ClN₂The product yield was 51%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝8.6Hz,2H),7.71–7.65(m,2H),7.58(d,J＝8.5Hz,2H),7.56–7.51(m,1H),7.45–7.38(m,1H),7.37(s,1H),5.20(s,1H),1.65(s,9H).

¹³C NMR(101MHz,cdcl3)δ154.16,147.75,139.55,137.98,131.65,129.65,128.35,127.96,125.85,122.20,121.46,118.04,106.08,51.96,29.33.

IR(neat)2957.73,1621.53,1594.85,1521.01,1443.87,1406.13,1232.21,1215.73.

HRMS(ESI+)calcd for C₁₉H₂₀ClN₂:311.13095,found:311.13034.

example 31

Preparation of novel Compound C as described in example 23₁₉H₁₉BrN₂The yield of the product is 50%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.09(d,J＝8.7Hz,2H),7.69(d,J＝8.8Hz,2H),7.55(t,J＝7.6Hz,1H),7.45–7.39(m,3H),7.37(s,1H),5.21(s,1H),1.66(s,9H).

¹³C NMR(101MHz,cdcl3)δ154.15,147.69,139.06,137.98,133.88,129.64,128.69,127.99,127.94,125.81,121.46,118.00,106.07,51.95,29.33.

IR(neat)2963.92,1621.28,1572.22,1522.46,1449.98,1432.54,1231.94,1217.38.

HRMS(ESI+)calcd for C₁₉H₂₀BrN₂:355.08044,found:355.07974.

example 32

Preparation of novel Compound C as described in example 23₁₉H₂₀N₂The yield of the product is 70%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.17(d,J＝7.6Hz,2H),7.71(d,J＝8.2Hz,2H),7.59–7.51(m,1H),7.50–7.32(m,5H),5.25(s,1H),3.75(s,2H),1.84–1.68(m,2H),1.60–1.44(m,2H),1.01(t,J＝7.8Hz,3H).

¹³C NMR(101MHz,cdcl3)δ154.85,138.15,129.78,128.57,128.21,127.79,126.78,125.64,121.50,117.50,106.58,31.93,29.84,20.60,14.17.

example 33

Preparation of novel Compound C as described in example 23₂₁H₂₂N₂The product yield was 64%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝7.9Hz,2H),7.71(d,J＝8.7Hz,2H),7.58–7.51(m,1H),7.49–7.32(m,5H),5.13(d,J＝6.6Hz,1H),4.43–4.28(m,1H),2.26(d,J＝8.9Hz,2H),1.82(d,J＝13.6Hz,2H),1.71(d,J＝12.9Hz,1H),1.61–1.44(m,2H),1.42–1.17(m,3H).

¹³C NMR(101MHz,cdcl3)δ154.03,149.13,140.45,138.23,129.66,128.57,128.14,127.80,126.74,125.51,121.40,117.45,106.32,49.91,33.47,26.23,25.33.

example 34

Preparation of novel Compound C as described in example 23₂₂H₁₈N₂The product yield was 74%; the structural formula of the compound is as follows:

characterization data for the resulting compounds included:

¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝7.4Hz,2H),7.77–7.71(m,2H),7.58(t,J＝7.6Hz,1H),7.53–7.34(m,9H),7.30(t,J＝7.3Hz,1H),5.52(s,1H),4.98(d,J＝5.3Hz,2H).

¹³C NMR(101MHz,cdcl3)δ156.82,154.47,149.07,140.21,140.13,138.21,129.89,128.78,128.59,128.27,127.85,127.40,126.81,125.80,121.50,117.44,107.21,46.09.

IR(neat)2954.64,1621.14,1566.94,1521.93,1453.54,1379.44,1356.99,1174.19.

HRMS(ESI+)calcd for C₂₂H₁₉N₂:311.15428,found:311.15353.

although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A preparation method of a polysubstituted nitrogen-containing aromatic heterocyclic compound is characterized in that the polysubstituted nitrogen-containing aromatic heterocyclic compound has a structure shown as a general formula (I) or (II):

in the general formula (I) or (II), R¹One selected from the following groups:

represents R¹(iii) a point of attachment to the remainder of the molecular structure represented by formula (I) or (II);

R²is hydrogen, R³、R⁴Each independently selected from methyl or ethyl ester, R⁵Is tert-butyl, R⁶Is hydrogen;

the reaction process of the method is as follows:

or

The method comprises the following specific steps: to the reaction vessel was added { Rh (COD) Cl }₂The 2, 2' -bipyridyl ligand and the solvent are evenly mixed, then the raw material A and the raw material B are added, after full reaction at room temperature, the raw material C or the raw material D or the precursor of the raw material D is added, and full reaction is carried out at room temperature to 130 ℃ to obtain the product.

2. The method of claim 1, wherein { rh (cod) Cl }₂The amount of the raw material A is 0.001-5% of the mass of the raw material A.

3. The method of claim 2, wherein { rh (cod) Cl }₂The dosage of the raw material A is 0.01-2.5% of the mass of the raw material A.

4. The method of claim 3, wherein { Rh (COD) Cl }₂The dosage of the raw material A is 0.05-0.1% of the mass of the raw material A.

5. The method according to claim 1, wherein the reaction solvent is one or more of water, dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl n-butyl ether, methanol, ethanol, isopropanol, benzene, toluene, acetonitrile, nitromethane, pentane, hexane;

and/or the reaction temperature is 120-130 ℃.

6. The method according to claim 2, wherein the reaction solvent is one or more of water, dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl n-butyl ether, methanol, ethanol, isopropanol, benzene, toluene, acetonitrile, nitromethane, pentane, hexane; and/or the reaction temperature is 120-130 ℃.

7. The process according to claim 1, wherein the reaction is completed, the solvent is removed by concentration, and the residue is purified.

8. The process according to claim 5, wherein the reaction is completed, the solvent is removed by concentration, and the residue is purified.

9. The method of claim 7, wherein the purification is a combination of one or more of column chromatography, distillation under reduced pressure, and recrystallization.

10. The method of claim 9, wherein the purification is: separating the mobile phase consisting of petroleum ether and ethyl acetate by column chromatography, and then carrying out reduced pressure distillation or recrystallization.