CN112574223B - Method for synthesizing 1, 2-dihydrobenzofuran pyridine compound - Google Patents

Method for synthesizing 1, 2-dihydrobenzofuran pyridine compound Download PDF

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CN112574223B
CN112574223B CN201910935808.1A CN201910935808A CN112574223B CN 112574223 B CN112574223 B CN 112574223B CN 201910935808 A CN201910935808 A CN 201910935808A CN 112574223 B CN112574223 B CN 112574223B
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周永贵
谢焕平
吴波
孙蕾
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Dalian Institute of Chemical Physics of CAS
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention provides a method for synthesizing 1, 2-dihydrobenzofuropyridine, wherein a catalytic system used in the method is metal copper and diphosphine ligand. The reaction can be carried out under the following conditions, temperature: 60 ℃; solvent: 1, 4-dioxane; the ratio of substrate to catalyst was 20/l. Copper-catalyzed addition/cyclization/isomerization tandem reaction of the copper-catalyzed aurantione-derived aza diene and terminal alkyne can obtain a corresponding 1, 2-dihydrobenzofuran pyridine compound, the yield can reach 99%, and then the reaction is carried out under an alkaline condition. The method has the advantages of simple operation, high yield, mild reaction conditions, better functional group tolerance and wider substrate application range. The 1, 2-dihydrobenzofuran pyridine compound obtained by the series reaction can be used for obtaining the benzofuran pyridine compound under the action of alkali, and has a pharmaceutical application value.

Description

Method for synthesizing 1, 2-dihydrobenzofuran pyridine compound
Technical Field
The invention belongs to the field of catalytic synthesis, and particularly relates to a method for synthesizing a 1, 2-dihydrobenzofuropyridine compound through addition/cyclization/isomerization reaction, and then aromatizing to obtain the benzofuropyridine compound.
Background
Dihydropyridine compounds are widely found in natural products as well as synthetic drugs of bioactive molecules. In particular, 1, 2-dihydropyridine compounds are used as an important synthetic intermediate, and can be used for synthesizing piperidine, indolizidines and quinolizidines compounds and the like. In addition, the aromatization products of 1, 2-dihydrobenzofuropyridines are also a class of molecules that may have topo inhibitory activity and cytotoxicity against some human cancer cells. Such as those of the following formula.
Figure BDA0002221558290000011
Because the 1, 2-dihydropyridine has potential medicinal value and important application thereof, the synthesis of the compound has important significance. Various strategies have been developed for this class of compounds: (1) condensation reaction of amine and carbonyl compound, (2) partial reduction after nucleophilic addition to pyridine or pyridinium; (3) polycyclic reaction.
Although there are various methods for synthesizing 1, 2-dihydrobenzofuropyridine compounds, some disadvantages and limitations have been reported in the methods such as: the conditions are harsh and the range of noble metals and substrates is limited.
Disclosure of Invention
Based on the background technology, the copper is used for catalyzing addition/cyclization/isomerization tandem reaction of the azadiene and alkyne to synthesize the 1, 2-dihydrobenzofuran pyridine compound, the catalytic system provides a new strategy for synthesizing the benzofuran pyridine compound, and the azadiene derived from the aurone has high reaction activity for synthesizing the heterocyclic compound due to the strong driving force for recovering the aromaticity.
The invention aims to provide a method for synthesizing a 1, 2-dihydrobenzofuran pyridine compound through a series reaction, which has the advantages of simple and practical operation, easily available raw materials, good yield, mild reaction conditions, good tolerance of functional groups of substrates and the like, and provides a new method for synthesizing the benzofuran pyridine compound.
In order to realize the purpose, the invention uses copper and diphosphine ligand as catalysts and uses azadiene as a substrate to synthesize the 1, 2-dihydrobenzofuran pyridine compound by addition/cyclization/isomerization tandem reaction.
The technical scheme of the invention is as follows:
on one hand, the method for synthesizing the 1, 2-dihydrobenzofuran pyridine compound is characterized in that copper and diphosphine ligands are used as catalysts, azadiene derived from aurone is used as a substrate, and the copper and diphosphine ligands and the azadiene are subjected to addition/cyclization/isomerization tandem reaction with terminal alkyne to synthesize the 1, 2-dihydrobenzofuran pyridine compound, and the reaction formula of the method is as follows:
Figure BDA0002221558290000021
in the formula:
R1is sulfonyl;
R2is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent; the substituent is halogen and C1-C20At least one of the alkyl substituents of (a);
R3is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent; the substituent is halogen and C1-C20At least one of the alkyl substituents of (a);
R4is phenyl, C1-7An alkyl group or a benzene ring having a substituent; the substituent is halogen and C1-C20At least one of the alkyl substituents of (a);
ar is phenyl or benzene ring containing substituent, and the substituent is halogen, naphthyl or C1-C20At least one alkyl substituent of (a).
Based on the above technical scheme, preferably, the base (base) in the method is at least one of triethylamine, diisopropylethylamine and potassium carbonate.
Based on the technical scheme, preferably, in the catalyst, copper is monovalent copper or divalent copper, and the ligand is a diphosphine ligand.
Based on the technical scheme, preferably, the organic solvent is at least one of tetrahydrofuran, acetonitrile, dichloromethane, trichloromethane, 1, 4-dioxane, toluene, p-xylene and mesitylene.
Based on the technical scheme, preferably, the diphosphine ligand is BINAP, DPEPhos, PPh3, PCy3 and Xantphos; the copper precursor is CuI, Cu (OTf)2,Cu(CH3CN)4BF4,Cu(CH3CN)4PF6。
Based on the technical scheme, preferably, the method comprises the following specific reaction steps:
adding a copper precursor, a diphosphine ligand and an organic solvent into a reaction bottle, stirring at room temperature, then adding the azadiene, the terminal alkyne and the alkali, putting into an oil bath at 60-100 ℃, stirring for reacting for 48-72h, removing the solvent under reduced pressure, and directly carrying out column chromatography (the volume ratio of petroleum ether and ethyl acetate in an eluent is 30:1) to obtain a corresponding 1, 2-dihydrobenzofuran pyridine compound; the molar ratio of the aza diene, the terminal alkyne, the catalyst and the alkali is 1:1.0-20.0:0.05-1.00: 0.5-1.0. The yield is the separation yield.
Based on the technical scheme, the molar ratio of the aza diene, the terminal alkyne, the catalyst and the base is preferably 1:3.0:0.05: 1.
Based on the technical scheme, preferably, the ligand is XantPhos; the copper precursor is Cu (CH)3CN)4BF4；
Based on the technical scheme, the reaction is preferably an addition/cyclization/isomerization tandem reaction of the aza diene and the terminal alkyne to synthesize the 1, 2-dihydrobenzofuran pyridine compound, and the molar ratio of the aza diene to the terminal alkyne to the catalyst to the alkali is 1:3.0:0.05: 1; r1Is Ts, R2Is hydrogen, R3Is hydrogen, R is phenyl, Ar is 3-bromophenyl or 4-isopropylphenyl, and the catalyst is Cu (CH)3CN)4BF4Xanthphos, triethylamine as the base, 1, 4-dioxane as the organic solvent, 60 ℃ as the temperature, and 99% yield of the 1, 2-dihydrobenzofuropyridine compound.
Based on the technical scheme, the catalyst is further preferably Cu (CH)3CN)4BF4And xanthphos.
Advantageous effects
The invention has the following advantages
1. The raw materials are simple and easy to obtain, and the operation is simple.
2. High reaction activity, complete conversion of raw materials and simple post-treatment.
3. Mild condition and high yield.
4. The tolerance to functional groups is good, and the reaction conditions are mild.
Detailed Description
The present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples. The starting terminal alkynes are commercially available, neither the metal precursors nor the ligands used are commercially available, and the starting azadienes can be synthesized according to known literature.
Specific references are as follows:
Xie,H.-P.；Wu,B.；Wang,X.-W.；Zhou,Y.-G.Chin.J.Catal.2018,40,1566.
examples 1 to 17
And (3) optimizing conditions: the kind of the organic solvent, the kind of the catalyst and the alkali are changed.
Adding Cu (CH) into a reaction bottle3CN)4BF4(1.5mg,0.005mmol) and ligand XantPhos (2.9mg,0.005 mmol) and 1, 4-dioxane (0.5mL) are stirred at room temperature for 1.5 hours, then aza diene (0.10mmol), terminal alkyne (0.30mmol) and triethylamine (0.10mmol) are added, the mixture is put into an oil bath at 60 ℃, after stirring and reacting for 24 hours, the solvent is removed under reduced pressure, and direct column chromatography (the volume ratio of eluent petroleum ether and ethyl acetate is 30:1) is carried out to obtain the corresponding 1, 2-dihydrobenzene furopyridine compound; the molar ratio of the aza-diene to the terminal alkyne to the catalyst to the base is 1:3.0:0.05: 1. The yield is the separation yield, the type of the organic solvent, the type of the catalyst and the alkali are changed, the configuration of the product is determined by using a single crystal, and the specific result is shown in the table.
Figure BDA0002221558290000041
TABLE 1 optimization of conditions for the synthesis of 1, 2-dihydrobenzofuropyridine compounds
Figure BDA0002221558290000042
Examples 18 to 38
Changing a substrate, and carrying out tandem reaction to synthesize a series of 1, 2-dihydrobenzofuran pyridine compounds.
Adding Cu (CH) into a reaction bottle3CN)4BF4(3.1mg,0.01mmol) and the ligands XantPhos (5.8mg,0.01 mmol) and 1, 4-dioxane (0.5mL) were stirred at room temperature for 1.5 h before addition of the aza-phosphineDiene (0.2mmol), terminal alkyne (0.6mmol) and triethylamine (0.2mmol) are put into an oil bath at 60 ℃, after stirring and reacting for 48 hours, the solvent is removed under reduced pressure, and the corresponding 1, 2-dihydrobenzofuran pyridine compound is obtained by direct column chromatography (the volume ratio of petroleum ether and ethyl acetate in eluent is 30: 1); the molar ratio of the aza diene to the terminal alkyne to the catalyst is 1:3.0: 0.05. The yield is the isolated yield. The variety of the starting materials and substrates in the reaction was varied to give 21 different examples, and the varied varieties are shown in Table 2.
Figure BDA0002221558290000051
TABLE 2 Synthesis of a series of 1, 2-dihydrobenzofuropyridine compounds by tandem reaction
Figure BDA0002221558290000052
Examples 39 to 50
Then under the action of alkali, the benzofuran pyridine compound is obtained, and the types of raw materials and substrates in the reaction are changed to obtain 12 different examples, wherein the changed types are shown in Table 3.
Figure BDA0002221558290000061
TABLE 3 Synthesis of a series of benzofuropyridine compounds
Figure BDA0002221558290000062
2,4-Diphenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3aa):91mg,95％yield,pale yellow
Figure BDA0002221558290000063
127.6,127.4,125.3,124.6,123.8,121.9,121.7,117.5,111.7,59.4,21.5.HRMS Calculated For C30H24NO3S[M+H]+478.1471,found:478.1473.
2-Phenyl-4-(o-tolyl)-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ba):91mg,93％yield,pale
Figure BDA0002221558290000064
130.3,129.7,129.6,128.9,128.8,128.4,127.8,127.3,126.0,125.1,124.6,123.7,123.1,122.1,116.1, 111.7,59.6,21.6,19.7.HRMS Calculated For C31H26NO3S[M+H]+492.1628,found:492.1635.
2-Phenyl-4-(m-tolyl)-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ca):92mg,94％yield,pale yellow solid,m.p.＝163-164℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝30:1).1H NMR(400
Figure BDA0002221558290000071
123.8,121.9,121.7,117.4,111.7,59.4,21.6,21.5.HRMS Calculated For C31H26NO3S[M+H]+492.4628, found:492.1618.
2-Phenyl-4-(p-tolyl)-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3da):94mg,96％yield,white solid,m.p.＝175-176℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,
Figure BDA0002221558290000072
492.1628,found:492.1615.
4-(4-Isopropylphenyl)-2-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ea):103mg,99％ yield,pale yellow solid,m.p.＝95-96℃,new compound,Rf＝0.40(hexanes/ethyl acetate＝30:1).1H
Figure BDA0002221558290000073
Calculated For C33H30NO3S[M+H]+520.1941,found:520.1931.
4-(4-Methoxyphenyl)-2-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3fa):94mg,93％ yield,pale yellow solid,m.p.＝169-170℃,new compound,Rf＝0.50(hexanes/ethyl acetate＝10:1).1H
Figure BDA0002221558290000074
found:508.1572.
4-(4-Chlorophenyl)-2-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ga):98mg,96％ yield,pale yellow solid,m.p.＝177-178℃,new compound,Rf＝0.55(hexanes/ethyl acetate＝10:1).1H
Figure BDA0002221558290000075
59.4,21.5.HRMS Calculated For C30H23ClNO3S[M+H]+512.1082,found:512.1100.
4-(3-Chlorophenyl)-2-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ha):99mg,97％ yield,pale yellow solid,m.p.＝70-72℃,new compound,Rf＝0.45(hexanes/ethyl acetate＝30:1).1H
Figure BDA0002221558290000081
For C30H23ClNO3S[M+H]+512.1082,found:512.1075.
4-(3-Bromophenyl)-2-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ia):109mg,99％ yield,pale yellow solid,m.p.＝75-76℃,new compound,Rf＝0.45(hexanes/ethyl acetate＝30:1).1H
Figure BDA0002221558290000082
21.6.HRMS Calculated For C30H23BrNO3S[M+H]+556.0577,found:556.0568.
4-(Naphthalen-1-yl)-2-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ja):103mg,98％ yield,pale yellow solid,m.p.＝185-187℃,new compound,Rf＝0.35(hexanes/ethyl acetate＝30:1).1H
Figure BDA0002221558290000083
124.5，124.2，123.7，122.1，111.8，59.6，21.8.HRMS Calculated For C34H26NO3S[M+H]+528.1628 found:528.1638.
8-Methyl-2,4-diphenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ka):94mg,96％yield,pale yellow solid,m.p.＝160-162℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝30:1).1H NMR(400
Figure BDA0002221558290000084
Calculated For C31H26NO3S[M+H]+492.1628,found:492.1623.
7-Methyl-2,4-diphenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3la):96mg,98％yield,pale yellow solid,m.p.＝139-141℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝30:1).1H NMR(400
Figure BDA0002221558290000085
found:492.1603.
1-(Methylsulfonyl)-2,4-diphenyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ma):71mg,89％yield, pale yellow solid,m.p.＝154-155℃,new compound,Rf＝0.15(hexanes/ethyl acetate＝30:1).1H NMR
Figure BDA0002221558290000091
7-Methyl-1-((4-nitrophenyl)sulfonyl)-2,4-diphenyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3na):62 mg,61％yield,pale yellow solid,m.p.＝192-193℃,new compound,Rf＝0.20(hexanes/ethyl acetate＝
Figure BDA0002221558290000092
Calculated For C32H17N2O5[M+H]+509.1132,found:509.1150.
4-Phenyl-2-(p-tolyl)-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ab):90mg,92％yield,pale yellow solid,m.p.＝199-201℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝30:1).1H NMR(400
Figure BDA0002221558290000093
111.7,59.3,21.5,21.2.HRMS Calculated For C31H26N-O3S[M+H]+492.1628,found:492.1620.
4-Phenyl-2-(m-tolyl)-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ac):88mg,90％yield,white solid,m.p.＝151-152℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,
Figure BDA0002221558290000094
124.7,124.4,123.7,121.9,121.8,117.4,111.6,59.4,21.5,21.4.HRMS Calculated For C31H26NO3S [M+H]+492.1628,found:492.1627.
2-(4-Methoxyphenyl)-4-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ad):93mg,92％ yield,white solid,m.p.＝201-202℃,new compound,Rf＝0.20(hexanes/ethyl acetate＝30:1).1H NMR
Figure BDA0002221558290000095
508.1577,found:508.1575.
2-(4-Fluorophenyl)-4-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ae):94mg,95％yield, white solid,m.p.＝193-194℃,new compound,Rf＝0.35(hexanes/ethyl acetate＝30:1).1H NMR(400
Figure BDA0002221558290000101
NMR(376 MHz,CDCl3)δ-113.8.HRMS Calculated For C30H23FNO3S[M+H]+496.1377,found: 496.1370.
2-(4-Bromophenyl)-4-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3af):101 mg,91％ yield,yellow solid,m.p.＝214-216℃,new compound,Rf＝0.35(hexanes/ethyl acetate＝30:1).1H
Figure BDA0002221558290000102
556.0574.
4-Phenyl-2-(thiophen-3-yl)-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ag):84mg,87％yield, white solid,m.p.＝90-91℃,new compound,Rf＝0.20(hexanes/ethyl acetate＝30:1).1H NMR(400
Figure BDA0002221558290000103
56.4,21.5.HRMS Calculated For C28H22NO3S2[M+H]+484.1036,found:484.1041.
2-(tert-Butyl)-4-phenyl-1-tosyl-1,2-dihydrobenzofuro[3,2-b]pyridine(3ah):10mg,11％yield, yellow oil,Rf＝0.45(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.11-8.02(m,1H),
Figure BDA0002221558290000104
2,4-Diphenylbenzofuro[3,2-b]pyridine(4a):43mg,89％yield,white solid,the known com-pound,[5]
Figure BDA0002221558290000105
2-Phenyl-4-(o-tolyl)benzofuro[3,2-b]pyridine(4b):45mg,90％yield,white solid,m.p.＝54-56℃, new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.37(d,J＝7.7
Figure BDA0002221558290000111
336.1383,found:336.1386.
2-Phenyl-4-(m-tolyl)benzofuro[3,2-b]pyridine(4c):48mg,95％yield,white solid,m.p.＝139-140 ℃,new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.42-8.33(m,
Figure BDA0002221558290000112
2-Phenyl-4-(p-tolyl)benzofuro[3,2-b]pyridine(4d):46mg,91％yield,white solid,m.p.＝120-122 ℃,new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.35(d,J＝
Figure BDA0002221558290000113
4-(4-Methoxyphenyl)-2-phenylbenzofuro[3,2-b]pyridine(4e):47mg,89％yield,white solid,m.p.＝ 141-142℃，new compound，Rf＝0.70(hexanes/ethyl acetate＝30:1).1H NMR(400MHz，CDCl3)δ
Figure BDA0002221558290000114
4-(4-Chlorophenyl)-2-phenylbenzofuro[3,2-b]pyridine(4f):47mg,93％yield,white solid,m.p.＝
Figure BDA0002221558290000115
8-Methyl-2,4-diphenylbenzofuro[3,2-b]pyridine(4g):46mg,91％yield,white solid,m.p.＝153-154 ℃,new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.24-8.12(m,
Figure BDA0002221558290000116
7-Methyl-2,4-diphenylbenzofuro[3,2-b]pyridine(4h):47mg,93％yield,white solid,m.p.＝150-151 ℃,new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.22(d,J＝
Figure BDA0002221558290000121
4-Phenyl-2-(p-tolyl)benzofuro[3,2-b]pyridine(4i):46mg,92％yield,white solid,m.p.＝186-187℃, new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.45-8.29(m,
Figure BDA0002221558290000122
2-(4-Methoxyphenyl)-4-phenylbenzofuro[3,2-b]pyridine(4j):49mg,93％yield,white solid,m.p.＝
Figure BDA0002221558290000123
HRMS Calculated For C24H18NO2[M+H]+352.1332,found:352.1325.
2-(4-Bromophenyl)-4-phenylbenzofuro[3,2-b]pyridine(4k):54mg,90％yield,white solid,m.p.＝ 213-215℃,new compound,Rf＝0.85(hexanes/ethyl acetate＝30:1).1H NMR(400MHz,CDCl3)δ8.32
Figure BDA0002221558290000124
4-Phenyl-2-(thiophen-3-yl)benzofuro[3,2-b]pyridine(4l):47mg,96％yield,white solid,m.p.＝
Figure BDA0002221558290000125

Claims (8)

1. A method for synthesizing a 1, 2-dihydrobenzofuran pyridine compound is characterized in that a copper complex formed by a copper precursor and a diphosphine ligand is used as a catalyst, an azadiene is used as a substrate, and the copper complex and a terminal alkyne undergo addition/cyclization/isomerization reaction to synthesize the 1, 2-dihydrobenzofuran pyridine compound, wherein the reaction formula of the method is as follows:
Figure FDA0003210540090000011
in the formula:
R1is sulfonyl groupA group;
R2is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent;
R3is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent;
R4is phenyl, C1-7An alkyl group or a benzene ring having a substituent;
ar is phenyl or a benzene ring containing a substituent;
the substituent is independently halogen, naphthyl or C1-C20At least one of alkyl groups of (a).
2. The method of claim 1, wherein the copper in the catalyst is monovalent copper or divalent copper.
3. The method according to claim 1, wherein the base in the method is at least one of triethylamine, diisopropylethylamine and potassium carbonate.
4. The method according to claim 1, wherein the solvent of the method is at least one of tetrahydrofuran, dichloromethane, chloroform, toluene, 1, 4-dioxane, acetonitrile, p-xylene and mesitylene.
5. The method according to claim 1, wherein the method comprises the following specific reaction steps:
adding a copper precursor and a diphosphine ligand into a reaction bottle, then adding an organic solvent, stirring at the temperature of 1-30 ℃ for 0.5-3h, adding an azadiene, an alkali and a terminal alkyne, stirring at the temperature of 60-100 ℃ for reaction for 48-72h, and then carrying out direct column chromatography to obtain the 1, 2-dihydrobenzofuran pyridine compound; the molar ratio of the aza diene, the terminal alkyne, the catalyst and the alkali is 1:1.0-3.0:0.05-1.00: 0.5-1.0.
6. The method of claim 1, wherein: the diphosphine ligand is BINAP, DPEPhos, PPh3，PCy3Xantphos; the copper precursor is CuI, Cu (OTf)2，Cu(CH3CN)4BF4，Cu(CH3CN)4PF6。
7. The method of claim 5, wherein: the molar ratio of the aza-diene to the terminal alkyne to the catalyst to the base is 1:3.0:0.05: 1.
8. The method of claim 5, wherein: r1Is p-toluenesulfonyl, R2Is hydrogen, R3Is hydrogen, R is phenyl, Ar is 3-bromophenyl or 4-isopropylphenyl, and the catalyst is Cu (CH)3CN)4BF4Xanthphos, 1, 4-dioxane as the organic solvent, 60 ℃ and 99% yield.
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