Application of diamide acid ligands in copper-catalyzed (hetero)aryl halide reactions

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to an application of a diamide acid ligand in a copper-catalyzed (hetero)aryl halide reaction. The application is a method of using a diamide acid ligand as a catalyst ligand to cause a (hetero)aryl halide to undergo a coupling reaction under copper catalysis, in particular a reaction to generate a C-O bond. The present invention provides a use of a diamide acid ligand in a copper-catalyzed (hetero)aryl halide coupling reaction. The catalytic system of the (hetero)aryl halide coupling reaction body in the present invention has good selectivity and applicability to different halides and coupling reagents.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and discloses a method for using diamide acid ligands as catalyst ligands to make (hetero)aryl halides undergo coupling reaction under copper catalysis, in particular to generate CO bonds. Background Art

[0002] Amide structures are a common chemical structure, many of which have biological activity. For example, a series of oxalamide structures discovered by Ma Dawei's research group can be used as ligands in copper-catalyzed coupling reactions of aryl halides, attracting the attention of many researchers.

[0003] The transition metal-catalyzed reaction of (hetero)aryl halides with nucleophiles is a common and efficient method for the generation of CN, CC, CO, CS, and CP, usually using metal catalysis such as palladium, copper, and tweezers. In recent years, some effective copper and multidentate ligand catalytic systems have been discovered, making the reaction conditions milder, the substrate range richer, and the reaction cost lower. However, it still has certain limitations, such as the unsatisfactory reaction effect of aryl chlorides, and the complex and difficult or expensive ligand preparation process.

[0004] In summary, the art still lacks a catalytic system with simple preparation process and good reaction effect. Summary of the invention

[0005] The purpose of the present invention is to solve the problems of the prior art and provide an application of a catalytic system that can be used for copper-catalyzed (hetero)aryl halide coupling reaction in copper-catalyzed (hetero)aryl halide coupling reaction. The application method is simple to operate, has mild reaction conditions, cheap and readily available raw materials, good substrate applicability, and good yield.

[0006] The technical solution adopted by the present invention to solve its technical problem is:

[0007] A use of a diamide acid ligand in a copper-catalyzed (hetero)aryl halide reaction, wherein the diamide acid ligand is at least one of the compounds represented by the following general formula I, general formula II, and general formula III:

[0008]

[0009] Among them, R 1 Selected from the following group: substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3-20 membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C1-C6 alkyl;

[0010] R 2 , R 3 , R 4 , R5 are independently selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl, halogen; R 2 , R 3 , R 4 , R 5 Can be the same or different;

[0011] R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Each of the following groups is independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryl-oxy, halogen, nitro, hydroxyl, and amino; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Can be the same or different;

[0012] X and Y are independently selected from the following groups: blank, substituted or unsubstituted C1-C6 saturated carbon chain, substituted or unsubstituted C1-C6 unsaturated carbon chain; X and Y may be the same or different;

[0013] Z is selected from the following group: empty (i.e., the benzene rings on both sides of Z are directly connected to form biphenyl), a substituted or unsubstituted C1-C6 saturated carbon chain, a substituted or unsubstituted C1-C6 unsaturated carbon chain, an oxy group (ether bond), a carbonyl group, a sulfone group, an amide group, a substituted or unsubstituted imino group;

[0014] The substituents are independently selected from halogen, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 heteroaryl or C6-C10 aryl-oxy; the number of substituents may be one or more, and when there are multiple substituents, the substituents may be the same or different;

[0015] In the above:

[0016] The aryl group is selected from phenyl, naphthyl, anthracenyl, benzyl, and biphenyl;

[0017] The heteroatom of the heteroaryl group is selected from one or more of N, O, and S, the number of heteroatoms is 1-6, and the heteroaryl group is a 3-20-membered heterocyclic group; more preferably, the heteroaryl group is a pyridyl group or a quinolyl group;

[0018] The cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0019] The halogen is selected from at least one of F, Cl, Br and I.

[0020] Preferably, the diamide acid ligand is selected from at least one of the following structures:

[0021] Table 1 Diamic acid ligands

[0022]

[0023]

[0024] Preferably, in the application, the reaction is a coupling reaction of a (hetero)aryl halide with a coupling reagent in the presence of a copper catalyst and a diamide acid ligand, and the coupling reaction comprises:

[0025] Reaction 1: Ar-X+ROH→Ar-OR;

[0026] Or reaction 2: Ar-X→Ar-OH;

[0027] Where:

[0028] X is selected from the group consisting of Cl, Br, I;

[0029] Ar-X is an aryl halide or a heteroaryl halide, and Ar is selected from the following group: a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted 3-20 membered heteroaryl group;

[0030] The substituents are one or more, and the substituents are selected from the following groups: halogen (F, Cl, Br, I), nitro, hydroxyl, cyano, amino, amino substituted by 1 or 2 C1-C6 alkyl, amino substituted by 1 or 2 C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 3-20 membered heteroaryl, C6-C10 aryl-oxy, C2-C10 ester (alkyl-C( C2-C10 acyl (alkyl-C(O)-), C2-C10 alkoxy-acyl (alkyl-OC(O)-), C2-C10 amide (alkyl-C(O)NH-, aryl-C(O)NH-), carboxyl (-COOH), hydroxy-C1-C10 alkylene, MeS-, sulfone, sulfonamide; wherein the two hydrogen atoms on the two adjacent carbon atoms on the aryl group can be replaced by -(CH2) n -substituted (n is 1, 2, 3, 4, 5 or 6);

[0031] R is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3-20 membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl;

[0032] More preferably, the C1-C6 alkyl group is at least one of an alkyl group containing 1 to 6 C, including but not limited to methyl, ethyl, propyl, butyl, tert-butyl, etc.;

[0033] More preferably, the C1-C6 alkoxy group is at least one of alkoxy groups containing 1 to 6 C, including but not limited to methoxy, ethoxy, propoxy, etc.;

[0034] Wherein, the heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the following group: N, O or S; the cycloalkyl or heterocyclic group can be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0035] The substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen (F, Cl, Br, I), cyano, oxygen (i.e., two hydrogen atoms on the same carbon atom on the substituted group are replaced by =O), C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-C(O)O-), C2-C10 acyl-alkoxy (alkyl-OC(O)-), C2-C10 acyl group (alkyl-C(O)-), C2-C10 amide group (alkyl / aryl NHC(O)-), carboxyl (-COOH), nitro, hydroxyl, amino, amino substituted by 1 or 2 C1-C6 alkyl, amino substituted by 1 or 2 C1-C6 alkoxy, C1-C6 alkylthio.

[0036] Preferably, the copper catalyst is at least one of cuprous iodide CuI, cuprous chloride CuCl, cuprous bromide CuBr, cupric chloride CuCl2, copper oxide CuO, cupric acetate Cu(OAc)2, and copper acetylacetonate Cu(acac)2, more preferably cuprous iodide CuI and cuprous chloride CuCl.

[0037] Preferably, the reaction temperature of the reaction is 80-160°C, more preferably 100-130°C.

[0038] Preferably, the reaction time is 5 to 24 hours, more preferably 7 to 10 hours.

[0039] Preferably, the addition process of the reactants and the reaction process are all carried out in an inert atmosphere, and the inert atmosphere is at least one of nitrogen, helium and argon.

[0040] Preferably, in the reaction 1, the coupling reagent is ROH (the definition of the R group is as described above); more preferably, the reaction is carried out in the presence of a base; more preferably, the base is at least one of lithium hydroxide LiOH, sodium hydroxide NaOH, potassium hydroxide KOH, sodium carbonate Na2CO3, potassium carbonate K2CO3, and potassium tert-butoxide t-BuOK, more preferably sodium carbonate Na2CO3, potassium hydroxide KOH, and lithium hydroxide LiOH.

[0041] More preferably, in the reaction 1, the molar ratio of the aryl halide or heteroaryl halide, coupling reagent, copper catalyst, ligand and base is 1: 1.0-2.5: (0.002-0.008): (0.002-0.008): (1-2), more preferably 1: (1.2-1.5): (0.003-0.005): (0.003-0.005): (1.2-1.5).

[0042] Preferably, in the reaction 1, the reaction is carried out in an organic solvent, more preferably the organic solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide, and more preferably the organic solvent is dimethyl sulfoxide.

[0043] Preferably, in the reaction 1, the amount of the organic solvent used is 0.8M-2M, more preferably 1M.

[0044] Preferably, in reaction 2, the coupling reagent is selected from the group consisting of H2O, hydroxide, alkali, and a mixture of alkali and water, preferably at least one of lithium hydroxide, potassium hydroxide, sodium hydroxide, and cesium carbonate, and more preferably potassium hydroxide.

[0045] Preferably, in reaction 2, the molar ratio of the aryl halide or heteroaryl halide, the coupling reagent, the copper catalyst, and the ligand is 1: 1.0-4.0: (0.001-0.005): (0.001-0.005), more preferably 1: (1.3-3.0): (0.002-0.004): (0.002-0.004).

[0046] Preferably, in the reaction 2, the reaction is carried out in a mixture of an organic solvent and water, and more preferably the organic solvent is dimethyl sulfoxide or N,N-dimethylformamide.

[0047] Preferably, in the reaction 2, the volume ratio of the organic solvent to water is (10-0):1, more preferably (4-0.2):1.

[0048] Preferably, in the reaction 2, the amount of solvent used is 0.8M-2M, more preferably 1M.

[0049] Preferably, the coupling reaction includes the following (1) and (2):

[0050] In an organic solvent, Ar-X reacts with ROH to obtain Ar-OR;

[0051] Ar-X+ROH→Ar-OR;

[0052] Wherein, the definitions of each group are as described above;

[0053] In an organic solvent, Ar-X is used to hydrolyze the OH - Reaction to obtain Ar-OH;

[0054] Ar-X → Ar-OH;

[0055] The definitions of the groups are as described above.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] (1) The reagents and substrates of the present invention are simple, economical, cheap and readily available, the reaction operation is simple, the conditions are mild, and the reaction is highly efficient.

[0058] (2) The reaction system has good substrate adaptability and good selectivity for different halides.

[0059] (3) The ligand preparation process is simple and can be prepared using commercially available products. DETAILED DESCRIPTION

[0060] The technical solution of the present invention is further clearly and completely described below through specific embodiments. It should be noted that the embodiments described in the present invention are implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operation processes are given, but they are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0061] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used in the examples are all available from commercial sources unless otherwise specified.

[0062] Example 1

[0063]

[0064] Add p-bromobenzonitrile (4mmol), CuI (0.4mmol), Ligand1 (0.4mmol), and LiOH (6mmol) to a Shrek reaction tube with a magnetic stirring bar. Evacuate the reaction vessel and backfill with argon three times, then add phenol (5.2mmol) and DMSO (5.0mL) under argon atmosphere. React the reaction mixture at 110°C for 10h at a stirring speed of 100-200rmp. After the reaction is completed, cool to room temperature, dilute with saturated brine, then extract with ethyl acetate three times and wash with saturated brine. Combine the organic phases and dry with anhydrous Na2SO4 and concentrate in vacuo. The residue is purified by flash column chromatography (mobile phase is petroleum ether / ethyl acetate (vv: 50-10:1)) to obtain the target product with a yield of 88%.

[0065] The product obtained 1 The H NMR data are characterized as follows: 1 H NMR(400MHz,Chloroform-d)δ7.65–7.58(m,2H),7.48–7.39(m,2H),7.26(t,J =7.6Hz,1H),7.09(d,J=8.0Hz,2H),7.06–6.99(m,2H),1.30(d,J=11.2Hz,0H).

[0066] Example 2

[0067]

[0068] The operation of this example is the same as that of Example 1, using different ligands, copper catalysts, bases, solvents, and time. The results are listed in the table below.

[0069]

[0070]

[0071] Example 3

[0072]

[0073] CuI (0.2mmol), Ligand 1 (0.2mmol), and Na2CO3 (4mmol) were added to a Shrek reaction tube with a magnetic stirring bar. The reaction vessel was evacuated and backfilled with argon three times, and then phenol (8mmol), bromobenzene (4mmol) and DMSO (4.0mL) were added under an argon atmosphere. The reaction mixture was reacted at 120°C for 10h at a stirring speed of 100-200rmp. After the reaction was completed, it was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times and washed with saturated brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (mobile phase was petroleum ether / ethyl acetate (vv: 50-10:1)) to obtain the target product with a yield of 87%.

[0074] The product obtained 1 The H NMR data are characterized as follows: 1 H NMR (400MHz, DMSO-d6) δ7.34 (t, J = 7.9 Hz, 1H), 6.99 (tt, J = 23.8, 7.7 Hz, 4H), 3.75 (d, J = 2.8 Hz, 2H).

[0075] Example 4

[0076]

[0077] CuI, Ligand 1, and Na2CO3 (4 mmol) were added to a Shrek reaction tube with a magnetic stirring bar. The reaction vessel was evacuated and backfilled with argon three times, and then phenol (8 mmol), bromobenzene (4 mmol), and then DMSO (4.0 mL) were added under an argon atmosphere. The reaction mixture was heated and reacted for 14 h at a stirring speed of 100-200 rpm. After the reaction was completed, it was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times and washed with saturated brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (mobile phase was petroleum ether / ethyl acetate (vv: 50-10:1)) to obtain the target product. The reaction was carried out using different amounts of Ligand 1, CuI and different reaction temperatures, and the results are listed in the table below.

[0078] The product obtained 1 The H NMR data are characterized as follows: 1 H NMR (400MHz, Chloroform-d) δ7.15 (d, J = 8.2Hz, 2H), 6.97–6.89 (m, 2H), 2.36 (s, 3H).

[0079]

[0080] Example 5

[0081]

[0082] Ar-X (4mmol), Ar'-OH (6mmol), CuI (0.4mmol), Ligand1 (0.4mmol), Na2CO3 (5.6mmol) were added to a Shrek reaction tube with a magnetic stirring bar. The reaction vessel was evacuated and backfilled with argon three times, and then DMSO (5.0mL) was added under an argon atmosphere. The reaction mixture was reacted at 120°C for 10h at a stirring speed of 100-200rmp. After the reaction was completed, it was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times and washed with saturated brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by rapid column chromatography (mobile phase was petroleum ether / ethyl acetate (vv: 50-10:1)) to obtain the target product. The results are listed in the table below.

[0083]

[0084]

[0085] Example 5

[0086]

[0087] Cu(acac)2(0.12mmol), Ligand8(0.12mmol), KOH(5.2mmol) were added to a Shrek reaction tube with a magnetic stirring bar, and the reaction vessel was evacuated and backfilled with argon three times. Then, bromobenzene(4mmol), DMSO(3.2ml), H2O(0.8ml) were added under argon atmosphere, and the reaction was carried out at 120℃ for 12h. After the reaction was completed, it was cooled to room temperature, 10ml of 2mol / L dilute hydrochloric acid was added, and then extracted with ethyl acetate three times and washed with saturated brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (mobile phase was petroleum ether / ethyl acetate (vv: 60~5:1)) to obtain the target product with a yield of 92%.

[0088] The product obtained 1 H NMR data characterize as follows: 1 H NMR (400MHz, Chloroform-d) δ7.34–7.24(m,3H),7.07–6.96(m,1H),6.97(d,J=7.4Hz,1H),6.92–6.84(m,3H),5.02(s,2H).

[0089] Example 6

[0090]

[0091] The operation of this example is the same as that of Example 5, using different copper catalysts, ligands, bases, reaction temperatures, and reaction times. The results are listed in the table below.

[0092]

[0093] Example 7

[0094]

[0095] Cu(acac)2, Ligand8, KOH (5.2mmol) were added to a Shrek reaction tube with a magnetic stirring bar, and the reaction vessel was evacuated and backfilled with argon three times. Then, p-bromoanisole (4mmol), organic solvent, and water were added under an argon atmosphere, and the reaction was carried out at 120°C for 12h. After the reaction was completed, it was cooled to room temperature, 10ml of 2mol / L dilute hydrochloric acid was added, and then extracted with ethyl acetate three times and washed with saturated brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by rapid column chromatography (mobile phase was petroleum ether / ethyl acetate (vv: 60~5:1)) to obtain the target product. The specific amounts of Ligand 8, Cu(acac)2, organic solvent, and water and the corresponding yields are shown in the following table.

[0096] The product obtained 1 H NMR data characterize as follows: 1 H NMR (400MHz, Chloroform-d): δ7.24-7.26 (d, J=8Hz, 2H), 6.75-6.77 (d, J=8Hz, 2H), 4.46 (s, br, 1H), 1.79 (s, 3H).

[0097]

[0098] Example 8

[0099]

[0100] Ar-X (4mmol), Cu(acac)2 (0.8mmol), Ligand8 (0.8mmol), KOH (5.2mmol) were added to a Shrek reaction tube with a magnetic stirring bar, and the reaction vessel was evacuated and backfilled with argon three times. Then, bromobenzene DMSO (3.2ml) and H2O (0.8ml) were added under an argon atmosphere, and the reaction was carried out at 120°C for 12h. After the reaction was completed, it was cooled to room temperature, 10ml of 2mol / L dilute hydrochloric acid was added, and then extracted with ethyl acetate three times and washed with saturated brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by rapid column chromatography (mobile phase was petroleum ether / ethyl acetate (vv: 60~5:1)) to obtain the target product. The structure of Ar-X, the structure and yield of the product, and the H NMR spectrum data of the product are shown in the following table.

[0101]

[0102]

[0103] It is understandable that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they are not described one by one here.

[0104] The above-described embodiments are only preferred solutions of the present invention and are not intended to limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solutions described in the claims.

Claims

1. Use of a diamide acid ligand in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: The diamide acid ligand is at least one of the compounds represented by the following general formula I, general formula II, and general formula III: Among them, R 1 Selected from the following group: substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3-20 membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C1-C6 alkyl; R 2 , R 3 , R 4 , R 5 are independently selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl, halogen; R 2 , R 3 , R 4 , R 5 Can be the same or different; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Each of the following groups is independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryl-oxy, halogen, nitro, hydroxyl, and amino; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Can be the same or different; X and Y are independently selected from the following groups: blank, substituted or unsubstituted C1-C6 saturated carbon chain, substituted or unsubstituted C1-C6 unsaturated carbon chain; X and Y may be the same or different; Z is selected from the following group: void, a substituted or unsubstituted C1-C6 saturated carbon chain, a substituted or unsubstituted C1-C6 unsaturated carbon chain, an oxy group, a carbonyl group, a sulfone group, an amide group, a substituted or unsubstituted imino group; The substituents are independently selected from halogen, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 heteroaryl or C6-C10 aryl-oxy; the number of substituents may be one or more, and when there are multiple substituents, the substituents may be the same or different; In the above: The aryl group is selected from phenyl, naphthyl, anthracenyl, benzyl, and biphenyl; The heteroatom of the heteroaryl group is selected from one or more of N, O, and S, the number of heteroatoms is 1-6, and the heteroaryl group is a 3-20-membered heterocyclic group; The cycloalkyl or heterocyclic group is independently a monocyclic, polycyclic, spirocyclic or bridged ring structure; The halogen is selected from at least one of F, Cl, Br and I; In the application, the reaction is a coupling reaction of an aryl halide or a heteroaryl halide with a coupling reagent in the presence of a copper catalyst and a diamide acid ligand, and the coupling reaction includes: Reaction 1: Ar-X+ROH→Ar-OR; Or reaction 2: Ar-X→Ar-OH; Where: X is selected from the group consisting of Cl, Br, I; Ar-X is an aryl halide or a heteroaryl halide, and Ar is selected from the following group: a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted 3-20 membered heteroaryl group; The substituents are one or more, and the substituents are selected from the following group: halogen, nitro, hydroxyl, cyano, amino, amino substituted by 1 or 2 C1-C6 alkyl groups, amino substituted by 1 or 2 C1-C6 alkoxy groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C6-C10 aryl groups, 3-20 membered heteroaryl groups, C6-C10 aryl-oxy groups, C2-C10 ester groups, C2-C10 acyl groups, C2-C10 alkoxy-acyl groups, C2-C10 amide groups, carboxyl groups, hydroxyl-C1-C10 alkylene groups, MeS-, sulfone groups, and sulfonamide groups; wherein the two hydrogen atoms on the two adjacent carbon atoms on the aryl group can be replaced by -(CH2) n -substituted, n is 1, 2, 3, 4, 5 or 6; R is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3-20 membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl; Wherein, the heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the following group: N, O or S; the cycloalkyl or heterocyclic group is independently a monocyclic, polycyclic, spirocyclic or bridged ring structure; One or more hydrogen atoms on the substituent group are replaced by a substituent selected from the following group: halogen, cyano, oxygen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-C(O)O-), C2-C10 acyl-alkoxy (alkyl-OC(O)-), C2-C10 acyl group (alkyl-C(O)-), C2-C10 amide group (alkyl / aryl NHC(O)-), carboxyl (-COOH), nitro, hydroxyl, amino, amino substituted by 1 or 2 C1-C6 alkyl, amino substituted by 1 or 2 C1-C6 alkoxy, C1-C6 alkylthio.

2. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: The diamide acid ligand is selected from at least one of the following structures:

3. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: The heteroaryl group in the general formula I, the general formula II and the general formula III is a pyridyl group or a quinolyl group.

4. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: The copper catalyst is at least one of cuprous iodide CuI, cuprous chloride CuCl, cuprous bromide CuBr, cupric chloride CuCl2, copper oxide CuO, copper acetate Cu(OAc)2, and copper acetylacetonate Cu(acac)2.

5. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: The reaction temperature of the reaction is 80-160°C.

6. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: The reaction time is 5 to 24 hours.

7. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: In the reaction 1, the reaction is carried out in the presence of a base, and the base is at least one of lithium hydroxide LiOH, sodium hydroxide NaOH, potassium hydroxide KOH, sodium carbonate Na2CO3, potassium carbonate K2CO3, and potassium tert-butoxide t-BuOK.

8. The use of a diamide acid ligand according to claim 7 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: In the reaction 1, the molar ratio of the aryl halide or heteroaryl halide, the coupling reagent, the copper catalyst, the ligand and the base is 1: 1.0-2.5: (0.002-0.008): (0.002-0.008): (1-2).

9. The use of a diamide acid ligand according to claim 1 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: In the reaction 2, the coupling reagent is selected from the following group: H2O, hydroxide, base, and a mixture of base and water.

10. The use of a diamide acid ligand according to claim 9 in a copper-catalyzed reaction of aryl halides or heteroaryl halides, characterized in that: In the reaction 2, the molar ratio of the aryl halide or heteroaryl halide, the coupling reagent, the copper catalyst, and the ligand is 1:1.0-4.0:(0.001-0.005):(0.001-0.005).

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