Hydroxyl substituted pyridine-2-carboxylic acid amide ligands and their use in copper catalyzed aryl halide coupling reactions

Abstract

The present application provides a class of hydroxyl-substituted pyridine-2-carboxylic acid amide ligands and their use in copper-catalyzed aryl halide coupling reactions. Specifically, the present application provides a class of hydroxyl-substituted pyridine-2-carboxylic acid amide ligands and their use; wherein the definitions of each group are as described in the specification. The ligands are used in a catalytic system for copper-catalyzed cross-coupling reactions of aryl halides (particularly aryl chlorides) with aromatic amine compounds.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis. Specifically, this invention provides a copper-catalyzed cross-coupling reaction of aryl halides and aromatic amines promoted by a hydroxylated pyridine-2-carboxylic acid amide ligand. Background Technology

[0002] Diarylamines, as important structural frameworks, are widely found in various bioactive molecules and marketed drugs. Furthermore, due to their excellent charge transport properties, they also have promising applications in organic small-molecule light-emitting semiconductors. The palladium-catalyzed Buchwald-Hartwig reaction is currently a commonly used method for preparing these compounds; however, most catalytic systems utilize expensive and highly toxic palladium catalysts and phosphine ligands. Constructing diarylamines through transition metal-catalyzed CN cross-coupling reactions, which are low-cost, have low reagent toxicity, and operate under mild conditions, is more attractive for large-scale industrial applications.

[0003] In recent years, ligand-promoted copper-catalyzed Ullmann coupling reactions have seen significant development, making them a commonly used method for constructing CN bonds (Angew. Chem. Int. Ed. 2017, 56, 16136.). This method complements palladium- and nickel-catalyzed reactions well, and due to the low cost and good biocompatibility of copper catalysts, they can be widely used in the large-scale industrial synthesis of pharmaceuticals, pesticides, and materials, meeting the needs of sustainable development and green chemistry. In 2005, Professor Fu Hua's group used piperidine-2-carboxylic acid as a ligand and cuprous iodide catalysis at 110 °C to achieve the coupling reaction of aryl bromides / iodoforms with aromatic amines, successfully constructing a series of diarylamine compounds. However, for the more inexpensive and readily available aryl chlorides, despite using highly reactive aromatic amines with nitro substitutions on the benzene ring as nucleophiles, the yield remained low at 25-31% after 36 hours of reaction at 110 °C (Adv. Synth. Catal. 2006, 348, 2197.). In 2008, Buchwald's research group used pyrrole-2-carboxylic acid as a ligand and cuprous iodide catalysis at 80 °C to achieve the coupling reaction of aryl iodides with aromatic amines. However, for brominated substrates, even when the temperature was increased to 100 °C, only moderate yields of 51-76% were obtained (J. Org. Chem. 2008, 73, 5167.).

[0004]

[0005] It can be seen that existing copper-catalyzed methods for constructing diarylamines are mainly limited to the relatively expensive and highly reactive aryl iodides and bromides due to the weak nucleophilicity of aromatic amines. The more affordable and industrially promising aryl chlorides have rarely been reported. In 2019, Professor Ma's research group used an oxalyl diamine ligand (N,N'-dibenzyloxalyl diamine DBO) developed by their group to achieve the CN-coupling reaction of aryl chloride / bromine / iodides with electron-deficient heteroaromatic amines under copper catalysis. Notably, this method achieved the highly challenging activation of chlorinated substrates, utilizing inexpensive copper salts and ligands and low catalyst dosage, greatly expanding its application in the synthesis of active compounds and drugs (Org. Lett. 2019, 21, 6874). However, the reaction results are not ideal for the more generalized aromatic amines.

[0006]

[0007] In summary, copper-catalyzed coupling reactions of aryl chlorides with aromatic amines can efficiently construct diarylamine compounds. This method is inexpensive, readily available, and environmentally friendly, making it highly promising for industrial applications. Suitable ligands are crucial for the success of these reactions. Currently, a simple, industrially applicable, and efficient copper-catalyzed coupling system for aryl chlorides with aromatic amines is lacking in this field. Summary of the Invention

[0008] One object of the present invention is to provide a catalytic system capable of being used for copper-catalyzed coupling reactions of aryl halides (especially aryl chlorides) with aromatic amines.

[0009] In a first aspect, the present invention provides the use of a compound of Formula I as a ligand for catalyzing the coupling reaction of an aryl halide with an aromatic amine compound; wherein the aryl halide is selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof.

[0010] The aromatic amine compounds are selected from the group consisting of: substituted or unsubstituted primary aryl amines, substituted or unsubstituted secondary aryl amines, substituted or unsubstituted primary heteroaryl amines, and substituted or unsubstituted secondary heteroaryl amines;

[0011] The compound of formula I has the structure shown in the following formula:

[0012]

[0013] in,

[0014] X1 is either CR5 or N;

[0015] X2 is either CR6 or N;

[0016] X3 is either CR7 or N;

[0017] n is 0 or 1;

[0018] R1, R5, R6, and R7 are each independently H, hydroxyl, substituted, or unsubstituted C. 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, C 1-3 Alkoxy (C 1-3 Alkyl-O-), C 1-3 Halogenated alkyl, substituted or unsubstituted C 6-10 Aryl-NH-C(O)-; and at least one of R1, R5, R6 and R7 is a hydroxyl group;

[0019] Alternatively, any two carbon atoms attached to adjacent ring atoms of R1, R5, R6, and R7 can form substituted or unsubstituted 6-10 aryl groups or substituted or unsubstituted 5-8 heteroaryl groups.

[0020] R2 and R3 are independently H and C, respectively. 1-3 alkyl;

[0021] R4 is H or a hydroxyl group;

[0022] Unless otherwise stated, substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, nitro, oxygen (i.e., two hydrogen atoms on the same carbon atom of the group are replaced by =O), cyano, unsubstituted, or substituted by one or more C groups. 1-6 alkyl or C 2-10 Acyl (alkyl-CO-) substituted amino, hydroxyl, unsubstituted or halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 3- to 20-membered heteroaryl, C 6-10 aryl-oxygen, C 2-10 Ester group (alkyl-COO-), C2-C 10 Acyl (alkyl-CO-), C 2-10 Acyl-alkoxy (alkyl-OOC-), C 2-10 amide group (alkylNHC(O)-, arylNHC(O)-), -COOH, hydroxyl -C1-C 10 The alkylene group, MeS-, sulfone group, sulfonamide group; wherein the two hydrogen atoms on the two adjacent carbon atoms of the aryl group can be -(CH2). m - Replacement (m is 1, 2, 3, 4, 5 or 6).

[0023] In another preferred embodiment, X1, X2, and X3 are not all N at the same time.

[0024] In another preferred embodiment, X1 and X3 are both N, and X2 is CR6.

[0025] In another preferred embodiment, X1 is CR5, X3 is CR7, and X2 is N.

[0026] In another preferred embodiment, R1 is a hydroxyl group and n is 1.

[0027] In another preferred embodiment,

[0028] R1, R5, R6, and R7 are each independently H, hydroxyl, phenyl, cyclopropane, trifluoromethyl, methoxy, methyl, And at least one of R1, R5, R6 and R7 is a hydroxyl group;

[0029] Alternatively, any two carbon atoms on adjacent ring atoms of R1, R5, R6, and R7 can together form a substituted or unsubstituted saturated six-membered ring or a substituted or unsubstituted nitrogen-containing saturated six-membered ring.

[0030] In another preferred embodiment, R2 and R3 are each independently H, methyl, or isopropyl.

[0031] In another preferred embodiment, R4 is H or a hydroxyl group.

[0032] In another preferred embodiment, R1 is OH.

[0033] In another preferred embodiment, the ligand is selected from the group consisting of:

[0034]

[0035]

[0036] In a second aspect of the invention, a method for coupling a aryl halide with an aromatic amine compound is provided, the method comprising: using a copper catalyst and a compound of formula I as a ligand to carry out the coupling reaction.

[0037]

[0038] The definitions of each group are as described in the first aspect of this invention;

[0039] The aryl halogenated compounds are selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof;

[0040] The aromatic amine compounds are selected from the group consisting of substituted or unsubstituted primary aryl amines, substituted or unsubstituted secondary aryl amines, substituted or unsubstituted primary heteroaryl amines, and substituted or unsubstituted secondary heteroaryl amines.

[0041] In another preferred embodiment, in the method, the molar ratio of the ligand to the aryl halide is (1-10):100, more preferably (3-5):100; and / or

[0042] The molar ratio of the ligand to the copper catalyst is (1-5):1, preferably 1:1; and / or

[0043] The molar ratio of the ligand to the aromatic amine compound is 1:(20-60), preferably 1:(30-50).

[0044] In another preferred embodiment, the reaction includes:

[0045]

[0046] In an inert solvent, using and A coupling reaction is performed to obtain

[0047] Among them, Y is selected from the following group: Cl, Br, I;

[0048] R5 is selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the aryl or heteroaryl comprises a group formed by coupling multiple aromatic rings or heteroaryl rings (such as biphenyl), and the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of: N, O, or S; the cycloalkyl or heterocyclic group can be a monocyclic, polycyclic, spirocyclic, or bridged ring structure;

[0049] Each is independently selected from the following group: substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted 3- to 20-membered heteroaryl groups;

[0050] The substitution refers to the substitution of one or more hydrogen atoms by a substituent selected from the group consisting of: halogen, nitro, cyano, unsubstituted or substituted amino, hydroxyl, unsubstituted or substituted with one or more (e.g., 1-5) C1-C6 alkyl or C2-C10 acyl (alkyl-CO-), unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 3- to 20-membered heteroaryl, C6-C10 aryl-oxy, and C2-C10 ester. (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 acyl-alkoxy (alkyl-OOC-), C2-C10 amide (alkylNHC(O)-, arylNHC(O)-), -COOH, hydroxy-C1-C10 alkylene, MeS-, C1-C6 alkylsulfonyl, sulfonamide; wherein, the two hydrogen atoms on the two adjacent carbon atoms of the aryl group can be -(CH2). m - Replacement (m is 1, 2, 3, 4, 5 or 6);

[0051] or and These are different aromatic rings in the same molecule, connected by substituted or unsubstituted chain or cyclic alkyl, aryl, or heterocyclic groups; wherein the heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O, or S; and the cycloalkyl or heterocyclic group can be a monocyclic, polycyclic, spirocyclic, or bridged ring structure.

[0052] In another preferred embodiment, the inert solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, DME, toluene, or combinations thereof; preferably ethanol or DMSO.

[0053] In another preferred embodiment, the reaction temperature is 90-130°C, preferably 120°C.

[0054] In a third aspect of the invention, a catalytic system for aryl coupling reactions is provided, the catalytic system comprising:

[0055] Copper catalysts, ligands, bases, and organic solvents;

[0056] The copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, CuTc, Cu(OAc)2, CuSO4, Cu2O, CuBr2, CuCl2, CuO, CuCN, Cu(acac)2, or combinations thereof; preferably Cu(OAc)2 or CuI.

[0057] The alkali is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, or combinations thereof; preferably potassium phosphate.

[0058] The organic solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, DME, toluene, or combinations thereof; preferably ethanol or DMSO.

[0059] The ligand has the structure shown in formula (I):

[0060]

[0061] The definitions of each group are as described in claim 1.

[0062] In a fourth aspect of the invention, a compound of formula I is provided:

[0063]

[0064] The definitions of each group are as described in the first aspect of this invention.

[0065] In another preferred embodiment, the compound of formula I is selected from the group consisting of:

[0066]

[0067]

[0068] In a fifth aspect of the invention, a method for preparing the compound described in the fourth aspect of the invention is provided, performed by a method selected from method (i) or (ii):

[0069] Method (i) includes the following steps:

[0070]

[0071] In an inert solvent, using and The reaction proceeds to obtain compound I;

[0072] Method (ii) includes the following steps:

[0073]

[0074] In an inert solvent, using and The reaction proceeds to obtain compound I;

[0075] The definitions of each group are as described in the first aspect of this invention.

[0076] In another preferred embodiment, in the method (i), the reaction is carried out in the presence of triethylamine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole.

[0077] In another preferred embodiment, the reaction temperature in method (i) is room temperature, i.e., 10-40°C.

[0078] In another preferred embodiment, in method (ii), the reaction is carried out in the presence of trimethylaluminum.

[0079] In another preferred embodiment, in method (ii), the reaction is carried out at a temperature gradient of -10°C to 50°C, with the gradient being 10°C / 5 min.

[0080] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0081] Through extensive and in-depth research, the inventors have developed hydroxylated pyridine-2-carboxylic acid amide ligands suitable for copper-catalyzed coupling reactions of aryl halides. Using a suitable catalytic system composed of these ligands, copper reagents, a base, and a solvent, copper-catalyzed coupling reactions of aryl halides and aryl amines can be achieved. In particular, this method effectively promotes copper-catalyzed coupling reactions involving aryl chlorides, which are difficult to occur under conventional conditions, to generate CN bonds. This method offers mild reaction conditions, wide applicability, and excellent prospects for industrial application. Based on this, the present invention was completed.

[0082] the term

[0083] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0084] The term "halogenated" refers to the replacement of one or more hydrogen atoms in a group with a halogen.

[0085] The term "alkyl" refers to a straight-chain or branched alkyl group. When an alkyl group is preceded by a carbon number limit (e.g., C1-C6), it means that the alkyl group contains 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0086] The term "cycloalkyl" refers to a bicyclic or tricyclic (fused, bridged, or spirocyclic) ring system having a saturated or partially saturated unit. The cycloalkyl group can have 3-20 carbon atoms. When a cycloalkyl group is preceded by a carbon number limitation (e.g., C3-C20), it indicates that the cycloalkyl group contains 3-20 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. The cycloalkyl group can be monocyclic, polycyclic, spirocyclic, or bridged.

[0087] As used herein, the term "alkoxy" refers to an alkyl group (e.g., -O-alkyl, wherein the alkyl group is as described above) linked by an oxygen atom, such as (but not limited to) methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups. When an alkoxy group is preceded by a carbon number limitation (e.g., C1-C6), it indicates that the cycloalkyl group contains 1-6 carbon atoms.

[0088] The term "aryl" refers to an aromatic hydrocarbon group that is monocyclic, bicyclic, or fused-ring, and may be substituted or unsubstituted. When an aryl group is preceded by a carbon number limit (e.g., C6-C20), it means that the aryl group contains 6-20 carbon atoms. Examples of aryl groups include (but are not limited to): phenyl, biphenyl, naphthyl, or similar groups (each carbon atom of which may be arbitrarily substituted).

[0089] The term "heteroaryl" refers to a monocyclic, bicyclic, or fused-ring aromatic group comprising at least one heteroatom selected from N, O, or S. The heteroaryl group can be 3- to 20-membered, having 1-5 aromatic cyclic groups, each independently selected from N, O, or S. Examples of heteroaryl groups include (but are not limited to): pyridine, pyrimidine, pyrrole, indazole, indole, furan, benzofuran, thiophene, or similar groups.

[0090] The term "heterocyclic group" refers to a saturated or partially saturated substituent of a monocyclic or fused ring, wherein the group comprises at least one identical or different heteroatom selected from N, O, or S. The heterocyclic group can be 3- to 20-membered, having 1-5 heteroatoms, each independently selected from N, O, or S. Examples of heterocyclic groups include (but are not limited to): nitrogen heterocyclic groups, oxygen heterocyclic groups, sulfur heterocyclic groups, nitrogen-oxygen heterocyclic groups, etc.

[0091] The term "ester group" refers to a group having an "alkyl-COO-" structure, where alkyl is defined as described above.

[0092] The term "acyl" refers to a group having an "alkyl-CO-" structure, wherein alkyl is defined as described above.

[0093] The term "amide group" refers to a group having an "alkylNHC(O)-" or "arylNHC(O)-" structure, wherein alkyl and aryl are defined as described above.

[0094] ligands

[0095] Unless otherwise specified, the ligands mentioned in this article refer to ligands used in copper-catalyzed aryl chloride coupling reactions.

[0096] The ligands available in this invention have the structure shown in formula (I) above. In a preferred embodiment of this invention, the ligand has the following structure (the definitions of each group are as described above):

[0097]

[0098] Where X1 is CR5 or N;

[0099] X2 is either CR6 or N;

[0100] X3 is either CR7 or N;

[0101] n is 0 or 1;

[0102] R1, R5, R6, and R7 are each independently H, hydroxyl, substituted, or unsubstituted C. 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, C 1-3 Alkoxy (C 1-3 Alkyl-O-), C 1-3 Halogenated alkyl, substituted or unsubstituted C 6-10 Aryl-NH-C(O)-; and at least one of R1, R5, R6 and R7 is a hydroxyl group;

[0103] Alternatively, any two carbon atoms attached to adjacent ring atoms among R1, R5, R6, and R7 can form substituted or unsubstituted rings. 6-10 5-8 membered heteroaryl groups, either substituted or unsubstituted;

[0104] R2 and R3 are independently H and C, respectively. 1-3 alkyl;

[0105] R4 is H or a hydroxyl group;

[0106] Unless otherwise stated, substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, nitro, oxygen (i.e., two hydrogen atoms on the same carbon atom of the group are replaced by =O), cyano, unsubstituted or substituted amino groups or amino groups substituted with one or more C1-6 alkyl or C2-10 acyl (alkyl-CO-), hydroxyl, unsubstituted or halogenated C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, 3- to 20-membered heteroaryl, C6-10 aryl-oxy, C2-C 10 Ester group (alkyl-COO-), C2-C 10Acyl (alkyl-CO-), C2-C 10 Acyl-alkoxy (alkyl-OOC-), C2-C 10 amide group (alkylNHC(O)-, arylNHC(O)-), -COOH, hydroxyl -C1-C 10 The alkylene group, MeS-, sulfone group, sulfonamide group; wherein the two hydrogen atoms on the two adjacent carbon atoms of the aryl group can be -(CH2). m - Replacement (m is 1, 2, 3, 4, 5 or 6).

[0107] Each of the above-mentioned ligands can be obtained commercially or prepared according to the preferred method provided in this invention.

[0108] It should be understood that, because the bond energies of C-Br and Cl bonds are lower than those of C-Cl bonds, coupling reactions of aryl bromides and aryl iodides are more likely to occur than those of aryl chlorides under the same conditions. Therefore, the above-mentioned ligands can be used not only for coupling reactions of aryl chlorides, but also for coupling reactions of aryl bromides and aryl iodides that are conventional in this field.

[0109] Copper-catalyzed coupling reactions of aryl chlorides

[0110] This invention provides a method for coupling reactions of copper-catalyzed aryl chlorides, wherein the method includes using a compound of formula (I) as described above as a ligand to carry out the above reaction.

[0111] Generally, aryl iodides and aryl bromides are highly reactive and can achieve corresponding coupling reactions well under the catalysis of transition metals such as palladium, copper, and nickel. Compared with bromo(iodinated) aromatics, chloroaromatics are cheaper and more readily available, and have greater application prospects. However, the high C-Cl bond energy makes it difficult for aryl chlorides to react under the conventional catalytic conditions of aryl bromides and aryl iodides.

[0112] For different reactants, the ligands and reaction conditions can be optimized within the scope of the disclosure of this invention to select the most suitable ligand type and reaction conditions (such as temperature, solvent, reactant ratio and reaction time). After reading the disclosure of this application, the above optimization is within the skill of those skilled in the art.

[0113] The coupling reaction is as follows:

[0114]

[0115] in, Selected independently from the following group: substituted or unsubstituted C6-C 20The aryl, substituted or unsubstituted 3- to 20-membered heteroaryl group; wherein the substitution refers to one or more hydrogen atoms on the aryl group being substituted by a substituent selected from the group consisting of: halogen, nitro, cyano, unsubstituted or substituted by one or two C1-C6 alkyl or C2-C6 alkyl groups. 10 Acyl (alkyl-CO-) substituted amino, hydroxyl, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C 10 aryl, 3- to 20-membered heteroaryl, C6-C 10 aryl-oxygen, C2-C 10 Ester group (alkyl-COO-), C2-C 10 Acyl (alkyl-CO-), C2-C 10 Acyl-alkoxy (alkyl-OOC-), C2-C 10 Amide groups (alkyl NHC(O)-, aryl NHC(O)-), -COOH, hydroxyl -C1-C 10 The alkylene group, MeS-, sulfone group, sulfonamide group; wherein, the two hydrogen atoms on the two adjacent carbon atoms of the aryl group can be -(CH2). m - Replacement (m is 1, 2, 3, 4, 5 or 6);

[0116] or and These are different aromatic rings in the same molecule, linked by substituted or unsubstituted chain or cyclic alkyl groups, or aryl groups, or heterocyclic groups; wherein the heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; the cycloalkyl or heterocyclic group can be a monocyclic, polycyclic, spirocyclic or bridged ring structure.

[0117] In the above reaction, the copper catalyst is selected from the group consisting of: CuI, CuBr, CuCl, CuTc, Cu(OAc)2, CuSO4, Cu2O, CuBr2, CuCl2, CuO, CuCN, Cu(acac)2, or combinations thereof; preferably Cu(OAc)2 or CuI.

[0118] In the above reaction, the ligand is not particularly limited and can be any of the ligands described above. Preferably, it is L-1.

[0119] In the above reaction, the molar ratio of the ligand to the reactant aryl halide is (1-10):100, preferably (3-5):100; the molar ratio with the copper catalyst is (1-5):1, preferably 1:1. The molar ratio of the ligand to the aromatic amine compound is 1:(20-60), more preferably 1:(30-50).

[0120] In the above reaction, the base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, or combinations thereof; preferably potassium phosphate.

[0121] In the above reaction, the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, DME, toluene, or combinations thereof; preferably ethanol or DMSO.

[0122] In the above reaction, the reaction temperature is 90-130℃, preferably 120℃.

[0123] Compared with the prior art, the main advantages of the present invention include:

[0124] 1. A catalytic system is provided for copper-catalyzed coupling reactions of aryl chlorides that can be carried out with high efficiency. The catalytic system enables aryl chloride coupling reactions that are difficult to carry out under conventional aryl bromide and aryl iodide coupling systems to proceed smoothly, and has good substrate compatibility and a wide range of applicability.

[0125] 2. Compared with the existing aryl chloride coupling reaction methods, the method of the present invention uses a low-cost copper catalyst system, and the ligand structure is simple, easy to prepare, requires less dosage, and is economical to react.

[0126] 3. The aryl chlorides used in the catalytic system of this invention have lower raw material costs and wider sources compared to other aryl halogens, and have good prospects for large-scale application.

[0127] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0128] Example 1:

[0129] Ligands L-1 to L-15 and L-19 to L-21 were prepared by preferred method (i):

[0130] Weigh out the corresponding amounts of pyridine-2-carboxylic acid (1.0 eq.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 eq.), and 1-hydroxybenzotriazole (1.5 eq.), and add them to a round-bottom flask equipped with a magnetic stir bar. Then add anhydrous N,N-dimethylformamide (DMF) (0.2 M) and stir until the solids dissolve. Next, add triethylamine (3 eq.) and the corresponding organic amine (1.5 eq.) to the solution sequentially. The reaction system is stirred continuously at room temperature for 10 hours. After stopping stirring, pour the reaction system into water and extract twice with dichloromethane. Combine the dichloromethane phases obtained from the separation, wash with 1 mol / L hydrochloric acid, separate the liquids, dry the organic phase, and then evaporate to dryness. Dissolve the obtained solid in dichloromethane, mix with an appropriate amount of silica gel, and purify by rapid column chromatography on a 300-400 mesh silica gel column.

[0131]

[0132]

[0133]

[0134]

[0135] Example 2:

[0136] Ligands L-16 to L-18 were prepared via preferred method (ii):

[0137] Install a reflux condenser and a dropping funnel on a three-necked flask equipped with a magnetic stirrer, and add the corresponding organic amine (1 eq.) and anhydrous dichloromethane (0.55 M). After cooling to -10 °C, slowly add 2 mol·dm³ dropwise while stirring thoroughly. -3 A hexane solution of trimethylaluminum (3 eq., as AlMe3) was added dropwise. After the addition was complete, the mixture was stirred at -10°C for 20 min, then brought to room temperature and stirred for another 20 min. Then, an anhydrous dichloromethane solution (0.55 M) of the corresponding methyl pyridine-2-carboxylate (1 eq.) was added dropwise.

[0138] After the addition is complete, the temperature is raised to 50°C and refluxed for 12 hours. After the reaction is complete, the system is cooled to 0°C, and water is slowly added dropwise with thorough stirring until no gas is produced. An appropriate amount of dilute hydrochloric acid is added to dissolve the insoluble white solid produced in the system, and then the mixture is separated. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, and an appropriate amount of silica gel is mixed. The mixture is then purified by rapid column chromatography (petroleum ether:ethyl acetate = 3:1) on a 300–400 mesh silica gel column.

[0139]

[0140]

[0141] Example 3:

[0142] 4,4'-Dimethoxydiphenylamine was synthesized by coupling reaction of p-chloroanisole and p-methoxyaniline:

[0143] Cuprous iodide (0.03 mmol), ligand (0.03 mmol), and potassium phosphate (1.5 mmol) were added to a 10 mL sealed tube. The tube was purged with argon three times under vacuum. Then, p-chloroanisole (1.0 mmol), p-methoxyaniline (1.5 mmol), and 1 mL of anhydrous dimethyl sulfoxide were added. The reaction mixture was stirred at 120–130 °C for 12 hours. After cooling, the reaction mixture was poured into 10 mL of NH3-NH4Cl buffer solution with a pH of approximately 9. The mixture was extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain the product 4,4'-dimethoxydiphenylamine.

[0144] 1 H NMR (500MHz, DMSO-d6) δ7.50(s,1H),6.95–6.88(m,4H),6.84–6.77(m,4H),3.68(s,6H). 13 C NMR (126MHz, DMSO-d6) δ154.25,137.90,119.52,114.77,55.66.

[0145] The experimental results for different ligands are listed in the table below.

[0146] Ligand number Yield (%) Ligand number Yield (%) L-1 94 L-7 47 L-2 84 L-10 98 L-3 82 L-11 96 L-5 76 L-12 96 L-6 34 L-19 24

[0147] Example 4:

[0148] p-Chloroanisole is coupled with various primary and secondary aromatic amines to synthesize the corresponding derivatives:

[0149] Anhydrous copper acetate (0.03–0.05 mmol), ligand (0.03–0.05 mmol), and potassium phosphate (1.5 mmol) were added to a 10 mL sealed tube. The tube was purged with argon three times under vacuum. Then, p-chloroanisole (1.0 mmol), the corresponding aromatic amine (1.5 mmol), and 1 mL of anhydrous ethanol or anhydrous dimethyl sulfoxide were added. The reaction mixture was stirred at 120 °C for 20 hours. After cooling, the reaction mixture was poured into 10 mL of NH3-NH4Cl buffer solution with a pH of approximately 9. The mixture was extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography to obtain the target compound.

[0150] This embodiment uses different aromatic amines, and the results are listed in the table below:

[0151]

[0152]

[0153]

[0154] Example 5:

[0155] Various aryl chlorides are coupled with primary and secondary aromatic amines to synthesize corresponding derivatives:

[0156] Add aryl chloride (1.0 mmol), anhydrous copper acetate (0.03–0.05 mmol), ligand (0.03–0.05 mmol), potassium phosphate (1.5 mmol), and aromatic amine (1.5 mmol) to a 10 mL sealed tube. For aryl chloride and aromatic amine, which are liquid at room temperature, add them via syringe after the argon purging step. Purge the sealed tube with argon three times, then add 1 mL of anhydrous ethanol or anhydrous dimethyl sulfoxide via syringe. Stir the reaction system at 120 °C for 20 hours. After cooling, pour the reaction system into 10 mL of NH3-NH4Cl buffer solution with a pH of approximately 9. Extract three times with 10 mL of ethyl acetate each time. Combine the organic phases, dry to anhydrous sodium sulfate, concentrate, and then purify by rapid column chromatography to obtain the target compound.

[0157] The results are listed in the table below:

[0158]

[0159]

[0160]

[0161] Example 6:

[0162] Modification of drug active molecules using the aforementioned coupling reaction:

[0163] In a 10 mL sealed tube, a chlorine-containing active pharmaceutical substrate (1.0 mmol), anhydrous copper acetate (0.03 mmol), a ligand (0.03 mmol), potassium phosphate (1.5 mmol), and an aromatic amine (1.5 mmol) were added. For aryl chlorides and aromatic amines that are liquid at room temperature, they were added via syringe after the argon purging step. The sealed tube was purged with argon three times, and then 1 mL of anhydrous ethanol was added via syringe. The reaction system was stirred at 120 °C for 20 hours. After cooling, the reaction system was poured into 10 mL of NH3-NH4Cl buffer solution with a pH of approximately 9. Extraction was performed three times with 10 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography to obtain the target compound.

[0164] The results are listed in the table below:

[0165]

[0166]

[0167] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for coupling reaction of aryl halides with aromatic amine compounds, characterized in that, The catalytic system used in the method includes: a copper catalyst, a ligand, potassium phosphate, and an organic solvent; The aryl halide is p-chloroanisole; The aromatic amine compounds mentioned are selected from p-methoxyaniline; The organic solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, ethanol, methanol, 1,4-dioxane, tetrahydrofuran, DME, toluene, or combinations thereof. The copper catalyst is CuI; The molar ratio of the ligand to the aryl halide is (3-5):100; The molar ratio of the ligand to the copper catalyst is 1:1; The molar ratio of the ligand to the aromatic amine compound is 1:(30-50); The ligand is selected from the following compounds: 。

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