WO2017012379A1 - 草酸酰胺类配体及其在铜催化芳基卤代物偶联反应中的用途 - Google Patents

草酸酰胺类配体及其在铜催化芳基卤代物偶联反应中的用途 Download PDF

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WO2017012379A1
WO2017012379A1 PCT/CN2016/079500 CN2016079500W WO2017012379A1 WO 2017012379 A1 WO2017012379 A1 WO 2017012379A1 CN 2016079500 W CN2016079500 W CN 2016079500W WO 2017012379 A1 WO2017012379 A1 WO 2017012379A1
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aryl
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French (fr)
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马大伟
周伟
樊梦阳
伍海波
殷俊力
夏尚华
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中国科学院上海有机化学研究所
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Priority to EP16827070.0A priority Critical patent/EP3326715B1/en
Priority to US15/746,646 priority patent/US10500577B2/en
Priority to JP2018503475A priority patent/JP6732008B2/ja
Publication of WO2017012379A1 publication Critical patent/WO2017012379A1/zh

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Definitions

  • the present invention relates to the field of organic synthesis.
  • the present invention provides a copper-catalyzed aryl halide coupling reaction promoted by an oxalic acid amide ligand, particularly a reaction for coupling to form C-N, C-O, and C-S bonds.
  • Oxalic acid amides have received extensive attention due to their various biological activities.
  • oxalic acid arylamide monomethyl ester can be used as a chemical hybridization reagent for chickpeas, and oxalic acid aryl diamide compounds can be inhibited as glycogen phosphorylase. Acting as a small molecule modulator on CD4-gp120 class proteins.
  • Ma Da for the research group used oxalic acid 2,6-dimethylphenyl monoamide carboxylic acid as a ligand for copper-catalyzed CN coupling reaction of aryl iodide, bromine and organic amine, which opened up this New uses for compounds.
  • this reaction is mainly applicable to the coupling reaction of an aryl iodide and a bromine.
  • Transition metal catalyzed aryl halides are coupled with suitable nucleophiles such as organic amines, active methylene compounds, alkynes, phenols, alcohols, thiophenols, sodium sulfinates, sodium sulfide, phosphates, etc.
  • suitable nucleophiles such as organic amines, active methylene compounds, alkynes, phenols, alcohols, thiophenols, sodium sulfinates, sodium sulfide, phosphates, etc.
  • the reaction is a very effective method for generating CN, CC, CO, CS, and CP bonds.
  • aryl iodide and aryl bromide have higher reactivity, and can be correspondingly catalyzed by transition metals such as palladium, copper, nickel, etc.; compared with bromine (iodo) aromatics, chlorination
  • Transition metals such as palladium, copper, nickel, etc.
  • bromine (iodo) aromatics chlorination
  • Aromatic hydrocarbons are cheap and easy to obtain, and have more application prospects; however, C-Cl bond energy is high, transition metals and oxidative addition achievements are difficult to occur, and the reaction is not as efficient as brominated and iodine.
  • the CN coupling reaction of palladium and nickel catalyzed aryl chlorides has been reported. It is an effective means to promote the reaction with a large sterically hindered phosphorus ligand.
  • the Hartwig group used a large sterically hindered phosphine with a ferrocene structure.
  • the ligand successfully completes the coupling reaction between the aromatic ring and the aromatic heterocyclic chloro compound and the primary amine, and the equivalent of the catalyst and the ligand in the system can be reduced even to one hundred thousandth of a molar equivalent, for the individual aromatic heterocyclic ring.
  • the substrate can be subjected to such a reaction at room temperature, which fully demonstrates the high efficiency of the catalyst system; in addition, the reaction has good compatibility with the substituent groups on the benzene ring.
  • the Pellón group used the promotion of the ortho-carboxy group of 2-chlorobenzoic acid to achieve the coupling reaction with aliphatic amine under the action of ultrasound. Both the primary amine and the secondary amine can be obtained in good yield. Co-products, however, this method is only effective for ortho-carboxy substituted substrates and is not universal (Docampo, ML; Pellón, RF; Estevez-Braun, A.; Ravelo, AGEur. J. Org. Chem. 2007, 4111. ). This reaction is essentially a nucleophilic substitution reaction rather than a coupling reaction, and the reaction temperature is very high.
  • Taillefer group Another report on the Ullmann coupling reaction of chlorinated aromatic hydrocarbons was reported by the Taillefer group. They used 2,2,6,6-tetramethyl-3,5-heptanedione as ligands to achieve chlorobenzene and phenols. CO coupling of compounds, the main disadvantage of this system is the need to add up to 0.8 equivalents of ligand to the reaction, thus reducing the economics of the reaction (Xia, N.; Taillefer, M. Chem. Eur. J. 2008, 14) , 6037.).
  • R is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted Substituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or An unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; said ring
  • the alkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R a is selected from (a) or (b):
  • each R" is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered hetero Aryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 ring An alkyl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 hetero atoms selected from the group consisting of N, O or S; the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure (preferably, N(R") 2 is NHR");
  • R b is selected from the group consisting of H, C1-C6 alkyl
  • R b and R together with an adjacent nitrogen atom constitute a substituted or unsubstituted 3- to 20-membered heteroaryl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6- C10 aryl, C6-C10 aryl-oxy, C2-C10 Ester group (alkyl-COO-), C2-C10 acyl-alkoxy (alkyl-OOC-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl /Aryl NHC(O)-), -COOH, nitro, hydroxy, amino, amino substituted by 1 or 2 C1-C6 alkyl;
  • aryl halide is selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or Its combination.
  • the R is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted quinolinyl, substituted Or unsubstituted Substituted or unsubstituted adamantyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted
  • R, R b and an adjacent nitrogen atom together form a substituted or unsubstituted group selected from the group consisting of:
  • the R is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, C1-C4 alkyl, pyridyl, diamond alkyl;
  • R a is selected from (a) or (b):
  • each R" is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered hetero Aryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 ring
  • R a when R a is NHR", said R" is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl Base, C1-C4 alkyl, pyridyl, adamantyl.
  • said R a is NHR
  • the one or more hydrogen atoms on the substituent group are substituted with a substituent selected from the group consisting of halogen, methyl, trifluoromethyl, ethyl, isopropyl, and tertiary. butyl, dimethylamino, methoxy, tert-butoxy, -Ac, CH 3 NHC (O ) -, phenyl, phenoxy, -COOH, an ester group, a nitro group, a cyano group, a hydroxyl group.
  • a substituent selected from the group consisting of halogen, methyl, trifluoromethyl, ethyl, isopropyl, and tertiary. butyl, dimethylamino, methoxy, tert-butoxy, -Ac, CH 3 NHC (O ) -, phenyl, phenoxy, -COOH, an ester group, a nitro group, a cyano group, a hydroxy
  • the aryl halide is an aryl chloride.
  • a method for coupling an aryl halide comprising: carrying out the coupling reaction using copper as a catalyst and a compound represented by the following formula I as a ligand :
  • R is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted Substituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or An unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; said ring
  • the alkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R a is selected from (a) or (b):
  • each R" is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered hetero Aryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 ring An alkyl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 hetero atoms selected from the group consisting of N, O or S; the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R b is selected from the group consisting of H, C1-C6 alkyl
  • R b and R together with an adjacent nitrogen atom constitute a substituted or unsubstituted 3- to 20-membered heteroaryl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6- An aryl group of C10, an aryl-oxy group of C6-C10, an ester group of C2-C10 (alkyl-COO-), an acyl-alkoxy group of C2-C10 (alkyl-OOC-), C2-C10 Acyl (alkyl-CO-), C2-C10 amide (alkyl/aryl NHC(O)-), -COOH, nitro, cyano, hydroxy, amino, 1 or 2 C1-C6 Alkyl substituted amino group;
  • aryl halide is selected from the group consisting of aryl chlorides, aryl bromides, aryl iodides, or combinations thereof.
  • the copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , or a combination thereof; preferably CuI, Cu 2 O, Cu(acac) 2 .
  • reaction is carried out in the presence of a base.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, and/or the base.
  • the hydrate, or a combination thereof; is preferably potassium phosphate, cesium carbonate or lithium hydroxide; most preferably potassium phosphate.
  • the molar ratio of the ligand to the reactant aryl halide is from 1 to 50:100, preferably from 5 to 20:100; the ligand and the copper catalyst The molar ratio is from 1 to 5:1, preferably from 1 to 2:1.
  • reaction comprises:
  • X is selected from the group consisting of N, O or S;
  • Y is selected from the group consisting of Cl, Br, and I;
  • the coupling reagent is selected from the group consisting of ammonia water, ammonia gas, ammonium salt (preferably ammonium chloride, ammonium carbonate, ammonium sulfate, ammonium hydrogen phosphate, or a combination thereof) / hydroxide solution (preferably potassium hydroxide) Solution), (having 2 to 19 carbon atoms, which may be saturated, partially unsaturated or aromatic), R c C(O)NHR 2 , R 1 SO 2 M (preferably, M is sodium, potassium), azidation Sodium, NHR 1 R 2 , R 1 OH, R 1 SH, hydroxide (preferably lithium hydroxide, or a mixture of potassium phosphate, potassium carbonate, cesium carbonate and water);
  • R 1 , R 2 , R c are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C6-C20 aromatic a substituted, 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, substituted or unsubstituted C1-C5 alkyl-C3-C20 cycloalkyl, substituted or unsubstituted 3- to 20-membered hetero a cyclo group, or a substituted or unsubstituted C1-C5 alkyl-3- to 20-membered hetero
  • R 1 and R 2 and an adjacent nitrogen atom together form a substituted or unsubstituted 3- to 20-membered heterocyclic group, a substituted or unsubstituted 3- to 20-membered heteroaryl;
  • R c and R 2 and the adjacent C(O)NH together form a substituted or unsubstituted 3- to 20-membered heterocyclic group, a substituted or unsubstituted 3- to 20-membered heteroaryl group;
  • heteroaryl or heterocyclic group has 1 to 5 hetero atoms selected from the group consisting of N, O or S;
  • the cycloalkyl or heterocyclic group may be monocyclic or polycyclic, Spiral or bridge ring structure;
  • the inert solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, or a combination thereof; preferably DMSO and/or DMF and/or DMSO/H 2 O .
  • reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • reaction comprises the following (1), (2), (3), (4), (5), (6), (7) or (8):
  • the ammonia source is selected from the group consisting of ammonia gas, ammonia water, ammonium chloride, ammonium carbonate, ammonium hydrogencarbonate, ammonium sulfate, ammonium nitrate, ammonium phosphate, diammonium hydrogen phosphate, sodium azide, preferably ammonia gas, ammonia water. , ammonium chloride and diammonium hydrogen phosphate.
  • reaction comprises the following (5):
  • the 3- to 20-membered ring may be saturated, unsaturated or aromatic, and the remaining groups are as defined above. Said.
  • reaction comprises the following (6):
  • R c is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted 3- to 20-membered heteroaryl group, a substituted or unsubstituted C7-C25 alkyl-aryl group, a substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl group, a substituted or unsubstituted C3-C20 cycloalkyl group, Or a substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 hetero atoms selected from the group consisting of N, O or S;
  • the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R c and R 2 and the adjacent C(O)NH together form a substituted or unsubstituted 3- to 20-membered heterocyclic group, a substituted or unsubstituted 3- to 20-membered heteroaryl group;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH,
  • reaction comprises the following (7):
  • reaction comprises the following (8):
  • the ligand is selected from the group consisting of LI-25, LI-27, L-II-7, L-II-9, L-II-31, L-II-38, L-II-64, most preferably L-II-38, L-II-31 or L-II-64.
  • the inert solvent may be DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, THF, 1,4-dioxane, preferably DMSO, DMF. , DMA or a combination thereof, most preferably DMSO.
  • the reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • the ligand is selected from the group consisting of LI-27, L-II-9, L-II-34, L-II-30, L-II- 38. L-II-64, L-II-71, L-II-73, most preferably L-II-38, L-II-64 or L-II-71.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a combination thereof; .
  • reaction (2) when the ammonia source is an ammonium salt, the reaction is carried out in the presence of a strong base (preferably in the presence of KOH).
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, preferably DMSO, DMF, DMA or a combination thereof; most preferably DMSO .
  • the reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • the ligand is preferably L-II-34.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a combination thereof; .
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, THF, 1,4-dioxane, or Combination; preferably DMSO.
  • the reaction temperature is 50 to 180 ° C, preferably 100 to 130 ° C.
  • the ligand in the reaction (4), is L-II-34.
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, THF, 1,4-dioxane, or Combination; preferably DMSO.
  • the reaction temperature is 50 to 180 ° C, preferably 100 to 130 ° C.
  • the ligand is preferably L-II-82.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a combination thereof; .
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane. Ring, or a combination thereof; preferably DMSO.
  • the reaction temperature is 50 to 180 ° C, preferably 100 to 130 ° C.
  • the ligand is preferably L-II-83, L-II-90.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a combination thereof; .
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane. Ring, or a combination thereof; preferably DMSO.
  • the reaction temperature is 50 to 180 ° C, preferably 100 to 130 ° C.
  • the ligand is preferably L-II-3, L-II-37.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a combination thereof; .
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane. Ring, or a combination thereof; preferably DMSO.
  • the reaction temperature is 50 to 180 ° C, preferably 100 to 130 ° C.
  • the ligand is preferably L-II-65, L-II-93.
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide. And/or a hydrate of the base, or a combination thereof; preferably lithium hydroxide.
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, THF, 1,4-dioxane, tert-butyl An alcohol, and/or a mixture of one or more of the foregoing solvents and water, or a combination thereof; preferably DMSO/H 2 O.
  • the reaction temperature is 50 to 180 ° C, preferably 100 to 130 ° C.
  • a catalytic system for an aryl coupling reaction comprising: a copper catalyst, a ligand, a base, an organic solvent;
  • the copper catalyst is selected from the group consisting of CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 Or a combination thereof; preferably CuI, Cu 2 O, Cu(acac) 2 ;
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, and/or a hydrate of the base. Or a combination thereof; preferably potassium phosphate, cesium carbonate, lithium hydroxide;
  • the solvent is selected from the group consisting of DMSO, DMF, DMA, NMP, acetonitrile, isopropanol, 1,4-dioxane, tetrahydrofuran, toluene, tert-butanol, or a combination thereof; preferably DMSO and/or DMF and / or DMSO / H 2 O;
  • the ligand has the structure shown by the following formula (I):
  • the catalytic system is used to carry out a coupling reaction of an aryl halide;
  • the aryl halide is selected from the group consisting of aryl chloride, aryl bromide, aryl iodide .
  • the catalytic system is used to carry out a coupling reaction of an aryl chloride.
  • R is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted Substituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or An unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; said ring
  • the alkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R a is selected from (a) or (b):
  • each R" is independently selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered hetero Aryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 ring An alkyl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 hetero atoms selected from the group consisting of N, O or S; the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R b is selected from the group consisting of H, C1-C6 alkyl
  • R b and R together with an adjacent nitrogen atom constitute a substituted or unsubstituted 3- to 20-membered heteroaryl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group;
  • R a is selected from (a), and R' is H, R is a methyl-substituted naphthyl group;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6- An aryl group of C10, an aryl-oxy group of C6-C10, an ester group of C2-C10 (alkyl-COO-), an acyl-alkoxy group of C2-C10 (alkyl-OOC-), C2-C10 Acyl (alkyl-CO-), C2-C10 amide (alkyl/aryl NHC(O)-), -COOH, nitro, cyano, hydroxy, amino, 1 or 2 C1-C6 Alkyl substituted amino group.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-
  • R, R a , R b , R', R 1 , R 2 , R 4 and Any one of them is a corresponding group in the corresponding specific compound in the present application.
  • the compound of the formula (I) is a structure as shown in Table 1 or Table 2.
  • a process for the preparation of a compound according to the fourth aspect of the invention which is carried out by a process selected from the group consisting of: (i), (ii) or (II):
  • Method (i) includes the steps of:
  • Method (ii) includes the steps of:
  • Method (II) includes the steps of:
  • the inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, and DMF.
  • the reaction is carried out in the presence of triethylamine.
  • the reaction is carried out at -5 ° C to 40 ° C.
  • the inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, and DMF.
  • the reaction is carried out at 10 ° C to 80 ° C (preferably at room temperature, i.e., 10 to 40 ° C).
  • the inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, and DMF.
  • reaction in the process (II), is carried out in the presence of triethylamine.
  • the reaction is carried out at -5 ° C to 40 ° C.
  • oxalic acid (mono and bis) amide ligands suitable for copper-catalyzed aryl chloride coupling reaction which are composed of copper ligands, bases and solvents.
  • a suitable catalytic system can be used for the copper-catalyzed coupling reaction of aryl halides, in particular, it can effectively promote the coupling of copper-catalyzed aryl chlorides which are difficult to occur under conventional conditions with various nucleophiles to form CN, CO, CS bond, a variety of useful small molecule compounds.
  • the method has mild reaction conditions, wide application range and good industrial application prospect.
  • halogen refers to fluoro, chloro, bromo, iodo.
  • halo means that one or more hydrogen atoms on the group are replaced by a halogen.
  • alkyl refers to a straight or branched alkyl group.
  • a carbon number limit such as C1-C6
  • cycloalkyl refers to a unit having a saturated or partially saturated unit, a bicyclic or tricyclic (a ring, bridged or spiro) ring system.
  • the cycloalkyl group may have 3 to 20 carbon atoms.
  • a certain cycloalkyl group has a carbon number limit (such as C3-C20)
  • Base or a similar group.
  • the cycloalkyl group may be in the form of a monocyclic, polycyclic, spiro or bridged ring.
  • alkoxy refers to an alkyl group (eg, -O-alkyl, wherein alkyl is as defined above) attached through an oxygen atom, such as, but not limited to, methoxy, ethoxy, Propyloxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
  • alkoxy group has a carbon number limitation (e.g., C1-C6), it means that the cycloalkyl group has 1 to 6 carbon atoms.
  • aryl refers to a monocyclic, bicyclic or fused ring aromatic hydrocarbon group which may be substituted or unsubstituted.
  • aryl group has a carbon number limit (e.g., C6-C20), it means that the aryl group has 6-20 carbon atoms.
  • Examples of aryl groups are, for example but not limited to, phenyl, biphenyl, naphthyl, or the like (each of which may be optionally substituted).
  • heteroaryl refers to a monocyclic, bicyclic or fused ring aromatic group, said group comprising at least one selected from the group consisting of N, A hetero atom of O or S.
  • the heteroaryl group may be 3- to 20-membered, having 1 to 5 aromatic ring groups each independently selected from a hetero atom of N, O or S.
  • Examples of heteroaryl groups are, for example but not limited to, pyridine, pyrimidine, pyrrole, oxazole, indole, furan, benzofuran, thiophene, or the like.
  • heterocyclyl refers to a saturated or partially saturated substituent of a monocyclic or fused ring comprising at least one identical or different heteroatom selected from N, O or S.
  • the heterocyclic group may be 3- to 20-membered, having 1 to 5 heterocyclic groups each independently selected from a hetero atom of N, O or S.
  • Examples of the heterocyclic group are, for example, but not limited to, a nitrogen heterocyclic group, an oxaheterocyclic group, a thioheterocyclic group, an oxynitride group, and the like.
  • ester group refers to a group having the structure "alkyl-COO-" wherein alkyl is as defined above.
  • acyl refers to a group having the structure "alkyl-CO-" wherein alkyl is as defined above.
  • amido refers to a group having the structure "alkyl NHC(O)-" or "aryl NHC(O)-” wherein alkyl, aryl are as defined above.
  • a ligand as referred to herein refers to a ligand used in a copper-catalyzed aryl chloride coupling reaction.
  • the ligands usable in the present invention have a structure as shown in the above formula (I), and preferred ligands have a structure selected from the group consisting of the following groups (the definitions of the respective groups are as described above):
  • the first type of ligand oxalic acid monoamide monomethyl ester / ethyl ester
  • R is phenyl, substituted phenyl, naphthyl, pyridyl, benzyl, substituted benzyl, adamantyl and the like.
  • More preferred oxalic acid monoamide ester ligands have the structure shown in Table 1 below:
  • the second type of ligand oxalic acid bisamide
  • each group is as defined above, preferably, R: phenyl, substituted phenyl, naphthyl, anthryl, benzyl, substituted benzyl, C1-C4 alkyl, pyridyl, adamantyl, and the like; R": phenyl, substituted phenyl, naphthyl, benzyl, substituted benzyl, C1-C4 alkyl, pyridyl, adamantyl, etc. (R may or may not be equal to R").
  • More preferred oxalic acid bisamide ligands have the structure shown in Table 2 below:
  • Each of the above ligands may be obtained commercially or prepared according to the preferred methods provided herein.
  • the above ligands can be used in the coupling reaction of aryl bromides and aryl iodides conventional in the art, in addition to the coupling reaction of aryl chlorides.
  • the present invention also provides a copper-catalyzed coupling reaction method for an aryl chloride, which comprises carrying out the above reaction using a compound of the formula (I) as described above as a ligand.
  • aryl iodide and aryl bromide have higher reactivity, and can be correspondingly catalyzed by transition metals such as palladium, copper, nickel, etc.; compared with bromine (iodo) aromatics, chlorination
  • Transition metals such as palladium, copper, nickel, etc.
  • bromine (iodo) aromatics chlorination
  • Aromatic hydrocarbons are cheap and easy to obtain, and have more application prospects; however, the C-Cl bond energy is high, which results in the aryl chlorides being difficult to react under the catalytic conditions of conventional aryl bromides and aryl iodides.
  • Ligand and reaction conditions can be optimized for different reactants within the scope of the present invention to select the most appropriate ligand type and reaction conditions (eg, temperature, solvent, reactant ratio, reaction time, etc.), in reading After the disclosure of the present application, the above optimization is within the skill of those skilled in the art.
  • ligand type and reaction conditions eg, temperature, solvent, reactant ratio, reaction time, etc.
  • the selection of the coupling reagent is not particularly limited, and may be a corresponding primary or secondary amine, or may be other ammonia sources such as ammonia, ammonia or even ammonium salt, sodium azide, and nitrogen-containing heteroaryl. Ring and so on.
  • the specific reaction process is as follows:
  • the reaction is as follows:
  • R 1 and R 2 are each independently 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 a cycloalkyl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group, or R1, R2 together with an adjacent N atom thereof form a 3- to 20-membered ring (eg, a substituted or unsubstituted pyrrole) , anthracene, azoles, benzoxazoles and aromatic heterocycles, or R 1 is R c C(O)-,
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH.
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably CuI. .
  • the ligand is not particularly limited and may be any of the ligands described above, preferably LI-25, LI-27, L-II-7, L-II-9, L-II-31.
  • a preferred base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate, cesium carbonate, and most preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO, DMF, most preferably DMSO.
  • the reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • the ammonia source is selected from the group consisting of ammonia gas, ammonia water, ammonium chloride, ammonium carbonate, ammonium hydrogencarbonate, ammonium sulfate, ammonium nitrate, ammonium phosphate, diammonium hydrogen phosphate, sodium azide, preferably ammonia gas, ammonia water. , ammonium chloride and diammonium hydrogen phosphate.
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably CuI.
  • the ligand 1 may be any of the above, preferably LI-27, L-II-9, L-II-38, L-II-64, L-II-71, L-II. -72, most preferably L-II-38 or L-II-71.
  • the base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably cesium carbonate or potassium phosphate, most preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO, DMF, most preferably DMSO.
  • the reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • the coupling reaction of the aryl chloride with the nitrogen-containing aromatic heterocycle is as follows:
  • the 3- to 20-membered ring may be saturated or unsaturated (preferably selected from the group consisting of pyrrole, pyrene, An azole, a benzoxazole and an corresponding aromatic heterocyclic ring);
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably Cu. 2 O.
  • the ligand is not particularly limited and may be any of the ligands described above, preferably L-II-82.
  • a preferred base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate, cesium carbonate, and most preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO, DMF, most preferably DMSO.
  • the reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • the coupling reaction of the aryl chloride with the amide is as follows:
  • R c and R 2 are each independently 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 a cycloalkyl group, or a substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 hetero atoms selected from the group consisting of N, O Or S; the cycloalkyl or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • R c and R 2 and the adjacent C(O)NH together form a substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3- to 20-membered heterocyclic group
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH.
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably Cu. 2 O.
  • the ligand is not particularly limited and may be any of the ligands described above, preferably L-II-83, L-II-90.
  • a preferred base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate, cesium carbonate, and most preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane.
  • Ring preferably DMSO, DMF, most preferably DMSO.
  • the reaction temperature is from 50 to 180 ° C, preferably from 100 to 130 ° C.
  • R 1 is selected from the group consisting of 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 not a substituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; said cycloalkane
  • the base or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH, -CN, MeS-, sulfone group, sulfonamide group.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably CuI.
  • the ligand is any one of 1, preferably L-II-34.
  • the base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO.
  • the reaction temperature is from 50 to 180 degrees, preferably from 100 to 130 degrees.
  • R 1 is selected from the group consisting of 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 not a substituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; said cycloalkane
  • the base or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH, -CN, MeS-, sulfone group, sulfonamide group.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably CuI.
  • the ligand is any one of 1, preferably L-II-34.
  • the base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO.
  • the reaction temperature is from 50 to 180 degrees, preferably from 100 to 130 degrees.
  • R 1 is selected from the group consisting of 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 not a substituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O or S; said cycloalkane
  • the base or heterocyclic group may be a monocyclic, polycyclic, spiro or bridged ring structure;
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH, -CN, MeS-, sulfone group, sulfonamide group.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably CuI.
  • the ligand is any one of 1, preferably L-II-3, L-II-37.
  • the base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane. Ring, preferably DMSO.
  • the reaction temperature is from 50 to 180 degrees, preferably from 100 to 130 degrees.
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(O)-, aryl Base NHC(O)-), -COOH, -CN, MeS-, sulfone group, sulfonamide group.
  • a substituent selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 Aryl-oxyl, C2-C10 ester (alkyl-COO-), C2-C10 acyl (alkyl-CO-), C2-C10 amide (alkyl NHC(
  • the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc) 2 , CuSO 4 , Cu 2 O, CuBr 2 , CuCl 2 , CuO, CuSCN, CuCN, Cu(acac) 2 , preferably Cu(acac) 2 .
  • the ligand is any one of 1, preferably L-II-65, L-II-93.
  • the base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, and/or a hydrate of the base, preferably lithium hydroxide.
  • the solvent may be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, tert-butanol, and/or a mixture of one or more of the foregoing solvents and water.
  • DMSO/H 2 O Preferably, DMSO/H 2 O.
  • the reaction temperature is from 50 to 180 degrees, preferably from 100 to 130 degrees.
  • a catalytic system capable of efficiently performing copper-catalyzed aryl chloride coupling reaction, which is difficult to carry out under conventional aryl bromide and aryl iodide coupling systems
  • the aryl chloride coupling reaction proceeds smoothly, and the substrate compatibility is good, and the catalytic system has a wide application range.
  • the method of the invention adopts a copper catalyst system with lower cost, and has a simple ligand structure, convenient preparation, less dosage and economical reaction.
  • the raw material aryl chlorinated materials used in the catalytic system of the invention have low raw material cost, wide source and good application prospects on a large scale.
  • 2,4,6-Trimethoxyaniline (30 mmol) and triethylamine (36 mmol) were dissolved in 150 mL of tetrahydrofuran, and the concentration of 2,4,6-trimethoxyaniline was 0.2 mol/L.
  • the ice water bath was cooled, stirred, and then oxalyl chloride monomethyl ester (33 mmol) was added dropwise, and the system became cloudy to give triethylamine hydrochloride. After the completion of the dropwise addition, the ice water bath was removed, and the room temperature was naturally restored. Stirring was continued for 1 to 2 hours. TLC was used to monitor the complete consumption of 2,4,6-trimethoxyaniline, and the stirring was stopped for post-treatment.
  • reaction solution was filtered under reduced pressure with a filter paper, and triethylamine hydrochloride was filtered.
  • the filter cake was rinsed with a small amount of tetrahydrofuran (not washed with ethyl acetate, or triethylamine hydrochloride dissolved).
  • the filtrate was concentrated under reduced pressure. EtOAc m.
  • oxalic acid monoamide monoethyl ester When oxalic acid monoamide monoethyl ester was prepared, oxalyl chloride monoethyl ester was used instead of oxalyl chloride monomethyl ester.
  • the oxalic acid monoamide monomethyl ester (10 mmol) of the above-obtained 2,4,6-trimethoxyaniline was dissolved in 10 mL of THF, and the substrate concentration was 1.0 mol/L.
  • Add 1.3mL benzylamine (12mmol) stir, heat to 70-80 ° C, 1 hour after TLC monitoring, the raw materials disappear, remove the heating, let stand, let the reaction bottle naturally cool to room temperature, then put it into the refrigerator to freeze, that is, precipitate White solid.
  • the filter paper was filtered under reduced pressure, dried in an infrared oven, and then drained with an oil pump to obtain a white solid of 2.94 g, yield 86%.
  • amines e.g., aqueous methylamine, diethylamine, etc.
  • benzylamine e.g., aqueous methylamine, diethylamine, etc.
  • the stir bar was sucked out with a strong magnetic bar, tetrahydrofuran was distilled off under reduced pressure, 50 mL of distilled water was added to the residue, and the solid of the bottle wall was scraped off with a spatula, all immersed in distilled water, and stirred to form a slurry.
  • the triethylamine hydrochloride was completely dissolved.
  • the filter paper was filtered under reduced pressure, and the filter cake was washed with a small amount of cold diethyl ether. Finally, the filter cake was scraped off, dried in an infrared oven, and then drained with an oil pump to obtain 5.45 g of a white solid. The yield was 86%.
  • Example 2 Coupling reaction of p-methylchlorobenzene with benzylamine to synthesize N-p-methylphenylbenzylamine
  • Example 3 Coupling reaction of p-methylchlorobenzene with benzylamine to synthesize N-p-methylphenylbenzylamine
  • Example 2 The operation of this example was the same as in Example 2, using different oxalic acid amide ligands, and the results obtained are shown in the following table.
  • Example 4 Coupling reaction of p-methylchlorobenzene with benzylamine to synthesize N-p-methylphenylbenzylamine
  • Example 5 Coupling reaction of p-methylchlorobenzene with various primary and secondary amines to synthesize corresponding aniline derivatives
  • This example uses different amines, including grade i, secondary aliphatic amines, aromatic amines, reaction conditions are A, B, condition A for amines with better reactivity, and condition B for amines with relatively weak reactivity, The results obtained are listed in the table below.
  • This example uses different chlorinated aromatic hydrocarbons and the results obtained are listed in the table below.
  • This example used different chlorinated aromatic hydrocarbons and different amines, and the results are shown in the table below.
  • reaction temperature was 105 °C.
  • This example uses different chlorinated aromatic hydrocarbons.
  • the reaction conditions are C and D.
  • Condition C is for chlorinated aromatic hydrocarbons with better reactivity
  • condition D is for chlorinated aromatic hydrocarbons with relatively weak reactivity. The results are shown in the table below. .
  • Example 2 This example was operated as in Example 2, using different ligands, copper salt catalysts, bases, solvents and temperatures. The results are shown in the table below.
  • a halogenated aromatic hydrocarbon substrate (1.0 mmol), phenol (1.2 mmol), cuprous iodide (0.05 mmol), ligand L-II-34 (0.1 mmol), potassium phosphate (2.0 mmol) were added to a 10 mL sealed tube. After argon was replaced by vacuum for 3 times, 1 mL of DMSO was added, and the reaction was uniformly stirred at 120 ° C for 30 hours. After cooling, the contents of the sealed tube were washed with ethyl acetate, and filtered through a silica gel and a celite column. Analysis gave the product diaryl ether. The results obtained are listed in the table below.
  • a halogenated aromatic hydrocarbon substrate (1.0 mmol), phenol (1.2 mmol), cuprous iodide (0.05 mmol), ligand L-II-37 (0.05 mmol), potassium phosphate (2.0 mmol) were added to a 10 mL sealed tube. After argon was replaced by vacuum for 3 times, 1 mL of DMSO was added, and the reaction was uniformly stirred at 80 ° C for 12 hours. After cooling, the contents of the sealed tube were washed with ethyl acetate, and filtered through a silica gel and a celite column. Analysis gave the product diaryl ether. The results obtained are listed in the table below.
  • Example 18 Coupling reaction of p-methoxychlorobenzene with pyrrole to synthesize N-p-methoxyphenylpyrrole
  • Example 2 The operation of this example was the same as in Example 1, using different oxalic acid amide ligands (supplement) experimental results in the table below.
  • Ligand number Yield/% Ligand number Yield/% Ligand number Yield/% L-II-82 51 L-II-83 42 L-II-84 25 L-II-85 48 L-II-86 twenty three L-II-87 18 L-II-88 36 L-II-89 17 L-II-21 32 L-II-79 28 L-II-80 33 L-II-81 30 L-II-98 twenty two L-II-99 36
  • Example 20 Coupling reaction of p-methoxychlorobenzene with benzamide to synthesize N-p-methoxyphenylbenzamide
  • Example 21 Coupling reaction of p-methoxychlorobenzene with benzamide to synthesize N-p-methoxyphenylbenzamide
  • Example 20 The operation of this example was the same as in Example 20, using different oxalic acid diamide ligands as experimental results.
  • Example 22 Coupling reaction of p-methoxychlorobenzene with benzamide to synthesize N-p-methoxyphenylbenzamide
  • Example 20 This example was operated as in Example 20, using different copper salt catalysts, bases, solvents and temperatures. The results obtained are shown in the table below.
  • Example 25 Copper-catalyzed synthesis of p-methoxyphenol by p-methoxychlorobenzene
  • Example 26 Copper-catalyzed synthesis of p-methoxyphenol by p-methoxychlorobenzene
  • Example 25 This example was operated as in Example 25, using different oxalic acid diamide ligands, and the results are shown in the table below.
  • Example 27 Copper-catalyzed synthesis of p-methoxyphenol by p-methoxychlorobenzene
  • Example 25 The operation of this example was the same as that of Example 25.
  • the ligand was selected from L-II-93, and different copper catalysts, bases and solvents were used. The results are shown in the following table.
  • Example 28 Copper-catalyzed aryl iodide/bromine synthesis of substituted phenol

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Abstract

本发明提供了草酸酰胺类配体及其在铜催化芳基卤代物偶联反应中的用途，具体地，本发明提供了一种如下式I所示的化合物的用途；其中，各基团的定义如说明书中所述。所述的式I化合物可以用作为铜催化芳基卤代物偶联反应中的配体，用于催化形成C-N、C-O、C-S键等芳基卤代物的偶联反应。

Description

草酸酰胺类配体及其在铜催化芳基卤代物偶联反应中的用途 技术领域
本发明涉及有机合成领域，具体地，本发明提供了一种草酸酰胺类配体促进的铜催化芳基卤代物偶联反应，特别是偶联生成C-N、C-O、C-S键的反应。
背景技术
草酸酰胺类化合物通常以其具有各类生物活性而受到广泛关注，如草酸芳基酰胺单甲酯可以作为鹰嘴豆类的化学杂交试剂，草酸芳基二酰胺化合物可以作为糖原磷酸化酶抑制剂，或者作为小分子调节剂作用于CD4-gp120类蛋白。直到最近，马大为课题组将草酸2,6-二甲基苯基单酰胺羧酸作为配体用于铜催化的芳基碘代物、溴代物与有机胺的C-N偶联反应，开辟了这类化合物的新用途。但是，该反应主要适用于芳基碘代物和溴代物的偶联反应。
过渡金属催化的芳基卤代物与合适的亲核试剂如有机胺、活泼亚甲基化合物、炔、苯酚、醇、苯硫酚、亚磺酸钠、硫化钠、磷酸酯等发生相应的偶联反应是非常有效的生成C-N、C-C、C-O、C-S、C-P键的方法。通常，芳基碘、芳基溴的反应活性较高，在钯、铜、镍等过渡金属的催化下能较好的实现相应的偶联反应；和溴(碘)代芳烃相比，氯代芳烃便宜易得，更具有应用前景；然而C-Cl键键能高，过渡金属与之氧化加成就很难发生，反应不如溴代物和碘代物高效。钯和镍催化的芳基氯代物的C-N偶联反应已有相关报道，采用大位阻的磷配体促进反应是一个有效的手段，2005年Hartwig小组使用具有二茂铁结构的大位阻膦配体，顺利完成了芳环和芳杂环氯代物与一级胺的偶联反应，该体系中催化剂和配体的当量甚至可以降低到十万分之一的摩尔当量，对于个别芳杂环底物在室温条件下就可以完成此类反应，充分显示了该催化体系的高效；此外，该反应对于苯环上的取代基团也有着很好的兼容性。
2011年，Buchwald小组发现利用不同的膦配体，可以使氯代芳烃分别和一级胺、二级胺发生偶联，该体系对于底物具有很广的兼容性，除了一般脂肪胺，带有杂环的芳香胺也能顺利发生偶联。
虽然金属钯和镍在催化的氯代芳烃的氨基化反应中有着很高的效率，但是在大规模应用上存在一些问题：1、体系中需要加入大位阻、结构较复杂的膦配体或氮杂卡宾配体来促进反应；2、钯催化剂的价格昂贵，且零价镍所需的反应操作相当苛刻，这在一定程度上限制了其应用。相比而言，铜催化剂廉价、稳定、易得，所使用的配体结构简单，可以明显避免这些缺陷。然而目前所报道的铜催化的偶联反应底物大多局限在碘代物和溴代物。
2007年，Pellón小组利用2-氯苯甲酸邻位羧基的促进作用，在超声作用下，实现了和脂肪胺的偶联反应，一级胺和二级胺都能以较好的收率得到偶联产物，然而该方法只对邻位羧基取代底物有效，不具普遍性(Docampo,M.L.；Pellón,R.F.；Estevez-Braun,A.；Ravelo,A.G.Eur.J.Org.Chem.2007,4111.)。这个反应本质上还是一个亲核取代反应而不是偶联反应，且反应温度非常高。
Figure PCTCN2016079500-appb-000001
另外一篇关于氯代芳烃的Ullmann偶联反应的报道来自Taillefer小组，他们利用2,2,6,6-四甲基-3,5-庚二酮为配体，实现了氯苯和酚类化合物的C-O偶联，该体系的主要缺点是需要在反应中加入高达0.8当量的配体，因而降低了反应的经济性(Xia,N.；Taillefer,M.Chem.Eur.J.2008,14,6037.)。
Figure PCTCN2016079500-appb-000002
R＝Me，OMe，COCH3，NO2，CN；R′＝Me，OMe，F，tBu
综上所述，本领域尚缺乏一种能够使反应高效进行的铜催化的芳基氯代物偶联反应的催化体系。
发明内容
本发明的目的是提供一种能够用于铜催化的芳基卤代物(特别是芳基氯代物)偶联反应的催化体系。
本发明的第一方面，提供了一种如下式I所示的化合物的用途：
Figure PCTCN2016079500-appb-000003
其中，R选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
Ra选自(a)或(b)：
(a)OR’；其中，所述的R’选自下组：取代或未取代的C1-C6烷基；或
(b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构(优选地，N(R”)2为NHR”)；
Rb选自下组：H、C1-C6的烷基；
或Rb与R以及相邻的氮原子共同构成取代或未取代的3-至20-元的杂芳基，或取代或未取代的3-至20-元的杂环基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10 的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基；
其特征在于，作为配体用于铜催化的芳基卤代物偶联反应；其中，所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物，或其组合。
在另一优选例中，所述的R选自下组：取代或未取代的苯基、取代或未取代的萘基、取代或未取代的苄基、取代或未取代的喹啉基、取代或未取代的
Figure PCTCN2016079500-appb-000004
取代或未取代的金刚烷基、取代或未取代的C1-C6烷基、取代或未取代的
Figure PCTCN2016079500-appb-000005
或R、Rb和相邻的氮原子共同构成取代或未取代的选自下组的基团：
Figure PCTCN2016079500-appb-000006
在另一优选例中，所述的R选自下组：取代或未取代的苯基、取代或未取代的萘基、取代或未取代的苄基、C1-C4烷基、吡啶基、金刚烷基；
所述的Ra选自(a)或(b)：
(a)OR’；其中，所述的R’选自下组：取代或未取代的C1-C6烷基；或
(b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
在另一优选例中，当所述的Ra为NHR”时，所述的R”选自下组：取代或未取代的苯基、取代或未取代的萘基、取代或未取代的苄基、C1-C4烷基、吡啶基、金刚烷基。
在另一优选例中，所述的Ra为NHR”。
在另一优选例中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、甲基、三氟甲基、乙基、异丙基、叔丁基、二甲胺基、甲氧基、叔丁氧基、-Ac、CH3NHC(O)-、苯基、苯氧基、-COOH、酯基、硝基、氰基、羟基。
在另一优选例中，所述的芳基卤代物为芳基氯代物。
本发明的第二方面，提供了一种芳基卤代物偶联反应方法，所述的方法包括：用铜作为催化剂，用如下式I所示的化合物作为配体，进行所述的偶联反应：
Figure PCTCN2016079500-appb-000007
其中，R选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
Ra选自(a)或(b)：
(a)OR’；其中，所述的R’选自下组：取代或未取代的C1-C6烷基；或
(b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
Rb选自下组：H、C1-C6的烷基；
或Rb与R以及相邻的氮原子共同构成取代或未取代的3-至20-元的杂芳基，或取代或未取代的3-至20-元的杂环基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、氰基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基；
其中，所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物，或其组合。
在另一优选例中，所述的铜催化剂选自下组：CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，或其组合；优选CuI、Cu2O、Cu(acac)2。
在另一优选例中，所述的反应在碱存在下进行。
在另一优选例中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸氢钠、碳酸氢钾、碳酸钠、氢氧化锂、氢氧化钠，和/或该碱的水合物，或其组合；优选为磷酸钾、碳酸铯、氢氧化锂；最优选为磷酸钾。
在另一优选例中，在所述反应中，所述配体与反应物芳基卤代物的摩尔比为1～50:100，优选为5～20:100；所述配体与铜催化剂的摩尔比为1～5:1，优选为1～2:1。
在另一优选例中，所述的反应包括：
Figure PCTCN2016079500-appb-000008
在惰性溶剂中，用
Figure PCTCN2016079500-appb-000009
与偶联试剂反应，得到
Figure PCTCN2016079500-appb-000010
化合物；
其中，X选自下组：N、O或S；
Y选自下组：Cl、Br、I；
Figure PCTCN2016079500-appb-000011
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、未取代或被1个或2个C1-C6的烷基或C2-C10的酰基(烷基-CO-)取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、3-至20-元的杂芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；其中，所述芳基上的两个相 邻的碳原子上的两个氢原子可以被-(CH2)n-取代(n为1、2、3、4、5或6)；
所述的偶联试剂选自下组：氨水、氨气、铵盐(优选为氯化铵、碳酸铵、硫酸铵、磷酸氢铵，或其组合)/氢氧化物溶液(优选为氢氧化钾溶液)、
Figure PCTCN2016079500-appb-000012
(具有2-19个碳原子，可以为饱和，部分不饱和或芳香性环)、RcC(O)NHR2、R1SO2M(优选地，M为钠、钾)、叠氮化钠、NHR1R2、R1OH、R1SH、氢氧化物(优选氢氧化锂，或磷酸钾、碳酸钾、碳酸铯与水的混合物)；
R1、R2、Rc各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C5烷基-C3-C20的环烷基、取代或未取代的3-至20-元的杂环基，或取代或未取代的C1-C5烷基-3-至20-元的杂环基；
或R1和R2以及相邻的氮原子共同形成取代或未取代的3-至20-元的杂环基、取代或未取代的3-至20-元的杂芳基；
或Rc和R2以及相邻的C(O)NH共同形成取代或未取代的3-至20-元的杂环基、取代或未取代的3-至20-元的杂芳基；
其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氰基、氧(即基团上同一个碳原子上的两个氢原子被＝O取代)、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基、C1-C6烷基-S-。
在另一优选例中，所述的惰性溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇，或其组合；优选为DMSO和/或DMF和/或DMSO/H2O。
在另一优选例中，所述的反应温度在50-180℃，优选100-130℃。
在另一优选例中，所述的反应包括以下(1)、(2)、(3)、(4)、(5)、(6)、(7)或(8)：
(1)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000013
与NHR1R2反应，得到
Figure PCTCN2016079500-appb-000014
Figure PCTCN2016079500-appb-000015
其中，各基团的定义如上文中所述；
(2)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000016
与氨源反应，得到
Figure PCTCN2016079500-appb-000017
Figure PCTCN2016079500-appb-000018
其中，各基团的定义如上文中所述；
所述的氨源选自下组：氨气、氨水、氯化铵、碳酸铵、碳酸氢铵、硫酸铵、硝酸铵、磷酸铵、磷酸氢二铵、叠氮化钠，优选氨气、氨水、氯化铵和磷酸氢二铵。
(3)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000019
与R1OH反应，得到
Figure PCTCN2016079500-appb-000020
Figure PCTCN2016079500-appb-000021
其中，各基团的定义如上文中所述；
(4)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000022
与R1SH反应，得到
Figure PCTCN2016079500-appb-000023
Figure PCTCN2016079500-appb-000024
其中，各基团的定义如上文中所述。
在另一优选例中，所述的反应包括以下(5)：
(5)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000025
与
Figure PCTCN2016079500-appb-000026
反应，得到
Figure PCTCN2016079500-appb-000027
Figure PCTCN2016079500-appb-000028
其中，
Figure PCTCN2016079500-appb-000029
为取代或未取代的含有N原子的3-至20-元的环，所述3-至20-元的环可以是饱和、不饱和的或芳香性的，其余各基团的定义如上文中所述。
在另一优选例中，所述的反应包括以下(6)：
(6)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000030
与
Figure PCTCN2016079500-appb-000031
反应，得到
Figure PCTCN2016079500-appb-000032
Figure PCTCN2016079500-appb-000033
其中，Rc选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
或Rc和R2以及相邻的C(O)NH共同形成取代或未取代的3-至20-元的杂环基、取代或未取代的3-至20-元的杂芳基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH，
其余各基团的定义如上文中所述。
在另一优选例中，所述所述的反应包括以下(7)：
(7)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000034
与R1SO2M反应，得到
Figure PCTCN2016079500-appb-000035
Figure PCTCN2016079500-appb-000036
其中，各基团的定义如上文中所述。
在另一优选例中，所述的反应包括以下(8)：
(8)在惰性溶剂中，用
Figure PCTCN2016079500-appb-000037
与氢氧化物或碱水解所得OH-反应，得到
Figure PCTCN2016079500-appb-000038
Figure PCTCN2016079500-appb-000039
其中，各基团的定义如上文中所述。
在另一优选例中，在反应(1)中，所述的配体选自下组：L-I-25、L-I-27、L-II-7、L-II-9、L-II-31、L-II-38、L-II-64，最优选为L-II-38、L-II-31或L-II-64。
在另一优选例中，在反应(1)中，所述的惰性溶剂可以为DMSO、DMF、DMA、NMP、乙腈、异丙醇、THF、1,4-二氧六环，优选DMSO、DMF、DMA或其组合，最优选DMSO。
在另一优选例中，在反应(1)中，所述的反应温度在50-180℃，优选100-130℃。
在另一优选例中，在反应(2)中，所述的配体选自下组：L-I-27、L-II-9、L-II-34、L-II-30、L-II-38、L-II-64、L-II-71、L-II-73，最优选L-II-38、L-II-64或L-II-71。
在另一优选例中，在反应(2)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(2)中，当所述的氨源为铵盐时，所述的反应在强碱存在下进行(优选为在KOH存在下进行)。
在另一优选例中，在反应(2)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇，优选DMSO、DMF、DMA或其组合；最优选DMSO。
在另一优选例中，在反应(2)中，所述的反应温度在50-180℃，优选100-130℃。
在另一优选例中，在反应(3)中，所述的配体优选L-II-34。
在另一优选例中，在反应(3)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(3)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇、THF、1,4-二氧六环，或其组合；优选DMSO。
在另一优选例中，在反应(3)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(4)中，所述的配体为L-II-34。
在另一优选例中，在反应(4)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇、THF、1,4-二氧六环，或其组合；优选DMSO。
在另一优选例中，在反应(4)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(5)中，所述的配体优选L-II-82。
在另一优选例中，在反应(5)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(5)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，或其组合；优选DMSO。
在另一优选例中，在反应(5)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(6)中，所述的配体优选L-II-83，L-II-90。
在另一优选例中，在反应(6)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(6)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，或其组合；优选DMSO。
在另一优选例中，在反应(6)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(7)中，所述的配体优选L-II-3,L-II-37。
在另一优选例中，在反应(7)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；优选磷酸钾。
在另一优选例中，在反应(7)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，或其组合；优选DMSO。
在另一优选例中，在反应(7)中，所述的反应温度为50-180℃，优选100-130℃。
在另一优选例中，在反应(8)中，所述的配体优选L-II-65，L-II-93。
在另一优选例中，在反应(8)中，所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化锂、氢氧化钠，和/或该碱的水合物，或其组合；优选氢氧化锂。
在另一优选例中，在反应(8)中，所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇、THF、1,4-二氧六环，叔丁醇，和/或前述一种或多种溶剂与水的混合物，或其组合；优选DMSO/H2O。
在另一优选例中，在反应(8)中，所述的反应温度为50-180℃，优选100-130℃。
本发明的第三方面，提供了一种芳基偶联反应的催化体系，所述的反应体系包括：铜催化剂、配体、碱、有机溶剂；
其中，所述的铜催化剂选自下组：CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO,CuSCN,CuCN,Cu(acac)2,或其组合；优选为CuI、Cu2O、Cu(acac)2；
所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸氢钠、碳酸氢钾、碳酸钠，氢氧化锂、氢氧化钠、四丁基氢氧化铵，和/或该碱的水合物，或其组合；优选为磷酸钾、碳酸铯、氢氧化锂；
所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇、1,4-二氧六环、四氢呋喃、甲苯、叔丁醇，或其组合；优选为DMSO和/或DMF和/或DMSO/H2O；
所述的配体具有以下式(I)所示的结构：
Figure PCTCN2016079500-appb-000040
其中，各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的催化体系用于进行芳基卤代物的偶联反应；所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物。
在另一优选例中，所述的催化体系用于进行芳基氯代物的偶联反应。
本发明的第四方面，提供了一种如下式(I)所示的化合物：
Figure PCTCN2016079500-appb-000041
其中，R选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
Ra选自(a)或(b)：
(a)OR’；其中，所述的R’选自下组：Me、Et；或
(b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳 基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
Rb选自下组：H、C1-C6的烷基；
或Rb与R以及相邻的氮原子共同构成取代或未取代的3-至20-元的杂芳基，或取代或未取代的3-至20-元的杂环基；
且当Ra选自(a)、R’为H时，R为甲基取代的萘基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、氰基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基。
在另一优选例中，所述的化合物中，R、Ra、Rb、R’、R1、R2、R4和
Figure PCTCN2016079500-appb-000042
中任一个分别为本申请中相应的具体化合物中所对应的基团。
在另一优选例中，所述的式(I)化合物为如表1或表2中所示的结构。
本发明的第五方面，提供了一种如本发明第四方面所述的化合物的制备方法，通过选自方法(i)、(ii)或(II)的方法进行：
方法(i)包括步骤：
Figure PCTCN2016079500-appb-000043
在惰性溶剂中，用R-NH-Rb和
Figure PCTCN2016079500-appb-000044
进行反应，得到式(I)化合物；
方法(ii)包括步骤：
Figure PCTCN2016079500-appb-000045
在惰性溶剂中，用R”-NH2和
Figure PCTCN2016079500-appb-000046
进行反应，得到式(I)化合物；
方法(II)包括步骤：
Figure PCTCN2016079500-appb-000047
在惰性溶剂中，用R-NH2和草酰氯反应，得到式(I)化合物；
其中，各基团的定义如本发明第四方面中所述。
在另一优选例中，所述的方法(i)中，所述的惰性溶剂选自下组：四氢呋喃、二氯甲烷、DMF。
在另一优选例中，所述的方法(i)中，所述的反应在三乙胺存在下进行。
在另一优选例中，所述的方法(i)中，所述的反应在-5℃～40℃下进行。
在另一优选例中，所述的方法(ii)中，所述的惰性溶剂选自下组：四氢呋喃、二氯甲烷、DMF。
在另一优选例中，所述的方法(ii)中，所述的反应在10℃～80℃(优选为室温，即10-40℃)下进行。
在另一优选例中，所述的方法(II)中，所述的惰性溶剂选自下组：四氢呋喃、二氯甲烷、DMF。
在另一优选例中，所述的方法(II)中，所述的反应在三乙胺存在下进行。
在另一优选例中，所述的方法(II)中，所述的反应在-5℃～40℃下进行。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，提供了一类适合用于铜催化芳基氯代物偶联反应的草酸(单、双)酰胺配体，通过该类配体与铜试剂、碱、溶剂组成的合适催化体系，可以用于芳基卤代物的铜催化偶联反应，特别是能够有效促进常规条件下难以发生的铜催化的芳基氯代物与多种亲核试剂的偶联，生成C-N、C-O、C-S键，合成众多有用的小分子化合物。该方法反应条件温和，适用范围广，具有很好的工业应用前景。
术语
如本文所用，术语“卤素”指氟、氯、溴、碘。
术语“卤代”指基团上的一个或多个氢原子被卤素所取代。
术语“烷基”指直链或支链烷基。当烷基前具有碳原子数限定(如C1-C6)时，指所述的烷基含有1-6个碳原子，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“环烷基”指具有饱和的或部分饱和的单元，二环或三环(并环、桥环或螺环)环系。所述的环烷基可以具有3-20个碳原子。当某个环烷基前具有碳原子数限定(如C3-C20)时，指所述的环烷基含有3-20个碳原子，例如环丙基、环丁基、环戊基、环庚基、或类似基团。所述的环烷基可以是单环、多环、螺环或桥环形式。
如本文所用，术语“烷氧基”指通过氧原子相连的烷基(例如，-O-烷基，其中烷基如上所述)，例如(但并不限于)甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。当烷氧基前具有碳原子数限定(如C1-C6)时，指所述的环烷基含有1-6个碳原子。
术语“芳基”指单环，二环或稠环的芳香族碳氢基团，所述的芳基可以是取代或未取代的。当一个芳基前具有碳原子数限定(如C6-C20)时，指所述的芳基含有6-20个碳原子。芳基的例子例如(但并不限于)：苯基、联苯基、萘基、或类似基团(其中的每个碳原子均可以被任意取代)。
术语“杂芳基”指单环，二环或稠环的芳香族基团，所述基团包括至少一个选自N、 O或S的杂原子。所述的杂芳基可以是3-至20-元的，具有1-5个各自独立地选自N、O或S的杂原子的芳香环基。杂芳基的例子例如(但并不限于)：吡啶、嘧啶、吡咯、吲唑、吲哚、呋喃、苯并呋喃、噻吩，或类似基团。
术语“杂环基”指单环或稠环的饱和或部分饱和取代基，所述基团包括至少一个相同或不同的选自N、O或S的杂原子。所述的杂环基可以是3-至20-元的，具有1-5个各自独立地选自N、O或S的杂原子的杂环基。杂环基的例子例如(但并不限于)：氮杂环基、氧杂环基、硫杂环基、氮氧杂环基等。
术语“酯基”指具有“烷基-COO-”结构的基团，其中，烷基定义如上所述。
术语“酰基”指具有“烷基-CO-”结构的基团，其中，烷基定义如上所述。
术语“酰胺基”指具有“烷基NHC(O)-”或者“芳基NHC(O)-”结构的基团，其中，烷基、芳基定义如上所述。
配体
除非特别说明，本文中所提到的配体指用于铜催化的芳基氯代物偶联反应中的配体。
本发明中可用的配体具有如前文式(I)所示的结构，优选的配体具有选自下组的结构(各基团的定义同上文中所述)：
第一类配体：草酸单酰胺单甲酯/乙酯
Figure PCTCN2016079500-appb-000048
其中各基团的定义如上文中所述，优选地，R为苯基、取代苯基、萘基、吡啶基、苄基、取代苄基、金刚烷基等。
更优选的草酸单酰胺酯类配体具有如下表1所示的结构：
表1草酸单酰胺单甲酯/乙酯配体
Figure PCTCN2016079500-appb-000049
Figure PCTCN2016079500-appb-000050
第二类配体：草酸双酰胺
Figure PCTCN2016079500-appb-000051
其中各基团的定义如上文中所述，优选地，R：苯基、取代苯基、萘基、蒽基、苄基、取代苄基、C1-C4烷基、吡啶基、金刚烷基等；R”：苯基、取代苯基、萘基、苄基、取代苄基、C1-C4烷基、吡啶基、金刚烷基等(R可以等于或不等于R”)。
更优选的草酸双酰胺类配体具有如下表2所示的结构：
表2草酸双酰胺
Figure PCTCN2016079500-appb-000052
Figure PCTCN2016079500-appb-000053
Figure PCTCN2016079500-appb-000054
Figure PCTCN2016079500-appb-000055
各个上述的配体可以是通过市售途径获得，或按照本发明所提供的优选方法制备得到。
应理解，由于C-Br和C-I键的键能小于C-Cl键，在同等条件下，芳基溴代物、芳基碘代物的偶联反应相较于芳基氯代物而言更易发生。因此，上述配体除了可以用于芳基氯代物的偶联反应之外，也可以用于本领域常规的芳基溴代物、芳基碘代物的偶联反应。
铜催化的芳基氯代物的偶联反应
本发明还提供了一类铜催化的芳基氯代物的偶联反应方法，所述的方法包括使用如前文所述的式(I)化合物作为配体进行上述反应。
通常，芳基碘、芳基溴的反应活性较高，在钯、铜、镍等过渡金属的催化下能较好的实现相应的偶联反应；和溴(碘)代芳烃相比，氯代芳烃便宜易得，更具有应用前景；然而C-Cl键键能高，这导致芳基氯代物在常规的芳基溴代物、芳基碘代物的催化条件下很难发生反应。
对于不同的反应物可以在本发明的公开范围内对配体和反应条件进行优化，从而选用最合适的配体种类和反应条件(如温度、溶剂、反应物比例和反应时间等)，在阅读了本申请的公开内容之后，上述优化是本领域技术人员的技能范围之内的。
几种最为优选的铜催化芳基氯代物偶联反应如下所示：
1.草酸(单、双)酰胺配体促进的铜催化的芳基氯代物的C-N偶联反应
C-N偶联反应中，偶联试剂的选择没有特别的限制，可以为相应的伯胺或仲胺，也可以为其他氨源如氨气、氨水乃至铵盐、叠氮化钠、含氮杂芳环等。具体反应过程如下所示：
偶联试剂为伯胺或仲胺的情况中，反应如下式所示：
Figure PCTCN2016079500-appb-000056
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000057
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
R1、R2各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基，或者R1、R2和与其相邻的N原子一起形成3-至20-元的环(如取代或未取代的吡咯、吲哚、唑类、苯并唑以及芳杂环)，或者R1为RcC(O)-，其中Rc选自：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH。
上述反应过程中，铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
所述的配体没有特别的限制，可以为上文中所述的任意一种配体，优选为L-I-25、L-I-27、L-II-7、L-II-9、L-II-31、L-II-38、L-II-64，最优选为L-II-31、L-II-38或L-II-64。
优选的碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾、碳酸铯，最优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，优选DMSO、DMF，最优选DMSO。
反应温度在50-180℃，优选100-130℃。
偶联试剂为其他氨源的情况中，反应如下所示：
Figure PCTCN2016079500-appb-000058
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000059
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-、芳基NHC(O)-)、C2-C10的酰胺基(烷基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
所述的氨源选自下组：氨气、氨水、氯化铵、碳酸铵、碳酸氢铵、硫酸铵、硝酸铵、磷酸铵、磷酸氢二铵、叠氮化钠，优选氨气、氨水、氯化铵和磷酸氢二铵。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
配体为1(Ligand)可以为上文中所述的任意一种，优选L-I-27、L-II-9、L-II-38、L-II-64、L-II-71、L-II-72，最优选L-II-38或L-II-71。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸铯、磷酸钾，最优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，优选DMSO、DMF，最优选DMSO。
反应温度在50-180℃，优选100-130℃。
在本发明的一个优选地实施方式中，芳基氯代物与含氮芳杂环的偶联反应如下式所示：
Figure PCTCN2016079500-appb-000060
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000061
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
Figure PCTCN2016079500-appb-000062
为取代或未取代的含有N原子的3-至20-元的环，所述3-至20-元的环可以是饱和的或不饱和的(优选地选自下组：吡咯、吲哚、唑类、苯并唑以及相应带有取代基的芳杂环)；
上述反应过程中，铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选Cu2O。
所述的配体没有特别的限制，可以为上文中所述的任意一种配体，优选为L-II-82。
优选的碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾、碳酸铯，最优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，优选DMSO、DMF，最优选DMSO。
反应温度在50-180℃，优选100-130℃。
在本发明的一个优选地实施方式中，芳基氯代物与酰胺的偶联反应如下式所示：
Figure PCTCN2016079500-appb-000063
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000064
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
Rc、R2各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
或Rc和R2以及相邻的C(O)NH共同形成取代或未取代的C3-C20的环烷基、取代或未取代的3-至20-元的杂环基
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH。
上述反应过程中，铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选Cu2O。
所述的配体没有特别的限制，可以为上文中所述的任意一种配体，优选为L-II-83，L-II-90。
优选的碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾、碳酸铯，最优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六 环，优选DMSO、DMF，最优选DMSO。
反应温度在50-180℃，优选100-130℃。
2.草酸(单、双)酰胺配体促进的铜催化的芳基氯代物的C-O偶联反应
Figure PCTCN2016079500-appb-000065
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000066
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、-CN、MeS-、砜基、磺酰胺基。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
配体为1所述的任意一种，优选L-II-34。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，优选DMSO。
反应温度在50-180度，优选100-130度。
3.草酸(单、双)酰胺配体促进的铜催化的芳基氯代物的C-S偶联反应
Figure PCTCN2016079500-appb-000067
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000068
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、-CN、MeS-、砜基、磺酰胺基。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
配体为1所述的任意一种，优选L-II-34。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，优选DMSO。
反应温度在50-180度，优选100-130度。
4.草酸(单、双)酰胺配体促进的铜催化的芳基氯代物的C-S偶联反应
Figure PCTCN2016079500-appb-000069
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000070
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、-CN、MeS-、砜基、磺酰胺基。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO、CuSCN、CuCN、Cu(acac)2，优选CuI。
配体为1所述的任意一种，优选L-II-3，L-II-37。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六 环，优选DMSO。
反应温度在50-180度，优选100-130度。
5.草酸(单、双)酰胺配体促进的铜催化的芳基氯代物的C-O偶联反应
Figure PCTCN2016079500-appb-000071
其中各基团的定义如上文中所述，
Figure PCTCN2016079500-appb-000072
选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、取代或未取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、-CN、MeS-、砜基、磺酰胺基。
铜催化剂可以为CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2，CuO,CuSCN,CuCN,Cu(acac)2,优选Cu(acac)2。
配体为1所述的任意一种，优选L-II-65，L-II-93。
碱可以为碳酸钾、碳酸铯、磷酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化锂、氢氧化钠、四丁基氢氧化铵，和/或该碱的水合物，优选氢氧化锂。
溶剂可以为DMSO、DMF、DMA、NMP、乙腈、叔丁醇、异丙醇、THF、1,4-二氧六环，叔丁醇，和/或前述一种或多种溶剂与水的混合物，优选DMSO/H2O。
反应温度在50-180度，优选100-130度。
与现有技术相比，本发明的主要优点包括：
1.提供了一类能够高效率地进行铜催化的芳基氯代物偶联反应的催化体系，所述的催化体系能够使在常规的芳基溴代物和芳基碘代物偶联体系下难以进行的芳基氯代物偶联反应顺利进行，且底物兼容性好，催化体系适用范围广。
2.相较于现有技术中的芳基氯代物偶联反应方法，本发明的方法采用成本较低的铜催化剂体系，且配体结构简单，制备方便，用量少，反应经济。
3.本发明的催化体系所使用的原料芳基氯代物与其他芳基卤代物相比，原料成本低，来源广泛，具有很好的大规模应用前景。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1、配体的合成(以L-I-27、L-II-9、L-II-31为例)
方法i：
Figure PCTCN2016079500-appb-000073
将2,4,6-三甲氧基苯胺(30mmol)和三乙胺(36mmol)溶于150mL四氢呋喃，2,4,6-三甲氧基苯胺的浓度为0.2mol/L。冰水浴冷却，搅拌，再滴加草酰氯单甲酯(33mmol)，体系变浑浊，产生三乙胺盐酸盐。滴加完毕后撤除冰水浴，自然恢复室温，继续搅拌1～2小时，TLC监测2,4,6-三甲氧基苯胺完全消耗，可停止搅拌进行后处理。
用滤纸对反应液减压抽滤，滤除三乙胺盐酸盐，滤饼再用少量四氢呋喃冲洗(不可用乙酸乙酯冲洗，否则三乙胺盐酸盐会溶解)。滤液减压浓缩后，对残余物进行硅胶柱层析纯化，洗脱剂为石油醚：乙酸乙酯＝5:1，得淡黄色固体7.48g，产率93％。
当制备草酸单酰胺单乙酯时，使用草酰氯单乙酯替代草酰氯单甲酯。
1H NMR(400MHz,CDCl3)δ8.12(s,1H),6.16(s,2H),3.94(s,3H),3.81(s,9H)；13C NMR(100MHz,CDCl3)δ161.49,160.64,156.07,154.55,105.72,91.18,56.10,55.66,53.73；HRMS(ESI)calcd.for C12H16NO6(M+H)+:270.0972,Found:270.0973.
方法ii：
Figure PCTCN2016079500-appb-000074
将上述所得的2,4,6-三甲氧基苯胺的草酸单酰胺单甲酯(10mmol)溶于10mL THF，底物浓度为1.0mol/L。再加入1.3mL苄胺(12mmol)，搅拌，加热至70～80℃，1小时后TLC监测，原料消失，撤除加热，静置，使反应瓶自然冷却至室温，再放入冰箱冷冻，即析出白色固体。待固体完全析出后，滤纸减压抽滤，红外烘箱烘干，再用油泵抽干，得白色固体2.94g，产率86％。
当制备其他酰胺时，使用其他胺(如甲胺水溶液，二乙胺等)替代苄胺。
1H NMR(400MHz,CDCl3)δ3.80(s,6H),3.81(s,3H),4.53(d,J＝6.4Hz,2H),6.16(s,2H),7.30-7.38(m,5H),7.79(br s,1H),8.51(s,1H)；13C NMR(100MHz,CDCl3)δ160.40,159.95,158.24,156.03,136.92,128.80,128.03,127.83,105.69,90.96,55.96,55.53,43.86；HRMS(ESI)calcd.for C18H21N2O5(M+H)+:345.1445,Found:345.1444.
方法II：
Figure PCTCN2016079500-appb-000075
将2-苯氧基苯胺(30mmol)和三乙胺(31.5mmol)溶于100mL四氢呋喃中，2-苯氧基苯胺的浓度为0.3mol/L。冰水浴冷却，搅拌，再滴加草酰氯(15.8mmol)，体系变浑浊，产生三乙胺盐酸盐。滴加完毕后撤除冰水浴，自然恢复室温，继续搅拌2小时，TLC监测至2-苯氧基苯胺完全消耗，即可停止搅拌进行后处理。
用强磁棒吸出搅拌子，减压蒸除四氢呋喃，向残余物中加50mL蒸馏水，用刮刀将瓶壁固体刮下，全部浸入蒸馏水中，搅拌成浆，此时三乙胺盐酸盐全部溶解到水中，而 二酰胺产物不溶。滤纸减压抽滤，滤饼用少量冷乙醚洗涤，最后刮下滤饼，红外烘箱烘干，再用油泵抽干，得白色固体5.45g，产率86％。
1H NMR(400MHz,CDCl3)δ9.96(s,2H),8.46(dd,J＝8.0,1.7Hz,2H),7.43–7.30(m,4H),7.22–7.01(m,10H),6.89(dd,J＝8.0,1.5Hz,2H)；13C NMR(100MHz,CDCl3)δ157.36,156.06,146.73,129.97,127.97,125.40,124.18,123.75,120.49,119.02,117.60；HRMS(ESI)calcd.for C26H21N2O4(M+H)+:425.1496,Found:425.1492.
其余配体(新化合物)的合成：
Figure PCTCN2016079500-appb-000076
Figure PCTCN2016079500-appb-000077
Figure PCTCN2016079500-appb-000078
Figure PCTCN2016079500-appb-000079
Figure PCTCN2016079500-appb-000080
Figure PCTCN2016079500-appb-000081
Figure PCTCN2016079500-appb-000082
以下配体按照方法II制备：
Figure PCTCN2016079500-appb-000083
Figure PCTCN2016079500-appb-000084
Figure PCTCN2016079500-appb-000085
实施例2、对甲基氯苯与苄胺偶联反应合成N-对甲基苯基苄胺
Figure PCTCN2016079500-appb-000086
在10mL封管中加入碘化亚铜(0.05mmol)，配体(0.1mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次，再加入对甲基氯苯(0.5mmol)，苄胺(0.75mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析(石油醚:乙酸乙酯＝50:1)，得产品N-对甲基苯基苄胺89mg，产率91％。
1H NMR(400MHz,CDCl3)δ7.34-7.21(m,5H),6.96(d,J＝8.0Hz,2H),6.54(d,J＝8.4Hz,2H),4.28(s,2H),3.88(br s,1H),2.22(s,3H)；13C NMR(100MHz,CDCl3)δ20.6,48.8,113.2,126.9,127.3,127.7,128.8,130.0,139.8,146.1；HRMS(ESI)calcd.for C14H16N(M+H)+:198.1283,Found:198.1287.
实施例3、对甲基氯苯与苄胺偶联反应合成N-对甲基苯基苄胺
本实施例操作同实施例2，采用不同的草酸酰胺配体，所得结果列于下表。
配体编号 产率/％ 配体编号 产率/％ 配体编号 产率/％
L-I-1 62 L-II-9 75 L-II-38 92
L-I-2 64 L-II-13 52 L-II-31 86
L-I-7 65 L-II-14 17 L-II-29 66
L-I-23 62 L-II-7 73 L-II-27 45
L-I-22 59 L-II-15 56 L-II-33 82
L-I-24 44 L-II-16 11 L-II-36 73
L-I-27 74 L-II-24 61 L-II-28 17
L-I-9 55 L-II-18 40 L-II-34 57
L-I-8 67 L-II-1 56 L-II-35 21
L-I-25 75 L-II-8 60 L-II-30 65
L-I-31 40 L-II-5 64 L-II-37 76
L-I-32 34 L-II-6 74 L-II-4 81
L-I-36 17 L-II-41 62 L-II-19 40
L-II-20 70 L-II-21 65 L-II-22 25
L-II-23 60 L-I-4 37 L-I-34 20
L-I-39 64 L-II-61 <10 L-II-59 46
L-II-60 10 L-II-58 81 L-II-62 63
L-II-63 76 L-II-66 89 L-II-64 92
L-II-65 44 L-II-67 <10 L-II-69 23
L-II-70 48 L-II-68 61 L-II-72 77
L-II-71 87 L-II-73 88 L-II-74 85
实施例4、对甲基氯苯与苄胺偶联反应合成N-对甲基苯基苄胺
Figure PCTCN2016079500-appb-000087
本实施例操作同实施例2，采用不同的铜盐催化剂、碱、溶剂和温度，所得结果列于下表。
编号 铜盐 X 碱 溶剂 温度/℃ 产率/％
1 CuI 10 K3PO4 DMSO 120 92
2 CuBr 10 K3PO4 DMSO 120 81
3 CuCl 10 K3PO4 DMSO 120 83
4 CuTc 10 K3PO4 DMSO 120 43
5 Cu(OAc)2 10 K3PO4 DMSO 120 56
6 CuSO4 10 K3PO4 DMSO 120 52
7 CuBr2 10 K3PO4 DMSO 120 49
8 CuCl2 10 K3PO4 DMSO 120 60
9 Cu2O 10 K3PO4 DMSO 120 67
10 CuI 10 K2CO3 DMSO 120 48
11 CuI 10 Cs2CO3 DMSO 120 61
12 CuI 10 Na2CO3 DMSO 120 38
13 CuI 10 KHCO3 DMSO 120 31
14 CuI 10 NaHCO3 DMSO 120 29
15 CuI 10 K3PO4 DMA 120 79
16 CuI 10 K3PO4 DMF 120 86
17 CuI 10 K3PO4 NMP 120 62
18 CuI 10 K3PO4 MeCN 120 49
19 CuI 10 K3PO4 1,4-dioxane 120 33
20 CuI 10 K3PO4 THF 120 30
21 CuI 5 K3PO4 DMSO 120 90
22 CuI 2.5 K3PO4 DMSO 120 81
23 CuI 1 K3PO4 DMSO 120 54
24 CuI 10 K3PO4 DMSO 110 63
25 CuI 10 K3PO4 DMSO 100 38
26a CuI 2.5 K3PO4 DMSO 120 81
a反应放大到5mmol的量，使用L-II-31为配体，同时苄胺减少到1.3当量，CuI减少 到2.5mol％，配体减少到5mol％，磷酸钾减少到1.0当量，溶剂DMSO的量为2mL，反应时间延长到41小时。
实施例5、对甲基氯苯与各类伯胺、仲胺偶联反应合成相应的苯胺衍生物
Figure PCTCN2016079500-appb-000088
在10mL封管中加入碘化亚铜(0.05mmol)，配体L-II-38(0.05或0.1mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次，再加入对甲基氯苯(1.0mmol)，胺(1.5mmol)和1mL DMSO，反应在120℃下均匀搅拌24或48小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品N-对甲基苯基胺。
本实施例使用不同的胺，包括i级、二级脂肪胺，芳香胺，反应条件有A、B两种，条件A针对反应活性较好的胺，条件B针对反应活性相对较弱的胺，所得结果列于下表。
Figure PCTCN2016079500-appb-000089
Figure PCTCN2016079500-appb-000090
Figure PCTCN2016079500-appb-000091
实施例6、芳基氯代物与苄胺偶联反应合成N-苄基苯胺衍生物
Figure PCTCN2016079500-appb-000092
在10mL封管中加入碘化亚铜(0.05mmol)，配体L-II-38(0.05mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次，再加入氯代芳烃(1.0mmol)，苄胺(1.5mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品N-苄基芳香胺。
本实施例使用不同的氯代芳烃，所得结果列于下表。
Figure PCTCN2016079500-appb-000093
Figure PCTCN2016079500-appb-000094
Figure PCTCN2016079500-appb-000095
Figure PCTCN2016079500-appb-000096
实施例7、取代芳香胺的合成(不同的芳基氯代物和不同的胺)
Figure PCTCN2016079500-appb-000097
在10mL封管中加入碘化亚铜(0.05mmol)，配体L-II-38(0.05mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次，再加入氯代芳烃(1.0mmol)，胺(1.5mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品取代芳香胺。
本实施例使用不同的氯代芳烃和不同的胺，所得结果列于下表。
Figure PCTCN2016079500-appb-000098
Figure PCTCN2016079500-appb-000099
实施例8、对氨基苄醇的合成
Figure PCTCN2016079500-appb-000100
在10mL封管中加入对氯苄醇(0.5mmol)，氨源(0.75mmol)，铜盐催化剂(0.05mmol)，配体(0.05mmol)，碱(0.5mmol)，抽真空置换氩气3次，再加入0.5mL溶剂，反应在110℃下均匀搅拌12小时，冷却后用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品对氨基苄醇(淡黄色固体)。
1H NMR(400MHz,CDCl3)δ7.11(d,J＝8.3Hz,2H),6.62(d,J＝8.3Hz,2H),4.49(s,2H),3.22(br s,2H)；13C NMR(100MHz,CDCl3)δ145.9,131.0,128.7,115.1,65.1；LC-MS(ESI,m/z):124.1(M+H)+.
本实施例采用不同的氨源、铜盐催化剂、配体、碱和溶剂，所得结果列于下表。
编号 氨源 铜盐 配体 碱 溶剂 产率/％
1 NH3·H2O CuI L-II-4 K3PO4 DMSO 33
2 NH3·H2O CuI L-II-37 K3PO4 DMSO 62
3 NH3·H2O CuI L-II-41 K3PO4 DMSO 31
4 NH3·H2O CuI L-II-2 K3PO4 DMSO 25
5 NH3·H2O CuI L-II-42 K3PO4 DMSO 30
6 NH3·H2O CuI L-II-8 K3PO4 DMSO <10
7 NH3·H2O CuI L-II-38 K3PO4 DMSO 90
8 NH3·H2O CuI L-II-31 K3PO4 DMSO 68
9 NH3·H2O CuI L-II-34 K3PO4 DMSO 82
10 NH3·H2O CuI L-II-27 K3PO4 DMSO 14
11 NH3·H2O CuI L-II-29 K3PO4 DMSO 42
12 NH3·H2O CuI L-II-30 K3PO4 DMSO 78
13 NH3·H2O CuI L-II-28 K3PO4 DMSO 23
14 NH3·H2O CuI L-II-36 K3PO4 DMSO 49
15 NH4Cl+KOH CuI L-II-1 K3PO4 DMSO 32
16 NH4Cl+KOH CuI L-II-3 K3PO4 DMSO 44
17 NH4Cl+KOH CuI L-II-4 K3PO4 DMSO 63
18 NH4Cl+KOH CuI L-II-5 K3PO4 DMSO 40
19 NH4Cl+KOH CuI L-II-6 K3PO4 DMSO 35
20 NH4Cl+KOH CuI L-II-7 K3PO4 DMSO 33
21 NH4Cl+KOH CuI L-II-9 K3PO4 DMSO 33
22 NH3·H2O CuI L-II-34 K3PO4 DMF 56
23 NH3·H2O CuI L-II-34 K3PO4 DMA 58
24 NH3·H2O CuI L-II-34 K3PO4 NMP 42
25 NH3·H2O CuI L-II-34 K3PO4 MeCN 16
26 NH3·H2O CuI L-II-34 K3PO4 1,4-dioxane <10
27 NH3·H2O CuI L-II-34 K3PO4 THF <10
28 NH4Cl+KOH CuI L-II-34 K3PO4 DMSO 67
29 (NH4)2CO3+KOH CuI L-II-34 K3PO4 DMSO 39
30 (NH4)2SO4+KOH CuI L-II-34 K3PO4 DMSO 59
31 (NH4)2HPO4+KOH CuI L-II-34 K3PO4 DMSO 70
32 NH3(gas,5atm) CuI L-II-34 K3PO4 DMSO 77
33 NaN3 CuI L-II-38 K3PO4 DMSO 43
34 NH3·H2O CuI L-II-34 K2CO3 DMSO 51
35 NH3·H2O CuI L-II-34 Na2CO3 DMSO 17
36 NH3·H2O CuI L-II-34 Cs2CO3 DMSO 90
37 NH3·H2O CuBr L-II-34 K3PO4 DMSO 71
38 NH3·H2O CuCl L-II-34 K3PO4 DMSO 73
39 NH3·H2O Cu2O L-II-34 K3PO4 DMSO 51
40 NH3·H2O Cu(OAc)2 L-II-34 K3PO4 DMSO 43
41 NH3·H2O CuTc L-II-34 K3PO4 DMSO 24
42a NH3·H2O CuI L-II-38 K3PO4 DMSO 68
43a NH3·H2O CuI L-II-64 K3PO4 DMSO 69
44a NH3·H2O CuI L-II-58 K3PO4 DMSO 44
45a NH3·H2O CuI L-II-37 K3PO4 DMSO 77
46a NH3·H2O CuI L-II-71 K3PO4 DMSO 87
47a NH3·H2O CuI L-II-73 K3PO4 DMSO 84
a使用2.0eq氨水(1.0mmol)做氨源，反应温度为105℃。
实施例9、芳香胺的合成
在10mL封管中加入碘化亚铜(0.05mmol)，配体L-II-71(0.05或0.1mmol)，磷酸钾(1.1mmol)，抽真空置换氩气3次，再加入氯代芳烃(1.0mmol)，1mL DMSO和氨水(2.0mmol)，反应在110℃或120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品芳香胺。
本实施例使用不同的氯代芳烃，反应条件有C、D两种，条件C针对反应活性较好的氯代芳烃，条件D针对反应活性相对较弱的氯代芳烃，所得结果列于下表。
Figure PCTCN2016079500-appb-000101
Figure PCTCN2016079500-appb-000102
Figure PCTCN2016079500-appb-000103
Figure PCTCN2016079500-appb-000104
实施例10、4-甲基二苯醚的合成
Figure PCTCN2016079500-appb-000105
在10mL封管中加入苯酚(1.5mmol)，碘化亚铜(0.1mmol)，配体L-II-31(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对甲基氯苯(1.0mmol)和1mL DMSO，反应在120℃下均匀搅拌14小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品4-甲基二苯醚0.1105g，产率60％。
1H NMR(400MHz,CDCl3)δ7.40–7.31(m,2H),7.21–7.15(m,2H),7.14–7.08(m,1H),7.06–7.01(m,2H),7.00–6.93(m,2H),2.38(s,3H)；13C NMR(100MHz,CDCl3)δ158.02,154.91,133.06,130.45,129.83,122.98,119.32,118.53,20.89
实施例11、4-甲基二苯醚的合成
Figure PCTCN2016079500-appb-000106
本实施例操作同实施例2，采用不同的配体、铜盐催化剂、碱、溶剂和温度，所得结果列于下表。
配体编号 铜盐 碱 溶剂 温度/℃ 产率/％
L-II-31 CuI K3PO4 DMSO 120 60
L-II-31 CuBr K3PO4 DMSO 120 57
L-II-31 CuCl K3PO4 DMSO 120 55
L-II-31 CuTc K3PO4 DMSO 120 50
L-II-31 Cu(OAc)2 K3PO4 DMSO 120 43
L-II-31 CuSO4 K3PO4 DMSO 120 49
L-II-31 CuBr2 K3PO4 DMSO 120 52
L-II-31 CuCl2 K3PO4 DMSO 120 56
L-II-31 Cu2O K3PO4 DMSO 120 53
L-II-31 CuI K2CO3 DMSO 120 15
L-II-31 CuI Cs2CO3 DMSO 120 49
L-II-31 CuI K3PO4 NMP 120 44
L-II-31 CuI K3PO4 DMF 120 33
L-II-31 CuI K3PO4 MeCN 120 41
L-II-31 CuI K3PO4 1,4-dioxane 120 37
L-II-31 CuI K3PO4 tBuOH 120 18
L-II-38 CuI K3PO4 DMSO 120 20
L-II-33 CuI K3PO4 DMSO 120 20
L-II-36 CuI K3PO4 DMSO 120 45
L-II-29 CuI K3PO4 DMSO 120 44
L-II-32 CuI K3PO4 DMSO 120 57
L-II-35 CuI K3PO4 DMSO 120 46
L-II-26 CuI K3PO4 DMSO 120 30
L-II-40 CuI K3PO4 DMSO 120 54
L-II-27 CuI K3PO4 DMSO 120 58
L-II-37 CuI K3PO4 DMSO 120 66
L-II-5 CuI K3PO4 DMSO 120 50
L-II-7 CuI K3PO4 DMSO 120 51
L-II-43 CuI K3PO4 DMSO 120 39
L-II-9 CuI K3PO4 DMSO 120 41
L-II-18 CuI K3PO4 DMSO 120 23
L-II-20 CuI K3PO4 DMSO 120 26
L-II-21 CuI K3PO4 DMSO 120 43
L-II-30 CuI K3PO4 DMSO 120 74
L-II-34 CuI K3PO4 DMSO 120 73
L-II-4 CuI K3PO4 DMSO 120 70
L-II-34 CuI K3PO4 DMSO 110 57
L-II-34 CuI K3PO4 DMSO 110 40
L-II-47 CuI K3PO4 DMSO 120 90
实施例12、对甲基氯苯和酚反应合成二芳基醚的反应
Figure PCTCN2016079500-appb-000107
在10mL封管中加入苯酚(1.2mmol)，碘化亚铜(0.05mmol)，配体L-II-34(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次，再加入对甲基氯苯(1.0mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产物二芳基醚。所得结果列于下表。
Figure PCTCN2016079500-appb-000108
Figure PCTCN2016079500-appb-000109
Figure PCTCN2016079500-appb-000110
实施例13、芳基氯代物和R1OH偶联反应合成二芳基醚和芳基烷基醚
Figure PCTCN2016079500-appb-000111
在10mL封管中加入卤代芳烃底物(1.0mmol)，酚(1.2mmol)，碘化亚铜(0.05mmol)，配体L-II-34(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次后加入1mL DMSO，反应在120℃下均匀搅30小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产物二芳基醚。所得结果列于下表。
Figure PCTCN2016079500-appb-000112
Figure PCTCN2016079500-appb-000113
实施例14、4,4’-二甲基二苯基硫醚的合成
Figure PCTCN2016079500-appb-000114
在10mL封管中加入4-甲基苯硫酚(1.5mmol)，碘化亚铜(0.1mmol)，配体L-II-34(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对甲基氯苯(1.0mmol)和1mL DMSO，反应在120℃下均匀搅拌14小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品4,4’-二甲基二苯基硫醚36.4mg，产率17％。
1H NMR(400MHz,CDCl3)δ2.32(s,6H),7.10(d,J＝7.8Hz,2H),7.22-7.25(m,4H)；13C NMR(100MHz,CDCl3)δ21.2,130.0,131.2,132.8,137.0.
实施例15、溴/碘代芳烃和胺反应合成芳香胺
Figure PCTCN2016079500-appb-000115
在10mL封管中加入溴/碘代芳烃底物(1.0mmol)，胺(1.2mmol)，碘化亚铜(0.05mmol)，配体L-II-38(0.05mmol)，磷酸钾(1.0mmol)，抽真空置换氩气3次后加入1mL DMSO，反应在20～70℃下均匀搅5～10小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产物芳香胺。所得结果列于下表。
Figure PCTCN2016079500-appb-000116
实施例16、溴代芳烃和酚反应合成二芳基醚
Figure PCTCN2016079500-appb-000117
在10mL封管中加入卤代芳烃底物(1.0mmol)，酚(1.2mmol)，碘化亚铜(0.05mmol)，配体L-II-37(0.05mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次后加入1mL DMSO，反应在80℃下均匀搅12小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产物二芳基醚。所得结果列于下表。
Figure PCTCN2016079500-appb-000118
Figure PCTCN2016079500-appb-000119
实施例17、对甲氧基氯苯与吡咯偶联反应合成N-对甲氧基苯基吡咯
Figure PCTCN2016079500-appb-000120
在10mL封管中加入氧化亚铜(0.1mmol)，配体(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次，再加入对甲氧基氯苯(1.0mmol)，吡咯(1.3mmol)和0.5mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析(石油醚:乙酸乙酯＝50:1)，N-对甲氧基苯基吡咯88mg，产率51％。
1H NMR(400MHz,CDCl3):δ7.29-7.33(m,2H),6.98-7.01(m,2H),6.90-6.96(m,2H),6.32(t,J＝2.0Hz,2H),3.83(s,3H).GC-MS(EI):m/z＝173[M]+.
实施例18、对甲氧基氯苯与吡咯偶联反应合成N-对甲氧基苯基吡咯
本实施例操作同实施例1，采用不同的草酰胺配体(补充)实验结果下表。
配体编号 产率/％ 配体编号 产率/％ 配体编号 产率/％
L-II-82 51 L-II-83 42 L-II-84 25
L-II-85 48 L-II-86 23 L-II-87 18
L-II-88 36 L-II-89 17 L-II-21 32
L-II-79 28 L-II-80 33 L-II-81 30
L-II-98 22 L-II-99 36    
实施例19、N-芳基杂环的合成
在10mL封管中加入氧化亚铜(0.1mmol)，配体(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次，再加入对甲氧基氯苯(1.0mmol)，氮杂芳基化合(1.3mmol)和0.5mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得N-芳基杂环化合物。
本实施例使用不同的氮杂芳环，所得结果列于下表。
Figure PCTCN2016079500-appb-000121
Figure PCTCN2016079500-appb-000122
实施例20对甲氧基氯苯与苯甲酰胺偶联反应合成N-对甲氧基苯基苯甲酰胺
Figure PCTCN2016079500-appb-000123
在10mL封管中加入氧化亚铜(0.1mmol)，配体L-II-83(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对甲氧基氯苯(1.0mmol)，苯甲酰胺(1.3mmol)和0.5mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析(石油醚:乙酸乙酯＝2:1)，N-对甲氧基苯基苯甲酰胺127mg，产率56％。
1H NMR(400MHz,CDCl3):δ7.85(d,J＝7.2Hz,3H),7.55-7.51(m,3H),7.46(t,J＝7.6Hz,2H),6.90(d,J＝8.8Hz,2H),3.81(s,3H).LC-MS(ESI,m/z):228.1(M+H)+.
实施例21、对甲氧基氯苯与苯甲酰胺偶联反应合成N-对甲氧基苯基苯甲酰胺
本实施例操作同实施例20，采用不同的草酸二酰胺配体实验结果下表。
Figure PCTCN2016079500-appb-000124
实施例22、对甲氧基氯苯与苯甲酰胺偶联反应合成N-对甲氧基苯基苯甲酰胺
Figure PCTCN2016079500-appb-000125
本实施例操作同实施例20，采用不同的铜盐催化剂、碱、溶剂和温度，所得结果列于下表。
编号 铜盐 碱 溶剂 温度/℃ 产率/％
1 CuI K3PO4 DMSO 120 40
2 CuBr K3PO4 DMSO 120 45
3 CuCl K3PO4 DMSO 120 41
4 CuTc K3PO4 DMSO 120 38
5 Cu(OAc)2 K3PO4 DMSO 120 37
6 Cu2O K3PO4 DMSO 120 56
7 CuBr2 K3PO4 DMSO 120 29
8 Cu2O K3PO4 DMSO 120 28
9 Cu2O K3PO4 DMSO 120 39
11 Cu2O K3PO4 DMF 120 28
12 Cu2O K3PO4 MeCN 120 42
13 Cu2O K3PO4 DMSO 130 58
14 Cu2O K3PO4 DMSO 140 55
实施例23、N-芳基苯甲酰胺的合成
在10mL封管中加入氧化亚铜(0.1mmol)，配体(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对甲氧基氯苯(1.0mmol)，酰胺(1.3mmol)和0.5mL DMSO，反应在120℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得N-芳基酰胺。
本实施例使用不同的氯苯和酰胺，所得结果列于下表。
Figure PCTCN2016079500-appb-000126
Figure PCTCN2016079500-appb-000127
实施例24、对氯苯甲醚与烷基或芳基亚磺酸钠的偶联
Figure PCTCN2016079500-appb-000128
在10mL封管中加入甲基亚磺酸钠(0.6mmol)，碘化亚铜(0.05mmol)，配体(0.1mmol)，磷酸钾(1.5mmol)，抽真空置换氩气3次，再加入对氯苯甲醚(0.5mmol)和1mL DMSO，反应在120℃下均匀搅拌24小时，冷却后用乙酸乙酯洗下封管内容物，并用硅胶和硅藻土小柱过滤，滤液浓缩后柱层析，得产品。
4-甲氧基甲磺酰苯:1H NMR(400MHz,CDCl3)δ3.05(s,3H),3.90(s,3H),7.04(dd,J＝7.5,2.1Hz,2H),7.88(dd,J＝7.5,2.1Hz,2H)；EI-MS(m/z)186(M+)
4-甲氧基苯磺酰苯：1H NMR(400MHz,CDCl3)δ3.84(s,3H),6.96(m,2H),7.51(m,3H),7.90(m,4H)；EI-MS(m/z)248(M+).
采用不同的配体所得结果列于下表。
Figure PCTCN2016079500-appb-000129
Figure PCTCN2016079500-appb-000130
实施例25、铜催化对甲氧基氯苯合成对甲氧基苯酚
Figure PCTCN2016079500-appb-000131
在10mL封管中加入乙酰丙酮铜(Cu(acac)2)(0.025mmol)，配体L-II-93(0.025mmol)，一水氢氧化锂(1.05mmol)，抽真空置换氩气3次，氩气下依次加入对甲氧基氯苯(0.5mmol)，0.8mL DMSO和0.2ml H2O，反应在130℃下均匀搅拌24小时；冷却后加入2ml的1mol/L盐酸，水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析(二氯甲烷:甲醇＝60:1)，得产品对甲氧基苯酚46mg，产率74％。
1H NMR(400MHz,CDCl3)δ6.79-6.61(m,4H),4.96(br s,1H),3.69(s,3H)；13C NMR(100MHz,CDCl3)δ55.9,114.9,116.1,149.6,153.7；ESI-MS:125.1(M+H)+
实施例26、铜催化对甲氧基氯苯合成对甲氧基苯酚
本实施例操作同实施例25，采用不同的草酸二酰胺配体，所得结果列于下表。
配体编号 产率/％ 配体编号 产率/％ 配体编号 产率/％
L-II-30 25 L-II-34 19 L-II-35 4
L-II-58 21 L-II-59 5 L-II-60 6
L-II-62 23 L-II-64 27 L-II-65 64
L-II-91 2 L-II-92 8 L-II-93 74
L-II-94 9 L-II-95 2 L-II-96 37
L-II-97 41        
实施例27、铜催化对甲氧基氯苯合成对甲氧基苯酚
本实施例操作同实施例25，配体选用L-II-93，采用不同的铜催化剂、碱、溶剂，所得结果列于下表。
Figure PCTCN2016079500-appb-000132
Figure PCTCN2016079500-appb-000133
实施例28、铜催化芳基氯合成取代苯酚
Figure PCTCN2016079500-appb-000134
在10mL封管中加入乙酰丙酮铜(Cu(acac)2)(0.025mmol)，配体L-II-93(0.025mmol)，一水氢氧化锂(1.05mmol)，抽真空置换氩气3次，氩气下依次加入芳基氯(0.5mmol)，0.8mL DMSO和0.2ml H2O，反应在130℃下均匀搅拌24小时；冷却后加入2mL的1mol/L盐酸，水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品取代苯酚。
Figure PCTCN2016079500-appb-000135
实施例28、铜催化芳基碘/溴合成取代苯酚
Figure PCTCN2016079500-appb-000136
在10mL封管中加入乙酰丙酮铜(Cu(acac)2)(0.1mmol)，配体L-II-65(0.1mmol)，一水氢氧化锂(4.2mmol)，抽真空置换氩气3次，氩气下依次加入对甲氧基碘苯或对甲氧基溴苯(2mmol)，1.6mL DMSO和0.4ml H2O，反应在80℃下均匀搅拌12小时；冷却后加入6mL的1mol/L盐酸，水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品对甲氧基苯酚(碘代物收率95％，溴代物收率93％)。
实施例29、对溴苯甲醚和苄胺的偶联反应
Figure PCTCN2016079500-appb-000137
在10mL封管中加入铜催化剂(0.01mmol)，配体(0.01mmol)，碱(1.5mmol)，抽真空置换氩气3次，再加入对溴苯甲醚(1.0mmol)，苄胺(1.5mmol)和1mL溶剂，反应在80℃下均匀搅拌12小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得产品N-对甲氧基苯基苄胺。
所得结果列于下表。
编号 铜催化剂 配体 碱 溶剂 温度/℃ 产率/％
1 CuI L-II-94 K3PO4 DMSO 80 45
2 CuI L-II-94 KOH DMSO 80 76
3 CuI L-II-94 NaOH DMSO 80 96
4 CuI L-II-94 NaOAc DMSO 80 94
5 Cu2O L-II-93 KOH DMSO 80 98
6 Cu2O L-II-93 NaOH DMSO 80 97
7 Cu2O L-I-16 KOH tBuOH 80 98
8* Cu2O L-I-16 NaOH tBuOH 70 94
*：70℃反应24小时。
实施例30、对甲氧基溴苯与其他偶联试剂的偶联反应
Figure PCTCN2016079500-appb-000138
在10mL封管中加入铜催化剂(0.1mmol)，配体(0.1mmol)，磷酸钾(2.0mmol)，抽真空置换氩气3次，再加入溴代芳烃(1.0mmol)，1mL DMSO和偶联试剂(2.0mmol)，反应在90℃下均匀搅拌24小时，冷却后加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取2次，合并有机相，用无水硫酸钠干燥，浓缩后柱层析，得相应的偶联产物。实验结果如下：
Figure PCTCN2016079500-appb-000139
Figure PCTCN2016079500-appb-000140
在本发明提及的所有文献都在本申请中引用作为参考，就如同每i篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种如下式I所示的化合物的用途：
    Figure PCTCN2016079500-appb-100001
    其中，R选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    Ra选自(a)或(b)：
    (a)OR’；其中，所述的R’选自下组：取代或未取代的C1-C6烷基；或
    (b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构(优选地，N(R”)2为NHR”)；
    Rb选自下组：H、C1-C6的烷基；
    或Rb与R以及相邻的氮原子共同构成取代或未取代的3-至20-元的杂芳基，或取代或未取代的3-至20-元的杂环基；
    所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基；
    其特征在于，作为配体用于铜催化的芳基卤代物偶联反应；其中，所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物，或其组合。
  2. 如权利要求1所述的用途，其特征在于，所述的R选自下组：取代或未取代的苯基、取代或未取代的萘基、取代或未取代的苄基、取代或未取代的喹啉基、取代或未取代的
    Figure PCTCN2016079500-appb-100002
    取代或未取代的金刚烷基、取代或未取代的C1-C6烷基、取代或未取代的
    Figure PCTCN2016079500-appb-100003
    或R、Rb和相邻的氮原子共同构成取代或未取代的选自下组的基团：
    Figure PCTCN2016079500-appb-100004
  3. 如权利要求1所述的用途，其特征在于，所述的R选自下组：取代或未取代的 苯基、取代或未取代的萘基、取代或未取代的苄基、C1-C4烷基、吡啶基、金刚烷基；
    所述的Ra选自(a)或(b)：
    (a)OR’；其中，所述的R’选自下组：取代或未取代的C1-C6烷基；或
    (b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构。
  4. 一种芳基卤代物偶联反应方法，其特征在于，所述的方法包括：用铜作为催化剂，用如下式I所示的化合物作为配体，进行所述的偶联反应：
    Figure PCTCN2016079500-appb-100005
    其中，R选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    Ra选自(a)或(b)：
    (a)OR’；其中，所述的R’选自下组：取代或未取代的C1-C6烷基；或
    (b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    Rb选自下组：H、C1-C6的烷基；
    或Rb与R以及相邻的氮原子共同构成取代或未取代的3-至20-元的杂芳基，或取代或未取代的3-至20-元的杂环基；
    所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、氰基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基；
    其中，所述的芳基卤代物选自下组：芳基氯代物、芳基溴代物、芳基碘代物，或其组合。
  5. 如权利要求4所述的方法，其特征在于，在所述反应中，所述配体与反应物芳基卤代物的摩尔比为1～50:100，优选为5～20:100；和/或
    所述配体与铜催化剂的摩尔比为1～5:1，优选为1～2:1。
  6. 如权利要求4所述的方法，其特征在于，所述的反应包括：
    Figure PCTCN2016079500-appb-100006
    在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100007
    与偶联试剂反应，得到
    Figure PCTCN2016079500-appb-100008
    化合物；
    其中，X选自下组：N、O或S；
    Y选自下组：Cl、Br、I；
    Figure PCTCN2016079500-appb-100009
    选自下组：取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基；其中，所述的取代指芳基上的一个或多个氢原子被选自下组的取代基取代：卤素、硝基、氰基、未取代或被1个或2个C1-C6的烷基或C2-C10的酰基(烷基-CO-)取代的氨基、羟基、未取代或卤代的C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、3-至20-元的杂芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH、羟基-C1-C10的亚烷基、MeS-、砜基、磺酰胺基；其中，所述芳基上的两个相邻的碳原子上的两个氢原子可以被-(CH2)n-取代(n为1、2、3、4、5或6)；
    所述的偶联试剂选自下组：氨水、氨气、铵盐(优选为氯化铵、碳酸铵、硫酸铵、磷酸氢铵，或其组合)/氢氧化物溶液(优选为氢氧化钾溶液)、
    Figure PCTCN2016079500-appb-100010
    (具有2-19个碳原子，可以为饱和，部分不饱和或芳香性环)、RcC(O)NHR2、R1SO2M(优选地，M为钠、钾)、叠氮化钠、NHR1R2、R1OH、R1SH、氢氧化物(优选氢氧化锂，或磷酸钾、碳酸钾、碳酸铯与水的混合物)；
    R1、R2、Rc各自独立地选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烯基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C5烷基-C3-C20的环烷基、取代或未取代的3-至20-元的杂环基，或取代或未取代的C1-C5烷基-3-至20-元的杂环基；
    或R1和R2以及相邻的氮原子共同形成取代或未取代的3-至20-元的杂环基、取代或未取代的3-至20-元的杂芳基；
    或Rc和R2以及相邻的C(O)NH共同形成取代或未取代的3-至20-元的杂环基、取代或未取代的3-至20-元的杂芳基；
    其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、氰基、氧(即基团上同一个碳原子上的两个氢原子被＝O取代)、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基、C1-C6烷基-S-。
  7. 如权利要求4所述的方法，其特征在于，所述的反应温度在50-180℃，优选100-130℃。
  8. 如权利要求4所述的方法，其特征在于，所述的反应包括以下(1)、(2)、(3)、(4)、 (5)、(6)、(7)或(8)：
    (1)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100011
    与NHR1R2反应，得到
    Figure PCTCN2016079500-appb-100012
    Figure PCTCN2016079500-appb-100013
    其中，各基团的定义如上文中所述；优选地，在反应(1)中，所述的反应温度在50-180℃，优选100-130℃；
    (2)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100014
    与氨源反应，得到
    Figure PCTCN2016079500-appb-100015
    Figure PCTCN2016079500-appb-100016
    其中，各基团的定义如上文中所述；优选地，在反应(2)中，所述的反应温度在50-180℃，优选100-130℃；
    所述的氨源选自下组：氨气、氨水、氯化铵、碳酸铵、碳酸氢铵、硫酸铵、硝酸铵、磷酸铵、磷酸氢二铵、叠氮化钠，优选氨气、氨水、氯化铵和磷酸氢二铵；
    (3)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100017
    与R1OH反应，得到
    Figure PCTCN2016079500-appb-100018
    Figure PCTCN2016079500-appb-100019
    其中，各基团的定义如上文中所述；优选地，在反应(3)中，所述的反应温度为50-180℃，优选100-130℃；
    (4)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100020
    与R1SH反应，得到
    Figure PCTCN2016079500-appb-100021
    Figure PCTCN2016079500-appb-100022
    其中，各基团的定义如上文中所述；优选地，在反应(4)中，所述的反应温度为50-180℃，优选100-130℃；
    (5)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100023
    与
    Figure PCTCN2016079500-appb-100024
    反应，得到
    Figure PCTCN2016079500-appb-100025
    Figure PCTCN2016079500-appb-100026
    其中，
    Figure PCTCN2016079500-appb-100027
    为取代或未取代的含有N原子的3-至20-元的环，所述3-至20-元的环可以是饱和、不饱和或芳香性的，其余各基团的定义如上文中所述；
    (6)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100028
    与
    Figure PCTCN2016079500-appb-100029
    反应，得到
    Figure PCTCN2016079500-appb-100030
    Figure PCTCN2016079500-appb-100031
    其中，Rc选自下组：H、取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或 取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    或Rc和R2以及相邻的C(O)NH共同形成取代或未取代的3-至20-元的杂环基、取代或未取代的3-至20-元的杂芳基；
    所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基NHC(O)-、芳基NHC(O)-)、-COOH，
    其余各基团的定义如上文中所述；
    (7)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100032
    与R1SO2M反应，得到
    Figure PCTCN2016079500-appb-100033
    Figure PCTCN2016079500-appb-100034
    其中，各基团的定义如上文中所述。
    (8)在惰性溶剂中，用
    Figure PCTCN2016079500-appb-100035
    与氢氧化物或碱水解所得OH-反应，得到
    Figure PCTCN2016079500-appb-100036
    Figure PCTCN2016079500-appb-100037
    其中，各基团的定义如上文中所述。
  9. 一种芳基偶联反应的催化体系，其特征在于，所述的反应体系包括：铜催化剂、配体、碱、有机溶剂；
    其中，所述的铜催化剂选自下组：CuI、CuBr、CuCl、CuTc、Cu(OAc)2、CuSO4、Cu2O、CuBr2、CuCl2、CuO,CuSCN,CuCN,Cu(acac)2,或其组合；优选为CuI、Cu2O、Cu(acac)2；
    所述的碱选自下组：碳酸钾、碳酸铯、磷酸钾、碳酸氢钠、碳酸氢钾、碳酸钠，氢氧化锂、氢氧化钠、四丁基氢氧化铵，和/或该碱的水合物，或其组合；优选为磷酸钾、碳酸铯、氢氧化锂；
    所述的溶剂选自下组：DMSO、DMF、DMA、NMP、乙腈、异丙醇、1,4-二氧六环、四氢呋喃、甲苯、叔丁醇，或其组合；优选为DMSO，和/或DMF，和/或DMSO/H2O；
    所述的配体具有以下式(I)所示的结构：
    Figure PCTCN2016079500-appb-100038
    其中，各基团的定义如权利要求1中所述。
  10. 一种如下式(I)所示的化合物：
    Figure PCTCN2016079500-appb-100039
    其中，R选自下组：取代或未取代的C1-C6烷基、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或 未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    Ra选自(a)或(b)：
    (a)OR’；其中，所述的R’选自下组：Me、Et；或
    (b)N(R”)2；其中，各个R”各自独立地选自下组：H、取代或未取代的C6-C20的芳基、取代或未取代的3-至20-元的杂芳基、取代或未取代的C7-C25的烷基-芳基、取代或未取代的C1-C5烷基-3-至20-元的杂芳基、取代或未取代的C3-C20的环烷基，或取代或未取代的3-至20-元的杂环基；其中，所述的杂芳基或杂环基中具有1-5个选自下组的杂原子：N、O或S；所述的环烷基或杂环基可以为单环、多环、螺环或桥环结构；
    Rb选自下组：H、C1-C6的烷基；
    或Rb与R以及相邻的氮原子共同构成取代或未取代的3-至20-元的杂芳基，或取代或未取代的3-至20-元的杂环基；
    且当Ra选自(a)、R’为H时，R为甲基取代的萘基；
    所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C10的芳基、C6-C10的芳基-氧基、C2-C10的酯基(烷基-COO-)、C2-C10的酰基-烷氧基(烷基-OOC-)、C2-C10的酰基(烷基-CO-)、C2-C10的酰胺基(烷基/芳基NHC(O)-)、-COOH、硝基、氰基、羟基、氨基、被1个或2个C1-C6的烷基取代的氨基。
  11. 如权利要求10所述的化合物，其特征在于，所述的式(I)化合物选自下组：
    Figure PCTCN2016079500-appb-100040
    Figure PCTCN2016079500-appb-100041
    Figure PCTCN2016079500-appb-100042
    Figure PCTCN2016079500-appb-100043
  12. 如权利要求10或11所述的化合物的制备方法，其特征在于，通过选自方法(i)、(ii)或(II)的方法进行：
    方法(i)包括步骤：
    Figure PCTCN2016079500-appb-100044
    在惰性溶剂中，用R-NH-Rb和
    Figure PCTCN2016079500-appb-100045
    进行反应，得到式(I)化合物；
    方法(ii)包括步骤：
    Figure PCTCN2016079500-appb-100046
    在惰性溶剂中，用R”-NH2和
    Figure PCTCN2016079500-appb-100047
    进行反应，得到式(I)化合物；
    方法(II)包括步骤：
    Figure PCTCN2016079500-appb-100048
    在惰性溶剂中，用R-NH2和草酰氯反应，得到式(I)化合物；
    其中，各基团的定义如权利要求10中所述。
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