Heterocyclic carboxylic acid amide ligand and applications thereof in copper catalyzed coupling reaction of aryl halogeno substitute

Abstract

Provided are a heterocyclic carboxylic acid amide ligand and applications thereof in a copper catalyzed coupling reaction. Specifically, provided are uses of a compound represented by formula (I), definitions of radical groups being described in the specifications. The compound represented by formula (I) can be used as the ligand in the copper catalyzed coupling reaction of the aryl halogeno substitute, and is used or catalyzing the coupling reaction for forming the aryl halogeno substitute having CN, CO, CS and other bonds. ##STR00001##

Claims

1. A method for coupling reaction of an aryl halide, comprising: carrying out the coupling reaction by using copper as a catalyst and a compound of following formula I as a ligand: ##STR00389## wherein R.sub.1 is selected from the group consisting of: a substituted or unsubstituted pyrrole and a substituted or unsubstituted indole; R.sup.2 is selected from the group consisting of: a 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, and 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure; R.sub.3 is selected from the group consisting of: hydrogen, and a substituted or unsubstituted C1-C6 alkyl; or R.sub.2 and R.sub.3 together with the connected N atom to form a substituted or unsubstituted pyrrole or a substituted or unsubstituted indole; wherein the aryl halide is an aryl chloride.

2. The method of claim 1, wherein in the coupling reaction, the molar ratio of the ligand to the reactant aryl halide is 1-50:100; and/or the molar ratio of the ligand to the copper catalyst is 1-5:1.

3. The method of claim 1, wherein the reaction comprises: ##STR00390## in an inert solvent, reacting ##STR00391## with a coupling reagent to obtain compound ##STR00392## wherein X is selected from the group consisting of: N, O and S; Y is selected from the group consisting of: Cl, Br, and I; ##STR00393## is selected from the group consisting of: a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl; wherein the substituted means that one or more hydrogen atoms on the aryl group is substituted by a substituent selected from the group consisting of: halogen, nitro, cyano, amino which is unsubstituted or substituted with 1 or 2 C1-C6 alkyl or C2-C10 acyl (alkyl-CO), hydroxy, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, 3- to 20-membered heteroaryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl group (alkyl-CO), C2-C10 acyl-alkoxy group (alkyl-OOC), C2-C10 amide group (alkyl-NHC(O), aryl-NHC(O)), COOH, hydroxy-C1-C10 alkylene, MeS, sulfonyl, sulfamine; wherein two hydrogen atoms on adjacent carbon atoms of the aryl may be substituted by (CH2)n- (n is 1, 2, 3, 4, 5 or 6); the coupling reagent is selected from the group consisting of: ammonia water, ammonia gas, ammonium salt/hydroxide solution, ##STR00394## (number of carbon atom is 2-20), R.sub.eC(O)NHR.sub.d, R.sub.cSO.sub.2M, sodium azide, NHR.sub.cR.sub.d, R.sub.cOH, R.sub.cSH, hydroxide, and salts that can be hydrolyzed to form hydroxide, wherein M is sodium or potassium; R.sub.c, R.sub.d, R.sub.e are each independently selected from the group consisting of: H, a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, 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 group, substituted or unsubstituted C1-C5 alkyl-(C3-C20 cycloalkyl group), substituted or unsubstituted 3- to 20-membered heterocyclic group, and substituted or unsubstituted C1-C5 alkyl-(3- to 20-membered heterocyclic group); or R.sub.c and R.sub.d together form a substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3- to 20-membered heterocyclic group; or R.sub.e and R.sub.d together form a substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of: N, O and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple cyclic, spiral or bridged ring structure; the substituted means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of: halogen, cyano, oxygen (i.e., two hydrogen atoms on the same carbon atom on the group are replaced by O), a 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 group (alkyl/aryl NHC(O)), COOH, nitro, hydroxy, amino, amino substituted by 1 or 2 C1-C6 alkyl groups, C1-C6 alkyl-S.

4. The method of claim 1, wherein the reaction temperature is 50-180 C.

5. The method of claim 1, wherein the reaction comprises (1), (2), (3), (4) or (5): (1) reacting ##STR00395## with NHR.sub.cR.sub.d in an inert solvent to give ##STR00396## wherein the groups are defined as above; (2) reacting ##STR00397## with ammonia source in an inert solvent to obtain ##STR00398## wherein the groups are defined as above; the ammonia source is selected from the group consisting of: ammonia gas, ammonium hydroxide, ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, ammonium sulfate, ammonium nitrate, ammonium phosphate, diammonium hydrogen phosphate, and sodium azide; (3) in an inert solvent, reacting ##STR00399## with R.sub.cOH to provide ##STR00400## wherein the groups are defined as above; (4) in an inert solvent, reacting ##STR00401## with R.sub.cSO.sub.2M to provide ##STR00402## wherein the groups are defined as above; (5) in an inert solvent, reacting ##STR00403## with R.sub.cSH to provide ##STR00404## wherein the groups are defined as above.

6. The method of claim 1 wherein the copper catalyst is selected from the group consisting of: CuI, CuBr, CuCl, CuTc, Cu(OAc).sub.2, CuSO.sub.4, Cu.sub.2O, CuBr.sub.2, CuCl.sub.2, CuO, CuSCN, CuCN, Cu(acac).sub.2, and combinations thereof.

7. The method of claim 1, wherein the reaction is carried out in the presence of a base selected from the group consisting of: potassium carbonate, cesium carbonate, potassium phosphate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, and combinations thereof.

8. The method of claim 5, wherein, in the reaction (1), the ligand is ##STR00405## in the reaction (2), the ligand is selected from the group consisting of: ##STR00406## in the reaction (3), the ligand is selected from the group consisting of: ##STR00407## or in the reaction (5), the ligand is ##STR00408##

9. The method of claim 1, wherein the compound is of following formula II structure: ##STR00409## wherein R.sub.2 is selected from the group consisting of: a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure; R.sub.4 is selected from the group consisting of: H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure; or, the compound is of following formula III structure: ##STR00410## wherein R.sub.2 is selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-(3- to 20-membered heteroaryl), substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of: N, O and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure; R.sub.5 is selected from the group consisting of: H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-(3- to 20-membered heteroaryl), substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of: N, O and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure; wherein the number of R.sub.5 substituent is 1-3, wherein the substitution position may be ortho or meta, and wherein each R.sub.5 may be the same or different; where the number of R.sub.5 substituent is 2, the adjacent R.sub.5 may be linked to form a ring.

10. The method of claim 1, wherein the ligand is selected from the group consisting of: ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418##

11. The method of claim 2, wherein in the coupling reaction, the molar ratio of the ligand to the reactant aryl halide is 5-20:100; and/or the molar ratio of the ligand to the copper catalyst is 1-2:1.

12. The method of claim 4, wherein the reaction temperature is 100-130 C.

13. The method of claim 5, wherein the ammonia source is selected from the group consisting of: ammonia gas, ammonium hydroxide, ammonium chloride, and diammonium hydrogen phosphate.

Description

EMBODIMENTS FOR CARRYING OUT THE INVENTION

(1) After long-term and intensive research, the inventors have provided a class of oxalic acid (mono or bis) amide ligands suitable for copper-catalyzed coupling reaction of aryl chloride. A suitable catalytic system composed by the ligand, copper, bases and solvents can be used for the copper-catalyzed coupling reaction of aryl halides, especially for promoting the copper-catalyzed coupling of aryl chlorides with various nucleophiles to form CN, CO, CS bond which are difficult to occur under conventional conditions, thus synthesizing many useful small molecule compounds. The method has various advantages, such as mild reaction, conditions, wide application range and good industrial application prospect.

Terms

(2) As used herein, the term halogen refers to fluorine, chlorine, bromine, and iodine.

(3) The term halogenated means that one or more hydrogen atoms on a group are replaced by halogens.

(4) The term alkyl refers to a straight or branched alkyl group. When the alkyl group is limited by the number of carbon atoms (such as C1-C6), it means that the alkyl group has 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

(5) The term cycloalkyl refers to a unit having a saturated or partially saturated monocyclic, bicyclic or tricyclic (cyclo, bridged or spiro) ring system. The cycloalkyl may have 3 to 20 carbon atoms. When a certain cycloalkyl has a carbon number limit (such as C3-C20), it means that the cycloalkyl group has 3-20 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. The cycloalkyl may be in the monocyclic, multiple cyclic, spiro or bridged ring form.

(6) As used herein, the term alkoxy refers to an alkyl (e.g., O-alkyl, wherein alkyl is as defined above) attached through an oxygen atom, such as, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like. When the alkoxy is limited by the number of carbon atoms (e.g., C1-C6), it means that the alkoxy has 1-6 carbon atoms.

(7) The term aryl refers to an aromatic hydrocarbon group of monocyclic, bicyclic or fused ring which may be substituted or unsubstituted. When an aryl is defined by the number of carbon atoms (e.g., C6-C20), it means that the aryl has 6-20 carbon atoms. Examples of aryl groups are, for example (but not limited to), phenyl, biphenyl, naphthyl, or the like (each carbon atom of which may be optionally substituted).

(8) The term heteroaryl refers to a aromatic group of monocyclic, bicyclic or fused ring comprising at least one heteroatom selected from N, O or S. The heteroaryl may be a 3- to 20-membered aromatic ring, having 1 to 5 heteroatoms each independently selected from N, O or S. Examples of heteroaryl are, for example (but not limited to), pyridine, pyrimidine, pyrrole, oxazole, indole, furan, benzofuran, thiophene, or the like.

(9) The term 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 a 3- to 20-membered heterocyclic group having 1 to 5 heteroatoms each independently selected from 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 oxynitridyl group, and the like.

(10) The term ester group refers to a group having the structure of alkyl-COO, wherein the alkyl is as defined above.

(11) The term acyl refers to a group having the structure alkyl-CO, wherein the alkyl is as defined above.

(12) The term amido refers to a group having the structure alkyl NHC(O) or aryl NHC(O), wherein the alkyl, aryl are as defined above.

(13) Ligand

(14) Unless otherwise stated, a ligand as referred herein refers to a ligand used in a copper-catalyzed coupling reaction of aryl chloride.

(15) The ligand which can be used in the present invention has a structure as shown in the above formula (I), and in a preferred embodiment of the present invention, the ligand has the following structure (each group is as described above):

(16) ##STR00175##

(17) Wherein R.sub.1 is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(18) R.sup.2 is selected from the group consisting of a 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, and substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heteroaryl or heterocyclic group has 1 to 5 heteroatoms selected from the group consisting of N, O and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure;

(19) R.sub.3 is selected from the group consisting of hydrogen, and a substituted or unsubstituted C1-C6 alkyl;

(20) or R.sub.2 and R.sub.3 together with the connected N atom to form a 3- to 20-membered saturated or unsaturated ring (e.g., a substituted or unsubstituted pyrrole, indole, azole, benzoxazole, and aromatic heterocycle).

(21) In another preferred embodiment, in the compound, any one of R.sub.1, R.sub.2, and R.sub.3 is the group corresponding to the group in the specific compounds in the present application.

(22) In another preferred embodiment, the structure of the ligand is as shown in Formula II:

(23) ##STR00176##

(24) Wherein R.sub.2 is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(25) R.sub.4 is selected from the group consisting of H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure.

(26) In another preferred embodiment, the number of R.sub.4 substituent is 1-4, the substitution position may be ortho or meta, and each R.sub.4 may be the same or different. When the number of R.sub.4 substituent is 2, the adjacent R.sub.4 may be linked to form a ring.

(27) In another preferred embodiment, the structure of the ligand is as shown in Formula

(28) ##STR00177##

(29) Wherein R.sub.2 is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure;

(30) R.sub.5 is selected from the group consisting of H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure.

(31) In another preferred embodiment, the number of R.sub.5 substituent is 1-3, the substitution position may be ortho or meta, and each R.sub.5 may be the same or different. When the number of R.sub.5 substituent is 2, the adjacent R.sub.5 may be linked to form a ring.

(32) In another preferred embodiment, the structure of the ligand is as shown in Formula VI:

(33) ##STR00178##

(34) Wherein R.sub.2 is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(35) R.sub.6 is selected from the group consisting of H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure.

(36) In another preferred embodiment, the number of R.sub.6 substituent is 1-4, the substitution position may be ortho or meta, and each R.sub.6 may be the same or different. When the number of R.sub.6 substituent is 2, the adjacent R.sub.6 may be linked to form a ring.

(37) In another preferred embodiment, the structure of the ligand is as shown in Formula Va, Vb, or Vc:

(38) ##STR00179##

(39) Wherein R.sub.2 is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(40) R.sub.7 is selected from the group consisting of H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure.

(41) In another preferred embodiment, the number of R.sub.7 substituent is 1 or 2, and each R.sub.7 may be the same or different. When the number of R.sub.7 substituent is 2, the adjacent R.sub.7 may be linked to form a ring (preferably 6-20 membered aromatic rings, such as benzene rings).

(42) In another preferred embodiment, the structure of the compound is as shown in the formula VIa, VIb, or VIc:

(43) ##STR00180##

(44) Wherein R.sub.2 is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure;

(45) R.sub.8 is selected from the group consisting of H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure.

(46) In another preferred embodiment, the number of R.sub.8 substituent is 1-3, and each R.sub.8 may be the same or different. When the number of R.sub.8 substituent is 2, the adjacent R.sub.8 may be linked to form a ring (preferably 6-20 membered saturated or unsaturated aromatic rings).

(47) In another preferred embodiment, the structure of the ligand is as shown in Formula VII:

(48) ##STR00181##

(49) Wherein R.sub.2 is selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-(3- to 20-membered heteroaryl), substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(50) R.sub.9 is selected from the group consisting of H, nitro, halogen, a substituted or unsubstituted C1-C6 alkyl, alkoxy (such as C1-C6 alkoxy), 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, Spiro or bridged ring structure;

(51) A is 3- to 12-membered saturated or unsaturated heterocyclic group wherein the heterocyclic group contains 1 to 4 heteroatoms each independently selected from N, O, and S.

(52) In another preferred embodiment, A is a 5-membered heterocyclic ring containing one N atom.

(53) In another preferred embodiment, A is furan, thiophene or pyrrole.

(54) In another preferred embodiment, the number of R.sub.9 substituent is 1-3, and each R.sub.9 may be the same or different. When the number of R.sub.9 substituent is 2, the adjacent two R.sub.9 may be linked to form a ring (preferably 6-20 membered saturated or unsaturated aromatic rings, such as benzene ring).

(55) Each of the above ligands may be obtained commercially, or prepared according to the preferred methods provided herein.

(56) It should be understood that since the bond energy of CBr and CI bonds is lower than that of CCl bond, the coupling reaction of aryl bromide and aryl iodide is more likely to occur, compared with the aryl chloride under the same conditions. Therefore, in addition to the coupling reaction of aryl chloride, the above ligand can also be used in the coupling reaction of aryl bromide or aryl iodide which is conventional in the art.

(57) Copper-Catalyzed Coupling Reaction of Aryl Chlorides

(58) The present invention also provides a copper-catalyzed coupling reaction method for aryl chlorides, which comprises carrying out the above reaction by using a compound of the formula (I) as described above as a ligand.

(59) Generally, aryl iodide and aryl bromide exhibit higher reactivity, so that the corresponding coupling reaction can be better realized under the catalyzation of transition metals such as palladium, copper, nickel, etc.; compared with brominated (iodinated) aromatic hydrocarbons, chlorinated aromatic hydrocarbons are cheaper and more promising; however, due to the high energy of CCl bond, the aryl chlorides are difficult to react under the conventional catalytic conditions for aryl bromides and aryl iodides.

(60) The ligands and reaction conditions can be optimized for different reactants within the scope of the present invention, thereby selecting the most suitable ligand type and reaction conditions (such as temperature, solvent, reactant ratio, reaction time, etc.). After the disclosure of the present application, the above optimization is within the skill of those skilled in the art.

(61) Several of the most preferred copper-catalyzed coupling reactions of aryl chloride are as follows:

(62) 1. Copper-Catalyzed CN Coupling Reaction of Aryl Chlorides Promoted by Heterocyclic Carboxylic Acid Amide Ligands

(63) In the above reaction, the selection of the coupling reagent is not particularly limited, which may be the corresponding primary or secondary amine, or may be another ammonia source such as ammonia gas, ammonium hydroxide or ammonium salt, sodium azide or the like. The specific reaction process is as follows:

(64) In the case where the coupling reagent is a primary or secondary amine, the reaction is as follows:

(65) ##STR00182##

(66) wherein the groups are defined as above.

(67) ##STR00183##
is selected from the group consisting of a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl; wherein said substituted refers to one or more hydrogen atoms on the aryl group are substituted by substituents selected from the group consisting of halogen, nitro, cyano, a substituted or unsubstituted amino, hydroxy, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO), C2-C10 amide group (alkyl NHC(O), aryl NHC(O)), COOH, hydroxy-C1-C10 alkylene, MeS, sulfonyl, sulfonamide group;

(68) R.sub.c, R.sub.d are each independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-(3- to 20-membered heteroaryl), substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein said heteroaryl or heterocyclic group has 1-5 heteroatoms selected from the group consisting of N, O and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure; the substituted means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of halogen, a C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO), C2-C10 amide (alkyl NHC(O), aryl NHC(O)), COOH.

(69) In the above reaction, the copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc).sub.2, CuSO.sub.4, Cu.sub.2O, CuBr.sub.2, CuCl.sub.2, CuO, CuSCN, CuCN, Cu(acac).sub.2, preferably CuI.

(70) The ligand is not particularly limited, and may be any of the ligands described above, preferably L53 or L103.

(71) A preferred base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogencarbonate, preferably potassium phosphate, cesium carbonate, and most preferably potassium phosphate.

(72) The solvent can be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO, DMF, most preferably DMSO.

(73) The reaction temperature is 50-180 C., preferably 100-130 C.

(74) In the cases where the coupling reagent is other ammonia source, the reaction is as follows:

(75) ##STR00184##
wherein the groups are defined as above.

(76) ##STR00185##
is selected from the group consisting of a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl; wherein said substituted means that one or more hydrogen atoms on the aryl group are substituted by substituents selected from the group consisting of halogen, nitro, cyano, a substituted or unsubstituted amino, hydroxy, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO, aryl NHC(O)), C2-C10 amide group (alkyl NHC(O)), COOH, hydroxy-C1-C10 alkylene, MeS, sulfonyl, sulfonamide group;

(77) The ammonia source is selected from the group consisting of ammonia gas, ammonium hydroxide, ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, ammonium sulfate, ammonium nitrate, ammonium phosphate, diammonium hydrogen phosphate, sodium azide, preferably ammonia gas, ammonium hydroxide, ammonium chloride and diammonium hydrogen phosphate.

(78) 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).

(79) The copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc).sub.2, CuSO.sub.4, Cu.sub.2O, CuBr.sub.2, CuCl.sub.2, CuO, CuSCN, CuCN, Cu(acac).sub.2, preferably CuI.

(80) The ligand is any one of the above, preferably L13, L15 or L31.

(81) The base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, preferably cesium carbonate or potassium phosphate, most preferably potassium phosphate.

(82) The solvent can be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO, DMF, most preferably DMSO.

(83) The reaction temperature is 50-180 C., preferably 100-130 C.

(84) 2. Copper-Catalyzed CO Coupling Reaction of Aryl Chlorides Promoted by Heterocyclic Carboxylic Acid Amide Ligands

(85) ##STR00186##

(86) wherein the groups are defined as above.

(87) ##STR00187##
is selected from the group consisting of a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl; wherein said substituted means that one or more hydrogen atoms on the aryl group are substituted by substituents selected from the group consisting of halogen, nitro, cyano, a substituted or unsubstituted amino, hydroxy, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO), C2-C10 amide group (alkyl NHC(O), aryl NHC(O)), COOH, hydroxy-C1-C10 alkylene, MeS, sulfonyl, sulfonamide group;

(88) R.sub.c is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(89) the substituted means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of halogen, a C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO), C2-C10 amide group (alkyl NHC(O), aryl NHC(O)), COOH, CN, MeS, sulfonyl, sulfonamide group.

(90) The copper catalyst may be CuI, CuBr, CuCl, CuTc, Cu(OAc).sub.2, CuSO.sub.4, Cu.sub.2O, CuBr.sub.2, CuCl.sub.2, CuO, CuSCN, CuCN, Cu(acac).sub.2, preferably CuI.

(91) The ligand is any one of the above, preferably L13, L15 or L35.

(92) The base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogencarbonate, preferably potassium phosphate.

(93) The solvent can be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO.

(94) The reaction temperature is 50-180 C., preferably 100-130 C.

(95) 3. Copper-Catalyzed CS Coupling Reaction of Aryl Chlorides Promoted by Heterocyclic Carboxylic Acid Amide Ligands

(96) ##STR00188##

(97) Wherein the groups are defined as above.

(98) ##STR00189##
is selected from the group consisting of a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl; wherein said substituted means that one or more hydrogen atoms on the aryl group are substituted by substituents selected from the group consisting of halogen, nitro, cyano, a substituted or unsubstituted amino, hydroxy, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO), C2-C10 amide group (alkyl NHC(O), aryl NHC(O)), COOH, hydroxy-C1-C10 alkylene, MeS, sulfonyl, sulfonamide group;

(99) R.sub.c is selected from the group consisting of a 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, and substituted or 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 and S; the cycloalkyl or heterocyclic group may be of monocyclic, multiple-cyclic, spiro or bridged ring structure;

(100) the substituted means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of halogen, a C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO), C2-C10 acyl (alkyl-CO), C2-C10 amide group (alkyl NHC(O), aryl NHC(O)), COOH, CN, MeS, sulfonyl, sulfonamide group.

(101) The ligand is any one described in 1, preferably L-92 or L-105.

(102) The base may be potassium carbonate, cesium carbonate, potassium phosphate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogencarbonate, preferably potassium phosphate.

(103) The solvent can be DMSO, DMF, DMA, NMP, acetonitrile, tert-butanol, isopropanol, THF, 1,4-dioxane, preferably DMSO.

(104) The reaction temperature is 50-180 C., preferably 100-130 C.

(105) Compared with the Prior Art, the Main Advantages of the Present Invention Includes:

(106) 1. A catalytic system capable of efficiently performing copper-catalyzed coupling reaction of aryl chloride is provided, which is able to promote coupling reaction of aryl chloride which are difficult to be carried out under conventional aryl bromide and aryl iodide coupling systems, and is of good substrate compatibility as well as wide application range.

(107) 2. Compared with the coupling reaction method of aryl chloride in the prior art, the method of the invention adopts a copper catalyst system with lower cost, while the ligand is of simple structure, easily to be prepared, and used in less amount, and the reaction is economical.

(108) 3. Compared with other aryl halides, the raw material, aryl chloride used in the catalytic system of the invention possesses advantages, such as low raw material cost, wide source, and good prospect of large-scale application.

(109) The present invention will be further illustrated below with reference to the specific examples. It should be understood that these examples are only to illustrate the invention but not to limit the scope of the invention. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacturer's instructions. Unless indicated otherwise, parts and percentage are calculated by weight.

Example 1: Ligand Types 1-4, Prepared by the Acyl Chloride Method

(110) ##STR00190##

(111) Benzimidazole-2-carboxylic acid or indol-2-carboxylic acid (1.0 eq) was added into a single-opening bottle, and DCM (0.5 M) and 1-2 drops of DMF were added and stirred (some substrates did not dissolve), the bottle was sealed with a rubber stopper, and a balloon was connected. Oxalyl chloride (3.0 eq) was added dropwise into the system, and a large amount of gas was released during the dropping process (the balloon was expanded by HCl, CO.sub.2, CO gas). After the addition, the mixture was stirred at room temperature for 2-3 hours, and the stirrer was taken out after the stirring was stopped. DCM and excess oxalyl chloride were removed by rotary evaporation, dried by suction to obtain the solid, which was acid chloride (there may be some salt formed with hydrochloric acid, so the reaction with the amine in the next step requires an excess of triethylamine). In the above formula, R corresponds to R.sub.2 of the formula I of the present invention.

(112) Benzylamine or substituted aromatic amine was dissolved in THF, and triethylamine was added, while the above acid chloride was added into the system under stirring (the solid can be directly scraped off and added in portions, or dissolved in THF and added dropwise). After the addition, the mixture was stirred at room temperature until the reaction was completed. The THF was removed by rotary distillation and dried. Water was added, suction filtered, and washed with cold diethyl ether to provide the solid.

(113) TABLE-US-00002 Structure of the ligand Structure characterization L-1, yield 90% .sup.1H NMR (400 MHz, CDCl.sub.3) 9.33 (s, 1H), 7.64 (dq, J = 8.1, 1.0 Hz, 1H), 7.44 (dq, J = 8.2, 0.9 Hz, 1H), 7.41-7.34 (m, 4H), 7.34-7.27 (m, 2H), 7.18-7.11 (m, 1H), 6.84 (dd, J = 2.2, 1.0 Hz, 1H), 6.45 (s, 1H), 4.69 (d, J = 5.8 Hz, 2H); HRMS (ESI) calcd for C.sub.16H.sub.15N.sub.2O (M + H).sup.+ 251.1179, found 251.1178. L-2, yield 92% .sup.1H NMR (400 MHz, CDCl.sub.3) 9.68 (s, 1H), 7.93 (s, 1H), 7.71-7.64 (m, 3H), 7.49-7.43 (m, 1H), 7.43-7.36 (m, 2H), 7.35-7.28 (m, 1H), 7.22-7.14 (m, 2H), 7.03 (dd, J = 2.1, 0.9 Hz, 1H); HRMS (ESI) calcd for C.sub.15H.sub.13N.sub.2O (M + H).sup.+ 237.1022, found 237.1025. L-3, yield 88% .sup.1H NMR (400 MHz, CDCl.sub.3) 9.77 (s, 1H), 8.63 (s, 1H), 8.53 (dd, J = 7.9, 1.7 Hz, 1H), 7.70 (dd, J = 8.0, 1.0 Hz, 1H), 7.49 (dd, J = 8.3, 0.9 Hz, 1H), 7.35- 7.27 (m, 1H), 7.20-7.14 (m, 1H), 7.14-7.07 (m, 1H), 7.07-7.01 (m, 2H), 6.95 (dd, J = 8.0, 1.5 Hz, 1H), 3.98 (s, 3H); HRMS (ESI) calcd for C.sub.16H.sub.15N.sub.2O.sub.2 (M + H).sup.+ 267.1128, found 267.1131. L-4, yield 90% .sup.1H NMR (400 MHz, d6-DMSO) 11.71 (s, 1H), 10.11 (s, 1H), 7.77-7.61 (m, 3H), 7.50-7.43 (m, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.21 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.01-6.89 (m, 2H), 3.75 (s, 3H); HRMS (ESI) calcd for C.sub.16H.sub.14N.sub.2NaO.sub.2 (M + Na).sup.+ 289.0947, found 289.0948. L-6, yield 95% .sup.1H NMR (500 MHz, d6-DMSO) 11.71 (s, 1H), 9.86 (s, 1H), 7.66 (dd, J = 8.0, 1.0 Hz, 1H), 7.46 (dd, J = 8.3, 1.0 Hz, 1H), 7.41-7.33 (m, 2H), 7.30 (dd, J = 7.5, 1.6 Hz, 1H), 7.27-7.16 (m, 3H), 7.07 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 2.27 (s, 3H); HRMS (ESI) calcd for C.sub.16H.sub.14N.sub.2NaO (M + Na).sup.+ 273.0998, found 273.0999. L-7, yield 85% .sup.1H NMR (400 MHz, CDCl.sub.3) 9.32 (s, 1H), 8.64-8.51 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.22-7.14 (m, 3H), 7.13-7.09 (m, 2H), 7.06 (td, J = 7.8, 1.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.90-6.86 (m, 1H); HRMS (ESI) calcd for C.sub.21H.sub.17N.sub.2O.sub.2 (M + H).sup.+ 329.1285, found 329.1290. L-10, yield 86% .sup.1H NMR (400 MHz, d6-DMSO) 11.74 (s, 1H), 9.94 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.43-7.34 (m, 2H), 7.34-7.17 (m, 4H), 7.11-7.03 (m, 1H), 3.23 (h, J = 6.7 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H); HRMS (ESI) calcd for C.sub.18H.sub.18N.sub.2NaO (M + Na).sup.+ 301.1311, found 301.1310. L-12, yield 90% .sup.1H NMR (400 MHz, D6-DMSO) 11.71 (s, 1H), 9.73 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 1.3 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.95 (s, 2H), 2.27 (s, 3H), 2.17 (s, 6H). .sup.13C NMR (101 MHz, D6-DMSO) 159.78, 136.58, 135.74, 135.45, 132.18, 131.42, 128.39, 127.12, 123.48, 121.56, 119.85, 112.34, 103.09, 20.57, 18.06. ESI-MS m/z 279.3(M + H).sup.+; HRMS Calcd. For C.sub.18H.sub.19N.sub.2O (M + H).sup.+ requires 279.1492 found: 279.1496. L-13, yield 91% .sup.1H NMR (500 MHz, d6-DMSO) 11.70 (s, 1H), 9.79 (s, 1H), 7.66 (dd, J = 8.0, 1.1 Hz, 1H), 7.46 (dd, J = 8.2, 1.0 Hz, 1H), 7.37 (dd, J = 2.2, 0.9 Hz, 1H), 7.21 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.14 (s, 3H), 7.07 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 2.22 (s, 6H); HRMS (ESI) calcd for C.sub.17H.sub.17N.sub.2O (M + H).sup.+ 265.1335, found 265.1338. 00 L-14, yield 89% .sup.1H NMR (500 MHz, d6-DMSO) 11.74 (s, 1H), 9.89 (s, 1H), 7.67 (d, J = 8.0, Hz, 1H), 7.48 (dd, J = 8.2, 0.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.32 (dd, J = 6.6, 2.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.21 (dd, J = 8.1, 1.0 Hz, 1H), 7.11-7.05 (m, 1H), 2.67 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H).; .sup.13C NMR (126 MHz, d6-DMSO) 160.23, 139.83, 136.69, 135.27, 131.43, 128.62, 127.54, 127.10, 126.50, 126.09, 123.58, 121.62, 119.86, 112.38, 103.47, 24.07, 14.18. ESI-MS m/z 265.3(M + H).sup.+; HRMS Calcd. For C.sub.17H.sub.16N.sub.2O (M + H).sup.+ requires 264.1263; found: 264.1262 01 L-15, yield 85% .sup.1H NMR (400 MHz, D6-DMSO) 11.63 (s, 1H), 9.81 (s, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.49-7.34 (m, 8H), 7.33-7.25 (m, 1H), 7.22-7.15 (m, 1H), 7.10 (s, 1H), 7.07-7.00 (m, 1H).; .sup.13C NMR (101 MHz, D6-DMSO) 160.21, 139.10, 137.96, 136.60, 134.38, 131.33, 130.36, 128.60, 128.30, 128.14, 127.87, 127.17, 126.98, 126.70, 123.57, 121.60, 119.82, 112.33, 103.34. ESI-MS m/z 313.3(M + H).sup.+; HRMS Calcd. For C.sub.21H.sub.16N.sub.2NaO (M + Na).sup.+ requires 335.1155; found: 335.1 158. 02 L-20, yield 90% .sup.1H NMR (400 MHz, d6-DMSO) 11.84 (s, 1H), 9.87 (s, 1H), 7.76 (dd, J = 7.1, 2.4 Hz, 1H), 7.45-7.38 (m, 2H), 7.38-7.31 (m, 2H), 7.27-7.19 (m, 3H), 7.12-6.96 (m, 5H); HRMS (ESI) calcd for C.sub.21H.sub.15FN.sub.2NaO.sub.2 (M + Na).sup.+ 369.1010, found 369.1010. 03 L-22, yield 90% .sup.1H NMR (400 MHz, D6-DMSO) 11.74 (s, 1H), 10.14 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 5.5 Hz, 2H), 7.48 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 7.24 (dt, J = 9.8, 7.6 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 2.33 (s, 3H); .sup.13C NMR (101 MHz, D6-DMSO) 159.67, 138.89, 137.84, 136.81, 131.56, 128.55, 127.05, 124.25, 123.75, 121.74, 120.66, 119.91, 117.35, 112.39, 103.83, 21.25. HRMS Calcd. For C.sub.16H.sub.14N.sub.2NaO (M + Na).sup.+ requires 273.0998; found: 273.1004._ 04 L-26, yield 93% .sup.1H NMR (400 MHz, d6-DMSO) 11.60 (s, 1H), 9.74 (s, 1H), 7.83-7.75 (m, 1H), 7.39-7.29 (m, 3H), 7.26-7.19 (m, 2H), 7.16 (d, J = 1.4 Hz, 1H), 7.12- 7.06 (m, 2H), 7.05-6.97 (m, 3H), 6.85 (dd, J = 8.9, 2.4 Hz, 1H), 3.75 (s, 3H); HRMS (ESI) calcd for C.sub.22H.sub.19N.sub.2O.sub.3 (M + H).sup.+ 359.1390, found 359.1390. 05 L-28, yield 80% .sup.1H NMR (400 MHz, d6-DMSO) 11.57 (s, 1H), 9.74 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.14 (s, 3H), 7.04 (dd, J = 8.4, 1.7 Hz, 1H), 2.38 (s, 3H), 2.21 (s, 6H); HRMS (ESI) calcd for C.sub.18H.sub.19N.sub.2O (M + H).sup.+ 279.1492, found 279.1494. 06 L-29, yield 92% .sup.1H NMR (400 MHz, D6-DMSO) 11.73 (s, 1H), 9.79 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.28-7.14 (m, 4H), 7.09-7.04 (m, 1H), 2.58 (q, J = 7.5 Hz, 4H), 1.12 (t, J = 7.6 Hz, 6H). .sup.13C NMR (101 MHz, D6-DMSO) 160.51, 141.96, 136.61, 133.67, 131.36, 127.43, 127.11, 126.17, 123.53, 121.57, 119.88, 112.36, 103.16, 24.56, 14.58. ESI-MS m/z 293.3(M + H).sup.+; HRMS Calcd. For C.sub.19H.sub.21N.sub.2O (M + H).sup.+ requires 293.1648; found: 293.1651. 07 L-30, yield 90% .sup.1H NMR (400 MHz, D6-DMSO) 11.72 (s, 1H), 9.79 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.47 (ddd, J = 12.2, 8.1, 2.1 Hz, 2H), 7.38-7.32 (m, 1H), 7.32-7.25 (m, 2H), 7.24-7.15 (m, 2H), 7.09-7.03 (m, 1H), 1.36 (s, 9H).; .sup.13C NMR (101 MHz, D6-DMSO) 160.93, 147.29, 136.62, 135.62, 132.07, 131.82, 127.33, 127.14, 126.88, 126.54, 123.54, 121.64, 119.85, 112.37, 103.34, 34.96, 30.92. ESI-MS m/z 293.3(M + H).sup.+; HRMS Calcd. For C.sub.19H.sub.21N.sub.2O (M + H).sup.+ requires 293.1648.; found: 293.1651. 08 L-31, yield 89% .sup.1H NMR (400 MHz, D6-DMSO) 11.60 (s, 1H), 9.37 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.30-7.23 (m, 1H), 7.23- 7.15 (m, 1H), 7.05 (t, J = 6.8 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 3.75 (s, 6H). .sup.13C NMR (101 MHz, D6-DMSO) 159.86, 156.34, 136.46, 131.75, 127.89, 127.16, 123.36, 121.57, 119.73, 114.33, 112.31, 104.48, 103.34, 55.73. ESI-MS m/z 297.3(M + H).sup.+; HRMS Calcd. For C.sub.17H.sub.17N.sub.2O.sub.3 (M + H).sup.+ requires 297.1234 found: 297.1236. 09 L-32, yield 87% .sup.1H NMR (400 MHz, D6-DMSO) 11.56 (s, 1H), 9.21 (s, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 8.2, 0.6 Hz, 1H), 7.29 (s, 1H), 7.22-7.14 (m, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.31 (s, 2H), 3.82 (s, 3H), 3.74 (s, 7H). .sup.13C NMR (101 MHz, D6-DMSO) 160.12, 159.50, 156.94, 136.40, 131.86, 127.16, 123.26, 121.51, 119.68, 112.27, 107.28, 103.14, 91.07, 55.72. ESI-MS m/z 327.4(M + H).sup.+; HRMS Calcd. For C.sub.18H.sub.19N.sub.2O.sub.4 (M + H).sup.+ requires 327.1339.; found: 327.1342. 0 L-33, yield 80% .sup.1H NMR (400 MHz, D6-DMSO) 11.91 (s, 1H), 10.63 (s, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 7.47 (dd, J = 8.3, 0.7 Hz, 1H), 7.27-7.19 (m, 1H), 7.11-7.04 (m, 1H), 3.11 (s, 3H).; .sup.13C NMR (101 MHz, D6-DMSO) 159.85, 136.92, 131.15, 126.96, 123.99, 121.83, 121.01, 119.99, 112.41, 104.68, 45.29. ESI-MS m/z 280.2(M + H).sup.+; HRMS Calcd. For C.sub.17H.sub.17N.sub.3O (M + H).sup.+ requires 279.1372; found: 279.1375. L-34, yield 81% .sup.1H NMR (400 MHz, D6-DMSO) 12.04 (s, 1H), 10.63 (s, 1H), 9.02 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 7.6, 1.2 Hz, 1H), 8.47 (dd, J = 8.3, 1.6 Hz, 1H), 7.77-7.72 (m, 2H), 7.72-7.64 (m, 2H), 7.51 (dd, J = 8.3, 0.6 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.30-7.23 (m, 1H), 7.15-7.08 (m, 1H).; .sup.13C NMR (101 MHz, D6-DMSO) 159.19, 149.23, 138.07, 137.24, 136.80, 133.93, 131.25, 127.90, 127.13, 127.10, 124.17, 122.43, 122.19, 121.95, 120.21, 116.56, 112.54, 103.35. ESI-MS m/z 288.3(M + H).sup.+; HRMS Calcd. For C.sub.18H.sub.14N.sub.3O (M + H).sup.+ requires 288.1131.; found: 288.1135. L-35, yield 90% .sup.1H NMR (400 MHz, D6-DMSO) 11.78 (s, 1H), 10.31 (s, 1H), 8.00-7.82 (m, 3H), 7.70 (d, J = 8.0 Hz, 1H), 7.57-7.41 (m, 5H), 7.23 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 2.40 (s, 3H). .sup.13C NMR (101 MHz, D6-DMSO) 160.33, 136.72, 133.24, 132.32, 131.25, 130.97, 130.90, 128.72, 127.86, 127.15, 126.85, 126.31, 125.25, 123.61, 123.06, 121.65, 119.89, 112.39, 103.61, 18.29. ESI-MS m/z 301.3(M + H).sup.+; HRMS Calcd. For C.sub.20H.sub.17N.sub.2O (M + H).sup.+ requires 301.1335.; found: 301.1339. L-36, yield 94% .sup.1H NMR (400 MHz, D6-DMSO) 11.74 (s, 1H), 9.81 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 7.21 (dd, J = 11.3, 4.0 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 9.4 Hz, 2H), 2.22 (s, 6H).; .sup.13C NMR (101 MHz, D6-DMSO) 161.49, 159.88, 159.09, 138.44, 138.35, 136.65, 131.14, 131.10, 127.08, 123.59, 121.59, 119.89, 114.15, 113.94, 112.36, 103.38, 18.18. ESI-MS m/z 283.2(M + H).sup.+; HRMS Calcd. For C.sub.17H.sub.16FN.sub.2O (M + H).sup.+ requires 283.1241.; found: 283.1246. L-37, yield 90% .sup.1H NMR (400 MHz, D6-DMSO) 11.73 (s, 1H), 9.79 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.28-7.14 (m, 4H), 7.09-7.04 (m, 1H), 2.58 (q, J = 7.5 Hz, 4H), 1.12 (t, J = 7.6 Hz, 6H). .sup.13C NMR (101 MHz, D6-DMSO) 160.51, 141.96, 136.61, 133.67, 131.36, 127.43, 127.11, 126.17, 123.53, 121.57, 119.88, 112.36, 103.16, 24.56, 14.58. ESI-MS m/z 293.3(M + H).sup.+; HRMS Calcd. For C.sub.19H.sub.21N.sub.2O (M + H).sup.+ requires 293.1648; found: 293.1651. L-38, yield 92% .sup.1H NMR (400 MHz, d6-DMSO) 11.70 (s, 1H), 9.78 (s, 1H), 7.86-7.74 (m, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.32-7.17 (m, 4H), 7.17-6.94 (m, 5H), 6.83 (d, J = 7.0 Hz, 1H), 2.48 (s, 3H); HRMS (ESI) calcd for C.sub.22H.sub.19N.sub.2O.sub.2 (M + H).sup.+ 343.1441, found 343.1445. L-39, yield 81% .sup.1H NMR (400 MHz, d6-DMSO) 11.72 (s, 1H), 9.76 (s, 1H), 7.81-7.72 (m, 1H), 7.39-7.30 (m, 3H), 7.26-7.16 (m, 2H), 7.10 (dt, J = 9.0, 7.7 Hz, 2H), 7.05-6.94 (m, 4H), 6.51 (d, J = 7.6 Hz, 1H), 3.87 (s, 3H); HRMS (ESI) calcd for C.sub.22H.sub.19N.sub.2O.sub.3 (M + H).sup.+ 359.1390, found 359.1390. L-40, yield 90% .sup.1H NMR (400 MHz, d6-DMSO) 11.60 (s, 1H), 9.74 (s, 1H), 7.83-7.75 (m, 1H), 7.39-7.29 (m, 3H), 7.26-7.19 (m, 2H), 7.16 (d, J = 1.4 Hz, 1H), 7.12- 7.06 (m, 2H), 7.05-6.97 (m, 3H), 6.85 (dd, J = 8.9, 2.4 Hz, 1H), 3.75 (s, 3H); HRMS (ESI) calcd for C.sub.22H.sub.19N.sub.2O.sub.3 (M + H).sup.+ 359.1390, found 359.1390. L-42, yield 90% .sup.1H NMR (400 MHz, d6-DMSO) 11.68 (s, 1H), 9.79 (s, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.14 (s, 3H), 7.10 (dd, J = 8.2, 7.1 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 2.52 (s, 3H), 2.22 (s, 6H); HRMS (ESI) calcd for C.sub.18H.sub.19N.sub.2O (M + H).sup.+ 279.1492, found 279.1491. L-43, yield 86% .sup.1H NMR (400 MHz, d6-DMSO) 11.56 (s, 1H), 9.75 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.14 (s, 3H), 7.12 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.9, 2.5 Hz, 1H), 3.77 (s, 3H), 2.21 (s, 6H); HRMS (ESI) calcd for C.sub.18H.sub.19N.sub.2O.sub.2 (M + H).sup.+ 295.1441, found 295.1447. 0 L-44, yield 81% .sup.1H NMR (400 MHz, d6-DMSO) 12.06 (s, 1H), 9.95 (s, 1H), 7.73 (dd, J = 7.4, 2.2 Hz, 1H), 7.40-7.30 (m, 3H), 7.30-7.12 (m, 4H), 7.12-7.05 (m, 1H), 7.05-6.95 (m, 3H), 6.82 (dd, J = 10.7, 7.6 Hz, 1H); HRMS (ESI) calcd for C.sub.21H.sub.16FN.sub.2O.sub.2 (M + H).sup.+ 347.1190, found 347.1188. L-45, yield 80% .sup.1H NMR (400 MHz, d6-DMSO) 11.34 (s, 1H), 10.37 (s, 1H), 8.25 (td, J = 7.9, 1.0 Hz, 2H), 8.21 (d, J = 7.8 Hz, 1H), 8.13 (dd, J = 7.8, 1.0 Hz, 1H), 8.11 (s, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.56-7.27 (m, 7H); HRMS (ESI) calcd for C.sub.21H.sub.16N.sub.3O.sub.3 (M + H).sup.+ 358.1186, found 358.1188. L-46, yield 90% .sup.1H NMR (500 MHz, d6-DMSO) 11.45 (s, 1H), 9.55 (s, 1H), 7.85-7.79 (m, 1H), 7.38-7.32 (m, 2H), 7.24-7.17 (m, 2H), 7.11 (dd, J = 2.2, 0.8 Hz, 1H), 7.09 (tt, J = 7.4, 1.1 Hz, 1H), 7.06 (s, 1H), 7.05-6.97 (m, 3H), 6.87 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H); HRMS (ESI) calcd for C.sub.23H.sub.21N.sub.2O.sub.4 (M + H).sup.+ 389.1496, found 389.1494. L-47, yield 92% .sup.1H NMR (400 MHz, d6-DMSO) 11.55 (s, 1H), 9.64 (s, 1H), 7.83-7.78 (m, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.39-7.32 (m, 2H), 7.24-7.17 (m, 3H), 7.12- 7.06 (m, 1H), 7.05-6.95 (m, 3H), 6.86 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 8.8, 2.3 Hz, 1H), 3.76 (s, 3H); HRMS (ESI) calcd for C.sub.22H.sub.19N.sub.2O.sub.3 (M + H).sup.+ 359.1390, found 359.1394. L-48, yield 90% .sup.1H NMR (400 MHz, d6-DMSO) 12.44 (s, 1H), 10.20 (s, 1H), 8.31 (s, 1H), 7.94-7.87 (m, 2H), 7.54-7.25 (m, 10H); HRMS (ESI) calcd for C.sub.21H.sub.16N.sub.3O.sub.3 (M + H).sup.+ 358.1186, found 358.1179. L-49 .sup.1H NMR (400 MHz, d6-DMSO) 11.60 (s, 1H), 9.74 (s, 1H), 7.84-7.73 (m, 1H), 7.41-7.28 (m, 4H), 7.26-7.18 (m, 2H), 7.15 (d, J = 2.1 Hz, 1H), 7.13- 7.06 (m, 1H), 7.06-6.95 (m, 4H), 2.36 (s, 3H); HRMS (ESI) calcd for C.sub.22H.sub.19N.sub.2O.sub.2 (M + H).sup.+ 343.1441, found 343.1445. L-51, yield 95% .sup.1H NMR (400 MHz, D6-DMSO) 11.59 (s, 1H), 9.31 (s, 1H), 7.11 (s, 3H), 7.02 (d, J = 3.5 Hz, 1H), 6.92 (d, J = 1.1 Hz, 1H), 6.15 (dd, J = 5.7, 2.4 Hz, 1H), 2.18 (s, 6H). .sup.13C NMR (101 MHz, D6-DMSO) 159.15, 135.85, 135.18, 127.66, 126.44, 125.95, 121.77, 110.68, 108.72, 18.19.. ESI-MS m/z 215.2(M + H).sup.+; HRMS Calcd. For C.sub.13H.sub.15N.sub.2O (M + H).sup.+ requires 215.1179; found: 215.1180 L-115, yield 90% .sup.1H NMR (500 MHz, CDCl.sub.3) 9.53 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.55-7.38 (m, 4H), 7.00 (s, 1H), 6.88 (s, 1H), 6.36 (dd, J = 6.0, 2.7 Hz, 1H), 2.47 (s, 3H). .sup.13C NMR (126 MHz, d6-DMSO) 160.21, 133.66, 132.75, 131.79, 131.55, 129.14, 128.23, 126.99, 126.57, 126.30, 125.58, 123.62, 122.47, 111.46, 109.29, 18.80. ESI-MS m/z 251.1 (M + H).sup.+ L-53, yield 92% .sup.1H NMR (400 MHz, CDCl.sub.3) 8.47 (s, 1H), 7.62 (s, 2H), 7.44-7.28 (m, 7H), 4.73 (d, J = 6.1 Hz, 2H); HRMS (ESI) calcd for C.sub.15H.sub.14N.sub.3O (M + H).sup.+ 252.1131, found 252.1131. L-54, yield 88% .sup.1H NMR (400 MHz, CDCl.sub.3) 9.77 (s, 1H), 7.91-7.84 (m, 2H), 7.75 (s, 2H), 7.51-7.40 (m, 4H), 7.29-7.24 (m, 1H); HRMS (ESI) calcd for C.sub.14H.sub.12N.sub.3O (M + H).sup.+ 238.0975, found 238.0975. 0 L-55, yield 85% .sup.1H NMR (400 MHz, CDCl.sub.3) 7.98 (s, 1H), 7.72-7.64 (m, 2H), 7.40-7.32 (m, 2H), 3.12 (d, J = 5.1 Hz, 3H); HRMS (ESI) calcd for C.sub.9H.sub.10N.sub.3O (M + H).sup.+ 176.0818, found 176.0817. L-56, yield 90% .sup.1H NMR (400 MHz, CDCl.sub.3) 9.21 (s, 1H), 7.64 (s, 2H), 7.41-7.35 (m, 2H), 7.25-7.12 (m, 3H), 2.30 (s, 6H); HRMS (ESI) calcd for C.sub.16H.sub.16N.sub.3O (M + H).sup.+ 266.1288, found 266.1290. L-57, yield 94% .sup.1H NMR (400 MHz, d6-DMSO) 13.42 (s, 1H), 10.12 (s, 1H), 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.54-7.43 (m, 6H), 7.42-7.23 (m, 5H); .sup.13C NMR (100 MHz, d6-DMSO) 157.1, 145.2, 142.3, 138.3, 135.4, 134.7, 134.0, 130.4, 128.9, 128.7, 128.1, 127.6, 125.9, 124.4, 124.4, 122.8, 120.0, 112.6; HRMS (ESI) calcd for C.sub.20H.sub.16N.sub.3O (M + H).sup.+ 314.1288, found 314.1286. L-58, yield 85% .sup.1H NMR (400 MHz, CDCl.sub.3) 11.31 (br s, 1H), 9.21 (s, 1H), 7.76-7.66 (m, 2H), 7.42-7.33 (m, 2H), 7.23 (s, 2H), 7.19-7.14 (m, 1H); HRMS (ESI) calcd for C.sub.10H.sub.10N.sub.3O (M + H).sup.+ 188.0818, found 188.0817. L-112, yield 90% .sup.1H NMR (500 MHz, d6-DMSO) 9.63 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.51-7.37 (m, 6H), 7.31 (m, J = 14.8, 7.4 Hz, 2H). .sup.13C NMR (126 MHz, d6-DMSO) 157.23, 147.30, 138.48, 134.83, 134.70, 130.74, 129.37, 129.25, 129.18, 128.56, 128.17, 125.77, 123.71.

Example 2 Ligand Types 5-8, Prepared by Active Acid Anhydride Method

(114) ##STR00235##

(115) Heterocyclic-2-carboxylic acid (1.0 eq.) was dissolved in THF (0.2 M), N-ethylmorpholine (NEM, 2.5 eq.) was added, and isobutyl chloroformate (1.0 eq.) was added dropwise under ice-water bath. After the addition was completed, the system was stirred for 15 minutes in an ice water bath, and the corresponding amine (1.2 eq.) was slowly added to the system. After the addition, the ice water bath was removed, and the mixture was warmed at room temperature and stirred overnight (part of weak nucleophilic and poorly reactive amines need to be heated to reflux). The obtained suspension was concentrated under reduced pressure, and then water was added. Ethyl acetate was added for extraction, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then vacuum concentrated and purified by silica gel chromatography to provide the amide of the corresponding heterocyclic-2-carboxylic acid, wherein R in the above formula corresponds to R.sub.2 of the formula I of the present invention. (Note: The Boc protecting groups on N in part of ligands need to be further removed, and the methods for removing the protecting groups are conventional Boc group deprotecting methods in the art, such as TFA deprotecting method)

(116) TABLE-US-00003 Structure of the ligand Structure characterization .sup.1H NMR (400 MHz, Chloroform-d) 9.94 (s, 1H), 8.76 (s, 1H), 8.64 (dd, J = 8.1, 1.5 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.48-7.32 (m, 2H), 7.20-7.08 (m, 4H), 7.05 (td, J = 7.8, 1.5 Hz, 1H), 6.89 (dd, J = 8.1, 1.5 Hz, 1H) .sup.1H NMR (500 MHz, d6-DMSO) 10.61 (s, 1H), 8.23 (dd, J = 28.2, 8.0 Hz, 2H), 7.64 (m, J = 26.0, 7.6 Hz, 2H), 7.19-7.09 (m, 3H), 2.20 (s, 6H). .sup.13C NMR (126 MHz, d6-DMSO) 158.61, 153.23, 135.99, 128.24, 128.16, 127.66, 127.50, 124.55, 123.53, 18.52. .sup.1H NMR (400 MHz, Chloroform-d) 10.32 (s, 1H), 8.65 (dd, J = 8.3, 1.2 Hz, 1H), 8.37 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 8.26 (dt, J = 7.8, 1.1 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H),7.54-7.41 (m, 6H), 7.37 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.34 (dd, J = 7.6, 1.7 Hz, 1H), 7.22 (td, J = 7.5, 1.2 Hz, 1H). .sup.1H NMR (400 MHz, Chloroform-d) 9.48 (s, 1H), 8.64 (dt, J = 4.8, 1.2 Hz, 1H), 8.30 (dt, J = 7.7, 1.2 Hz, 1H), 7.91 (td, J = 7.7, 1.8 Hz, 1H), 7.50 (ddd, J = 7.7, 4.8, 1.3 Hz, 1H), 7.19-7.06 (m, 3H), 2.30 (s, 6H). 0 .sup.1H NMR (500 MHz, CDCl.sub.3) 7.58-7.53 (m, 1H), 7.49-7.43 (m, 1H), 7.39- 7.23 (m, 5H), 7.04 (dq, J = 8.0, 3.9 Hz, 1H), 6.74 (m, 1H), 4.57 (dd, J = 8.1, 3.7 Hz, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) 161.92, 138.91, 138.16, 130.07, 128.70, 128.24, 127.84, 127.66, 127.52, 43.91. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.69 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.29 (s, 1H), 7.13 (dd, J = 13.6, 5.8 Hz, 5H), 2.29 (s, 7H). .sup.1H NMR (500 MHz, CDCl.sub.3) 8.55 (d, J = 8.1 Hz, 1H), 8.36 (s, 1H), 7.52 (d, J = 5.0 Hz, 1H), 7.49 (d, J = 3.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.17 (dd, J = 13.4, 7.2 Hz, 2H), 7.11-7.03 (m, 4H), 6.91 (d, J = 8.1 Hz, 1H). .sup.1H NMR (500 MHz, CDCl.sub.3) 8.50 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.50-7.39 (m, 5H), 7.31 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 3.7 Hz, 1H), 7.02 (t, J = 4.3 Hz, 1H). .sup.1H NMR (500 MHz, CDCl.sub.3) 9.03 (s, 1H), 8.64 (dd, J = 8.1, 1.2 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.47-7.38 (m, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.23-7.12 (m, 4H), 7.12-7.05 (m, 1H), 6.92 (dd, J = 8.1, 0.9 Hz, 1H). .sup.13C NMR (126 MHz, CDCl.sub.3) 156.55, 156.33, 154.85, 148.59, 146.19, 130.04, 129.05, 127.65, 127.17, 124.48, 124.18, 123.98, 123.83, 122.75, 120.96, 119.10, 117.55, 112.00, 111.38. .sup.1H NMR (500 MHz, DMSO-d6) = 9.92 (s, 1H), 7.90 (d, J = 7.8, 1H), 7.23- 7.13 (m, 2H), 7.01 (t, J = 7.4, 1H), 3.73 (dd, J = 9.1, 5.2, 1H), 3.28 (s, 1H), 2.96 (M, 1H), 2.85 (M, 1H), 2.21 (s, 3H), 2.10-1.99 (m, 1H), 1.87-1.76 (m, 1H), 1.70-1.60 (m, 2H). .sup.13C NMR (125 MHz, DMSO-d6) 172.99, 136.19, 130.16, 127.94, 126.26, 123.82, 120.82, 60.83, 46.71, 30.39, 26.05, 17.21. MS-ESI: 205.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.12H.sub.17ON.sub.2 (M + H.sup.+): 205.1335, Found: 205.1335. .sup.1H NMR (500 MHz, DMSO-d6) = 9.39 (s, 1H), 7.05 (s, 3H), 3.73 (dd, J = 8.8, 5.4, 1H), 2.92 (t, J = 6.6, 2H), 2.12 (s, 6H), 2.08-2.01 (m, 1H), 1.87- 1.78 (m, 1H), 1.74-1.65 (m, 211). .sup.13C NMR (125 MHz, DMSO-d6) 172.94, 135.05, 134.88, 127.57, 126.15, 60.44, 46.81, 30.73, 25.82, 18.04. MS-ESI: 219.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.13H.sub.19ON.sub.2 (M + H.sup.+): 219.1492, Found: 219.1491. .sup.1H NMR (500 MHz, DMSO-d6) = 10.03 (s, 1H), 7.94 (dd, J = 8.0, 0.9, 1H), 7.23-7.13 (m, 2H), 7.04 (dt, J = 7.5, 1.2, 1H), 3.74 (dd, J = 9.l, 5.1, 1H), 3.01- 2.93 (m, 1H), 2.87-2.80 (m, 1H), 2.58 (q, J = 7.5, 2H), 2.10-1.99 (m, 1H), 1.86-1.76 (m, 1H), 1.70-1.61 (m, 2H), 1.16 (t, J = 7.6, 3H). .sup.13C NMR (125 MHz, DMSO-d6) 173.04, 135.55, 133.58, 128.58, 126.29, 124.05, 121.03, 60.82, 46.74, 30.36, 26.09, 23.93, 13.88. MS-ESI: 219.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.13H.sub.19ON.sub.2 (M + H.sup.+): 219.1492, Found: 221.1490. .sup.1H NMR (500 MHz, DMSO-d6) = 10.19 (s, 1H), 8.28 (d, J = 7.4, 1H), 7.05- 6.99 (m, 2H), 6.92-6.88 (m, 1H), 3.85 (s, 3H), 3.73 (dd, J = 9.2, 5.3, 1H), 3.30 (s, 1H), 2.97 (dt, J = 10.2, 6.6, 1H), 2.77 (dt, J = 10.2, 6.5, 1H), 2.08- 1.99 (m, 1H), 1.85-1.75 (m, 1H), 1.63 (p, J = 6.9, 2H). .sup.13C NMR (125 MHz, DMSO-d6) 173.15, 148.06, 127.24, 123.37, 120.46, 118.34, 110.79, 60.97, 55.86, 46.70, 30.29, 26.07. MS-ESI: 221.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.12H.sub.17O.sub.2N.sub.2 (M + H.sup.+): 221.1285, Found: 221.1283. .sup.1H NMR (500 MHz, DMSO-d6) = 10.09 (s, 1H), 8.30 (dd, J = 8.2, 1.0, 1H), 7.50 (t, J = 7.3, 2H), 7.43 (t, J = 7.4, 1H), 7.40-7.32 (m, 3H), 7.25 (dd, J = 7.6, 1.6, 1H), 7.16 (dt, J = 7.5, 1.2, 1H), 3.60 (dd, J = 9.2, 4.7, 1H), 3.01 (s, 1H), 2.77-2.68 (m, 1H), 2.48-2.42 (m, 1H), 1.99-1.89 (m, 1H), 1.78-1.70 (m, 1H), 1.59-1.43 (m, 2H). .sup.13C NMR (125 MHz, DMSO-d6) 173.25, 137.89, 134.97, 131.96, 129.96, 129.07, 128.75, 128.04, 127.66, 123.70, 120.00, 60.55, 46.35, 30.32, 25.81. MS-ESI: 267.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.17H.sub.19ON.sub.2 (M + H.sup.+); 267.1492, Found: 267.1490. 0 .sup.1H NMR (500 MHz, CDCl.sub.3) 8.01 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.7, 0.8 Hz, 1H), 7.53-7.40 (m, 3H), 7.30 (dd, J = 3.5, 0.7 Hz, 1H), 6.62 (dd, J = 3.5, 1.8 Hz, 1H), 2.48 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 156.93, 147.88, 144.30, 133.67, 132.80, 130.69, 128.79, 128.17, 127.83, 126.71, 125.35, 122.18, 115.32, 112.52, 109.99, 18.80. ESI-MS m/z 252.1 (M + H).sup.+ .sup.1H NMR (400 MHz, Chloroform-d) 9.59 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.42 (ddd, J = 7.9, 6.8, 1.3 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 4.06-3.98 (m, 1H), 3.18- 3.07 (m, 2H), 2.39 (s, 3H), 2.34-2.24 (m, 2H), 2.24-2.12 (m, 1H), 1.98- 1.76 (m, 2H); .sup.13C NMR (101 MHz, Chloroform-d) 174.12, 132.82, 132.53, 130.41, 130.12, 128.91, 128.13, 127.01, 126.38, 125.18, 122.28, 61.01, 47.64, 31.19, 26.49, 18.80. MS-ESI: 255.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.16H.sub.19ON.sub.2 (M + H.sup.+): 255.1492, Found: 255.1490. .sup.1H NMR (400 MHz, Chloroform-d) 7.43 (s, 1H), 7.34-7.21 (m, 5H), 7.13- 7.01 (m, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.55-4.35 (m, 3H), 4.17 (s, 1H), 3.59 (dd, J = 16.3, 10.7 Hz, 1H), 3.10 (dd, J = 16.3, 8.9 Hz, 1H); .sup.13C NMR (101 MHz, Chloroform-d) 173.84, 149.58, 138.26, 128.81, 128.14, 127.87, 127.74, 127.61, 124.91, 120.72, 111.04, 61.45, 43.16, 35.74. .sup.1H NMR (400 MHz, Chloroform-d) 9.56 (s, 1H), 8.51 (dd, J = 8.1, 1.4 Hz, 1H), 7.34-7.27 (m, 2H), 7.18 (td, J = 7.8, 1.5 Hz, 1H), 7.14-7.04 (m, 4H), 7.01-6.93 (m, 3H), 6.85 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.43 (ddd, J = 10.8, 8.5, 5.9 Hz, 1H), 4.20 (d, J = 5.8 Hz, 1H), 3.59 (dd, J = 16.3, 10.8 Hz, 1H), 3.10 (dd, J = 16.3, 8.5 Hz, 1H); .sup.13C NMR (101 MHz, Chloroform-d) 172.11, 156.71, 149.17, 145.62, 129.84, 129.53, 128.08, 127.62, 124.73, 124.45, 124.38, 123.48, 121.02, 120.78, 118.97, 117.88, 111.33, 61.89, 35.53. .sup.1H NMR (500 MHz, CDCl.sub.3) 9.13 (s, 1H), 6.62 (s, 2H), 4.82 (t, J = 7.7 Hz, 1H), 3.19 (m, J = 18.7, 11.5, 7.3 Hz, 2H), 2.33 (m, J = 15.3, 7.1 Hz, 1H), 2.04 (s, 3H), 1.94-1.78 (m, 8H). .sup.13C NMR (126 MHz, dmso) 167.18, 136.55, 135.13, 131.48, 128.94, 59.82, 46.00, 30.20, 23.98, 20.94, 18.27. ESI-MS m/z 233.2 (M + H).sup.+ .sup.1H NMR (500 MHz, d6-DMSO) 9.80 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.81- 7.73 (m, 2H), 7.54-7.37 (m, 3H), 4.76 (s, 1H), 4.27 (d, J = 26.7 Hz, 1H), 4.02 (t, J = 8.1 Hz, 1H), 3.03 (dd, J = 11.4, 4.2 Hz, 1H), 2.86 (d, J = 11.4 Hz, 1H), 2.34-2.22 (m, 3H), 2.10 (dd, J = 13.0, 8.1 Hz, 1H), 1.92 (ddd, J = 13.0, 8.1, 5.1 Hz, 1H), 1.22 (s, 1H). .sup.13C NMR (126 MHz, dmso) 174.22, 132.80, 132.67, 131.60, 130.89, 129.09, 128.23, 126.81, 126.56, 125.53, 123.24, 71.91, 60.20, 55.77, 40.64, 18.64. ESI-MS m/z 271.2 (M + H).sup.+ .sup.1H NMR (400 MHz, Chloroform-d) 8.85 (s, 1H), 7.83-7.66 (m, 3H), 7.47- 7.39 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.22-7.11 (m, 2H), 6.90 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.68-4.45 (m, 2H), 3.64 (dd, J = 16.3, 10.5 Hz, 1H), 3.32 (dd, J = 16.2, 8.3 Hz, 1H), 2.32 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) 173.01, 149.54, 132.92, 132.74, 130.34, 129.32, 128.79, 128.18, 128.15, 127.78, 127.44, 126.54, 125.28, 124.89, 122.06, 120.83, 111.35, 61.66, 35.99, 18.66. .sup.1H NMR (400 MHz, Chloroform-d) 9.40 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 7.42-7.34 (m, 4H), 7.31-7.23 (m, 3H), 7.21-7.15 (m, 1H), 7.12-7.02 (m, 2H), 6.87-6.80 (m, 1H), 6.51 (d, J = 7.8 Hz, 1H), 4.43-4.32 (m, 1H), 3.96 (s, 1H), 3.62 (dd, J = 16.6, 11.1 Hz, 1H), 3.19 (dd, J = 16.6, 7.2 Hz, 1H). .sup.13C NMR (101 MHz, Chloroform-d) 172.19, 148.72, 138.11, 134.67, 132.42, 130.07, 129.37, 128.93, 128.53, 128.39, 127.77, 127.62, 124.79, 124.34, 121.10, 120.54, 111.79, 61.13, 35.79. .sup.1H NMR (500 MHz, d6-DMSO) 9.49 (s, 1H), 7.86 (dd, J = 14.0, 7.9 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.51-7.38 (m, 4H), 3.41 (dd, 10.3, 3.0 Hz, 1H), 3.04 (d, J = 12.6 Hz, 1H), 2.68-2.58 (m, 1H), 2.33-2.25 (m, 4H), 2.02-1.92 (m, 2H), 1.87-1.79 (m, 1H), 1.67-1.33 (m, 7H). .sup.13C NMR (126 MHz, dmso) 173.04, 133.06, 132.67, 131.64, 131.08, 129.08, 128.15, 126.89, 126.49, 125.51, 123.54, 60.44, 45.76, 30.53, 26.21, 24.50, 18.67. ES1-MS m/z 269.2 (M + H).sup.+ 1H NMR (500 MHz, CDCl3) 9.89 (s, 1H), 8.71 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 8.36 (dt, J = 7.8, 1.0 Hz, 1H), 7.96 (td, J = 7.8, 1.7 Hz, 2H), 7.86 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.55 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.51-7.42 (m, 3H), 2.50 (s, 3H). 13C NMR (126 MHz, dmso) 163.87, 150.45, 149.13, 138.45, 133.37, 132.72, 131.81, 131.11, 129.10, 128.24, 127.33, 127.21, 126.67, 125.59, 123.48, 122.84, 18.77. ESI-MS m/z 263.2 (M + H)+ 0 .sup.1H NMR (500 MHz, CDCl.sub.3) 7.92 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.82-7.76 (m, 2H), 7.60 (d, J = 5.0 Hz, 2H), 7.47 (m, 3H), 7.24-7.18 (m, 1H), 2.48 (d, J = 8.6 Hz, 3H). .sup.13C NMR (126 MHz, dmso) 160.78, 139.99, 133.66, 132.74, 131.95, 131.33, 131.23, 129.50, 129.12, 128.61, 128.32, 127.39, 126.82, 125.70, 123.40, 18.69. ESI-MS m/z 268.2 (M + H).sup.+ .sup.1H NMR (500 MHz, d6-DMSO) 9.53 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.55-7.38 (m, 4H), 7.00 (s, 1H), 6.88 (s, 1H), 6.36 (dd, J = 6.0, 2.7 Hz, 1H), 2.47 (s, 3H). .sup.13C NMR (126 MHz, d6-DMSO) 160.21, 133.66, 132.75, 131.79, 131.55, 129.14, 128.23, 126.99, 126.57, 126.30, 125.58, 123.62, 122.47, 111.46, 109.29, 18.80. ESI-MS m/z 251.1 (M + H).sup.+ .sup.1H NMR (500 MHz, DMSO-d6) = 10.62 (s, 1H), 8.09-8.03 (m, 1H), 8.00- 7.94 (m, 1H), 7.84 (d, J = 8.2, 1H), 7.67 (d, J = 7.2, 1H), 7.61-7.49 (m, 3H), 4.62 (t, J = 7.8, 1H), 3.37 (s, 1H), 3.35-3.26 (m, 2H), 2.58-2.50 (m, 1H), 2.13 (td, J = 14.8, 7.3, 1H), 2.00 (p, J = 7.2, 2H). .sup.13C NMR (125 MHz, DMSO-d6) 168.34, 134.17, 132.76, 128.68, 128.25, 126.64, 126.63, 126.00, 122.98, 122.60, 60.08, 46.25, 30.34, 24.10. MS-ESI: 241.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.15H.sub.17ON.sub.2 (M + H.sup.+): 241.1335, Found: 241.1335. .sup.1H NMR (500 MHz, DMSO-d6) = 10.58 (s, 1H), 8.01 (d, J = 7.4, 1H), 7.95 (d, J = 7.6, 1H), 7.89 (d, J = 8.4, 1H), 7.72 (d, J = 8.2, 1H), 7.63-7.54 (m, 2H), 7.49 (t, J = 7.9, 1H), 4.78 (s, 1H), 4.27 (s, 1H), 4.04 (t, J = 8.3, 1H), 3.00-2.88 (m, 2H), 2.11 (dd, J = 13.2, 8.4, 1H), 1.93-1.83 (m, 1H). .sup.13C NMR (126 MHz, DMSO-d6) 173.43, 133.62, 132.88, 128.48, 126.23, 126.07, 125.76, 124.31, 120.80, 118.29, 71.61, 60.21, 55.04, 40.02, 39.85, 39.78, 39.69, 39.52, 39.35, 39.19, 39.02. MS-ESI: 257.1 (M + H.sup.+); HRMS (ESI) Calcd. for C.sub.15H.sub.17O.sub.2N.sub.2 (M + H.sup.+): 257.1285, Found: 257.1285.

Example 3. Synthesis of N-benzyl-4-methylaniline by Coupling Reaction of 1-chloro-4-methylbenzene with Benzylamine

(117) ##STR00264##

(118) Copper (I) iodide (0.05 mmol), ligand (0.1 mmol) and potassium phosphate (1.0 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 1-chloro-4-methylbenzene (0.5 mmol), benzylamine (0.75 mmol) and 1 mL of DMSO were added. The reaction mixture was homogeneously stirred at 120 C. for 24 hours. After cooling, water and ethyl acetate were added and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give the product N-benzyl-4-methylaniline. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.34-7.21 (m, 5H), 6.96 (d, J=8.0 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 4.28 (s, 2H), 3.88 (br s, 1H), 2.22 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 20.6, 48.8, 113.2, 126.9, 127.3, 127.7, 128.8, 130.0, 139.8, 146.1; HRMS (ESI) calcd. for C.sub.14H.sub.16N (M+H).sup.+: 198.1283, Found: 198.1287.

(119) Experimental results for different heterocyclic carboxylic acid amide ligands are listed in the following table.

(120) TABLE-US-00004 No. of ligand yield/% No. of ligand yield/% No. of ligand yield/% L-1 17 L-2 12 L-3 21 L-7 21 L-32 23 L-53 24 L-54 10 L-55 5 L-96 9 L-103 31 L-102 26 L-106 34 L-107 29

Example 4. Synthesis of the Corresponding Aniline Derivatives by the Coupling Reaction of 1-chloro-4-methylbenzene with Various Primary and Secondary Amines

(121) ##STR00265##

(122) Copper iodide (0.05 mmol), ligand L-103 (0.05 or 0.1 mmol), potassium phosphate (1.0 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 1-chloro-4-methylbenzene (1.0 mmol), amine (1.5 mmol) and 1 mL of DMSO were added. The reaction mixture was homogeneously stirred at 120 C. for 24 or 48 hours. After cooling, water and ethyl acetate were added and separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to give the product N-p-methylphenyl amine.

(123) Different amines were used in this example, and the obtained results are shown in the table below.

(124) TABLE-US-00005 Product and yield Characterization data of products .sup.1H NMR (500 MHz, CDCl.sub.3) 7.07 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.42 (br s, 1H), 3.16 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.68 (p, J = 7.2 Hz, 2H), 1.53-1.34 (m, 6H), 1.00 (t, J = 6.8 Hz, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3) 146.25, 129.60, 126.11, 112.81, 44.31, 31.62, 29.54, 26.82, 22.58, 20.28, 13.98; LC-MS (ESI, m/z): 192.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.00 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 3.83 (t, J = 5 Hz, 2H), 3.29 (t, J= 5 Hz, 211), 2.25 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 145.67, 129.68, 127.15, 113.46, 61.02, 46.42, 20.30; LC-MS (ESI, m/z): 152.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.99 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 8.0 Hz, 2H), 4.99 (t, J = 4.5 Hz, 1H), 4.06-3.95 (m, 2H), 3.92-3.80 (m, 2H), 3.25 (t, J = 6.5 Hz, 2H), 2.23 (s, 3H), 2.01 (td, J = 6.5, 4.5 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 146.00, 129.55, 126.27, 112.90, 103.59, 64.77, 39.45, 32.92, 20.26; HRMS (DART) calcd. for C.sub.12H.sub.18NO.sub.2 (M + H).sup.+: 208.1332, Found: 208.1333. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.27-7.17 (m, 2H), 7.13-7.00 (m, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 3.60 (br s, 1H), 3.39 (t, J = 7.1 Hz, 2H), 2.95 (td, J = 7.1, 1.1 Hz, 2H), 2.25 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 161.18 (d, J = 244.8 Hz), 145.50, 130.94 (d, J = 5.0 Hz), 129.66, 127.98 (d, J = 8.1 Hz), 126.41, 126.24 (d, J = 16.0 Hz), 123.96 (d, J = 3.6 Hz), 115.21 (d, J = 22.2 Hz), 112.96, 44.04, 28.99 (d, J = 1.8 Hz), 20.26; HRMS (DART) calcd. for C.sub.15H.sub.17NF (M + H).sup.+: 230.1340, Found: 230.1340. 0 .sup.1H NMR (400 MHz, CDCl.sub.3) 7.36 (dd, J = 1.9, 0.9 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 6.32 (dd, J = 3.2, 1.8 Hz, 1H), 6.23 (dd, J = 3.2, 0.9 Hz, 1H), 4.30 (s, 2H), 3.89 (br s, 1H), 2.25 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 152.89, 145.26, 141.70, 129.60, 127.08, 113.24, 110.21, 106.77, 41.63, 20.31; LC-MS (ESI, m/z): 188.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.99 (d, J = 8.3 Hz, 2H), 6.90-6.74 (m, 3H), 6.56 (d, J = 8.3 Hz, 2H), 5.95 (s, 2H), 4.22 (s, 2H), 3.86 (br s, 1H), 2.25 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 147.78, 146.57, 145.74, 133.52, 129.66, 126.68, 120.46, 1 12.94, 108.18, 107.96, 100.88, 48.34, 20.32; HRMS (DART) calcd. for C.sub.15H.sub.16NO.sub.2 (M + H).sup.+: 242.1176, Found: 242.1175.

Example 5. Synthesis of (4-aminophenyl)methanol

(125) ##STR00272##

(126) Chlorobenzyl alcohol (0.5 mmol), ammonia source (0.75 mmol), copper salt catalyst (0.05 mmol), ligand (0.05 mmol) and base (0.5 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 0.5 mL of solvent was added. The reaction mixture was homogeneously stirred at 110 C. for 24 hours. After cooling, the mixture was filtered through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the product (4-aminophenyl) methanol (light yellow solid).

(127) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.11 (d, J=8.3 Hz, 2H), 6.62 (d, J=8.3 Hz, 2H), 4.49 (s, 2H), 3.22 (br s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 145.9, 131.0, 128.7, 115.1, 65.1; LC-MS (ESI, m/z): 124.1 (M+H).sup.+.

(128) Different ammonia sources, copper salt catalysts, ligands, bases and solvents were used in the example, and the obtained results are listed in the following table.

(129) TABLE-US-00006 copper ammonia salt yield/ No. source catalyst ligand base solvent % 1 NH.sub.3H.sub.2O CuI L-1 K.sub.3PO.sub.4 DMSO 27 2 NH.sub.3H.sub.2O CuI L-2 K.sub.3PO.sub.4 DMSO 42 3 NH.sub.3H.sub.2O CuI L-3 K.sub.3PO.sub.4 DMSO 44 4 NH.sub.3H.sub.2O CuI L-4 K.sub.3PO.sub.4 DMSO 35 5 NH.sub.3H.sub.2O CuI L-5 K.sub.3PO.sub.4 DMSO 35 6 NH.sub.3H.sub.2O CuI L-6 K.sub.3PO.sub.4 DMSO 64 7 NH.sub.3H.sub.2O CuI L-7 K.sub.3PO.sub.4 DMSO 66 8 NH.sub.3H.sub.2O CuI L-8 K.sub.3PO.sub.4 DMSO 39 9 NH.sub.3H.sub.2O CuI L-9 K.sub.3PO.sub.4 DMSO 38 10 NH.sub.3H.sub.2O CuI L-11 K.sub.3PO.sub.4 DMSO 34 11 NH.sub.3H.sub.2O CuI L-12 K.sub.3PO.sub.4 DMSO 78 12 NH.sub.3H.sub.2O CuI L-13 K.sub.3PO.sub.4 DMSO 84 13 NH.sub.3H.sub.2O CuI L-14 K.sub.3PO.sub.4 DMSO 77 14 NH.sub.3H.sub.2O CuI L-15 K.sub.3PO.sub.4 DMSO 89 15 NH.sub.3H.sub.2O CuI L-20 K.sub.3PO.sub.4 DMSO 46 16 NH.sub.3H.sub.2O CuI L-25 K.sub.3PO.sub.4 DMSO 67 17 NH.sub.3H.sub.2O CuI L-26 K.sub.3PO.sub.4 DMSO 49 18 NH.sub.3H.sub.2O CuI L-28 K.sub.3PO.sub.4 DMSO 71 19 NH.sub.3H.sub.2O CuI L-29 K.sub.3PO.sub.4 DMSO 60 20 NH.sub.3H.sub.2O CuI L-30 K.sub.3PO.sub.4 DMSO 45 21 NH.sub.3H.sub.2O CuI L-31 K.sub.3PO.sub.4 DMSO 91 22 NH.sub.3H.sub.2O CuI L-32 K.sub.3PO.sub.4 DMSO 78 23 NH.sub.3H.sub.2O CuI L-33 K.sub.3PO.sub.4 DMSO 21 24 NH.sub.3H.sub.2O CuI L-38 K.sub.3PO.sub.4 DMSO 55 25 NH.sub.3H.sub.2O CuI L-39 K.sub.3PO.sub.4 DMSO 57 26 NH.sub.3H.sub.2O CuI L-42 K.sub.3PO.sub.4 DMSO 69 27 NH.sub.3H.sub.2O CuI L-44 K.sub.3PO.sub.4 DMSO 34 28 NH.sub.3H.sub.2O CuI L-46 K.sub.3PO.sub.4 DMSO 41 29 NH.sub.3H.sub.2O CuI L-47 K.sub.3PO.sub.4 DMSO 43 30 NH.sub.3H.sub.2O CuI L-48 K.sub.3PO.sub.4 DMSO 25 31 NH.sub.3H.sub.2O CuI L-49 K.sub.3PO.sub.4 DMSO 60 32 NH.sub.3H.sub.2O CuI L-51 K.sub.3PO.sub.4 DMSO 24 33 NH.sub.3H.sub.2O CuI L-54 K.sub.3PO.sub.4 DMSO 14 34 NH.sub.3H.sub.2O CuI L-96 K.sub.2CO.sub.3 DMSO 10 35 NH.sub.3H.sub.2O Cu.sub.2O L-15 K.sub.3PO.sub.4 DMSO 52 36 NH.sub.3H.sub.2O CuTc L-15 K.sub.3PO.sub.4 DMSO 80 37 NH.sub.3H.sub.2O CuI L-15 K.sub.3PO.sub.4 DMSO 60 38 NH.sub.3H.sub.2O CuI L-15 K.sub.3PO.sub.4 DMSO 57 39 NH.sub.3H.sub.2O CuI L-43 K.sub.3PO.sub.4 DMSO 67 40 NH.sub.3H.sub.2O CuI L-45 K.sub.3PO.sub.4 DMSO 14 41 NH.sub.4Cl + KOH CuI L-15 K.sub.3PO.sub.4 DMSO 60 42 NH.sub.3 (gas, 5 atm) CuI L-15 K.sub.3PO.sub.4 DMSO 79 43 NaN.sub.3 CuI L-15 K.sub.3PO.sub.4 DMSO 46 44 (NH.sub.4).sub.2CO.sub.3 + CuI L-15 K.sub.3PO.sub.4 DMSO 39 KOH 45 (NH.sub.4).sub.2SO.sub.4 + CuI L-15 K.sub.3PO.sub.4 DMSO 55 KOH 46 (NH.sub.4).sub.2HPO.sub.4 + CuI L-15 K.sub.3PO.sub.4 DMSO 72 KOH

Example 6. Synthesis of Aromatic Amines

(130) Copper iodide (0.05 mmol), ligand L-15 (0.05 or 0.1 mmol), potassium phosphate (1.1 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then aryl chloride (1.0 mmol), 1 mL of DMSO and ammonium hydroxide (2.0 mmol) were added. The reaction mixture was homogeneously stirred at 110 C. or 120 C. for 24 hours. After cooling, water and ethyl acetate were added and separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to give the product aromatic amines.

(131) Different aryl chlorides were used in the example, and the obtained results are listed in the following table.

(132) TABLE-US-00007 Product and yield Characterization data of products .sup.1H NMR (400 MHz, CDCl.sub.3) 6.84-6.75 (m, 2H), 6.63-6.55 (m, 2H), 3.51 (s, 2H), 1.28 (s, 9H); .sup.13C NMR (100 MHz, CDCl.sub.3) 147.05, 142.38, 125.34, 115.39, 77.71, 28.68.; LC-MS (ESI, m/z): 166.2 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (dd, J = 8.5, 0.6 Hz, 1H), 6.92 (t, J = 1.3 Hz, 1H), 6.89 (dd, J = 2.3, 0.6 Hz, 1H), 6.69 (dd, J = 8.5, 2.3 Hz, 1H), 3.60 (br, 1H), 2.26 (d, J = 1.3 Hz, 3H).; .sup.13C NMR (100 MHz, CDCl.sub.3) 143.35, 140.78, 131.17, 130.53, 123.10, 122.19, 114.54, 106.62, 13.80; HRMS (ESI) calcd, for C.sub.9H.sub.10NS (M + H).sup.+: 164.0528. Found; 164.0532. .sup.1H NMR (400 MHz, CDCl.sub.3) 5.93 (t, J = 2.1 Hz, 1H), 5.87 (d, J = 2.1 Hz, 2H), 3.74 (s, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3) 161.59, 148.53, 93.63, 90.77, 55.02; LC-MS (ESI, m/z): 154.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 8.6, 2.3 Hz, 1H), 4.04 (br s, 2H), 2.67 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 158.95, 149.34, 148.01, 135.91, 128.53, 120.22, 118.34, 117.62, 108.34, 25.04; HRMS (ESI) calcd, for C.sub.10H.sub.11N.sub.2 (M + H).sup.+: 159.0917. Found: 159.0919. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.95 (d, J = 8.4 Hz, 1H), 7.29-7.21 (m, 2H), 7.11 (dd, J = 8.1, 1.3 Hz, 1H), 6.90 (dd, J = 7.5, 1.2 Hz, 1H), 4.95 (s, 2H), 2.71 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 156.10, 143.44, 137.85, 136.04, 126.89, 126.31, 122.11, 115.84, 110.10, 25.22; LC-MS (ESI, m/z): 159.1 (M + H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.74 (s, 1H), 8.03 (s, 1H), 7.95-7.87 (m, 1H), 7.84- 7.75 (m, 1H), 7.71-7.62 (m, 1H), 7.62-7.53 (m, 1H), 4.11 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 142.97, 137.12, 128.96, 128.63, 127.99, 127.73, 127.03, 126.05, 120.12; LC-MS (ESI, m/z): 145.1 (M + H).sup.+. 0 .sup.1H NMR (400 MHz, CDCl.sub.3) 8.65 (dd, J = 4.2, 1.6 Hz, 1H), 7.94-7.86 (m, 2H), 7.27 (dd, J = 8.2, 4.3 Hz, 1H), 7.16 (dd, J = 8.9, 2.6 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 3.96 (s, 2H).; .sup.13C NMR (100 MHz, CDCl.sub.3) 146.50, 144.85, 143.14, 133.75, 130.19, 129.74, 121.60, 121.29. 107.20; LC-MS (ESI, m/z): 145.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.62 (d, J = 8.1 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 6.13 (dd, J = 8.1, 2.3 Hz, 1H), 5.86 (s, 2H), 3.45 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 148.18, 141.46, 140.30, 108.58, 106.89, 100.65, 98.08; LC-MS (ESI, m/z): 138.1 (M + H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.66 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 4.23 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 148.27, 145.09, 144.97, 141.02, 138.09, 130.47, 122.23, 107.93; LC-MS (ESI, m/z): 146.1 (M + H).sup.+. .sup.1H NMR (500 MHz, d6-DMSO) 8.17-8.10 (m, 1H), 7.50 (br s, 1H), 7.19 (d, J = 1.4 Hz, 1H), 6.42-6.36 (m, 2H), 5.65 (br s, 2H); .sup.13C NMR (125 MHz, d6-DMSO) 147.05, 146.47, 131.18, 126.71, 110.36, 106.49, 92.25; LC-MS (ESI, m/z): 134.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.79 (dd, J = 8.3, 1.4 Hz, 1H), 7.67 (dd, J = 8.3, 1.2 Hz, 1H), 7.56 (d, J = 1.5 Hz, 0H), 7.35-7.23 (m, 1H), 6.59 (s, 1H), 4.94 (br s, 2H), 2.58 (d, J = 1.0 Hz, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3) 155.88, 148.30, 142.39, 130.38, 123.91, 123.22, 122.70, 122.58, 112.40, 18.80; LC-MS (ESI, m/z): 159.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.16 (d, J = 8.0 Hz, 2 H), 6.60 (d, J = 8.0 Hz, 2 H), 3.49 (br s, 2 H), 1.27 (s, 9 H); .sup.13C NMR (100 MHz, CDCl.sub.3) 143.9, 141.3, 126.1, 115.0, 33.9, 31.6; LC-MS (ESI, m/z): 150.2 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.25 (d, J = 7.1 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.6, 2.7 Hz, 1H), 3.84 (br s, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) 145.26, 132.18, 128.81 (q, J = 31.0 Hz), 122.98 (q, J = 273.1 Hz), 120.34 (q, J = 1.9 Hz), 118.80, 113.76 (q, J = 5.6 Hz); LC-MS (ESI, m/z): 195.9 (M + H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) 6.32 (t, J = 2.0 Hz, 1H), 6.28 (t, J = 1.9 Hz, 1H), 6.09 (t, J = 2.1 Hz, 1H), 3.73 (s, 3H), 3.63 (s, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) 161.28, 148.47, 135.41, 108.05, 104.53, 99.41, 55.39; LC-MS (ESI, m/z): 158.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.18 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 3.53 (s. 2H), 2.41 (s, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3) 145.17, 131.02, 125.65, 115.74, 18.77; LC-MS (ESI, m/z): 140.1 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.83-6.76 (m, 2H), 6.70-6.63 (m, 2H), 3.89-3.81 (m, 4H), 3.43 (s, 2H), 3.08-2.95 (m, 4H); .sup.13C NMR (125 MHz, CDCl.sub.3) 144.57, 140.44, 118.33, 116.36, 67.22, 51.25. 0 .sup.1H NMR (400 MHz, CDCl.sub.3) 7.15-7.06 (m, 2H), 6.94-6.86 (m, 2H), 6.69-6.60 (m, 2H), 6.27-6.18 (m, 2H), 3.60 (s, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) 144.65, 133.04, 122.49, 119.81, 115.78, 109.56. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.76-6.68 (m, 4H), 3.33 (br s, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3) 134.8, 120.3, 116.7; LC-MS (ESI, m/z): 109.2 (M + H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 4.40 (br s, 2H), 6.60 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 99.7, 114.3, 120.2, 133.6, 150.5; LC-MS (ESI, m/z): 119.1 (M + H).sup.+.

Example 7. Synthesis of 1-methyl-4-phenoxybenzene

(133) ##STR00293##

(134) Phenol (1.5 mmol), copper iodide (0.1 mmol), ligand (0.1 mmol) and potassium phosphate (1.5 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 1-chloro-4-methylbenzene (1.0 mmol) and 1 mL of DMSO were added. The reaction mixture was homogeneously stirred at 120 C. for 24 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtrated through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the product 1-methyl-4-phenoxybenzene.

(135) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40-7.31 (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); .sup.13C NMR (100 MHz, CDCl.sub.3) 158.02, 154.91, 133.06, 130.45, 129.83, 122.98, 119.32, 118.53, 20.89

(136) The results obtained by using different ligands are listed in the following table.

(137) TABLE-US-00008 No. of ligand yield/% No. of ligand yield/% No. of ligand yield/% L-1 19 L-2 38 L-3 30 L-6 58 L-7 45 L-10 44 L-13 68 L-14 62 L-15 64 L-17 44 L-21 26 L-29 42 L-30 32 L-31 29 L-32 22 L-35 69 L-37 59 L-40 48 L-57 37 L-96 26 L-103 19 L-16 14 L-18 10 L-19 7 L-22 21 L-23 32 L-24 11 L-27 8 L-34 17 L-36 58 L-50 11 L-52 28 L-56 54 L-58 10 L-59 9 L-60 19

Example 8. Synthesis of Diaryl Ether and Aryl Alkyl Ether Via Coupling Reaction of Aryl Chloride and R.SUB.c.OH

(138) ##STR00294##

(139) Aryl halide substrate (1.0 mmol), phenol (1.2 mmol), copper iodide (0.05 mmol), ligand L-13 (0.1 mmol), and potassium phosphate (2.0 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 1 mL of DMSO was added. The reaction mixture was homogeneously stirred at 120 C. for 30 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtrated through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the product diaryl ether. The obtained results are shown in the following table.

(140) TABLE-US-00009 aryl chloride and phenol product and yield Characterization data of the product .sup.1H NMR (400 MHz, CDCl.sub.3) 3.83 (s, 3H), 6.94 (m, 4H), 7.01 (m, 2H), 7.58 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) 55.9, 105.4, 115.5, 117.3, 119.2, 122.1, 134.3, 148.1, 157.3, 162.8; GC-MS (EI, m/z): 225.1 (M.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.90 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 9.0 Hz), 6.92-6.88 (4H, m), 3.80 (3H, s), 2.55 (3H, s); .sup.13C NMR (100 MHz, CDCl.sub.3) 196.6, 162.9, 156.6, 148.4, 131.3, 130.5, 121.6, 116.3, 115.0, 55.6, 26.3; GC-MS (EI, m/z): 242.1 (M.sup.+). 00 .sup.1H NMR (400 MHz, CDCl.sub.3) 7.80 (2H, d, J = 9.0 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.42 (2H, m), 7.26 (1H, m), 7.18 (1H, m), 7.06 (2H, d, J = 8.9 Hz), 6.92 (2H, d, J = 9.0 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3) 156.4, 156.0, 140.0, 134.3, 129.7, 127.6, 126.9, 126.4, 124.3, 121.0, 119.3, 114.9, 112.2, 55.6; GC-MS (EI, m/z): 250.1 (M.sup.+). 01 02 .sup.1H NMR (400 MHz, CDCl.sub.3) 7.69 (1H, s), 7.43-7.45 (2H, d, J = 8.8), 7.13-7.14 (2H, d, J = 8.2), 6.94-6.95 (2H, d, J = 8.8), 6.89-6.91 (2H, d, J = 8.4), 2.34 (3H, s), 2.17 (3H, s); .sup.13C NMR (100 MHz, CDCl.sub.3) 168.8, 155.2, 154.4, 135.9, 133.3, 133.0, 130.5, 129.0, 122.1, 119.2, 118.9, 24.6, 20.9; LC-MS (ESI, m/z): 242.1 (M + H).sup.+. 03 04 .sup.1H NMR (400 MHz, CDCl.sub.3) 7.56 (d, J = 8.6 Hz, 2H), 7.29-7.25 (m, 1H), 7.04-6.99 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.87-6.84 (m, 2H), 2.36 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 160.7, 155.7, 140.4, 129.8, 127.0, 125.3, 124.6, 122.9, 120.6, 117.9, 117.0, 21.4; GC-MS (EI, m/z): 252.1 (M.sup.+). 05 06 .sup.1H NMR (400 MHz, CDCl.sub.3) 2.27 (3H, s), 6.58 (2H, s), 6.73 (1H, s), 6.9-7.1 (4H, m); .sup.13C NMR (100 MHz, CDCl.sub.3) 21.7, 116.4, 116.6 (d, J = 23 Hz), 120.9 (d, J = 8.6 Hz), 120.9, 125.3, 140.0, 153.5 (d, J = 2.6 Hz), 158.0, 1159.1 (d, J = 241 Hz); GC-MS (EI, m/z): 216.1 (M.sup.+).

Example 9. Coupling of 4-chloroanisole with Sodium Methylsulfinate

(141) ##STR00307##

(142) Sodium methanesulfinate (0.6 mmol), copper iodide (0.05 mmol), ligand (0.1 mmol) and potassium phosphate (1.5 mmol) were added into a 10 mL of Schlenk tube. The tube was evacuated and filled with argon for three times, and then 4-chloroanisole (0.5 mmol) and 1 mL of DMSO were added. The reaction mixture was homogeneously stirred at 120 C. for 24 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtered through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the product 4-methoxy phenyl methyl sulfone.

(143) .sup.1H NMR (400 MHz, CDCl.sub.3) 3.05 (s, 3H), 3.90 (s, 3H), 7.04 (dd, J=7.5, 2.1 Hz, 2H), 7.88 (dd, J=7.5, 2.1 Hz, 2H); EI-MS (m/z) 186 (M+)

(144) The results obtained by using different ligands are listed in the following table.

(145) TABLE-US-00010 Ligand yield/% Ligand yield/% Ligand yield/% L-54 24 L-88 50 L-89 52 L-90 31 L-91 26 L-92 80 L-95 45 L-96 40 L-104 47 L-105 50 L-108 36 L-109 44 L-115 53 L-35 52

Example 10. Coupling of 4-chloroanisole with Sodium Methylsulfinate

(146) ##STR00308##

(147) The operation of this example was the same as that of Example 9 except that different copper catalysts, bases, solvents and reaction temperatures were used. The experiment results are shown in the following table:

(148) TABLE-US-00011 No. Copper salt base solvent temperature yield/% 1 CuI Cs.sub.2CO.sub.3 DMSO 120 31 2 CuI K.sub.2CO.sub.3 DMSO 120 60 3 CuI K.sub.3PO.sub.4 DMSO 120 80 4 CuBr K.sub.3PO.sub.4 DMSO 120 50 5 CuCl.sub.2 K.sub.3PO.sub.4 DMSO 120 18 6 Cu.sub.2O K.sub.3PO.sub.4 DMSO 120 22 7 CuCl K.sub.3PO.sub.4 DMSO 120 45 8 CuSCN K.sub.3PO.sub.4 DMSO 120 35 9 Cu.sub.2S K.sub.3PO.sub.4 DMSO 120 18 10 CuI K.sub.3PO.sub.4 DMF 120 65 11 CuI K.sub.3PO.sub.4 NMP 120 73 12 CuI K.sub.3PO.sub.4 toluene 120 36

Example 11. Coupling of Aryl Chloride with Sodium Alkylsulfinate or Sodium Arylsulfinate

(149) ##STR00309##

(150) Sodium alkylsulfinate or sodium arylsulfinate (0.6 mmol), copper iodide (0.05 mmol), ligand (0.1 mmol) and potassium phosphate (1.5 mmol) were added into a 10 mL Schlenk tube. The tube was evacuated and filled with argon for three times, and then aryl chloride (0.5 mmol) and 1 mL of DMSO were added. The reaction mixture was homogeneously stirred at 120 C. for 24 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtered through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the corresponding product.

(151) TABLE-US-00012 Product and yield Characterization data of products 0 .sup.1H NMR (400 MHz, CDCl.sub.3) 3.84 (s, 3H), 6.96 (m, 2H), 7.51 (m, 3H), 7.90 (m, 4H); EI-MS (m/z) 248 (M.sup.+) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.99 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 7.0 Hz, 2H), 7.48 (t, J = 7.3 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 3.08 (s, 3H) .sup.1H NMR (500 MHz, CDCl.sub.3) 7.94-7.85 (m, 2H), 7.71 (t, J = 8.9 Hz, 2H), 7.46 (d, J = 8.9 Hz, 1H), 3.04 (s, 3H), 2.23 (s, 3H)

Example 12. Synthesis of Aromatic Amines by Reaction of Aryl Bromides/Iodides and Amines

(152) Aryl bromide/iodide substrates (1.0 mmol), amine (1.2 mmol), copper iodide (0.05 mmol), ligand (0.05 mmol) and potassium phosphate (1.0 mmol) were added into a 10 mL of Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 1 mL of DMSO was added. The reaction mixture was homogeneously stirred at 80 C. for 48 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtrated through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the product aromatic amines. The obtained results are shown in the following table.

(153) TABLE-US-00013 aryl halide ligand yield ligand yield 61% 20% 16% 37% 0 75% 10% 48% 54% 74% 43% 51% 58%

Example 13. Synthesis of Arylsulfide by Reaction of 4-methyl iodobenzene and 4-methoxy thiophenol

(154) ##STR00328##

(155) Copper iodide (0.1 mmol), ligand (0.1 mmol) and potassium phosphate (1.5 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then 4-methyl iodobenzene (0.5 mmol), 4-methoxy thiophenol (0.6 mmol), and 1 mL of DME were added. The reaction mixture was homogeneously stirred at 80 C. for 24 hours. After cooling, water and ethyl acetate were added and separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to give the product (N-4-methoxyphenyl)-4-methoxy thiophenol.

(156) .sup.1H NMR (500 MHz, CDCl.sub.3) 7.38 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 3.81 (s, 2H), 2.32 (s, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) 159.47, 136.12, 134.34, 129.79, 129.39, 125.63, 114.89, 55.35, 45.84, 21.01, 8.66. ESI-MS m/z 231.4 (M+H).sup.+

(157) The results obtained by using different ligands are listed in the following table.

(158) TABLE-US-00014 Ligand yield/% Ligand yield/% Ligand yield/% L-13 70 L-62 50 L-63 56 L-65 65 L-54 60 L-71 56 L-79 48 L-82 50 L-84 44 L-96 63 L-112 72 L-113 61 L-114 70 L-74 31 L-75 42 L-76 36 L-61 37 L-64 57 L-68 39 L-69 53 L-70 61 L-66 36 L-67 45 L-77 71 L-78 65 L-86 31 L-80 43 L-81 52 L-83 54 L-85 43 L-87 26

Example 14. Synthesis of Arylsulfide by Reaction of Iodobenzene and Thiophenol

(159) ##STR00329##

(160) Copper iodide (0.05 mmol), ligand (0.1 mmol) and potassium phosphate (1.0 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then substituted iodobenzene (0.5 mmol), substituted thiophenol (0.6 mmol), and 1 mL of DME were added. The reaction mixture was homogeneously stirred at 80 C. for 24 hours. After cooling, water and ethyl acetate were added and separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to give the product arylsulfide.

(161) TABLE-US-00015 Product and yield Characterization data of products 0 .sup.1H NMR (500 MHz, CDCl.sub.3) 7.38 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.81 (s, 2H), 2.32 (s, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) 159.47, 136.12, 134.34, 129.79, 129.39, 125.63, 114.89, 55.35, 45.84, 21.01, 8.66. ES1-MS m/z 231.4 (M + H).sup.+ .sup.1H NMR (500 MHz, CDCl.sub.3) 7.42 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.6 Hz, 3H), 6.86 (d, J = 9.0 Hz, 4H), 3.80 (d, J = 4.0 Hz, 7H). .sup.13C NMR (101 MHz, CDCl.sub.3) 159.97, 159.02, 132.77, 132.69, 128.46, 127.48, 114.81, 114.67, 55.37. ESI-MS m/z 247.1 (M + H).sup.+ .sup.1H NMR (500 MHz, CDCl.sub.3) 7.78 (d, J= 8.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.99-6.92 (m, 1H), 3.85 (s, 2H), 2.53 (s, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) 197.12, 160.69, 146.88, 136.83, 133.90, 128.81, 125.83, 121.41, 115.39, 55.44, 26.44. ESI-MS m/z 259.4 (M + H).sup.+ .sup.1H NMR (500 MHz, CDCl.sub.3) 7.23 (dd, J = 8.6, 2.6 Hz, 1H), 6.82 (d, 8.5 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 3.76 (d, J = 23.4 Hz, 5H)..sup.13C NMR (101 MHz, CDCl.sub.3) 158.54, 146.24, 134.00, 131.47, 128.86, 123.49, 115.81, 114.66, 55.38. ESI-MS m/z 232.1 (M + H).sup.+ .sup.1H NMR (500 MHz, CDCl.sub.3) 8.16 (s, 1H), 7.36 (dd, J = 28.9, 8.7 Hz, 4H), 7.14 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 2.11 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) 169.03, 159.58, 136.49, 134.39, 133.09, 129.95, 125.29, 120.88, 115.00, 55.41, 24.39. ESI-MS m/z 274.1 (M + H).sup.+

Example 15. Reaction of 4-Methoxy Bromobenzene and Other Coupling Reagent

(162) ##STR00335##

(163) Copper salt catalyst (0.1 mmol), ligand (0.1 mmol) and potassium phosphate (1.0 mmol) were added into a 10 mL Schlenk tube. The tube was then evacuated and filled with argon for three times, and then aryl chloride (1.0 mmol), 1 mL of DMSO and nucleophile (2.0 mmol) were added. The reaction mixture was homogeneously stirred at 90 C. for 24 hours. After cooling, water and ethyl acetate were added and separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to give the coupling product.

(164) TABLE-US-00016 Coupling Copper reagent catalyst ligand Product and yield NH.sub.3H.sub.2O CuI L-15 PhOH CuI L-13 MeSO.sub.2Na CuI L-92

Example 16. Coupling of Aryl Chloride with Sodium Alkylsulfinate or Sodium Arylsulfinate (Gram-Level Reaction)

(165) ##STR00339##

(166) Sodium alkylsulfinate or sodium arylsulfinate (6.5 mmol), copper iodide (0.5 mmol), ligand (0.5 mmol) and potassium phosphate (5.0 mmol) were added into a 10 mL Schlenk tube. The tube was evacuated and filled with argon for three times, and then aryl chloride (5 mmol) and 3 mL of DMSO were added. The reaction mixture was homogeneously stirred at 120 C. for 24-36 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtered through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the corresponding product.

(167) TABLE-US-00017 Product and yield Characterization data of products 0 .sup.1H NMR (500 MHz, CDCl.sub.3) 7.87 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.03 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 163.68, 132.26, 129.49, 114.51, 55.73, 44.82. MS-EI: 186 (M.sup.+) .sup.1H NMR (500 MHz, CDCl3) 7.83 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 3.03 (s, 3H), 2.46 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 144.80, 137.87, 130.09, 127.53, 44.77, 21.77; MS-EI: 170 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 8.01 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.64-7.59 (m, 3H), 7.49 (t, J = 7.4 Hz, 3H), 7.46- 7.41 (m, 1H), 3.10 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 146.87, 139.26, 139.21, 129.25, 128.83, 128.14, 128.05, 127.53, 44.78; MS-EI: 232 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 7.82 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 3.03 (s, 3H), 2.53 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 147.34. 136.35, 127.79, 125.62, 44.83, 14.91; MS-EI: 202 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 7.69 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 4.19 (s, 2H), 3.00 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 151.57, 129.53, 129.75, 114.19, 45.12; MS-EI: 171 (M.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) = 8.17 (d, J = 8.2, 2H), 8.05 (d, J = 8.3, 2H), 3.32 (s, 3H). .sup.1H NMR (500 MHz, DMSO-d6) = 7.71 (d, J = 9.0, 2H), 7.08 (d, J = 9.0, 2H), 3.73 (t, J = 5.0, 4H), 3.28 (t, J = 5.0, 4H), 3.10 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 154.01, 128.97, 128.49, 113.48, 65.78, 46.82, 44.19. .sup.1H NMR (500 MHz, CDCl3) 7.52 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.44-7.42 (m, 1H), 7.18-7.15 (m, 1H), 3.87 (s, 3H), 3.05 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 160.22, 141.86, 130.62, 120.29, 119.58, 111.95, 55.86, 44.58; MS-EI: 186 (M.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) = 7.49 (dd, J = 11.1, 2.0, 1H), 7.42 (dd, J = 8.4, 2.0, 1H), 6.88 (t, J = 8.5, 1H), 6.16 (s, 2H), 3.10 (s, 3H). .sup.13C NMR (125 MHz, DMSO-d6) 149.71, 147.80, 141.90, 141.80, 126.04, 126.00, 124.69, 124.67, 114.93, 114.89, 114.24, 114.08, 44.21. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.50 (dd, J = 8.2, 1.8 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.10 (s, 2H), 3.02 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 152.31, 148.49, 134.13, 123.43, 108.71, 107.65, 102.60, 44.90; MS-EI: 200 (M.sup.+); HRMS (EI) Calcd. for C.sub.8H.sub.8O.sub.4S (M.sup.+): 200.0143, Found: 200.0146. 0 .sup.1H NMR (500 MHz, DMSO-d6) = 8.86 (d, J = 2.0, 1H), 8.46 (dd, J = 8.1, 0.9, 1H), 8.22 (dd, J = 8.5, 2.1, 1H), 8.11 (d, J = 8.5, 1H), 7.88 (d, J = 7.7, 1H), 7.84-7.78 (m, 1H), 7.66-7.60 (m, 1H), 3.34 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 178.03, 142.33, 138.87, 135.86, 133.57, 129.89, 129.15, 128.26, 128.21, 128.06, 128.00, 127.53, 126.77, 43.44. .sup.1H NMR (500 MHz, DMSO-d6) = 8.00 (t, 1H), 7.62 (d, J = 7.2, 1H), 7.15 (d, J = 8.3, 1H), 3.94 (s, 3H), 3.28 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 163.42, 154.85, 141.14, 115.65, 113.90, 53.90, 39.56. .sup.1H NMR (500 MHz, CDCl3) 7.71-7.68 (m, 2H), 7.15-7.12 (m, 1H), 3.17 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 141.82, 133.78, 133.55, 128.0, 46.20; MS-EI: 162 (M.sup.+); HRMS (EI) Calcd. for C.sub.5H.sub.6O.sub.2S.sub.2 (M.sup.+): 161.9809, Found: 161.9806. .sup.1H NMR (500 MHz, CDCl3) 8.28 (d, J = 1.8 Hz, 1H), 7.68 (dd, J = 8.7, 1.8 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.32-7.27 (m, 4H), 7.10 (d, J = 6.3 Hz, 2H), 6.69 (d, J = 2.9 Hz, 2H), 5.36 (s, 2H), 3.04 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 138.42, 136.49, 131.60, 131.06, 128.96, 128.30, 128.03, 126.78, 121.83, 120.15, 110.46, 103.49, 50.48, 45.21; MS-EI: 285 (M.sup.+); HRMS (EI) Calcd. for C.sub.16H.sub.15NO.sub.2S (M.sup.+): 285.0824, Found: 285.0831. .sup.1H NMR (500 MHz, DMSO-d6) = 8.40 (d, J = 0.9, 1H), 7.89- 7.78 (m, 2H), 7.61 (s, 1H), 7.27 (t, J = 7.4, 2H), 7.21 (t, J = 7.3, 1H), 7.04 (d, J = 7.2, 2H), 4.31 (q, J = 7.1, 2H), 3.21 (s, 3H), 1.29 (t, J = 7.1, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 160.72, 140.58, 137.83, 133.44, 129.69, 128.55, 127.20, 126.16, 124.79, 123.16, 122.90, 112.37, 112.01, 60.91, 47.53, 44.12, 14.02. MS-ESI: 358 (M + H).sup.+

Example 17. Coupling of Aryl Iodide or Aryl Bromide with Sodium Alkylsulfinate or Sodium Arylsulfinate (Gram-Level Reaction)

(168) ##STR00355##

(169) Sodium alkylsulfinate or sodium arylsulfinate (6.5 mmol), copper iodide (of which the dosage was shown in the following table), ligand (of which the dosage was shown in the following table) and potassium phosphate (5.0 mmol) were added into a 10 mL Schlenk tube. The tube was evacuated and filled with argon for three times, and then aryl chloride (5 mmol) and 4 mL of DMSO were added. The reaction mixture was homogeneously stirred at corresponding temperature for 24 hours. After cooling, the contents of the of Schlenk tube were washed with ethyl acetate, and filtered through silica gel and diatomite plug. The filtrate was concentrated and purified by column chromatography to give the corresponding product.

(170) TABLE-US-00018 Product and yield Characterization data of products .sup.1H NMR (500 MHz, CDCl.sub.3) 7.87 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.03 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 163.68. 132.26, 129.49, 114.51, 55.73, 44.82. MS-EI: 186 (M.sup.+) .sup.1H NMR (500 MHz, CDCl3) 8.01 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.64-7.59 (m, 3H), 7.49 (t, J = 7.4 Hz, 3H), 7.46-7.41 (m, 1H), 3.10 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 146.87, 139.26, 139.21, 129.25, 128.83, 128.14, 128.05, 127.53, 44.78; MS-EI: 232 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 7.82 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 3.03 (s, 3H), 2.53 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 147.34, 136.35, 127.79, 125.62, 44.83, 14.91; MS-EI: 202 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 7.83 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.77 (s, 2H), 3.01 (s, 3H), 2.64 (s, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 147.43, 139.44, 127.67, 127.34, 64.24, 44.69; MS-EI: 186 (M.sup.+); HRMS (EI) Calcd. for C.sub.8H.sub.10O.sub.3S (M.sup.+): 186.0351, Found: 186.0347. 0 .sup.1H NMR (500 MHz, CDCl3) 7.69 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 4.19 (s, 2H), 3.00 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 151.57, 129.53, 129.75, 114.19, 45.12; MS-EI: 171 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 8.23 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 3.98 (s, 3H), 3.08 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 165.54, 144.39, 134.99, 130.66, 127.61, 52.87, 44.44; MS-EI: 214 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 8.06 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 3.08 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 144.48, 133.27, 128.24, 117.58, 117.14, 44.25; MS-EI: 181 (M.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) = 7.89 (d, J = 8.3, 2H), 7.55 (d, J = 8.3, 2H), 3.85 (s, 2H), 3.63 (s, 3H), 3.21 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 171.40, 140.84, 139.86, 130.89, 127.44, 52.35, 43.97. MS-ESI: 228.9 (M + H).sup.+ .sup.1H NMR (500 MHz, CDCl3) 8.46 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 3.08 (s, 3H), 2.65 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 196.21, 141.52, 138.15, 133.21, 131.53, 130.09, 127.32, 44.51, 26.86; MS-EI: 198 (M.sup.+). .sup.1H NMR (500 MHz, DMSO-d6) = 7.25 (t, J = 7.9, 1H), 7.08 (t, J = 2.0, 1H), 7.02-6.96 (m, 1H), 6.87-6.81 (m, 1H), 5.65 (s, 2H), 3.10 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 150.01, 141.84, 130.32, 118.62, 113.76, 111.41, 44.12. MS-ESI: 171.9 (M + H).sup.+. .sup.1H NMR (500 MHz, CDCl3) 11.48 (s, 1H), 9.96 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.8, 2.3 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 3.06 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 195.87, 165.41, 135.28, 134.12, 132.27, 120.10, 119.36, 44.75; MS-EI; 200 (M.sup.+); HRMS (EI) Calcd. for C.sub.8H.sub.8N.sub.3O.sub.4S (M.sup.+): 200.0143, Found: 200.0146. .sup.1H NMR (500 MHz, CDCl3) 8.02 (dd, J = 7.9, 1.4 Hz, 1H), 7.51 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 3.06 (s, 3H), 2.70 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 138.79, 137.62, 133.77, 132.80, 129.30, 126.80, 43.76, 20.35; MS-EI: 170 (M.sup.+). .sup.1H NMR (500 MHz, CDCl3) 9.55 (s, 1H), 8.77 (dd, J = 4.7, 1.5 Hz, 1H), 8.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.64 (dd, J = 8.1, 4.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 3.64 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 161.38, 151.52, 149.93, 139.71, 138.03, 137.16, 129.14, 126.27, 125.04, 120.24, 45.15; MS-EI: 276 (M.sup.+). .sup.1H NMR (500 MHz, d6-DMSO) 8.35 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 6.99 (s, 2H), 6.52 (d, J = 8.9 Hz, 1H), 3.11 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 162.49, 148.66, 135.80, 123.77, 107.18, 44.51; MS-EI: 172 (M.sup.+); HRMS (EI) Calcd. for C.sub.6H.sub.8N.sub.2O.sub.2S (M.sup.+): 172.0306, Found: 172.0312. 0 .sup.1H NMR (400 MHz, CDCl3) 9.09 (d, J = 3.8 Hz, 1H), 8.53 (s, 1H), 8.34-8.27 (m, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.2, 4.2 Hz, 1H), 3.14 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 153.68, 149.88, 138.32, 137.49, 131.64, 129.36, 127.44, 126.05, 122.92, 44.62; MS-EI: 207 (M.sup.+); .sup.1H NMR (500 MHz, DMSO-d6) = 9.57 (s, 1H), 7.99 (d, J = 8.2, 1H), 7.90 (dd, J = 7.9, 1.4, 1H), 7.74-7.68 (m, 1H), 7.44-7.38 (m, 1H), 3.26 (s, 3H), 2.13 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 168.87, 136.49, 134.66, 129.18, 125.61, 125.19, 43.42, 24.07. MS-ESI: 214 (M + H).sup.+ .sup.1H NMR (500 MHz, CDCl3) 8.28 (d, J = 1.8 Hz, 1H), 7.68 (dd, J = 8.7, 1.8 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.32-7.27 (m, 4H), 7.10 (d, J = 6.3 Hz, 2H), 6.69 (d, J = 2.9 Hz, 2H), 5.36 (s, 2H), 3.04 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 138.42, 136.49, 131.60, 131.06, 128.96, 128.30, 128.03, 126.78, 121.83, 120.15, 110.46, 103.49, 50.48, 45.21; MS-EI: 285 (M.sup.+); HRMS (EI) Calcd. for C.sub.16H.sub.15NO.sub.2S (M.sup.+): 285.0824, Found: 285.0831. .sup.1H NMR (500 MHz, DMSO-d6) = 8.40 (d, J = 0.9, 1H), 7.89-7.78 (m, 2H), 7.61 (s, 1H), 7.27 (t, J = 7.4, 2H), 7.21 (t, J = 7.3, 1H), 7.04 (d, J = 7.2, 2H), 4.31 (q, J = 7.1, 2H), 3.21 (s, 3H), 1.29 (t, J = 7.1, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 160.72, 140.58, 137.83, 133.44, 129.69, 128.55, 127.20, 126.16, 124.79, 123.16, 122.90, 112.37, 112.01, 60.91, 47.53, 44.12, 14.02. MS-ESI: 357 (M.sup.+) .sup.1H NMR (500 MHz, DMSO-d6) = 9.47 (s, 1H), 8.67 (d, J = 5.7, 1H), 8.65 (s, 1H), 8.36 (d, J = 8.6, 1H), 8.13 (dd, J = 8.6, 1.6, 1H), 8.07 (d, J = 5.7, 1H), 3.37 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 152.59, 144.37, 142.01, 134.25, 129.55, 129.09, 126.81, 123.78, 121.36, 43.21. .sup.1H NMR (500 MHz, CDCl3) 7.79 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.88 (d, J = 1.2 Hz, 3H), 3.19-3.11 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H). .sup.13C NMR (125 MHz, CDCl.sub.3) 163.79, 131.30, 128.48, 114.37, 55.86, 55.79. 15.97; MS-EI: 214 (M.sup.+); HRMS (EI) Calcd. for C.sub.10H.sub.14O.sub.3S (M.sup.+): 214.0664, Found: 214.0657. .sup.1H NMR (500 MHz, CDCl3) 9.06-9.01 (m, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 8.8, 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 3.33-3.21 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H). .sup.13C NMR (125 MHz, CDCl.sub.3) 153.51, 149.73, 137.35, 134.83, 131.0, 130.98, 127.37, 127.24, 122.72, 55.67, 15.73; MS-EI: 235 (M.sup.+); HRMS (EI) Calcd. for C.sub.12H.sub.13NO.sub.2S (M.sup.+): 235.0667, Found: 235.0663. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.93-7.90 (m, 2H), 7.88 (d, J = 9.0 Hz, 2H), 7.56-7.51 (m, 1H), 7.51-7.46 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 163.50, 142.50, 133.26, 132.97, 130.03, 129.33, 127.45, 114.64, 55.78; MS-EI: 248 (M.sup.+) .sup.1H NMR (500 MHz, CDCl3) 8.03-7.97 (m, 4H), 7.70 (d, J = 8.5 Hz, 2H), 7.60-7.55 (m, 3H), 7.52 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.43-7.38 (m, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 146.31, 141.86, 140.24, 139.29, 133.32, 129.45, 129.18, 128.72, 128.33, 128.07, 127.78, 127.48; MS-EI: 294 (M.sup.+); HRMS (EI) Calcd. for C.sub.18H.sub.14O.sub.2S (M.sup.+): 294.0715, Found: 294.0718. .sup.1H NMR (500 MHz, CDCl3) 8.06-8.01 (m, 4H), 7.95 (d, J = 7.8 Hz, 2H), 7.61-7.57 (m, 1H), 7.54-7.50 (m, 2H), 2.61 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 196.80, 145.54, 140.88, 140.45, 133.78, 129.60, 129.19, 128.10, 127.97, 27.02; MS-EI: 260 (M.sup.+); HRMS (EI) Calcd. for C.sub.14H.sub.12O.sub.3S (M.sup.+): 260.0507, Found: 260.0513. 0 .sup.1H NMR (500 MHz, DMSO-d6) = 7.93 (d, J = 7.6, 2H), 7.83 (d, J = 8.5, 2H), 7.65 (t, J = 7.3, 1H), 7.59 (t, J = 7.6, 2H), 7.42 (d, J = 8.5, 2H), 2.49 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d6) 146.56, 141.44, 136.55, 133.48, 129.67, 127.70, 127.08, 125.63, 13.85. .sup.1H NMR (500 MHz, DMSO-d6) = 7.94 (d, J = 7.4, 2H), 7.70 (dd, J = 8.1, 1.3, 1H), 7.66 (t, J = 7.4, 2H), 7.58 (t, J = 7.6, 2H), 7.33-7.26 (m, 1H), 6.79 (d, J = 8.3, 1H), 6.70-6.65 (m, 1H), 6.17 (s, 2H). .sup.13C NMR (126 MHz, DMSO-d6) 147.23, 141.39, 134.97, 133.30, 129.29, 129.09, 126.64, 119.65, 117.28, 115.87. .sup.1H NMR (500 MHz, CDCl3) 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.09 (dd, J = 8.9, 2.1 Hz, 1H), 8.03-8.00 (m, 2H), 7.59- 7.56 (m, 1H), 7.54-7.50 (m, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) 153.48, 149.63, 141.25, 139.44, 137.47, 133.62, 131.51, 129.56, 129.22, 127.96, 127.48, 126.59, 122.78; MS-EI: 269 (M.sup.+); HRMS (EI) Calcd. for C.sub.15H.sub.11NO.sub.2S (M.sup.+): 269.0511, Found: 269.0521. .sup.1H NMR (500 MHz, CDCl3) 9.20 (s, 1H), 8.81 (dd, J = 8.1, 1.6 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.05-8.02 (m, 2H), 7.70-7.67 (m, 1H), 7.64 (d, J = 1.1 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 160.87, 151.64, 150.14, 141.12, 139.97, 138.13, 137.40, 133.39, 129.13, 128.75, 128.50, 126.06, 124.84, 102.14; MS-EI: 338 (M.sup.+); HRMS (EI) Calcd. for C.sub.18H.sub.14N.sub.2O.sub.3S (M.sup.+): 338.0725, Found: 338.0721 .sup.1H NMR (500 MHz, CDCl3) 7.98 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 3.7 Hz, 1H), 7.63 (d, J = 4.9 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.09-7.06 (m, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 143.12, 142.17, 134.01, 133.49, 133.41, 129.42, 127.97, 127.40; MS-EI: 224 (M.sup.+); HRMS (EI) Calcd. for C.sub.10H.sub.8O.sub.2S.sub.2 (M.sup.+): 223.9966, Found: 223.9967. .sup.1H NMR (500 MHz, DMSO-d6) = 9.42 (s, 1H), 8.77 (s, 1H), 8.64 (d, J = 5.7, 1H), 8.30 (d, J = 8.7, 1H), 8.12-8.01 (m, 4H), 7.68 (t, J = 7.3, 1H), 7.62 (t, J = 7.5, 2H). .sup.13C NMR (126 MHz, DMSO-d6) 152.57, 144.49, 142.22, 140.30, 134.33, 134.01, 129.98, 129.81, 128.86, 127.64, 127.32, 123.92, 121.34. .sup.1H NMR (500 MHz, CDCl3) 9.19 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 2.8 Hz, 1H), 8.76 (d, J = 3.8 Hz, 1H), 8.60-8.56 (m, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.07 (dd, J = 8.9, 1.7 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.44 (dd, J = 8.1, 4.8 Hz, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 154.0, 153.79, 149.72, 148.88, 138.44, 137.92, 137.44, 135.46, 131.85, 129.65, 127.45, 126.20, 124.03, 122.94; MS-EI: 270 (M.sup.+); HRMS (EI) Calcd. for C.sub.14H.sub.10N.sub.2O.sub.2S (M.sup.+): 270.0463, Found: 270.0466. .sup.1H NMR (500 MHz, CDCl3) 9.41 (s, 1H), 9.12 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 4.6 Hz, 1H), 8.77 (d, J = 4.7 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 7.76 (dd, J = 8.1, 4.7 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.49 (dd, J = 8.1, 4.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 160.32, 153.51, 151.88, 149.64, 149.36, 140.26, 138.26, 137.99, 137.23, 136.83, 129.20, 126.42, 125.02, 123.24, 120.08; MS-EI: 339 (M.sup.+); HRMS (EI) Calcd. for C.sub.17H.sub.13N.sub.3O.sub.3S (M.sup.+): 339.0678, Found: 339.0673. .sup.1H NMR (500 MHz, DMSO-d6) = 8.60 (s, 1H), 8.24 (d, J = 8.5, 1H), 8.00 (d, J = 7.9, 2H), 7.96 (d, J = 5.5, 1H), 7.86 (d, J = 8.6, 1H), 7.68-7.61 (m, 2H), 7.59 (t, J = 7.6, 2H). .sup.13C NMR (126 MHz, DMSO-d6) 143.91, 141.49, 139.35, 137.27, 133.46, 130.71, 129.63, 127.20, 124.52, 124.08, 123.31, 121.82.

(171) All literatures mentioned in the present application are incorporated herein by reference, as though each one is individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents also fall within the scope defined by the appended claims.