A class of bridged carboxylic acid-containing bifunctionalized phosphine ligands, their preparation methods and applications

Abstract

This invention belongs to the field of chemical catalysis technology, and discloses a class of bridged carboxylic acid-containing bifunctionalized phosphine ligands or their racemates or enantiomers, as well as their preparation methods and applications. The bridged carboxylic acid-containing bifunctionalized phosphine ligands or their racemates or enantiomers of this invention have the structures shown in Formulas I-V: wherein, R 1 R' is a C1-C5 straight-chain alkyl group; R' is any one of substituted or unsubstituted aryl, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. The bridged carboxylic acid-containing bifunctionalized phosphine ligand of this invention, with biphenyl as its backbone, achieves complete transfer of facet chirality to axial chirality through a desymmetry reaction via precise chiral recognition and control. The resulting chiral ligand exhibits advantages such as high reactivity, good enantioselectivity, and a wide substrate adaptability. It is particularly effective in palladium-catalyzed asymmetric C-H bond-activated arylization reactions of halogenated compounds and can be applied to asymmetric C-H bond-activated arylization reactions.

Description

Technical Field

[0001] This invention belongs to the field of chemical catalysis technology, and specifically relates to a class of bridged bifunctional phosphine ligands containing carboxylic acids, or their racemates or enantiomers, as well as their preparation methods and applications. Background Technology

[0002] In asymmetric catalysis, the matching of substrate, catalyst, and ligands is crucial. Due to the lack of ligand universality, even small changes in substrate structure can lead to significant alterations in catalytic activity and enantioselectivity. Therefore, the design of chiral ligands and the development of novel catalytic reactions remain hot topics in asymmetric catalysis development (Angew. Chem. Int. Ed. 2002, 41, 2008-2022.). Chiral phosphine ligands are among the most widely used classes of ligands in asymmetric catalysis. Chiral monophosphine ligands, especially those with a biaryl skeleton, have attracted considerable attention due to their strong chiral induction ability. In 1991, Hayashi et al. developed (S)-2-diphenylphosphine-2'-methoxy-1,1'-binaphthyl (MOP) and successfully applied it in asymmetric hydrosilylation reactions (J. Am. Chem. Soc. 1991, 113, 9887-9888.). The dihedral angle of bisphosphine ligands plays a crucial role in asymmetric catalysis, and a suitable dihedral angle is essential for achieving excellent enantioselectivity. A 2004 report described the synthesis of a series of chiral side-chain bisphosphine ligands using central chiral compounds such as methanesulfonates or p-toluenesulfonates of chiral alcohols (PNAS 2004, 16, 5815-5820. J.Am.Chem.Soc.2006, 128, 5955-5965.). The synthesis successfully achieved efficient transfer from central chirality to axial chirality, obtaining chiral bisphosphine ligands with a single configuration without resolution, and successfully applied them in asymmetric hydrogenation reactions. Building upon this, the applicant of this invention has successively developed chiral biphenyl O,P-monophosphine ligands and N,P-monophosphine ligands with tunable dihedral angles, achieving superior performance compared to the naphthyl monophosphine ligand MOP in asymmetric Suzuki reactions.

[0003] CH bond activation has long been a research hotspot in chemistry. Constructing various chiral structures (central chirality, planar chirality, and axial chirality) through direct C-H bond activation remains a challenging task. In zero-valent palladium-catalyzed CH bond activation and subsequent C-C coupling reactions, CH bond activation is the decisive step in chirality control, accomplished through a concerted metal deprotonation (CMD) mechanism. Therefore, chiral ligands (trivalent phosphine compounds, N-heterocarbenes) or chiral bases (carboxylates or phosphates) can serve as chiral control sources to achieve asymmetric catalytic reactions. A 2018 report described the successful asymmetric CH bond activation arylation reaction using a bifunctionalized ligand containing phosphine and carboxylic acid (Angew. Chem. Int. Ed. 2018, 57, 1394-1398). By introducing carboxylate functional groups into the phosphine ligand molecule, the removal of inert CH bonds is facilitated during the catalytic cycle. However, the overall framework of these bifunctional monophosphine ligands is binaphthalene, and its dihedral angles and electronic effects are relatively simple, thus limiting the applicable substrates and resulting in a very limited number of successful catalytic examples. Furthermore, effective ligands and catalytic systems are currently lacking for asymmetric CH bond activation arylation reactions of heterocyclic compounds and electron-donating substrates.

[0004] In conclusion, based on previous research, further development of novel and diverse phosphine ligands is needed to provide stronger support for asymmetric catalysis. Summary of the Invention

[0005] In order to overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide a class of bridged bifunctionalized phosphine ligands containing carboxylic acids.

[0006] Another objective of this invention is to provide a method for preparing the above-mentioned bridged carboxylic acid-containing bifunctionalized phosphine ligand.

[0007] Another object of the present invention is to provide the application of the above-mentioned bridged carboxylic acid-containing bifunctionalized phosphine ligand.

[0008] The objective of this invention is achieved through the following solution:

[0009] A class of bridged, carboxylic acid-containing bifunctionalized phosphine ligands, or their racemates or enantiomers, have structures as shown in Formulas I-V:

[0010]

[0011] Among them, R 1 R' is a C1-C5 straight-chain alkyl group; R' is any one of substituted or unsubstituted aryl, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

[0012] Furthermore, in R', the substitution refers to the substitution of one or more hydrogen atoms of aryl, alkyl, or cycloalkyl groups by fluorine, chlorine, bromine, iodine, aryl, substituted amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, alkoxy, nitro, or trifluoromethyl groups.

[0013] R 2 R 3 R 4 The same or different are any one of hydrogen, fluorine atom, chlorine atom, bromine atom, iodine atom, trimethylsilyl, triethylsilyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyloxy, substituted amino, trifluoromethyl, cyano, nitro, substituted or unsubstituted aryl.

[0014] Furthermore, R 2 R 3 R 4 In this context, the substitution refers to the substitution of one or more hydrogen atoms of aryl, alkyl, cycloalkyl, amino, or hydroxyl groups by fluorine, chlorine, bromine, iodine, aryl, substituted amino, cyano, C1-C5 alkyl, C1-C20 hydroxyl groups, nitro, or trifluoromethyl groups.

[0015] Furthermore, R 2 R 3 R 4 In this context, the substitution refers to the substitution of one or more hydrogen atoms of aryl, alkyl, cycloalkyl, amino, or hydroxyl groups by fluorine, chlorine, bromine, iodine, aryl, substituted amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C1-C20 hydroxyl groups, nitro, or trifluoromethyl.

[0016] Preferably, the aryl groups mentioned above are each independently a C6-C20 aryl group.

[0017] Preferably, the alkyl groups mentioned above are each independently a C1-C20 alkyl group.

[0018] Preferably, the cycloalkyl groups mentioned above are each independently a C3-C20 cycloalkyl group.

[0019] Furthermore, the bridged carboxylic acid-containing bifunctionalized phosphine ligand or its racemate or enantiomer has the structure shown in Formulas I-V, wherein R 1 R is a C1-C5 straight-chain alkyl group; R' is a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C4-C7 cycloalkyl group; R 2 R 3 R 4The same or different elements are any one of hydrogen, fluorine, chlorine, bromine, iodine, trimethylsilyl, triethylsilyl, C1-C5 alkyl, C4-C7 cycloalkyl, C1-C5 alkylalkyloxy, arylalkyloxy, C1-C5 alkyl-substituted amino, trifluoromethyl, and substituted or unsubstituted aryl. The substitution in the substituted or unsubstituted aryl group refers to the substitution of one or more hydrogen atoms of the aryl group by fluorine, chlorine, bromine, iodine, aryl, substituted amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, alkyloxy, nitro, or trifluoromethyl.

[0020] The It is a side chain containing a chiral center and has the function of controlling the dihedral angle; the For the reason The product obtained after removing the Lg (leaving group), wherein the Lg is a hydroxyl group, a carboxyl group, an acyl chloride, a halogen, a methanesulfonate, a p-toluenesulfonate, or a trifluoromethanesulfonate.

[0021] The The non-chiral sidechain for controlling the dihedral angle size; For the reason The product obtained after removing the Lg (leaving group), wherein the Lg is a hydroxyl group, a carboxyl group, an acyl chloride, a halogen, a methanesulfonate, a p-toluenesulfonate, or a trifluoromethanesulfonate.

[0022] The or The number of carbon atoms in each group is either the same or different, ranging from 1 to 20.

[0023] As a preferred embodiment, the The following are examples of alcohols: 1,3-butanediol (R) or (S), 2,3-butanediol (R,R) or (S,S), 1,2-diphenylethylene glycol (R,R) or (S,S), 1,4-dibenzyloxybutanediol (R,R) or (S,S), 2,4-pentanediol (R,R) or (S,S), 2,5-hexanediol (R,R) or (S,S), 3,4-hexanediol (R,R) or (S,S), 1-phenylethane-1,2-diol (R) or (S), 1,2-decanediol (R) or (S), 2,9-decanediol (R,R) or (S,S), 3,8-decanediol (R,R) or (S,S). S,S), 4,7-decanediol (R,R) or (S,S), 5,6-decanediol (R,R) or (S,S), cis-1,2-cyclohexanediol, trans-1,2-cyclohexanediol (R,R) or (S,S), cis-1,2-cyclopentanediol, trans-1,2-cyclopentanediol (R,R) or (S,S), (1S,2S,3R,5S)-(+)-2,3-pinenediol, (3S,5S)-(+)-3,5-heptanediol, (3R,5R)-(-)-3,5-heptanediol, 2,6-heptanediol (R,R) or (S,S), cis-3 Chiral diols such as 4-tetrahydrofurandiol, 3,6-octanediol (R,R) or (S,S), 2,7-octanediol (R,R) or (S,S), 2,8-nonanediol (R,R) or (S,S), 3,7-nonanediol (R,R) or (S,S), 4,6-nonanediol (R,R) or (S,S), cis-1,2-cyclohexanediol, trans-1,2-cyclohexanediol, (+)-2,3-O-isopropylidene-L-threitol, (-)-2,3-O-isopropylidene-D-threitol, or 2,2'-bicaprol (R) or (S), 2,2'-binaphthyldicarboxylic acid (R) (R,R) or (S), L-tartaric acid, D-tartaric acid, 2,3-dibromosuccinic acid (R,R) or (S,S), 2,3-dimercaptosuccinic acid (R,R) or (S,S), (S)-(-)-2-isobutylsuccinic acid-1-ethyl ester, (+)-di-p-methoxybenzoyl-D-tartaric acid, (-)-di-p-methoxybenzoyl-L-tartaric acid, 1,2-cyclohexanedicarboxylic acid (R,R) or (S,S), citrate (R) or (S), L-malic acid, D-malic acid, methylsuccinic acid (R) or (S); or methanesulfonates, p-methylbenzenesulfonates or trifluoromethanesulfonates of the above chiral diols.

[0024] The It includes condensation-terminal halogenated compounds such as 1,1-dibromopropane, 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, 1,6-dibromoethane, 1,7-dibromoheptane, 1,8-dibromooctane, 1,9-dibromononane, 1,10-dibromodecane, ethylene glycol, etc., or their methanesulfonates or p-toluenesulfonates, 1,3-dibromobenzene, 1,4-dibromobenzene, α,α-dibromoo-xylene, α,α-dibromo-m-xylene, and α,α-dibromo-p-xylene.

[0025] This invention also provides a method for preparing the above-mentioned bridged carboxylic acid-containing bifunctionalized phosphine ligand, specifically:

[0026] When R 2 R 3 R 4 When the hydrogen is present, the compound of formula I or formula III is prepared by a method comprising the following steps, with the reaction equations as follows:

[0027]

[0028] (1) Using 2,2',6,6'-tetrahydroxybiphenyl (compound 1) as the starting material, and... (Compound 2) undergoes a nucleophilic substitution reaction to form a cyclization, yielding a biphenyl compound (compound 3) or its enantiomer (compound 3') with central and axial chirality;

[0029] Furthermore, the reaction temperature can be 20-100℃; the reaction time can be 1-50h; the reaction is carried out in the presence of an inorganic base; and the reaction environment is an organic solvent environment.

[0030] (2) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, a biphenyl compound or its enantiomer reacts with trifluoromethanesulfonic anhydride to give a bis(trifluoromethanesulfonic acid) ester compound (compound 4) or its enantiomer (compound 4').

[0031] Furthermore, the molar ratio of the biphenyl compound or its enantiomer to trifluoromethanesulfonic anhydride is preferably 1:2 to 1:8; the reaction temperature can be -20 to 40°C; the reaction time can be 1 to 24 hours; and the reaction environment is an organic solvent environment.

[0032] (3) A bis(trifluoromethanesulfonate) compound (compound 4) or its enantiomer (compound 4') and The reaction yields trifluoromethanesulfonate phosphonium oxide (compound 5) or its enantiomer (compound 5');

[0033] Furthermore, the bis(trifluoromethanesulfonate) compound or its enantiomers with... The preferred molar ratio is 1:1 to 1:4; the reaction temperature can be 60-140℃; the reaction time can be 1-40h; the reaction is carried out under the catalysis of a complex catalyst formed by a transition metal and a phosphine ligand; the reaction environment is an organic solvent environment.

[0034] (4) Hydrolyze the trifluoromethanesulfonate phosphonium oxide compound (compound 5) or its enantiomer (compound 5') under alkaline conditions and then acidify it to obtain hydroxyphosphonium oxide compound (compound 6) or its enantiomer (compound 6').

[0035] Furthermore, the reaction environment is an organic solvent environment; the alkaline conditions can be achieved by adding an inorganic base, such as adding 1-5 mol / L of inorganic base to an organic solvent; the acidification can be carried out under the action of an inorganic acid, such as acidification with 1-3 mol / L of inorganic acid; the reaction temperatures of hydrolysis and acidification can be the same or different, respectively, ranging from 0-40℃; the reaction times of hydrolysis and acidification can be the same or different, respectively, ranging from 1-24 h.

[0036] (5) A hydroxyphosphonic oxide (compound 6) or its enantiomer (compound 6') is reacted with an etherifying agent to give an etherified product (compound 7) or its enantiomer (compound 7');

[0037] Furthermore, the molar ratio of the hydroxyphosphorus oxide compound (compound 6) or its enantiomer (compound 6') to the etherifying agent is preferably 1:1 to 1:10; the reaction temperature can be 0-80°C; the reaction time can be 1-60 h; the reaction is carried out in the presence of an inorganic base; and the reaction environment is an organic solvent environment.

[0038] (6) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, the etherified product (compound 7) or its enantiomer (compound 7') is reduced by trichlorosilane to give an etherified phosphine compound (compound 8) or its enantiomer (compound 8');

[0039] Furthermore, the molar ratio of the etherified product or its enantiomer to trichlorosilane is preferably 1:1 to 1:30; the reduction reaction temperature can be 60-140℃; the reaction time can be 7-40h; and the reaction environment is an organic solvent environment.

[0040] (7) Hydrolyze the etherified phosphine compound (compound 8) or its enantiomer (compound 8') under alkaline conditions, and then acidify it to obtain a compound of formula I or formula III.

[0041] Furthermore, the reaction environment is a mixed solvent of organic solvent and water; the alkaline conditions can be achieved by adding an inorganic base, such as adding 1-5 mol / L of inorganic base; the acidification can be carried out under the action of inorganic acid, such as acidification with 1-3 mol / L of inorganic acid; the reaction temperatures of hydrolysis and acidification can be the same or different, respectively, ranging from 0-40℃; the reaction times of hydrolysis and acidification can be the same or different, respectively, ranging from 1-48 h.

[0042] When R 2 R 3 R 4 When the hydrogen is present, the compound of formula II or formula IV is prepared by a method comprising the following steps, with the reaction equations shown below:

[0043] (1) Using 2,2',6,6'-tetrahydroxybiphenyl (compound 1) as the starting material, and... (Compound 2) undergoes a nucleophilic substitution reaction to form a cyclization, yielding a biphenyl compound (compound 3) or its enantiomer (compound 3') with central and axial chirality;

[0044] Furthermore, the reaction temperature can be 20-100℃; the reaction time can be 1-50h; the reaction is carried out in the presence of an inorganic base; and the reaction environment is an organic solvent environment.

[0045] (2) Biphenyl compound (compound 3) or its enantiomer (compound 3') and A cyclization reaction occurs to give a diphenyl ether compound (compound 10) or its enantiomer (compound 10');

[0046] Furthermore, the reaction temperature can be 20-100℃; the reaction time can be 1-50h; the reaction is carried out in the presence of an inorganic base; and the reaction environment is an organic solvent environment.

[0047] (3) Reaction of a biphenyl ether compound (compound 10) or its enantiomer (compound 10') with a lithium salt or inorganic base of 4,4'-di-tert-butylbiphenyl yields a biphenyl hydroquinone compound (compound 11) or its enantiomer (compound 11') with exposed phenolic hydroxyl groups.

[0048] Furthermore, the reaction temperature can be -78 to 0°C; the reaction time can be 1 to 48 hours; and the reaction environment is an organic solvent environment.

[0049] (4) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, a biphenyl compound (compound 11) or its enantiomer (compound 11') with exposed phenolic hydroxyl groups reacts with trifluoromethanesulfonic anhydride to give a bis(trifluoromethanesulfonic acid) ester compound (compound 12) or its enantiomer (compound 12').

[0050] Furthermore, the molar ratio of the biphenyl compound with exposed phenolic hydroxyl groups (compound 11) or its enantiomer (compound 11') to trifluoromethanesulfonic anhydride is preferably 1:2 to 1:8; the reaction temperature can be -20 to 40°C; the reaction time can be 1 to 24 hours; and the reaction environment is an organic solvent environment.

[0051] (5) A bis(trifluoromethanesulfonate) compound (compound 12) or its enantiomer (compound 12') and The reaction yields trifluoromethanesulfonate phosphonium oxide (compound 13) or its enantiomer (compound 13');

[0052] Furthermore, the bis(trifluoromethanesulfonate) compound or its enantiomers with... The preferred molar ratio is 1:1 to 1:4; the reaction temperature can be 60-140℃; the reaction time can be 1-40h; the reaction is carried out under the catalysis of a complex catalyst formed by a transition metal and a phosphine ligand; the reaction environment is an organic solvent environment.

[0053] (6) Hydrolyze the trifluoromethanesulfonate phosphonium oxide compound (compound 13) or its enantiomer (compound 13') under alkaline conditions and then acidify it to obtain hydroxyphosphonium oxide compound (compound 14) or its enantiomer (compound 14').

[0054] Furthermore, the reaction environment is an organic solvent environment; the alkaline conditions can be achieved by adding an inorganic base, such as adding 1-5 mol / L of inorganic base to an organic solvent; the acidification can be carried out under the action of an inorganic acid, such as acidification with 1-3 mol / L of inorganic acid; the reaction temperatures of hydrolysis and acidification can be the same or different, respectively, ranging from 0-40℃; the reaction times of hydrolysis and acidification can be the same or different, respectively, ranging from 1-24 h.

[0055] (7) A hydroxyphosphonic compound (compound 14) or its enantiomer (compound 14') is reacted with an etherifying agent to give an etherified product (compound 15) or its enantiomer (compound 15');

[0056] Furthermore, the molar ratio of the hydroxyphosphine oxide compound (compound 14) or its enantiomer (compound 14') to the etherifying agent is preferably 1:1 to 1:10; the reaction temperature can be 0-80°C; the reaction time can be 1-60 h; the reaction is carried out in the presence of an inorganic base; and the reaction environment is an organic solvent environment.

[0057] (8) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, the etherified product (compound 15) or its enantiomer (compound 15') is reduced by trichlorosilane to give an etherified phosphine compound (compound 16) or its enantiomer (compound 16').

[0058] Furthermore, the molar ratio of the etherified product (compound 15) or its enantiomer (compound 15') to trichlorosilane is preferably 1:1 to 1:30; the reduction reaction temperature can be 60-140°C; the reaction time can be 7-40 h; and the reaction environment is an organic solvent environment.

[0059] (9) The etherified phosphine compound (compound 16) or its enantiomer (compound 16') is hydrolyzed under alkaline conditions and then acidified to obtain compound II or compound IV.

[0060] Furthermore, the reaction environment is a mixed solvent of organic solvent and water; the alkaline conditions can be achieved by adding an inorganic base, such as adding 1-5 mol / L of inorganic base; the acidification can be carried out under the action of inorganic acid, such as acidification with 1-3 mol / L of inorganic acid; the reaction temperatures of hydrolysis and acidification can be the same or different, respectively, ranging from 0-40℃; the reaction times of hydrolysis and acidification can be the same or different, respectively, ranging from 1-48 h.

[0061] Furthermore, in the preparation method of the compounds having the structures shown in Formulas I to V of the present invention, the organic bases containing lone pairs of electrons on the nitrogen atom may be the same or different and may be at least one of the following: trimethylamine, triethylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diethylaniline, tripropylamine, pyridine, N,N-dimethylpyridine, 1,4-diazabicyclo[2,2,2]octane, diazabicyclododecane, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, quinine, 1-methylmorpholine, and 1-methyl-2,2,6,6-tetramethylpiperidine.

[0062] The etherifying agents mentioned above, whether the same or different, are bromocarboxylic acid esters.

[0063] The inorganic bases mentioned above, whether the same or different, can be at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, and cesium fluoride.

[0064] The complex catalysts composed of the aforementioned transition metals and phosphine ligands, whether identical or different, can be at least one of the following: NiCl2(dppe), NiCl2(dppp), NiCl2(dppb), PdCl2(dppe), PdCl2(dppp), PdCl2(dppb), Pd(OAc)2(dppe), Pd(OAc)2(dppp), and Pd(OAc)2(dppb).

[0065] The organic solvents mentioned above, whether the same or different, may be at least one of the following: diethyl ether, acetonitrile, benzene, toluene, xylene, dimethyl sulfoxide, tetrahydrofuran, methyl tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, dichloromethane, chloroform, carbon disulfide, carbon tetrachloride, 1,4-dioxane, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, pyrrolidone, N-methylpyrrolidone, etc.

[0066] The inorganic acids mentioned above, whether the same or different, can be at least one of hydrochloric acid, sulfuric acid, and nitric acid.

[0067] When R 2 R 3 R 4 When the hydrogen content is non-hydrogen, the preparation method differs in that the biphenyl compound (compound 3) or its enantiomer (compound 3') is first prepared at the R... 2 R 3 R 4 The selective introduction of fluorine, chlorine, bromine, or iodine atoms, or the introduction of trimethylsilyl, triethylsilyl, alkyl, cycloalkyl, substituted amino, trifluoromethyl, cyano, nitro, substituted or unsubstituted aryl groups through conventional coupling reactions, followed by subsequent steps, yields the corresponding compound.

[0068]

[0069] The racemic mixture required above can be easily prepared using achiral or racemic starting materials and methods similar to the above reactions, based on well-known principles.

[0070] The present invention relates to a bridged, carboxylic acid-containing bifunctionalized phosphine ligand with a biphenyl backbone. Through precise chiral recognition and control, a complete transfer of facet chirality to axial chirality is achieved via a desymmetry reaction, yielding the target optically pure bifunctionalized monophosphine ligand. The synthetic method of this invention is simple and economical, and purification can be achieved by silica gel column chromatography, avoiding a complex chiral resolution process. The obtained chiral ligand exhibits advantages such as high reactivity, good enantioselectivity, and a wide substrate adaptability. It is particularly effective in palladium-catalyzed asymmetric CH-bond activated arylization reactions of halogenated compounds and can be applied to such reactions.

[0071] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0072] (1) The bridging carboxylic acid-containing bifunctionalized phosphine ligand of the present invention has both a bridging chiral chain and axial chirality.

[0073] (2) The bridging carboxylic acid-containing bifunctionalized phosphine ligands and their enantiomers or racemates of the present invention can effectively adjust the electronegativity, rigidity, chiral environment and dihedral angle of the biphenyl skeleton by changing the structure and length of the chiral or achiral side chains.

[0074] (3) The bridged carboxylic acid-containing bifunctionalized phosphine ligands of the present invention have the advantages of high reactivity, good enantioselectivity and wide substrate applicability: excellent catalytic effect can be obtained in the asymmetric CH bond activated arylation reaction, and the product can achieve a yield of up to 99% and an enantiomeric excess of 99% (ee); the substrate applicability is wide, and it has excellent catalytic efficiency for benzene ring skeleton and heterocyclic skeleton, as well as substrates containing electron-donating or electron-withdrawing functional groups.

[0075] (4) The bridged carboxylic acid-containing bifunctional phosphine ligand of the present invention is simple and economical to prepare. It can be separated and purified by silica gel column chromatography, avoiding the complicated chiral resolution process. Detailed Implementation

[0076] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, all materials involved in the following embodiments are commercially available. Unless otherwise specified, all methods described are conventional methods. The amounts of each component are expressed in molar volumes (mol, L).

[0077] Example 1: The preparation of (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid is used as an example.

[0078]

[0079] (1) Synthesis of (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2,2'-dihydroxybiphenyl

[0080] Under nitrogen protection, 4.04 mol of 2,2',6,6'-tetrahydroxybiphenyl and 9.39 mol of cesium carbonate were suspended in 120 v / v of dry N,N-dimethylformamide (DMF), and the mixture was heated to 80 °C and stirred for 1 hour to obtain a suspension. Then, 4.06 mol of (2R,3R)-2,3-butanediol methanesulfonate was dissolved in 40 v / v of dry DMF and slowly added dropwise to the suspension over 4 hours. The suspension was then stirred at 80 °C for 12 hours, and the DMF was removed by vacuum distillation. The residue after distillation was poured into 1 mol / L hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and after solvent removal, the crude product was purified by silica gel column chromatography to obtain product (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2,2'-dihydroxybiphenyl in 65% yield.

[0081] Product Result Analysis: 1 H NMR (300MHz, d6-DMSO): δ1.28 (d, J = 5.4Hz, 6H), 3.72-3.74 (m, 2H), 6.63 (d, J = 7.6Hz, 2H), 6.67 (d, J = 7.6Hz, 2H), 7.13 (t, J = 7.6Hz, 2H), 9.15 (s, 2H). 13 CNMR(75MHz,d6-DMSO):δ18.70,85.46,111.18,112.33,115.80,128.54,155.19,159.79.MS(ESI):[M] - 270.9,C 16 H 16 O4.

[0082] (2) Synthesis of (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2,2'-ditrifluoromethanesulfonate biphenyl

[0083] 17.28 moles of the product from step (1) were dissolved in 50 volumes of anhydrous pyridine, and 69.12 moles of trifluoromethanesulfonic anhydride were slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was carried out under an ice-water bath for 1 hour, then slowly raised to room temperature and stirred overnight. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was diluted to 1000 volumes of ethyl acetate, and then washed successively with 5% dilute hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine. The organic phase was dried with anhydrous sodium sulfate, and after the solvent was removed by evaporation, the crude product was purified by column chromatography to obtain product (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2,2'-ditrifluoromethanesulfonate biphenyl, with a yield of 90%.

[0084] Product Results Analysis: 1H NMR (300MHz, CDCl3): δ1.40-1.42 (m, 6H), 3.88-3.94 (m, 2H), 7.22 (d, J = 8.1Hz, 4H), 7.50 (d, J = 8.1Hz, 2H). 13 CNMR (75MHz, CDCl3): δ18.71,86.58,111.87,116.11,117.27,120.22,120.35,122.36,124.59,131.08,146.77,160.56.MS(ESI):[M+Na] + 558.

[0085] (3) Synthesis of (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-2'-trifluoromethanesulfonate-biphenyl:

[0086] Under nitrogen protection, 15.6 moles of the product from step (2), 31.2 moles of diphenylphosphine oxide, 3.1 moles of 1,4-bis(diphenylphosphinebutane) (dppb), and 3.1 moles of palladium acetate were added to a reaction flask. Then, 15 volumetric parts of diisopropylethylamine and 100 volumetric parts of dimethyl sulfoxide were added, and the mixture was heated to 110°C and reacted for 24 hours. After the reaction, the residue was diluted to 400 volumetric parts of ethyl acetate and washed with water, 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and after the solvent was evaporated, the crude product was purified by column chromatography to obtain product (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-2'-trifluoromethanesulfonate biphenyl, with a yield of 92%.

[0087] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.36-1.39(m,6H),3.81-3.89(m,2H),6.94-6.99(m,2H),7.26-7.55(m,12H),7.75-7.80(m,2H). 13CNMR (101MHz, CDCl3): δ18.86,19.01,86.38,87.12,116.71,121.25,125.67, 125.69,127.95,128.08,128.19,128.31,129.79,129.85,129.93,130.05,13 0.18,131.19,131.22,131.56,131,58,131,68,131.78,131.93,132.03,132.12,132.22,132.92,133.07,133.73,134.77,147.99,159.81,160.47,160.59. 31 P NMR (162MHz, CDCl3): δ27.71.MS (ESI): [M+H] + 589.

[0088] (4) Synthesis of (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-2'-hydroxybiphenyl:

[0089] At room temperature, 10.2 moles of the product from step (3) were dissolved in a 2 / 1 mixture of 100 volumes of 1,4-dioxane and methanol. 35 volumes of 3 mol / L NaOH solution were slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 1 with dilute hydrochloric acid, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the crude product was purified by column chromatography after the solvent was evaporated to obtain product (R)-[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-2'-hydroxybiphenyl, with a yield of 98%.

[0090] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.29(d,J=5.8Hz,3H)1.34(d,J=5.8Hz,3H),3.74-3.82(m,2H),6.27(d,J=7.9Hz,1H),6.81(d,J= 8.0Hz,1H),6.90-7.00(m,2H),7.18-7.22(m,2H);7.28-7.41(m,5H);7.48-7.60(m,3H);7.76-7.81(m,2H);9.57(S,1H). 13CNMR (101MHz, CDCl3): δ18.92,18.95,85.91,87.17,114.29,118.62,123 .05,123.09,126.92,126.95,127.86,127.99,128.50,128.63,128.97,12 9.12,129.34,129.82,130.19,130.31,130.83,130.88,130.93,131.37,1 31.39,132.11,132.13,132.40,133.27,133.35,159.67,160.46,160.60. 31 P NMR (162MHz, CDCl3): δ33.72.MS (ESI): [M+H] + 457.

[0091] (5) Synthesis of (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}acetic acid

[0092] Under nitrogen protection, 4.38 moles of the product from step (4) were dissolved in 40 volumes of acetone, and 21.9 moles of anhydrous potassium carbonate were added. Then, 21.9 moles of ethyl 2-bromoacetate were slowly added, and the mixture was refluxed and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed by depressurization to obtain the crude product (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-ethyl acetate. No further processing was required before adding it to the next reaction step.

[0093] Under nitrogen protection, ethyl(R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-ethyl acetate was dissolved in dry toluene. 48.20 moles of triethylamine were added, and after the reaction mixture was cooled to 0°C, 17.53 moles of trichlorosilane were added. The reactants were transferred to an oil bath and heated to 110°C, then refluxed for 12 hours. After cooling to room temperature, toluene was added for dilution, and the reaction was quenched by slowly adding saturated sodium bicarbonate aqueous solution while stirring for 15 minutes. The mixture was filtered through diatomaceous earth, and the residue was washed with toluene. The filtrates were combined, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain the crude product (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-ethyl acetate.

[0094] Ethyl (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid was dissolved in a mixture of 10 parts by volume of tetrahydrofuran and 10 parts by volume of water under nitrogen protection. 8.76 moles of lithium hydroxide were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 2. The mixture was extracted multiple times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid (L1). The overall yield of the three-step reaction was 71%.

[0095] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.31 (d, J = 6.4Hz, 3H); 1.36 (d, J = 6.4Hz, 3H); 3.72-3.89 (m, 2H); 4.57-4.70 (m, 2H); 6 .55-6.58(m,2H); 6.76-6.79(m,1H),7.03-7.07(m,2H); 7.14-7.22(m,5H); 7.28-7.40(m,6H); 11.39(S,1H). 13 C NMR (101MHz, CDCl3): δ18.92,18.99,65.59,85.90,86.70,99.98,106.35,116.06,122.97,128.01,128.09,128.70,128.77,128. 81,129.33,129.51,129.53,130.35,133.17,133.36,134.12,134.31,134.77,137.06,153.27,159.33,159.41,160.65,170.50. 31 P NMR (162MHz, CDCl3): δ5.85.MS (ESI): [M+H] + 514.

[0096] Example 2: The preparation of (S)-2-{[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid is used as an example.

[0097]

[0098] (1) Synthesis of (S)-[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2,2'-dihydroxybiphenyl

[0099] Under nitrogen protection, 4.04 mol of 2,2',6,6'-tetrahydroxybiphenyl and 9.39 mol of cesium carbonate were suspended in 120 v / v of dry N,N-dimethylformamide (DMF), and the mixture was heated to 80 °C and stirred for 1 hour to obtain a suspension. Then, 2.67 mol of p-toluenesulfonate of (2S,4S,)-2,4-pentanediol was dissolved in 40 v / v of dry DMF and slowly added dropwise to the suspension over 4 hours. The suspension was then stirred at 80 °C for 12 hours, and the DMF was removed by vacuum distillation. The residue after distillation was poured into 1 mol / L hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and after solvent removal, the crude product was purified by silica gel column chromatography to obtain (S)-[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2,2'-dihydroxybiphenyl in 60% yield.

[0100] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.37(d,J=6.5Hz,6H),1.87(t,J=4.12Hz,2H),4.58-4.65(m,2H),5.44(s,2H),6.71-6.77(m,4H),7.25(t,8.1Hz,2H). 13 C NMR (101MHz, CDCl3): δ22.18,40.80,75.05,75.16,109.97,110.99,113.30,153.63,158.40.MS(EI):[M] + 286.

[0101] (2) Synthesis of (S)-[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2,2'-ditrifluoromethanesulfonate biphenyl

[0102] 8.73 moles of the product from step (1) were dissolved in 25 volumes of anhydrous pyridine, and 43.66 moles of trifluoromethanesulfonic anhydride were slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was carried out under an ice-water bath for 1 hour, then slowly raised to room temperature and stirred overnight. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was diluted to 500 volumes of ethyl acetate. Then, it was washed successively with 5% dilute hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, and after the solvent was removed by evaporation, the crude product was purified by column chromatography to obtain the product with a yield of 93%.

[0103] Product Result Analysis: 1H NMR (400MHz, CDCl3): δ1.41 (d, J = 6.4Hz, 6H), 1.90 (t, J = 4.1Hz, 2H), 4.60-4.67 (m, 2H), 7.13-7.19 (m, 4H), 7.47 (t, J = 8.4Hz, 2H). 19 F{ 1 H}NMR(376MHz,CDCl3)δ-74.21.MS(ESI):[M+H] + 551.

[0104] (3) Synthesis of (S)-[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2-diphenylphosphine-2'-trifluoromethanesulfonate biphenyl

[0105] Under nitrogen protection, 7.8 mol of the product from step (2), 15.6 mol of diphenylphosphine oxide, 1.55 mol of 1,4-bis(diphenylphosphinebutane) (dppb), and 1.55 mol of palladium acetate were added to a reaction flask. Then, 7.5 v / v of diisopropylethylamine and 50 v / v of dimethyl sulfoxide were added, and the mixture was heated to 110 °C and reacted for 24 hours. After the reaction, the residue was diluted to 400 v / v of ethyl acetate and washed with water, 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and after the solvent was evaporated, the crude product was purified by column chromatography to obtain the product with a yield of 93%.

[0106] Product Result Analysis: 1 H NMR (400MHz, CDCl3) δ1.31-1.35(m,6H),1.7-1.71(m,1H),1.82-1.85(m,1H),4.49-4. 54(m,2H),6.83-6.90(m,2H),7.18-7.31(m,5H),7.37-7.57(m,7H),7.69-7.75(m,2H); 31 P NMR (162MHz, CDCl3): δ28.05ppm.MS (ESI): [M+H] + 603.

[0107] (4) Synthesis of (S)-[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2-diphenylphosphine-2'-hydroxybiphenyl

[0108] At room temperature, 5.1 moles of the product from step (3) were dissolved in a 2 / 1 mixture of 50 volumes of 1,4-dioxane and methanol. 16 volumes of 3 mol / L NaOH solution were slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 1 with dilute hydrochloric acid, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography to obtain the final product, with a yield of 95%.

[0109] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.25-1.34(m,6H),1.60-1.65(m,1H),1.84-1.90(m,1H),4.44-4.52(m,2H),6.62-6.24(m,2H),6.72-6.74(m,1 H),6.77-6.85(m,1H),6.96(t,J=8.1Hz,1H),7.18-7.23(m,2H),7.29-7.35(m,3H),7.34-7.59(m,5H),7.76-7.81(m,2H),9.36(s,1H); 31 PNMR (162MHz, CDCl3): δ33.63ppm.[M+H] + 471.

[0110] (5) Synthesis of (S)-2-{[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}acetic acid

[0111] Under nitrogen protection, 4.38 moles of the product from step (4) were dissolved in 40 volumes of acetone, and 21.9 moles of anhydrous potassium carbonate were added. Then, 21.9 moles of ethyl 2-bromoacetate were slowly added, and the mixture was refluxed and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed by depressurization to obtain the crude product (S)-2-{[6,6'-((R,R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-ethyl acetate. No further processing was required before adding it to the next reaction step.

[0112] Under nitrogen protection, the above-mentioned (S)-2-{[6,6'-((R,R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-ethyl acetate was dissolved in dry toluene, and 48.20 moles of triethylamine were added. After the reaction mixture was cooled to 0°C, 17.53 moles of trichlorosilane were added. The reactants were transferred to an oil bath and heated to 110°C, and refluxed for 12 hours. After cooling to room temperature, toluene was added for dilution, and the reaction was quenched by slowly adding saturated sodium bicarbonate aqueous solution while stirring for 15 minutes. The mixture was filtered through diatomaceous earth, and the residue was washed with toluene. The filtrates were combined, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain the crude product (S)-2-{[6,6'-((R,R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-ethyl acetate.

[0113] Under nitrogen protection, the above-mentioned (S)-2-{[6,6'-((R,R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid was dissolved in a mixed solution of 10 parts by volume of tetrahydrofuran and 10 parts by volume of water. 8.76 moles of lithium hydroxide were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 2. The mixture was extracted multiple times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain (S)-2-{[6,6'-((R,R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid (L2). The overall yield of the three-step reaction was 65%.

[0114] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.23-1.25(d,J=6.4Hz,3H),1.37-1.39(d,J=6.6Hz,3H),1.60-1.65(m,1H),1.88-1.95(m,1H),4. 44-4.50(m,2H),4.71(s,2H),6.49-6.51(m,2H),6.64-6.67(m,1H),7.04-7.16(m,6H),7.20-7.40(m,7H),11.30(s,1H); 31 P NMR (162MHz, CDCl3): δ-7.22ppm; 13CNMR (101MHz, CDCl3): δ21.33,22.90,40.89,65.38,74.18,76.53,99.99,104.52,111.56,118.05,119.26,127.01,127.87 ,128.68,128.81,129.63,131.61,131.85,133.50,133.69,134.21,134.39,136.86,153.22,158.06,158.40,170.66;[M+H] + 513.

[0115] Example 3: Preparation of (R)-2-[(6,6'-pentanedioloxy)-2-diphenylphosphine-1,1'-biphenyl-2'-oxy]-acetic acid

[0116]

[0117] (1) Synthesis of (R)-2,2'-(S)-1,2-propanediol oxy-6,6'-pentanediol oxybiphenyl

[0118] A solution of 6 moles of (R)-[6,6'-((S)-1,2-propanedioloxy)]-2,2'-dihydroxybiphenyl, 6 moles of 1,5-dibromopentane, 14 moles of potassium carbonate, and 150 parts by volume of DMF was reacted at 80 °C for 12 h with stirring. The DMF was removed by vacuum distillation, the product was dissolved in ethyl acetate, washed with brine, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the product was obtained by silica gel column chromatography in 83% yield.

[0119] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.27-1.30(m,2H),1.34-1.37(m,3H),1.78-1.83(m,4H),3.95-3 .99(m,4H),4.35-4.39(m,1H),4.39-4.44(m,2H),6.61-6.72(m,4H),7.14-7.24(m,2H).

[0120] (2) Synthesis of (R)-2,2'-dihydroxy-6,6'-pentanediol-oxybiphenyl

[0121] Add 3.34 mol and 45.2 mol of the product from step (1) to a reaction flask, dissolve in 50 volume parts of THF, and stir at 0°C for 1 h. Remove the solvent by vacuum distillation, and purify the crude product by silica gel column chromatography to obtain a light yellow solid with a yield of 95%.

[0122] Product Result Analysis: 1H NMR (400MHz, CDCl3): δ1.26-1.29(m,2H),1.73-1.77(m,4H),3.93-3.96(m,4H),5.45(s,2H),6.57-6.61(m,4H),7.14-7.18(m,2H).

[0123] (3) Synthesis of (R)-(6,6'-pentanedioloxy)-2,2'-ditrifluoromethanesulfonate biphenyl

[0124] 4.32 moles of the product from step (2) were dissolved in 50 parts by volume of anhydrous pyridine, and 17.28 moles of trifluoromethanesulfonic anhydride were slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was carried out under an ice-water bath for 1 hour, then slowly raised to room temperature and stirred overnight. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was diluted to 300 parts by volume of ethyl acetate, and then washed successively with 5% dilute hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, and after the solvent was removed by evaporation, the crude product was purified by column chromatography to obtain the product with a yield of 88%.

[0125] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.62-1.66(m,2H),1.77-1.83(m,4H),4.15-4.20(m,2H),4.38-4.44(m,2H),7.03-7.07(m,4H),7.45-7.49(m,2H).

[0126] (4) Synthesis of (R)-(6,6'-pentanedioloxy)-2-diphenylphosphine-2'-trifluoromethanesulfonate-biphenyl:

[0127] Under nitrogen protection, 3.8 mol of the product from step (3), 7.8 mol of diphenylphosphine oxide, 0.78 mol of 1,4-bis(diphenylphosphinebutane) (dppb), and 0.78 mol of nickel chloride were added to a reaction flask. Then, 3.75 v / v of diisopropylethylamine and 20 v / v of dimethyl sulfoxide were added, and the mixture was heated to 110 °C and reacted for 24 hours. After the reaction, the residue was diluted to 100 v / v of ethyl acetate and washed with water, 1 mol / L dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, and after the solvent was evaporated, the crude product was purified by column chromatography to obtain the product with a yield of 90%.

[0128] Product Result Analysis: 1H NMR (400MHz, CDCl3): δ1.24-1.35(m,2H),1.46-1.53(m,2H),1.62-1.68(m,2H),3.93-3.98(m,1H),4.09-4.14(m,1H),4.19-4.24(m,1H) ),4.34-4.39(m,1H),6.72-6.76(m,2H),7.02-7.07(m,1H),7.19-7.25(m,2H),7.29-7.33(m,2H),7.37-7.63(m,7H),7.67-7.72(m,2H). 31 P NMR (162MHz, CDCl3): δ28.07.MS (ESI): [M+H] + 603.

[0129] (5) Synthesis of (R)-(6,6'-pentanedioloxy)-2-diphenylphosphine-2'-hydroxybiphenyl:

[0130] At room temperature, 2.54 moles of the product from step (4) were dissolved in a 2 / 1 mixture of 25 volume parts of 1,4-dioxane and methanol. 8.5 volume parts of 3 mol / L NaOH solution were slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 1 with dilute hydrochloric acid, and the reaction solution was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography to obtain the final product with a yield of 90%.

[0131] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.46-1.77(m,6H),3.73-3.78(m,1H),4.00-4.05(m,1H),4.08-4.16(m,1H),4.37-4.43(m,1H),5.97-5.99(m,1H) ),6.69-6.71(m,1H),6.74-6.80(m,1H),6.92-6.96(m,1H),7.16-7.21(m,3H),7.28-7.34(m,2H),7.43-7.60(m,5H),7.81-7.86(m,2H). 31 P NMR (162MHz, CDCl3): δ32.20.MS (ESI): [M+H] + 471.

[0132] (6) Synthesis of (R)-2-[(6,6'-pentanedioloxy)-2-diphenylphosphine-1,1'-biphenyl-2'-oxy]acetic acid

[0133] Under nitrogen protection, 2.17 moles of the product from step (5) were dissolved in 40 volumes of acetone, 10.95 moles of anhydrous potassium carbonate were added, and 10.95 moles of ethyl 2-bromoacetate were slowly added. The mixture was refluxed and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed by depressurization to obtain the crude product (R)-2-[(6,6'-pentanedioloxy)-2-diphenylphosphine-1,1'-biphenyl-2'-oxy]-ethyl acetate. No further processing was required before adding it to the next reaction step.

[0134] Under nitrogen protection, the above-mentioned (R)-2-[(6,6'-pentanedioloxy)-2-diphenylphosphine-1,1'-biphenyl-2'-oxy]-ethyl acetate was dissolved in dry toluene, and 24.10 moles of triethylamine were added. After the reaction mixture was cooled to 0°C, 8.76 moles of trichlorosilane were added. The reactants were transferred to an oil bath and heated to 110°C, and refluxed for 12 hours. After cooling to room temperature, toluene was added for dilution, and the reaction was quenched by slowly adding saturated sodium bicarbonate aqueous solution while stirring for 15 minutes. The mixture was filtered through diatomaceous earth, and the residue was washed with toluene. The filtrates were combined, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain the crude product (R)-2-[(6,6'-pentanedioloxy)-2-diphenylphosphine-1,1'-biphenyl-2'-oxy]-ethyl acetate.

[0135] Under nitrogen protection, the above-mentioned (R)-2-[(6,6'-pentanedioloxy)-2-diphenylphosphine-1,1'-biphenyl-2'-oxy]-ethyl acetate was dissolved in a mixed solution of 5 parts by volume of tetrahydrofuran and 5 parts by volume of water. 4.38 moles of lithium hydroxide were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 2. The product (L21) was obtained by multiple extractions with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography. The overall yield of the three-step reaction was 63%.

[0136] Product Result Analysis: 1 H NMR (400MHz, CDCl3): δ1.45-1.67(m,4H),3.72-3.78(m,1H),3.97-4.03( m,1H),4.06-4.11(m,1H),4.33-4.38(m,1H),4.61(s,2H),5.95(d,J=8.36 Hz,1H),6.37(d,J=8.32Hz,1H),6.86-6.91(m,1H),6.98-7.02(m,1H),7. 17-7.26(m,3H),7.31-7.42(m,4H),7.46-7.58(m,3H),7.81-7.86(m,2H). 13C NMR (101MHz, CDCl3): δ23.27,25.60,25.88,66.30,66.94,68.54,102.69,104.99,117.86,126.34,126.47,127.34,127.47,128.08, 128.24,128.38,128.50,129.92,130.74,130.84,131.05,131.82,131.85,131.92,132.15,132.24,156.40,156.60,157.34,157.49. 31 P NMR (162MHz, CDCl3): δ5.80.MS (ESI): [M+H] + 529.

[0137] Example 4: Application of (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid (L1) in asymmetric CH bond activated arylation reaction

[0138]

[0139] In a glove box, substrate SM1 (0.1 mmol, 1.0 equiv), Pd2dba3 (2.5 mol%), ligand (R)-2-{[6,6'-((S,S)-2,3-butanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}acetic acid (10 mol%), and Cs2CO3 (1.5 equiv) were placed in a 20 mL single-necked reaction tube. 2 mL of solvent (DME, ethylene glycol dimethyl ether) was added, the tube was sealed, and the reaction was stirred at 80 °C for 48 h. Separation by column chromatography yielded a 96% fraction, and HPLC analysis showed an enantiomeric excess (ee) of 92%.

[0140] Example 5: Application of (S)-2-{[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}-acetic acid (L2) in asymmetric CH bond activation arylation reaction

[0141] In a glove box, substrate SM1 (0.1 mmol, 1.0 equiv), Pd2dba3 (2.5 mol%), ligand (S)-2-{[6,6'-((2R,4R)-2,4-pentanedioloxy)]-2-diphenylphosphine-1,1'-biphenyl-2'-oxy}acetic acid (10 mol%), and Cs2CO3 (1.5 equiv) were placed in a 20 mL single-necked reaction tube. 2 mL of solvent (DME, ethylene glycol dimethyl ether) was added, the tube was sealed, and the reaction was stirred at 80 °C for 48 h. Separation by column chromatography yielded a 92% fraction, and HPLC analysis showed an enantiomeric excess (ee) of 92%.

[0142] Example 6: A series of phosphine ligand compounds L1-L22 were synthesized according to the preparation methods disclosed in the above examples and the specification, and conventional techniques in the art, as shown in Table 1.

[0143] Under the same experimental conditions as in Example 4, different phosphine ligands were substituted, and their effects on catalyzing asymmetric CH bond activation arylation reactions were measured, compared with existing ligands C23-C29. The results are shown in Table 1.

[0144] Table 1

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] As shown in Table 1, the bridging carboxylic acid-containing bifunctionalized phosphine ligands of this invention exhibit superior catalytic performance in the study of asymmetric CH bond-activated arylation reactions, outperforming other known ligands with similar structures. This is because the biphenyl skeleton possesses both bridging chiral chains and axial chirality, effectively regulating the electronegativity, rigidity, chiral environment, and dihedral angle of the biphenyl skeleton. Simultaneously, the introduction of carboxylic acid functional groups into the ligands allows for coordination between the bifunctionalized ligands and the central metal during the catalytic cycle, forming a more ordered transition state that facilitates efficient removal of inert CH bonds. Excellent yields were also obtained when using its racemic mixture for CH bond-activated arylation reactions. The results for C29 demonstrate the importance of the ligand's carboxyl group.

[0151] Example 7: Application of ligand L8 in asymmetric CH bond activated arylation reaction

[0152] Under the same reaction conditions as in Example 4, but with different reaction substrates, the effects of asymmetric CH bond activation arylation were investigated, as shown in Table 2:

[0153]

[0154] Table 2

[0155] Serial Number <![CDATA[Y 1 ]]> <![CDATA[Y 2 ]]> <![CDATA[Y 3 ]]> <![CDATA[Y 4 ]]> Yield ee(%) 1 H H Me H 99 94 2 H H F H 99 95 3 H H OMe H 99 95 4 H Me H Me 99 92 5 H Me H H 99 92 6 H F H H 99 95 7 H OMe H H 99 92 8 H <![CDATA[CO2Me]]> H H 99 96 9 H Cl H H 99 94 10 Me H H H 99 83 11 OMe H H H 99 96

[0156] As shown in Table 2, the bridging carboxylic acid-containing bifunctionalized phosphine ligands of the present invention have a wide range of substrate applicability in asymmetric CH bond activated arylation reactions, and exhibit excellent reactivity and enantioselectivity for benzene ring skeleton substrates and substrates containing electron-donating or electron-withdrawing functional groups.

[0157] Example 8: Application of ligand L8 in the catalytic asymmetric CH bond activation arylation reaction of iodinated substrates

[0158]

[0159] In a glove box, substrate SM2 (0.1 mmol, 1.0 equiv), Pd2dba3 (2.5 mol%), ligand L8 (10 mol%), and Cs2CO3 (1.5 equiv) were placed in a 20 mL single-necked reaction tube, and 2 mL of solvent (DME, ethylene glycol dimethyl ether) was added. The tube was sealed, and the reaction was stirred at 50 °C for 20 h. Separation by column chromatography yielded a 91% fraction, and HPLC analysis showed an enantiomeric excess (ee) of 99%.

[0160] Under the same experimental conditions as in Example 8, different substituted phosphine ligands were used, and their effects on catalyzing asymmetric CH bond activation arylation reactions were measured. Ligands C23, C26, and C28 were used as ligands for comparison, and the results are shown in Table 3.

[0161] Table 3

[0162] Serial Number ligands Yield ee(%) 1 L8 91 99 2 L14 82 96 3 L20 73 78 4 L21 72 89 5 C23 32 96 6 C26 68 81 7 C28 30 26

[0163] Example 9: Application of ligand L8 in the asymmetric CH bond activation arylation reaction of pyridine heterocyclic brominated substrates

[0164]

[0165] In a glove box, substrate SM3 (0.1 mmol, 1.0 equiv), Pd2dba3 (2.5 mol%), ligand L8 (10 mol%), and Cs2CO3 (1.5 equiv) were placed in a 20 mL single-necked reaction tube, and 2 mL of solvent (DME, ethylene glycol dimethyl ether) was added. The tube was sealed, and the reaction was stirred at 80 °C for 48 h. Separation by column chromatography yielded a 96% fraction, and HPLC analysis showed an enantiomeric excess (ee) of 96%.

[0166] Under the same experimental conditions as in Example 9, different substituted phosphine ligands were used, and their effects on catalyzing asymmetric CH bond activation arylation reactions were measured, with C26 and C28 ligands used as comparisons. The results are shown in Table 4.

[0167] Table 4

[0168] Serial Number ligands Yield ee(%) 1 L8 96 96 2 L14 80 90 3 L21 65 80 4 C26 55 70 5 C28 15 23

[0169] Example 10: Application of ligand L8 in the asymmetric CH bond activation arylation reaction of brominated substrates with p-toluenesulfonyl protected amino groups

[0170]

[0171] In a glove box, substrate SM4 (0.1 mmol, 1.0 equiv), Pd2dba3 (2.5 mol%), ligand L8 (10 mol%), and Cs2CO3 (1.5 equiv) were placed in a 20 mL single-necked reaction tube, and 2 mL of solvent (DME, ethylene glycol dimethyl ether) was added. The tube was sealed, and the reaction was stirred at 60 °C for 48 h. Separation by column chromatography yielded an 89% fraction, and HPLC analysis showed an enantiomeric excess (ee) of 95%.

[0172] Under the same experimental conditions as in Example 10, different substituted phosphine ligands were used, and their effects on catalyzing asymmetric CH bond activation arylation reactions were measured, with C26 and C28 ligands used as comparisons. The results are shown in Table 5.

[0173] Table 5

[0174] Serial Number ligands Yield ee(%) 1 L8 89 95 2 L14 80 85 3 L21 76 81 4 C26 67 69 5 C28 24 25

[0175] Example 11: Application of ligand L8 in the asymmetric CH bond activation arylation reaction of brominated substrates

[0176]

[0177] In a glove box, substrate SM5 (0.1 mmol, 1.0 equiv), Pd2dba3 (2.5 mol%), ligand L8 (10 mol%), and Cs2CO3 (1.5 equiv) were placed in a 20 mL single-necked reaction tube, and 2 mL of solvent (DME, ethylene glycol dimethyl ether) was added. The tube was sealed, and the reaction was stirred at 80 °C for 48 h. Separation by column chromatography yielded an 85% isolated product, and HPLC analysis showed an enantiomeric excess (ee) of 93%.

[0178] Under the same experimental conditions as in Example 11, different substituted phosphine ligands were used, and their effects on catalyzing asymmetric CH bond activation arylation reactions were measured, with C23 and C28 ligands used as comparisons. The results are shown in Table 6.

[0179] Table 6

[0180] Serial Number ligands Yield ee(%) 1 L8 85 93 2 L14 72 85 3 C23 60 80 4 C28 16 20

[0181] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A class of bridged, carboxylic acid-containing, bifunctionalized phosphine ligands, characterized in that... It has the structure shown in Equations I-V as follows: ； Among them, R 1 It is a C1-C5 straight-chain alkyl group; R' represents any one of substituted or unsubstituted aryl, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl groups; the substitution refers to the substitution of one or more hydrogen atoms of the aryl, alkyl, or cycloalkyl groups by fluorine, chlorine, bromine, iodine, aryl, amino, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, nitro, or trifluoromethyl groups. R 2 R 3 R 4 The same or different are any one of hydrogen, fluorine atom, chlorine atom, bromine atom, iodine atom, trimethylsilyl, triethylsilyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, C1-C5 alkyl-substituted amino, trifluoromethyl, cyano, nitro, substituted or unsubstituted aryl; R 2 R 3 R 4 In this context, substitution refers to the substitution of one or more hydrogen atoms of aryl, alkyl, or cycloalkyl groups by fluorine, chlorine, bromine, iodine, aryl, amino, cyano, C1-C5 alkyl, C1-C20 alkyloxy, nitro, or trifluoromethyl groups. The aforementioned aryl groups are each independently a C6-C20 aryl group; The aforementioned alkyl groups are each independently a C1-C20 alkyl group; The aforementioned cycloalkyl groups are each independently a C3-C20 cycloalkyl group; The It is a side chain containing a chiral center and has the function of controlling the dihedral angle; the For the reason What is obtained after removing Lg; The 1,3-Butanediol ( R )or( S ), 2,3-butanediol ( R , R )or( S , S ), 1,2-diphenylethylene glycol ( R , R )or( S , S ), 1,4-dibenzyloxybutanediol ( R , R )or( S , S ), 2,4-pentanediol ( R , R )or( S , S ), 2,5-hexanediol ( R , R )or( S , S ), 3,4-hexanediol ( R , R )or( S , S ), 1-phenylethane-1,2-diol ( R )or( S ), 1,2-decanediol ( R )or( S ), 2,9-decanediol ( R , R )or( S , S ), 3,8-decanediol ( R , R )or( S , S ), 4,7-decanediol ( R , R )or( S , S ), 5,6-decanediol ( R , R )or( S , S ), cis-1,2-cyclohexanediol, trans-1,2-cyclohexanediol ( R , R )or( S , S ), cis-1,2-cyclopentanediol, trans-1,2-cyclopentanediol ( R , R )or( S , S (1) S ,2 S ,3 R 5 S )-(+)-2,3-pinenediol, (3 S 5 S )-(+)-3,5-heptanediol, (3 R 5 R )-(-)-3,5-heptanediol, 2,6-heptanediol R , R )or( S , S ), cis-3,4-tetrahydrofurandiol, 3,6-octanediol ( R , R )or( S , S ), 2,7-octanediol ( R , R )or( S , S ), 2,8-nonanediol ( R , R )or( S , S ), 3,7-nonanediol ( R , R )or( S , S ), 4,6-nonanediol ( R , R )or( S , S ), cis-1,2-cyclohexanediethanol, trans-1,2-cyclohexanediethanol, (+)-2,3-O-isopropylidene- L -Threitol, (-)-2,3-O-isopropylidene- D -Threitol chiral diol, or 2,2'-binaphthol ( R )or( S ), 2,2'-binaphthyl dicarboxylic acid ( R )or( S L-tartaric acid, D-tartaric acid, 2,3-dibromosuccinic acid ( R , R )or( S , S ), 2,3-dimercaptosuccinic acid ( R , R )or( S , S ), ( S )-(-)-2-isobutylsuccinic acid-1-ethyl ester, (+)-di-p-methoxybenzoyl- D -Tartrate, (-)-di-p-methoxybenzoyl- L tartaric acid, 1,2-cyclohexanedicarboxylic acid ( R , R )or( S , S ), citric acid ( R )or( S ), L - Malic acid, D - Malic acid, methylsuccinic acid ( R )or( S ); or methanesulfonates, p-toluenesulfonates, or trifluoromethanesulfonates of the above chiral diols; The The non-chiral sidechain for controlling the dihedral angle size; For the reason What is obtained after removing Lg; The The compounds are 1,1-dibromopropane, 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, 1,7-dibromoheptane, 1,8-dibromooctane, 1,9-dibromononane, 1,10-dibromodecane, ethylene glycol condensed terminal halogenated compounds, ethylene glycol condensed terminal methanesulfonates, ethylene glycol condensed terminal p-toluenesulfonates, 1,3-dibromobenzene, 1,4-dibromobenzene, α,α-dibromoo-xylene, α,α-dibromo-m-xylene, or α,α-dibromo-p-xylene; The or The number of carbon atoms in each group is either the same or different, ranging from 1 to 20.

2. The bridged carboxylic acid-containing difunctionalized phosphine ligand or its racemate or enantiomer as described in claim 1, characterized in that: It has the structure shown in Equations I-V, where R 1 R is a C1-C5 straight-chain alkyl group; R' is a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C4-C7 cycloalkyl group; R 2 R 3 R 4 The same or different are any one of hydrogen, fluorine atom, chlorine atom, bromine atom, iodine atom, trimethylsilyl, triethylsilyl, C1-C5 alkyl, C4-C7 cycloalkyl, C1-C5 alkyl-substituted amino, trifluoromethyl, substituted or unsubstituted aryl.

3. The method for preparing the bridged carboxylic acid-containing bifunctionalized phosphine ligand according to any one of claims 1-2, specifically: When R 2 R 3 R 4 When the hydrogen is present, the compound of formula I or formula III is prepared by a method comprising the following steps: ； (1) Using 2,2',6,6'-tetrahydroxybiphenyl as the starting material, and... A nucleophilic substitution reaction occurs to form a cyclization, yielding a biphenyl compound or its enantiomer with central and axial chirality; (2) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, a biphenyl compound or its enantiomer reacts with trifluoromethanesulfonic anhydride to give a bis(trifluoromethanesulfonic acid) ester compound or its enantiomer. (3) Di(trifluoromethanesulfonate) compounds or their enantiomers and The reaction yields trifluoromethanesulfonate phosphonium oxides or their enantiomers; (4) Hydrolyze the trifluoromethanesulfonate phosphonium oxide compound or its enantiomer under alkaline conditions and then acidify it to obtain the hydroxyphosphonium oxide compound or its enantiomer; (5) A hydroxyphosphonic oxide or its enantiomer reacts with an etherifying agent to give an etherified product or its enantiomer; (6) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, the etherified product or its enantiomer is reduced by trichlorosilane to obtain an etherified phosphine compound or its enantiomer; (7) Hydrolyze the etherified phosphine compound or its enantiomer under alkaline conditions and then acidify it to obtain a compound of formula I or formula III.

4. The method for preparing the bridged carboxylic acid-containing bifunctionalized phosphine ligand according to any one of claims 1-2, specifically: When R 2 R 3 R 4 When the hydrogen is present, the compound of formula II or formula IV is prepared by a method comprising the following steps, with the reaction equations shown below: ； (1) Using 2,2',6,6'-tetrahydroxybiphenyl as the starting material, and... A nucleophilic substitution reaction occurs to form a cyclization, yielding a biphenyl compound or its enantiomer with central and axial chirality; (2) Bisphenol compounds or their enantiomers and A cyclization reaction occurs to yield a diphenyl ether compound or its enantiomer; (3) React a biphenyl ether compound or its enantiomer with a lithium salt or inorganic base of 4,4'-di-tert-butylbiphenyl to obtain a biphenyl diphenol compound or its enantiomer with exposed phenolic hydroxyl groups; (4) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, a biphenyl compound or its enantiomer with a naked phenolic hydroxyl group reacts with trifluoromethanesulfonic anhydride to give a bis(trifluoromethanesulfonic acid) ester compound or its enantiomer. (5) Di(trifluoromethanesulfonate) compounds or their enantiomers and The reaction yields trifluoromethanesulfonate phosphonium oxides or their enantiomers; (6) Hydrolyze the trifluoromethanesulfonate phosphonium oxide compound or its enantiomer under alkaline conditions and then acidify it to obtain the hydroxyphosphonium oxide compound or its enantiomer; (7) React the hydroxyphosphonium oxide compound or its enantiomer with an etherifying agent to obtain the etherified product or its enantiomer. (8) In the presence of an organic base containing a lone pair of electrons on a nitrogen atom, the etherified product or its enantiomer is reduced by trichlorosilane to obtain an etherified phosphine compound or its enantiomer; (9) The etherified phosphine compound or its enantiomer is hydrolyzed under alkaline conditions and then acidified to obtain compound of formula II or formula IV.

Images