Imidazoline nitrogen-nitrogen phosphorus ligands, methods of making and uses thereof

Abstract

The application belongs to the field of catalysts, and provides an imidazoline nitrogen-nitrogen-phosphorus ligand having a structure shown in formula I or a tautomer, an enantiomer or a diastereomer thereof; the ligand catalyst has the advantages of high catalytic efficiency, wide substrate application range, high yield and good enantioselectivity.

Description

Technical Field

[0001] This invention relates to the field of organic chemical ligand technology, specifically to an imidazoline nitrogen-phosphorus ligand, its preparation method, and its uses. Background Technology

[0002] Chiral imidazoline skeletons can be synthesized from natural or non-natural amino alcohols, making their preparation simple. Furthermore, imidazoline skeletons are easily modulated by electronic or steric effects, exhibiting structural diversity. Therefore, chiral imidazoline skeletons are widely used in chiral ligand structures and play an important role in transition metal-catalyzed asymmetric reactions.

[0003] In recent years, with the development of free radical asymmetric chemistry, there is an urgent need to develop chiral ligands with different skeleton types to effectively regulate the stereoselectivity of free radical intermediates. Chiral oxazoline-derived nitrogen-phosphorus ligands have been successfully applied to asymmetric cross-coupling reactions involving free radical intermediates, asymmetric 1,2-bifunctionalization reactions of alkenes, and oxidative asymmetric coupling reactions of alkyl C-H bonds. Compared with chiral oxazoline ligands, chiral imidazoline ligands have stronger electronegativity and can significantly enhance the reducing power of metals after coordination, exhibiting superior reaction results in some reactions. Due to the diversity of free radical reaction types, the development of chiral imidazoline-derived nitrogen-phosphorus ligands can meet the needs of different reactions and lead to the development of new reaction types. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides imidazoline nitrogen-phosphorus ligands, which have advantages such as high catalytic efficiency, wide substrate applicability, high yield, and good enantioselectivity.

[0005] On the one hand, the present invention provides an imidazoline nitrogen-phosphorus ligand having the structure shown in Formula I or its tautomers, enantiomers, and diastereomers;

[0006]

[0007] R 1 Selected from: hydrogen, halogen, ester group, alkyl, alkoxy, cycloalkyl, haloalkyl, aryl, arylalkyl;

[0008] R 2 Selected from: aryl, arylalkyl; optionally, the aryl or arylalkyl group is substituted by one or more substituents each independently selected from halogen, alkyl, alkoxy, alkenyl, alkynyl, phenyl, trifluoromethyl, ester, trifluoromethylphenyl;

[0009] R 3 Selected from: hydrogen, alkyl or aryl, and R 3 With R 2 different;

[0010] R 4 Selected from: hydrogen, alkyl, alkoxy, phenyl, benzyl;

[0011] R 5 Selected from: hydrogen, alkyl, cycloalkyl, aryl; optionally, the aryl group is substituted by one or more substituents selected from: alkyl-substituted aryl, aryl, halogen, alkyl, haloalkyl;

[0012] R 6 Selected from: hydrogen, alkyl, alkoxy, cycloalkyl, ester, halogen, haloalkyl, aryl, arylalkyl; optionally, the aryl or arylalkyl group is substituted by one or more substituents each independently selected from halogen or cyano;

[0013] W is PR2:

[0014] R is selected from aryl or cycloalkyl; optionally, the aryl or cycloalkyl group is surrounded by m Rs. 7 Replace; where R 7 Selected from: alkyl, alkoxy, haloalkyl, halogen, aryl, aryloxy;

[0015] m is an integer of 1, 2, 3, 4, or 5. When m ≥ 2, there are two or more R... 7 Same or different.

[0016] In some embodiments, the imidazoline nitrogen-phosphorus ligands of the present invention have the structure shown in Formula II or its tautomers, enantiomers, and diastereomers;

[0017]

[0018] Where Q is aryl; n is 0, 1 or 2.

[0019] In some embodiments, the halogens present at different locations may be the same or different, and each halogen is independently selected from: fluorine, chlorine, and bromine.

[0020] In some embodiments, the ester groups appearing at different positions may be the same or different, and each ester group is independently selected from: alkyl-C(=O)O-, alkyl-OC(=O)-, aryl-C(=O)O-, aryl-OC(=O)-.

[0021] In some embodiments, each of the ester groups is independently selected from: C 1-6 Alkyl-C(=O)O-, C 6-10 Aryl-C(=O)O-.

[0022] In some embodiments, the ester groups are each independently selected from: methyl-C(=O)O-, tert-butyl-C(=O)O-, ethyl-C(=O)O-, methyl-OC(=O)-, tert-butyl-OC(=O)-, and ethyl-OC(=O)-.

[0023] In some embodiments, each of the alkyl groups is independently selected from: C 1-6 alkyl.

[0024] In some embodiments, each of the alkyl groups is independently selected from: C 1-4 alkyl.

[0025] In some embodiments, each of the alkyl groups is independently selected from: methyl, ethyl, n-propyl, isopropyl, tert-butyl.

[0026] In some embodiments, each of the alkyl groups is independently selected from: C 1-6 Alkyl group.

[0027] In some embodiments, each of the alkoxy groups is independently selected from: C 1-4 Alkyl group.

[0028] In some embodiments, each of the alkoxy groups is independently selected from: methoxy, ethoxy, n-propoxy, isopropoxy, and tert-butoxy.

[0029] In some embodiments, each of the cycloalkyl groups is independently selected from 3- to 6-membered cycloalkyl groups.

[0030] In some embodiments, the cycloalkyl groups are each independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] In some embodiments, each of the haloalkyl groups is independently selected from: halo-C 1-6 alkyl.

[0032] In some embodiments, each of the haloalkyl groups is independently selected from: C 1-4 Halogenated alkyl groups.

[0033] In some embodiments, the alkyl halogroups are each independently selected from: trifluoromethyl, pentafluoroethyl.

[0034] In some embodiments, each of the aryl groups is independently selected from: C 6-10 Aryl group; preferably, each of the aryl groups is independently selected from: phenyl, naphthyl.

[0035] In some embodiments, each of the aryl alkyl groups is independently selected from: C 6-10 Aryl C 1-6 alkyl.

[0036] In some embodiments, each of the aryl alkyl groups is independently selected from: C 6-10 Aryl C 1-4 Alkyl, diC 6-10 Aryl C 1-6 alkyl.

[0037] In some embodiments, each of the aryl alkyl groups is independently selected from: benzyl, phenylethyl, naphthylmethyl, and diphenylmethyl.

[0038] In some embodiments, each of the alkenyl groups is independently selected from: C 2-6 Alkenyl group.

[0039] In some embodiments, each of the alkenyl groups is independently selected from: C 2-4 Alkenyl group.

[0040] In some embodiments, each of the alkenyl groups is independently selected from: vinyl, propenyl, allyl.

[0041] In some embodiments, the alkynyl groups are each independently selected from: C 2-6 Alkyne group.

[0042] In some embodiments, the alkynyl groups are each independently selected from: C 2-4 Alkyne group.

[0043] In some embodiments, the alkynyl groups are each independently selected from: ethynyl, propynyl, and propynyl.

[0044] In some embodiments, R 1 Selected from: hydrogen, halogen, trifluoromethyl.

[0045] In some embodiments, R 3 Selected from: hydrogen, methyl.

[0046] In some embodiments, R 4 Selected from: hydrogen, methyl, ethyl, benzyl.

[0047] In some embodiments, R 5 Selected from: isopropyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl; wherein the phenyl group is optionally substituted by one or more substituents selected from halogen, tert-butyl, methyl, trifluoromethyl, methoxy, isopropyl, 4-tert-butylphenyl.

[0048] In some embodiments, R 6 Selected from: hydrogen, fluorine, methyl.

[0049] In some embodiments, R 2 Selected from: phenyl, trifluoromethylphenyl, methylphenyl, chlorophenyl, dimethylphenyl, benzyl, 4-fluorobenzyl, 4-chlorobenzyl, phenethyl, naphthyl, naphthylmethyl.

[0050] In some embodiments, W is PR2;

[0051] R is selected from phenyl or cyclohexyl; optionally, phenyl or cyclohexyl is surrounded by m R's. 7 Replace; where R 7 Selected from: methyl, ethyl, propyl, butyl, methoxy, trifluoromethyl, phenyl, dimethylphenyl;

[0052] m is an integer of 1, 2, 3, 4, or 5. When m ≥ 2, there are two or more R... 7 Same or different.

[0053] In some embodiments, the imidazoline nitrogen-phosphorus ligands of the present invention have one of the following structures or tautomers, enantiomers, or diastereomers thereof:

[0054]

[0055]

[0056] On the other hand, the present invention provides a method for preparing the imidazoline nitrogen-phosphorus ligand of the present invention, comprising the following steps:

[0057]

[0058] Compound S1 and compound S2 react to give intermediate S3;

[0059] Intermediate S3 reacts with compound S4 to give intermediate S5;

[0060] Intermediate S5 is reduced to obtain intermediate S6;

[0061] Intermediate S6 reacts with compound S7 to yield imidazoline nitrogen-phosphorus ligands;

[0062] R 1 R 2 R 3 R 4 R 5 R 6 W is as defined in this invention.

[0063] In some embodiments, the method for preparing the imidazoline nitrogen-phosphorus ligand includes the following steps:

[0064] Compound S1 reacts with a Lewis acid, a carbodiimide condensing agent, a catalyst, and compound S2 to give intermediate S3.

[0065] Intermediate S3 reacts with a chlorinating reagent and compound S4 to give intermediate S5;

[0066] Intermediate S5 was reduced on carbon by palladium to obtain intermediate S6;

[0067] Intermediate S6 reacts with a carbodiimide condensing agent, a catalyst, and compound S7 to give product I.

[0068] In some embodiments, the carbodiimide condensing agent is selected from: dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI).

[0069] In some embodiments, the chlorination reagent is selected from: thionyl chloride (SO2Cl2) and phosphorus pentachloride (PCl5).

[0070] In some embodiments, the catalyst is selected from pyridine, triethylamine, and diethylamine.

[0071] In some embodiments, the carbodiimide condensing agent is EDCI, and the catalyst is DMAP.

[0072] On the other hand, the present invention provides the application of the ligands described in the present invention or the ligands prepared by the preparation method described in the present invention in asymmetric reactions.

[0073] The ligands of the present invention can be applied to asymmetric catalytic reactions, especially to the synthesis of chiral alkynyl α-alkyl sulfide compounds via asymmetric carbon-sulfur cross-coupling reactions.

[0074] Beneficial effects

[0075] This invention utilizes chiral imidazoline and amidephosphine as the core skeleton to synthesize a novel class of nitrogen-phosphorus compounds that can serve as ligands for asymmetric reactions. Particularly noteworthy is the tunable electronic and steric effects of the imidazoline fragment and phosphorus on the ligands, as well as the tunable electronic and steric effects of the chiral imidazoline substituents. These compounds exhibit unique advantages in radical asymmetric reactions: high catalytic efficiency, broad substrate applicability, high yield, and good enantioselectivity. The ligands of this invention can be widely applied to the asymmetric cross-coupling reactions of different types of propargyl bromides with sodium thiobenzenesulfonate, and also hold significant importance for developing novel catalytic systems to address other types of radical asymmetric reactions.

[0076] Terminology Explanation

[0077] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0078] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0079] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0080] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0081] EDCI refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0082] DMAP refers to 4-dimethylaminopyridine.

[0083] As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0084] As used herein, "cycloalkyl" refers to a non-aromatic carbon ring, which typically has 3 to 8 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0085] As used herein, "alkoxy group" refers to -O- (alkyl) and -O- (cycloalkyl), wherein alkyl and cycloalkyl are defined as described herein, wherein the alkyl group contains 1 to 20 carbon atoms, and the cycloalkyl group contains 3 to 8 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by oxygen bridges.

[0086] As used herein, "ester group" refers to -C(O)O (alkyl) or -C(O)O (phenyl), wherein the alkyl and phenyl groups are as defined herein, and the alkyl group contains 1 to 20 carbon atoms. For ester-substituted phenyl groups, they can be formed by the phenolic hydroxyl group of the benzene ring and a carboxylic acid, such as PhOCOCH3 and PhOPiv, or by the carboxyl group of the benzene ring and an alcohol, such as PhCOOCH3.

[0087] The term "halogen" as used in this article refers to fluorine, chlorine, bromine, and iodine.

[0088] In this article, "trifluoromethyl" refers to -CF3; and "cyano" refers to -CN.

[0089] As used in this article, "aryl" refers to a 6-membered carbon-ring aromatic ring, such as benzene; a bicyclic system in which at least one ring is both carbon-ringed and aromatic, such as naphthalene, indane, and 1,2,3,4-tetrahydronaphthalene; and a tricyclic system in which at least one ring is both carbon-ringed and aromatic, such as fluorene.

[0090] The term "dimethylphenyl" as used in this article refers to a phenyl group with two methyl substituents, which can be substituted with 2,3,2,4,2,5,2,6,3,4,3,5,3,6,4,5,4,6,5,6.

[0091] The arylalkyl group is a combination of the aryl group and the alkyl group described in this invention, and is attached to the rest of the molecule through the alkyl group. For example, it can be naphthylmethyl, benzyl, etc. The arylalkyl group can be C10 ... 6-10 Aryl C 1-6 Alkyl group. The aryl alkyl group may be benzyl, phenylethyl, or naphthylmethyl. The aryl alkyl group may also be a diaryl alkyl group, such as diphenylmethyl.

[0092] The term "naphthylmethyl" or "naphthylmethyl" as used in this article refers to

[0093] In this article, “benzyl” refers to PhCH2-; and “phenylethyl” refers to PhCH2CH2-.

[0094] The term "trifluoromethylphenyl-substituted phenyl or benzyl" as used in this article refers to phenyl or benzyl substituted with p-trifluoromethylphenyl, ortho-trifluoromethylphenyl, or meta-trifluoromethylphenyl.

[0095] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0096] The term "enantiomer" refers to two non-overlapping but mirror-image isomers of a compound.

[0097] The term "diastereomer" refers to a stereoisomer that has two or more chiral neutral molecules that are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatography, for example, HPLC.

[0098] Unless otherwise expressly indicated, the descriptive terms “each…independently”, “…each…independently”, and “…independently” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0099] The terms “optional,” “optionally,” or “arbitrarily” mean that the event or situation described below may, but is not necessarily, occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, “optionally replaced by…” means that the replacement may or may not occur.

[0100] When the terms “independent” and “arbitrarily” are used together, for example, “independently and arbitrarily replaced by…”, it means that specific options are replaced by or not replaced by each other without affecting each other.

[0101] As described in this paper, a ring system formed by a substituent R being bonded to a central ring (as shown in the following equations) represents any substituted or reasonable position of substituent R on ring A. For example, equation f represents any possible substituted position on ring A, as shown in equations f1-f4:

[0102]

[0103] All chemicals were purchased commercially available and did not undergo further purification. Dichloromethane, trichloromethane, and tetrahydrofuran used in the experiments were all anhydrous solvents. Thin-layer chromatography (TLC) was performed using 60F254 silica gel plates. Silica gel column chromatography was performed using Qingdao marine silica gel (particle size 0.040-0.063 mm). TLC colorimetry was performed using UV light (254 nm, 360 nm) or iodine. NMR spectra were characterized using a Bruker DPX400 nuclear magnetic resonance instrument. 1 H NMR is 400 MHz. 31 PNMR was performed at 162 MHz using deuterated chloroform as the solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts are expressed in ppm, and coupling constants are expressed in Hz. 1 In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, m represents multiplet, and br represents broad peak. Detailed Implementation

[0104] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0105] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0106] Synthesis scheme

[0107]

[0108] Step 1: Place o-nitrobenzoic acid compound S1 (12 mmol), chiral amino alcohol S2 (10 mmol), EDCI (3.84 g, 20 mmol), and DMAP (1.22 g, 10 mmol) into a 50 mL reaction flask, add 20 mL of dichloromethane, and then stir the reaction at room temperature for 12 hours. Monitor the reaction by TLC until compound S2 is completely consumed. After vacuum concentration, the reaction solution is purified by silica gel column chromatography to obtain intermediate S3 (60-80% yield).

[0109] Step 2: Under argon protection, intermediate S3 (5 mmol) was dissolved in 5 mL of chloroform and placed in a 25 mL sealed tube. Thionyl chloride (0.4 mL, 5.5 mmol) was slowly added dropwise under ice bath conditions. The mixture was slowly heated and refluxed for 2–4 hours, then cooled to room temperature. Phosphorus pentachloride (1.15 g, 5.5 mmol) was added under argon protection, and the mixture was refluxed for 6–12 hours. After the reaction system cooled to room temperature, the reaction solution was concentrated under vacuum and then dissolved again in 15 mL of chloroform. Triethylamine (2.1 mL, 15 mmol) and amine compound S4 (6 mmol) were added under ice bath conditions. The mixture was reacted for half an hour, then refluxed for 5–8 hours. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain intermediate nitro compound S5 (50–80% yield).

[0110] Step 3: Dissolve intermediate nitro compound S5 (2 mmol) in 10 mL of methanol, add 10% wet palladium on carbon, use a hydrogen balloon to replace the hydrogen three times, and react in a hydrogen atmosphere (hydrogen balloon). Monitor the reaction by TLC until compound S5 is completely consumed. After filtration and vacuum concentration, the crude product of intermediate S6 (90-100% yield) is obtained.

[0111] Step 4: The intermediate amino compounds S6 (2 mmol), S7 (2.2 mmol), EDCI (4 mmol), and DMAP (21 mmol) were placed in a 25 mL reaction flask, and 10 mL of dichloromethane was added. The mixture was then stirred at room temperature for 12 hours. The reaction was monitored by TLC until compound S6 was completely consumed. The reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain product I (50-80% yield).

[0112] Example 1

[0113]

[0114] L1 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L1:1 H NMR (400MHz, CDCl3) δ12.26 (s, 1H), 8.51 (d, J = 8.4Hz, 1H), 7.83-7.72 (m, 1H), 7.37- 7.22(m,13H),7.16(d,2H),7.09-6.99(m,4H),6.95(d,J=8.0Hz,2H),6.75(t,J=7.6 Hz,1H),6.61(d,J=7.9Hz,2H),4.57-4.42(m,1H),3.96(t,J=9.9Hz,1H),3.54(t,J= 8.7Hz, 1H), 2.98 (dd, J=13.7, 6.4Hz, 1H), 2.74 (dd, J=13.8, 6.9Hz, 1H), 2.25 (s, 3H). 13 C NMR (100MHz, CDCl3) δ166.8,161.7,141.3,141.2,141.1,139.0,138.8,138.6,138.5(2) ,138.4(8),138.4(0),136.7,134.9,134.3,134.1(2),134.0(9),133.9(2),133.8(9),13 2.4,131.0,130.6(5),130.5(9),130.1,129.6,128.6,128.5(4),128.5(1),128.5,128.4(4),128.4(2),127.4(1),127.3(7),123.7,122.3,121.5,117.1,65.5,58.3,42.0,20.9. 31 P NMR (162MHz, CDCl3) δ -8.22. HRMS (ESI) m / z precise mass calculation value: C 42 H 36 ClN3OP[M+H] + 664.2279, Detected value: 664.2278.

[0115] Example 2

[0116]

[0117] L2 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L2: 1H NMR (400MHz, CDCl3) δ12.26 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 7.82-7.73 (m, 1H ),7.38-7.24(m,13H),7.18-7.11(m,4H),7.09-7.01(m,4H),6.77(t,J=7.6 Hz,1H),6.66-6.56(m,2H),4.58-4.41(m,1H),3.99(t,J=9.9Hz,1H),3.61- 3.50(m,1H),3.03-2.91(m,1H),2.74(dd,J=13.8,6.8Hz,1H),1.26(s,9H). 13 C NMR (100MHz, CDCl3) δ1166.9,161.6,147.3,141.4,141.1,141.0,138.9,138.8,138.6,1 38.5,138.4,136.6,134.9,134.1(2),134.0(9),133.9(2),133.8(9),132.4,131.0,130 .6(4),130.5(9),130.2,128.6(1),128.5(5),128.5(1),128.4(9),128.4(4),128.4(2),127.4(1),127.3(8),125.8,123.0,122.4,121.5,117.2,65.5,58.2,42.0,34.4,31.4. 31 P NMR (162MHz, CDCl3) δ-8.20. HRMS (ESI) m / z precise mass calculation value: C 45 H 42 ClN3OP[M+H] + 706.2749, Detected value: 706.2745.

[0118] Example 3

[0119]

[0120] L3 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L3: 1H NMR (400MHz, CDCl3) δ12.24 (s, 1H), 8.50 (d, J = 8.4Hz, 1H), 7.82-7.73 (m, 1H ),7.38-7.24(m,13H),7.18-7.11(m,4H),7.09-7.01(m,4H),6.77(t,J=7.6 Hz,1H),6.66-6.56(m,2H),4.58-4.41(m,1H),3.97(t,J=9.9Hz,1H),3.61- 3.50(m,1H),3.01-2.90(m,1H),2.72(dd,J=13.8,6.8Hz,1H),1.24(s,9H). 13 C NMR (100MHz, CDCl3) δ1166.9,161.6,147.3,141.4,141.1,141.0,138.9,138.8,138.6,1 38.5,138.4,136.6,134.9,134.1(2),134.0(9),133.9(2),133.8(9),132.4,131.0,130 .6(4),130.5(9),130.2,128.6(1),128.5(5),128.5(1),128.4(9),128.4(4),128.4(2),127.4(1),127.3(8),125.8,123.0,122.4,121.5,117.2,65.5,58.2,42.0,34.4,31.4. 31 P NMR (162MHz, CDCl3) δ -8.17. HRMS (ESI) m / z precise mass calculation value: C 45 H 42 ClN3OP[M+H] + 706.2749, Detected value: 706.2745.

[0121] Example 4

[0122]

[0123] L4 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L4: 1H NMR(400MHz, CDCl3)δ12.09(s,1H),8.49(s,1H),7.86(s,1H),7.49-7.28(m,4H),7.26-7 .19(m,4H),7.19-7.15(m,1H),7.14-7.05(m,3H),7.03-6.95(m,6H),6.89-6.83(m,1H), 6.77-6.72(m,2H),4.60-4.49(m,1H),4.05(t,J=10.0Hz,1H),3.69-3.61(m,1H),3.05(d d, J=13.8, 6.2Hz, 1H), 2.82 (dd, J=13.8, 6.9Hz, 1H), 2.27 (d, J=2.9Hz, 12H), 1.33 (s, 9H). 31 PNMR (162MHz, CDCl3) δ -8.57.

[0124] Example 5

[0125]

[0126] L5 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L5: 1 H NMR (400MHz, CDCl3) δ12.15(s,1H),8.45(s,1H),7.88(s,1H),7.60-7.50(m,8H),7.46-7.25(m,13 H),7.20(ddd,J=7.2,3.8,1.7Hz,1H),7.18-7.11(m,4H),7.03(dd,J=11.5,8.0Hz,3H),6.79(td,J =7.6,1.2Hz,1H),6.67(d,J=8.2Hz,2H),4.50(dq,J=10.4,6.9Hz,1H),3.98(t,J=10.1Hz,1H),3.5 8(dd,J=9.8,7.5Hz,1H), 2.99(dd,J=13.8,6.1Hz,1H), 2.76(dd,J=13.8,6.9Hz,1H), 1.25(s,9H). 31 PNMR (162MHz, CDCl3) δ -9.73.

[0127] Example 6

[0128]

[0129] L6 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L6: 1H NMR (400MHz, CDCl3) δ12.32(s,1H),8.52(s,1H),7.85(s,1H),7.36-7.28(m,11H),7.26-7.19 (m,4H),7.17-7.12(m,2H),7.08-6.99(m,2H),6.95(d,J=8.1Hz,2H),6.76(td,J=7.6,1.2Hz, 1H),6.62(d,J=7.9Hz,2H),4.54(dtd,J=10.1,7.7,5.5Hz,1H),3.96(t,J=9.9Hz,1H),3.57(d d, J=9.6, 7.7Hz, 1H), 3.11 (dd, J=13.6, 5.6Hz, 1H), 2.73 (dd, J=13.7, 8.0Hz, 1H), 2.26 (s, 3H). 31 PNMR (162MHz, CDCl3) δ -8.09.

[0130] Example 7

[0131]

[0132] L7 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L7: 1 H NMR (400MHz, CDCl3) δ12.31(s,1H),8.54(d,J=8.4Hz,1H),7.81(d,J=6.5Hz,1H),7.73(d,J=7. 9Hz, 1H), 7.61 (dd, J=14.1, 8.4Hz, 2H), 7.48-7.25 (m, 15H), 7.16 (t, J=9.0Hz, 3H), 7.06 (q, J=7. 3Hz,4H),6.80(d,J=8.7Hz,1H),6.69(t,J=7.6Hz,1H),4.56(dq,J=13.7,7.3Hz,1H),4.12(t,J =9.9Hz, 1H), 3.72 (t, J = 8.6Hz, 1H), 3.01 (dd, J = 13.7, 6.3Hz, 1H), 2.78 (dd, J = 13.8, 6.8Hz, 1H). 31 PNMR (162MHz, CDCl3) δ-8.40.

[0133] Example 8

[0134]

[0135] L8 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L8: 1H NMR(400MHz, CDCl3)δ12.20(s,1H),8.53(s,1H),7.79(s,1H),7.55-7.50(m,2H),7.44- 7.35(m,5H),7.36-7.28(m,11H),7.26(s,2H),7.20-7.15(m,2H),7.13-7.01(m,4H),6. 81(t,J=7.6Hz,1H),6.74(d,J=8.1Hz,2H),4.53(dt,J=13.7,6.8Hz,1H),4.05(t,J=9.9 Hz,1H),3.72-3.59(m,1H),3.00(dd,J=13.8,6.3Hz,1H),2.77(dd,J=13.8,6.9Hz,1H). 31 PNMR (162MHz, CDCl3) δ -8.33.

[0136] Example 9

[0137]

[0138] L9 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L9: 1 H NMR (400MHz, CDCl3) δ12.21 (s, 1H), 8.53 (d, J = 8.5Hz, 1H), 7.78 (s, 1H), 7.48-7.41 (m,4H),7.39-7.28(m,12H),7.17(d,J=8.1Hz,2H),7.10-7.03(m,3H),6.79(t,J=7. 6Hz,1H),6.72(d,J=8.1Hz,1H),4.53(dq,J=14.0,7.1Hz,1H),4.04(t,J=9.9Hz,1H ),3.69-3.58(m,1H),3.06-2.95(m,1H),2.76(dd,J=13.8,6.8Hz,1H),1.34(s,8H). 31 PNMR (162MHz, CDCl3) δ -8.38.

[0139] Example 10

[0140]

[0141] L10 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L10: 1H NMR (400MHz, CDCl3) δ12.19(s,1H),8.56(s,1H),7.78(d,J=7.2Hz,1H),7.38-7.27(m,12H),7.2 1-7.15(m,2H),7.13-7.03(m,5H),6.98(d,J=7.8Hz,1H),6.76(td,J=7.6,1.2Hz,1H),6.68(s,1H ),6.62-6.55(m,1H),4.52(dq,J=9.6,7.1Hz,1H),4.02(t,J=9.9Hz,1H),3.64(dd,J=9.6,7.9Hz, 1H), 3.02 (dd, J=13.8, 6.4Hz, 1H), 2.78 (dd, J=13.8, 7.0Hz, 1H), 1.35-1.23 (m, 3H), 1.13 (s, 9H). 31 PNMR (162MHz, CDCl3) δ-8.28.

[0142] Example 11

[0143]

[0144] L11 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L11: 1 H NMR (400MHz, CDCl3) δ12.15 (s, 1H), 8.52 (s, 1H), 7.74 (d, J = 7.2Hz, 1H), 7.36-7.21 (m, 11H) ,7.20-7.11(m,3H),7.10-7.02(m,4H),6.98(d,J=7.8Hz,2H),6.74(td,J=7.6,1.2Hz,1H),6 .65(s,1H),6.60-6.52(m,1H),4.50(dq,J=9.6,7.1Hz,1H),4.00(t,J=9.9Hz,1H),3.62(dd, J=9.6,7.9Hz,1H),3.00(dd,J=13.8,6.4Hz,1H),2.76(dd,J=13.8,7.0Hz,1H),2.12(s,6H). 31 PNMR (162MHz, CDCl3) δ-8.30.

[0145] Example 12

[0146]

[0147] L12 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L12: 1H NMR (400MHz, CDCl3) δ12.28 (s, 1H), 8.53 (d, J = 8.3Hz, 1H), 7.77 (s, 1H), 7.37-7.26 (m ,12H),7.24(s,1H),7.16(d,J=8.3Hz,2H),7.10-6.95(m,6H),6.77(t,J=7.6Hz,1H),6 .62(d,J=8.0Hz,2H),4.50(p,J=7.1Hz,1H),3.99(t,J=9.9Hz,1H),3.57(t,J=8.7Hz,1 H), 2.99 (dd, J=13.8, 6.3Hz, 1H), 2.78 (dp, J=27.1, 7.0Hz, 2H), 1.19 (d, J=6.9Hz, 6H). 31 PNMR (162MHz, CDCl3) δ -8.29.

[0148] Example 13

[0149]

[0150] L13 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L13: 1 H NMR (400MHz, CDCl3) 1 HNMR(400MHz,Chloroform-d)δ11.98(s,1H),8.53(d,J=8.4Hz,1H),7.75(s,1H), 7.40-7.26(m,15H),7.15(d,J=8.3Hz,2H),7.09-6.98(m,4H),6.87-6.80(m,1H), 6.69(d,J=8.3Hz,2H),4.54(dq,J=9.8,6.7Hz,1H),4.05(t,J=9.8Hz,1H),3.67(d d, J=9.6, 7.2Hz, 1H), 2.96 (dd, J=13.8, 6.4Hz, 1H), 2.75 (dd, J=13.9, 6.6Hz, 1H). 31 PNMR (162MHz, CDCl3) δ -8.42.

[0151] Example 14

[0152]

[0153] L14 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L14: 1H NMR (400MHz, CDCl3) δ12.26(s,1H),8.53(d,J=8.5Hz,1H),7.78(s,1H),7.45(d,J=8.0Hz,2H) ,7.36-7.27(m,12H),7.24(d,J=7.8Hz,3H),7.17-7.10(m,2H),7.09-7.00(m,2H),6.81-6.74 (m,1H),6.60(d,J=8.1Hz,2H),4.55(dq,J=10.2,6.9Hz,1H),4.02(t,J=10.0Hz,1H),3.58(dd ,J=9.7,7.6Hz,1H),3.06(dd,J=13.8,6.5Hz,1H),2.83(dd,J=13.8,6.6Hz,1H),1.25(s,9H). 31 PNMR (162MHz, CDCl3) δ -8.36.

[0154] Example 15

[0155]

[0156] L15 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L15: 1 H NMR (400MHz, CDCl3) δ12.29 (s, 1H), 8.53 (d, J = 8.1Hz, 1H), 7.84 (s, 1H), 7.37-7.27 (m, 12H ),7.25-7.22(m,2H),7.22-7.18(m,1H),7.18-7.12(m,4H),7.04(dt,J=6.1,3.6Hz,2H),6. 78(t,J=7.6Hz,1H),6.65(d,J=8.2Hz,2H),4.61-4.46(m,1H),3.98(t,J=9.9Hz,1H),3.59 (t, J=8.8Hz, 1H), 3.12 (dd, J=13.6, 5.6Hz, 1H), 2.73 (dd, J=13.7, 8.1Hz, 1H), 1.26 (s, 9H). 31 PNMR (162MHz, CDCl3) δ-8.40.

[0157] Example 16

[0158]

[0159] L16 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L16: 1H NMR (400MHz, CDCl3) δ12.27 (s, 1H), 8.53 (d, J = 8.4Hz, 1H), 7.79 (s, 1H), 7.38-7.26 (m, 12H), 7.24(d,J=1.6Hz,1H),7.18-7.13(m,2H),7.13-7.01(m,4H),6.93-6.84(m,2H),6.81-6.75( m,1H),6.64(d,J=8.2Hz,2H),4.50(dq,J=10.1,7.2Hz,1H),3.98(t,J=9.9Hz,1H),3.58(dd, J=9.6,7.7Hz,1H),3.02(dd,J=13.8,6.1Hz,1H),2.74(dd,J=13.8,7.2Hz,1H),1.26(s,9H). 31 PNMR (162MHz, CDCl3) δδ-8.23.

[0160] Example 17

[0161]

[0162] L17 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L17: 1 H NMR(400MHz, CDCl3)12.28(s,1H),8.54(d,J=8.2Hz,1H),7.84(s,1H),7.37-7.27(m, 12H),7.26-7.12(m,8H),7.08-7.00(m,2H),6.77(td,J=7.6,1.2Hz,1H),6.65(d,J=8 .2Hz,2H),4.54(dtd,J=10.1,7.9,5.6Hz,1H),3.98(t,J=9.9Hz,1H),3.59(dd,J=9.6 ,7.7Hz,1H),3.12(dd,J=13.7,5.6Hz,1H),2.73(dd,J=13.7,8.1Hz,1H),1.26(s,9H). 31 PNMR (162MHz, CDCl3) δ-8.25.

[0163] Example 18

[0164]

[0165] L18 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L18: 1H NMR (400MHz, CDCl3) δ12.18(s,1H),8.51(d,J=8.4Hz,1H),7.80(s,1H),7.33(dd,J=6.2,2.9Hz,2H) ,7.26-7.18(m,4H),7.17-7.12(m,2H),7.10-7.06(m,1H),7.02(d,J=7.9Hz,1H),6.98-6.88(m,8H) ,6.76(t,J=7.6Hz,1H),6.63(d,J=7.9Hz,2H),4.59-4.46(m,1H),3.93(t,J=9.8Hz,1H),3.56(t,J= 8.7Hz, 1H), 3.12 (dd, J=13.6, 5.6Hz, 1H), 2.73 (dd, J=13.3, 7.8Hz, 1H), 2.25 (s, 3H), 2.21 (s, 12H). 31 PNMR (162MHz, CDCl3) δ-8.30.

[0166] Example 19

[0167]

[0168] L19 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L19: 1 H NMR (400MHz, CDCl3) δ12.23(s,1H),8.52(s,1H),7.83(s,1H),7.33(dd,J=5.8,3.3Hz, 2H),7.26-7.12(m,10H),7.12-6.98(m,6H),6.95(d,J=8.0Hz,2H),6.76(t,J=7.6Hz,1 H), 6.63 (d, J = 7.9Hz, 2H), 4.53 (p, J = 7.5Hz, 1H), 3.95 (t, J = 10.0Hz, 1H), 3.57 (t, J = 8. 7Hz, 1H), 3.11 (dd, J = 13.7, 5.5Hz, 1H), 2.73 (t, J = 11.0Hz, 1H), 2.26 (d, J = 2.7Hz, 9H). 31 PNMR (162MHz, CDCl3) δ-8.22.

[0169] Example 20

[0170]

[0171] L20 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L20: 1H NMR(400MHz, CDCl3)δ11.03(s,1H),8.24(s,1H),7.78(s,1H),7.36-7.32(m,2H), 7.32-7.26(m,11H),7.25-7.17(m,4H),7.16-7.08(m,3H),7.06-6.95(m,2H),6.7 2(d,J=7.9Hz,2H),6.56(ddd,J=9.7,8.4,1.0Hz,1H),4.61-4.50(m,1H),4.02(t, J=9.9Hz,1H),3.70(s,1H),3.15(dd,J=13.8,5.5Hz,1H),2.70(t,J=11.4Hz,1H). 31 PNMR (162MHz, CDCl3) δ-8.15.

[0172] Example 21

[0173]

[0174] L21 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L21: 1 H NMR (400MHz, CDCl3) δ12.47(s,1H),8.53(s,1H),7.61(s,1H),7.29(dd,J=9.6,3.6Hz,10H),7.25-7.11(m,9H),7.06(d,J=8.0Hz,1H), 7.01(dd,J=7.8,3.8Hz,1H),6.86-6.65(m,3H),4.62(q,J=8.1Hz,1H),4.07(d,J=8.6Hz,1H),3.00(q,J=8.7,7.5Hz,2H),1.27(s,12H). 31 PNMR (162MHz, CDCl3) δ-7.91.

[0175] Example 22

[0176]

[0177] L22 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L22: 1H NMR (400MHz, CDCl3) δ12.32(s,1H),8.60(d,J=8.4Hz,1H),7.62(dd,J=7.6,1.5Hz,1H),7.50(t,J= 5.0Hz,1H),7.37-7.26(m,15H),7.17(d,J=6.7Hz,2H),7.13-7.08(m,3H),7.07-7.03(m,2H),7.02- 6.97(m,3H),6.89-6.82(m,1H),6.56(d,J=8.3Hz,2H),5.25(d,J=10.5Hz,1H),5.00(td,J=10.0,5. 2Hz, 1H), 2.49 (t, J = 11.9Hz, 1H), 2.35 (dd, J = 14.1, 5.2Hz, 1H), 2.14 (s, 2H), 1.21 (d, J = 4.4Hz, 9H). 31 PNMR (162MHz, CDCl3) δ -7.87.

[0178] Example 23

[0179]

[0180] L23 was synthesized according to the method described in the synthesis protocol. Characterization data of ligand L23: 1 H NMR (400MHz, CDCl3) δ12.61 (s, 1H), 8.53 (d, J = 8.4Hz, 1H), 7.92 (s, 1H), 7.42-7.27 (m, 11 H),7.25-7.11(m,6H),7.11-7.00(m,4H),6.73(t,J=7.6Hz,1H),6.61(d,J=8.1Hz,2H),4 .14(dq,J=8.4,4.8,3.5Hz,1H),3.52(s,1H),2.98(dd,J=13.5,5.1Hz,1H),2.65(dd,J=1 3.3, 7.4Hz, 1H), 1.70 (d, J = 6.9Hz, 1H), 1.56 (s, 1H), 1.25 (s, 9H), 0.80 (t, J = 7.4Hz, 3H). 31 P NMR (162MHz, CDCl3) δ-8.17.

[0181] Example 24

[0182]

[0183] L24 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L24: 1H NMR (400MHz, CDCl3) δ12.39 (s, 1H), 8.44 (d, J = 8.4Hz, 1H), 7.87-7.77 (m, 1H), 7.42-7.26 (m, 12H), 7.25-7.22 (m, 1H), 7. 21-7.15(m,2H),7.10-7.02(m,2H),6.83-6.67(m,3H),4.02-3.91(m,2H),3.61-3.49(m,1H),1.27(s,9H),0.78(s,9H). 31 PNMR (162MHz, CDCl3) δ -8.74.

[0184] Example 25

[0185]

[0186] L25 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L25: 1 H NMR (400MHz, CDCl3) δ12.28 (s, 1H), 8.53 (d, J = 8.5Hz, 1H), 7.80 (s, 1H), 7.37-7.26 (m, 11H), 7.2 5-7.21(m,1H),7.06(ddt,J=17.5,14.0,6.7Hz,4H),6.96(d,J=8.1Hz,2H),6.93-6.86(m,2H),6 .76(t,J=7.6Hz,1H),6.62(d,J=7.9Hz,2H),4.50(dq,J=10.2,7.2Hz,1H),3.96(t,J=9.9Hz,1H) ,3.55(t,J=8.6Hz,1H),3.01(dd,J=13.8,6.1Hz,1H),2.74(dd,J=13.8,7.2Hz,1H),2.26(s,3H). 31 PNMR (162MHz, CDCl3) δ-8.25.

[0187] Example 26

[0188]

[0189] L26 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L26: 1H NMR (400MHz, CDCl3) δ12.21(s,1H),8.53(d,J=8.1Hz,1H),7.80(s,1H),7.32(dt,J= 15.2,4.0Hz,13H),7.15(t,J=7.8Hz,2H),7.12-6.96(m,5H),6.90(t,J=8.6Hz,2H),6 .77(t,J=7.6Hz,1H),6.70(d,J=7.8Hz,2H),4.59-4.43(m,1H),4.00(t,J=9.9Hz,1H ), 3.61 (t, J = 8.6Hz, 1H), 3.01 (dd, J = 13.8, 6.1Hz, 1H), 2.75 (dd, J = 13.9, 7.1Hz, 1H). 31 PNMR (162MHz, CDCl3) δ-8.28.

[0190] Example 27

[0191]

[0192] L27 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L27: 1 H NMR (400MHz, CDCl3) δ12.35 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 7.82 (s, 1H), 7.37-7.27 (m, 11H), 7.26-7.20(m,2H),7.08(dt,J=8.9,4.8Hz,3H),7.00(d,J=8.0Hz,1H),6.94-6.86(m,2H),6. 75(t,J=7.6Hz,1H),6.68(d,J=1.9Hz,4H),4.50(p,J=7.1Hz,1H),3.92(t,J=9.9Hz,1H),3.7 4(s,3H),3.50(t,J=8.8Hz,1H),3.02(dd,J=13.8,6.1Hz,1H),2.75(dd,J=13.8,7.1Hz,1H). 31 PNMR (162MHz, CDCl3) δ-8.30.

[0193] Example 28

[0194]

[0195] L28 was synthesized according to the method described in the synthetic protocol. Characterization data of ligand L28: 1H NMR (400MHz, CDCl3) δ10.67(s,1H),8.02(s,2H),7.67(d,J=14.5Hz,1H),7.41(t,J=7.9Hz, 2H),7.35(td,J=7.6,1.3Hz,1H),7.32-7.27(m,5H),7.27-7.20(m,5H),7.13(dd,J=22.5,6 .8Hz,3H),7.04-6.99(m,1H),6.99-6.91(m,2H),4.38(s,1H),3.54(s,1H),3.41(s,1H),3. 22(s,1H),2.95(d,J=13.7Hz,1H),1.67(s,4H),1.55(d,J=12.5Hz,1H),1.30-0.91(m,6H). 31 P NMR (162MHz, CDCl3) δ-8.14.

[0196] Catalytic Application Example 1

[0197] The application of the ligands of this invention to the synthesis of chiral α-alkyl compounds via radical asymmetric carbon-sulfur cross-coupling reactions represents the first realization of a transition metal-catalyzed stereoconvergent carbon-sulfur cross-coupling reaction, providing a new strategy for the synthesis of chiral α-alkyl compounds.

[0198] Synthesis route:

[0199]

[0200] CuI (cuprous iodide, 7.5 mol% equivalent), ligand L (6 mol%), sodium thiobenzenesulfonate (47.2 mg, 0.24 mmol, 1.2 equivalent), and rubidium carbonate (2.0 equivalent) were added to a Schlenk tube equipped with a magnetic stirrer and dried in an oven. Argon gas was purged three times, followed by the addition of propargyl bromide (0.2 mmol, 1.0 equivalent), water (2.0 equivalent), and chloroform (2.0 mL). The reaction was then carried out at -20 °C. After the reaction was complete (monitored by TLC), the precipitate was filtered off and washed with solvent. The product 1 was obtained by purification by silica gel column chromatography after concentration under reduced pressure.

[0201] Characterization data of product 1: It was a colorless oily substance. HPLC resolution conditions: Chiralcel OZ-3 (n-hexane / isopropanol = 99 / 1, flow rate 0.7 mL / min, λ = 214 nm), t R (minor) = 11.27min,t R (major) = 13.58 min. 1HNMR(400MHz, CDCl3)δ7.99-7.93(m,2H),7.64-7.59(m,1H),7.56-7.51(m,2H),4.17 (dd,J=7.6,5.2Hz,1H),1.98-1.78(m,2H),1.05(d,J=7.3Hz,3H),1.01-0.95(m,21H). 13 C NMR (100MHz, CDCl3) δ 145.5, 133.7, 129.4, 127.0, 103.6, 87.9, 44.2, 29.6, 18.6, 11.1(5), 11.1(3). HRMS (ESI) m / z precise mass calculation C 20 H 33 O2S2Si[M+H] + 397.1686, measured value 397.1682.

[0202] The results of using the ligands of the present invention for the above reactions are shown in Table 1 below (L1-L28 represent the ligands of Examples 1-28, L29 represents the ligand reported in patent CN113105392A, and L30 represents the chiral oxazoline nitrogen phosphorus ligand).

[0203]

[0204] Table 1

[0205]

[0206]

[0207] As can be seen, the ligands of this invention can be used with copper salts as catalysts for the asymmetric carbon-sulfur cross-coupling reaction of propargyl brominated substrates and sodium thiobenzenesulfonate to synthesize chiral alkynyl α-alkyl sulfide compounds with good yields and excellent enantioselectivity. The reaction is most effective using ligand L2 (91% yield, 90% ee), while its transconfiguration ligand L3 yields the chiral product of the other configuration (88% yield, -90% ee). When using the ligand L29 with a similar skeleton reported in patent CN113105392A, the reaction yield and ee value are significantly reduced (48% yield, 80% ee); while the yield using chiral oxazoline ligands is extremely low (15%). This indicates that our newly synthesized ligands are more advantageous for this type of reaction.

[0208] Catalytic Application Example 2

[0209] The application of the ligands of this invention to the synthesis of chiral α-alkyl compounds via radical asymmetric carbon-sulfur cross-coupling reactions can be used in the synthesis of intermediates for the drug stepronin (an expectorant). Currently, stepronin is administered in a racemic form; the method of this invention holds promise for the synthesis of chiral stepronin.

[0210] Synthesis route:

[0211]

[0212] Synthesis of intermediate 2:

[0213] Using the method described in Catalytic Application Example 1, CuI (cuprous iodide, 7.5 mol% equivalent), ligand L2 (6 mol%), sodium thiobenzenesulfonate (1.2 equivalent), and rubidium carbonate (2.0 equivalent) were added to an oven-dried Schlenk tube equipped with a magnetic stir bar. Argon gas was purged three times, followed by the addition of propargyl bromide E2 (1.0 mmol, 1.0 equivalent), water (2.0 equivalent), and chloroform (20.0 mL). The reaction was then carried out at -20 °C. After the reaction was complete (monitored by TLC), the precipitate was filtered off and washed with solvent. The concentrate was then concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 2 (90% yield, 91% ee).

[0214] Characterization data of intermediate 2: colorless oily substance; HPLC resolution conditions: Chiralcel OZ-3 (n-hexane / isopropanol = 99 / 1, flow rate 0.7 mL / min, λ = 214 nm), t R (minor) = 11.20 min, t R (major) = 12.44 min. 1 HNMR (400MHz, CDCl3) δ7.99-7.93 (m, 2H), 7.66-7.59 (m, 1H), 7.58-7.51 (m, 2H), 4.24 (q, J = 7.0Hz, 1H), 1.62 (d, J = 7.0Hz, 3H), 1.02-0.95 (m, 21H). 13 C NMR (100MHz, CDCl3): δ 145.3, 133.8, 129.4, 127.0, 104.8, 87.2, 37.5, 23.4, 18.6, 11.1. HRMS (ESI) m / z precise mass calculation C 19 H 30 NaO2S2Si[M+Na] + 405.1349, measured value 405.1347.

[0215] Synthesis of intermediate 3:

[0216] Intermediate 2 (1.0 equivalent), 1,10-phenanthroquinone (1.2 equivalent, 5 mol% equivalent), and sodium carbonate (0.5 equivalent) were added to a Schlenk tube equipped with a magnetic stir bar and dried in an oven. Argon gas was purged three times, followed by the addition of 2-thiophenecarboxaldehyde (1.2 equivalent) and acetonitrile, and the reaction was carried out under blue light irradiation. After the reaction was complete (monitored by TLC), the precipitate was filtered off and washed with solvent. The precipitate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 3 (80% yield).

[0217] Characterization data of intermediate 3: It is a colorless oily substance; 1 H NMR (400MHz, CDCl3) δ7.77(dd,J=3.9,1.2Hz,1H),7.62(dd,J=5.0,1.2Hz,1H),7.10(d d, J=5.0, 3.8Hz, 1H), 4.56 (q, J=6.9Hz, 1H), 1.65 (d, J=6.9Hz, 3H), 1.10-1.03 (m, 21H).

[0218] Synthesis of intermediate 4:

[0219] Intermediate 3 (1.0 equivalent) was dissolved in ultradry tetrahydrofuran (1.0 M), followed by the slow addition of a tetrabutylammonium fluoride tetrahydrofuran solution (1.0 M, 1.1 equivalent) at -20 °C. After the reaction was complete (monitored by TLC), the reaction was quenched with saturated brine. The organic phase was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 4 (90% yield).

[0220] Characterization data of intermediate 4: It is a colorless oily substance; 1 H NMR (400MHz, CDCl3) δ7.76 (dd, J=3.9, 1.2Hz, 1H), 7.64 (dd, J=5.0, 1.2Hz, 1H), 7.11 (dd, J= 5.0, 3.8Hz, 1H), 4.51 (qd, J = 7.1, 2.5Hz, 1H), 2.36 (d, J = 2.5Hz, 1H), 1.65 (d, J = 7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ182.2,141.3,133.2,131.4,128.0,83.4,71.3,28.9,22.5.

[0221] Synthesis of intermediate 5:

[0222] Intermediate 4 (1.0 equivalent) was dissolved in a mixed solvent of water and acetic acid, followed by the slow addition of potassium permanganate (4.0 equivalent) at -20°C. After the reaction was complete (monitored by TLC), the reaction was quenched with saturated brine. The organic phase was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 5 (20% yield).

[0223] Characterization data of intermediate 5: It is a colorless oily substance; 1 H NMR (400MHz, CDCl3) δ10.07(s,1H),7.79(dd,J=3.9,1.2Hz,1H),7.66(dd,J=5.0,1. 1Hz, 1H), 7.11 (dd, J = 5.0, 3.9Hz, 1H), 4.44 (q, J = 7.3Hz, 1H), 1.63 (d, J = 7.4Hz, 3H).

[0224] Intermediate 5 can be further converted into (S)-stironine 6.

[0225] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. An imidazoline nitrogen-phosphorus ligand, characterized in that, The ligand has one of the following structures or its enantiomers or diastereomers: 。 2. The application of the ligand according to claim 1 in asymmetric reactions, wherein, The asymmetric catalytic reaction is as follows: .

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