Asymmetric bidentate phosphine ligand and synthesis method thereof

Abstract

The invention provides an asymmetric bidentate phosphine ligand and a synthesis method thereof. The ligand has a structure as shown in a formula I, R1 and R2 are independently selected from H or C1C6 alkyl groups, and R3 and R4 are different substituent groups and are independently selected from one of C1C6 alkyl groups, C1C6 alkoxy groups and C6C15 aryl groups. According to the ligand, different substituent groups are introduced into two ends, a traditional symmetrical structure is broken, and the electronic effect and the space environment can be adjusted, so that the selectivity and the activity of the ligand in a catalytic reaction are improved. Meanwhile, the invention provides a synthesis method of the compound, and the synthesis method is simple in process, mild in condition and simple and convenient in post-treatment, and has good magnification and industrialization potential.

Description

Technical Field

[0001] This invention relates to organophosphorus chemistry, specifically to an asymmetric bidentate phosphine ligand and its synthesis method. Background Technology

[0002] Bidentate phosphine ligands play a crucial role in homogeneous reactions catalyzed by transition metals. They stabilize metal centers through chelation effects and can finely regulate the electron density and spatial environment of metal centers, thereby significantly affecting the activity, selectivity and stability of catalytic reactions.

[0003] Among numerous bidentate phosphine ligands, Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene) and its derivatives are representative successful ligands. Their structure is characterized by a rigid oxanthracene skeleton connecting two phosphorus atoms, forming a natural bite angle of approximately 108°. This unique bite angle makes Xantphos-like ligands particularly suitable for reactions requiring large coordination angles, such as palladium-catalyzed Buchwald-Hartwig amination, carbonylation reactions, and some CS-CO coupling reactions. Their rigid structure prevents monodentate coordination, ensuring catalyst stability and unique reactivity.

[0004] Currently, commercially available and widely reported Xantphos ligands typically have symmetrical substituents attached to their two phosphorus atoms, such as the classic PPh2 group. In addition, derivatives such as Xantphos-P(Ar)2 (with identical aryl groups on both phosphorus atoms) or Xantphos-P(Alkyl)2 (with identical alkyl groups on both phosphorus atoms) have also emerged. While these symmetrical ligands have achieved great success, their ligand design has inherent limitations: 1) Limited electronic property tuning: In symmetrical Xantphos ligands, the two phosphorus atoms provide exactly the same electronic effect. This limits researchers' ability to asymmetrically fine-tune the electron density of the metal center. In some complex or sensitive catalytic cycles, different stages of the reaction (such as oxidative addition, migratory insertion, and reductive elimination) may have different electron requirements for the metal center, and symmetrical electron supply may not be optimal. 2) Homogeneous steric hindrance tuning: Symmetrical substituents mean that the spatial environment provided by the ligand around the metal complex is similar in the direction of the two coordination sites. When the rate-determining step or enantioselectivity control of a catalytic reaction (if combined with other chiral sources) depends on spatial shielding in a specific direction of the metal center, this homogeneous spatial environment lacks modulatory capabilities. 3) Insufficient diversity of ligand structures and properties: Symmetrical design greatly limits the diversity of ligand libraries derived from the Xantphos skeleton. Although modulatory effects can be achieved by changing substituents on the xanthracene skeleton or para-substituents on phosphorus, the synergistic effects or novel properties that may result from differentiated combinations of substituents on the two phosphorus atoms have not yet been explored and utilized.

[0005] This method essentially falls under the category of synthetic research on bidentate phosphine ligands, a field in which significant research efforts have already been invested. Traditional methods typically rely on nucleophilic substitution reactions between phosphine halides and air-sensitive organometallic reagents (a) I. Wauters, W. Debrouwer, CV Stevens, Beilstein J Org. Chem. 2014, 10, 1064-1096; b) H. 2-Yorimitsu, Beilstein J Org. Chem. 2013, 9, 1269-1277. There are also reports of using transition metal catalysis or photoinducible strategies to form triphenylphosphine bonds from aryl halides and air-sensitive secondary phosphines (W. Liu, H. Hou, H. Jing, S. Huang, W. Ou, C. Su, Org. Lett. 2023, 25, 8350-8355). Arylphosphines can also be obtained by reducing the corresponding phosphine oxides with an excess of sensitive or expensive reducing agents (such as LiAlH4, HSiCl3) (J. Xue, YS Zhang, Z. Huan, JD Yang, JP Cheng, J.Am. Chem. Soc. 2023, 145, 15589-15599.). Other studies have also been conducted to synthesize these important structures. However, these strategies are generally limited in terms of synthetic scope, selectivity, and compatibility with different functional groups. Against this backdrop, reductive radical cross-electrophilic coupling has emerged as a promising strategy for constructing triphenylphosphines without the need for sensitive organometallic substrates or secondary phosphine reagents. However, such cases are rare, possibly because the generation and transformation of aryl radicals through conventional strategies are challenging. In 2006, Oshima and Yorimitsu reported a novel reductive radical phosphinelation reaction using tris(trimethylsilyl)silane as a reducing agent to achieve the reaction of aryl halides with phosphine chlorides in refluxed benzene (A. Sato, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006, 128, 4240-4241.). In this reaction, the formation of the aryl radical depends on halogen atom abstraction involving the silane. Despite these advances, developing new strategies to obtain structurally diverse bidentate phosphine compounds remains a pressing need.

[0006] In summary, various synthetic methods have been developed for symmetric bidentate phosphine ligands based on the Xantphos skeleton over the years, but the development of asymmetric bidentate phosphine ligands based on the Xantphos skeleton remains a major technical challenge in this field. Summary of the Invention

[0007] Based on the technical challenges mentioned in the background section, this invention provides an asymmetric bidentate phosphine ligand and its synthesis method.

[0008] In a first aspect, the present invention provides an asymmetric bidentate phosphine ligand having the structure shown in Formula I.

[0009] .

[0010] In this embodiment, R1 and R2 are independently selected from H, C1-C6 alkyl groups, and R3 and R4 are different substituents. In this technical solution, the present invention provides a structure in which different groups are attached to both ends of a bidentate phosphine ligand.

[0011] Furthermore, the C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and cyclohexyl. Those skilled in the art will understand that the R1 and R2 groups, as substituents in the Xantphos skeleton, are not subject to many structural restrictions, and common organic groups can be used as substituents in the skeleton.

[0012] Furthermore, R3 and R4 are selected from C1-C6 alkyl, C1-C6 alkoxy, and C6-C6 alkyl groups. 15 One type of aryl substituent. Specifically, the two ends of the bidentate phosphine ligand can be selected from common alkyl, alkoxy, and aryl substituents.

[0013] Further, the C1-C6 alkyl group is selected from one of methyl, ethyl, isopropyl, propyl, butyl, tert-butyl, pentyl, hexyl, and cyclohexyl; the C1-C6 alkoxy group is selected from one of methoxy, ethoxy, and tert-butoxy; the C6-C... 15 Aryl groups are selected from , and One of the following, wherein R5 and R6 are independently selected from H, Cl, F, methyl, methoxy, trifluoromethyl, vinyl, and tert-butyl. Those skilled in the art will understand that other common alkyl groups having 1-6 carbon atoms are also applicable, as are other common alkoxy groups having 1-6 carbon atoms; and other common aryl groups having 6-12 carbon atoms are also applicable.

[0014] On the other hand, the present invention provides a method for synthesizing asymmetric bidentate phosphine ligands, comprising the following steps.

[0015] S1. Place the organic solvent in the reactor and cool it to -50 to -90°C. Add halooxanthracene and dibenzohexacyclic sulfoxide compound to the reactor respectively. Add trifluoromethanesulfonic anhydride dropwise to the reactor. After the addition is complete, continue the reaction for a certain period of time. After post-processing, obtain compound II.

[0016] In the compound of formula II, X is a halogen, and Y is selected from one of 0, O and S. When Y is 0, it means that the heterocycle containing Y is a five-membered thiophene heterocycle; when Y is O, it means that the heterocycle containing Y is a six-membered oxygen-sulfur heterocycle; when Y is S, it means that the heterocycle containing Y is a six-membered disulfur heterocycle.

[0017] S2. Place the compound of formula II into a reactor, add a certain amount of 2,4,6-tris(diphenylamino)-3,5-difluorobenzyl nitrile, a disubstituted phosphine compound, N-ethyl diisopropylamine and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate to the reactor, remove the air in the reactor to make the reactor an inert reaction environment, add a certain amount of organic solvent to the reactor, and stir the reaction under blue LED irradiation at room temperature for a certain period of time to obtain the compound of formula III.

[0018] The Q is one of H, Cl, R7O-, ArO-, and (R7)2N-, where R7 is a C1-C6 alkyl group and Ar is a C6-C6 alkyl group. 12 Aryl.

[0019] S3. Place the compound of formula III into a reactor, add an organic solvent, and cool to -50 to -90°C. At this temperature, add a certain amount of n-butyllithium dropwise and react for a certain time. After adding a certain amount of disubstituted phosphine halide compound, raise the reaction temperature to room temperature and react for a certain time. After the reaction is completed, the reaction solution is post-processed to obtain the compound of formula I.

[0020] Wherein, T is a halogen.

[0021] Furthermore, X in the compound of formula II is selected from chlorine, bromine, and iodine.

[0022] Furthermore, the T in the disubstituted phosphine halide compound is selected from chlorine, bromine, and iodine.

[0023] Furthermore, R7 is selected from one of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and cyclohexyl; and Ar is... R8 is selected from one of H, Cl, methyl, ethyl, methoxy, trifluoromethyl and tert-butyl.

[0024] Further, in step S1, the post-processing includes the following operations: pouring the reaction solution into a saturated sodium bicarbonate solution, extracting the saturated sodium bicarbonate solution with an organic solvent; and washing, drying and removing the organic solvent from the organic layer to obtain compound of formula II.

[0025] Further, in step S3, the post-processing includes the following operations: pouring the reaction solution into water and extracting it multiple times with an organic solvent; washing the combined organic phases with saturated brine, drying them with an anhydrous desiccant and removing the organic solvent to obtain compound I.

[0026] The beneficial technical effects of this invention are as follows: First, by designing and synthesizing an asymmetric bidentate phosphine ligand with the structure shown in Formula I, different substituents (R3 and R4) are introduced at both ends of the ligand, breaking the structural limitations of traditional symmetric bidentate phosphine ligands. This asymmetry can effectively regulate the electronic effects and spatial environment of the ligand, thereby enhancing the coordination regulation ability to the metal center in catalytic reactions. It is expected to significantly improve the selectivity (such as regioselectivity and enantioselectivity) and reactivity of catalytic reactions, expanding its application potential in asymmetric catalysis, coupling reactions, and other fields.

[0027] Secondly, the disclosed synthetic route is clear and feasible. By constructing the heterocyclic skeleton step by step and gradually introducing phosphine centers and differentiated aryl groups, the efficient and specific preparation of the target ligand is achieved. Key steps employ strategies such as low-temperature lithiation, nucleophilic substitution, and photocatalysis, which are mild and compatible with multiple functional groups, contributing to improved product yield and purity. Furthermore, the post-processing of each intermediate product can be completed using conventional methods such as washing and extraction, giving this synthetic process good scalability and industrialization value. Attached Figure Description

[0028] Appendix Figure 1 This is the 1H NMR spectrum of the target compound in Example 3.

[0029] Appendix Figure 2 This is the carbon NMR spectrum of the target compound in Example 3.

[0030] Appendix Figure 3 This is the 1H NMR spectrum of the target compound in Example 4.

[0031] Appendix Figure 4 This is the carbon NMR spectrum of the target compound in Example 4.

[0032] Appendix Figure 5 This is the 1H NMR spectrum of the target compound in Example 6.

[0033] Appendix Figure 6 This is the carbon NMR spectrum of the target compound in Example 6. Detailed Implementation

[0034] In this section, specific embodiments will be shown to illustrate specific implementations of the present invention. The examples shown are not intended to limit the scope of the claims.

[0035] Example 1 25 mL of dichloromethane was placed in a reactor and cooled to -78°C. Dibenzothiophene oxide (780 mg, 3.90 mmol, 1.1 equivalents) and bromoxyanthracene (1.440 g, 3.60 mmol, 1.0 equivalents) were added dropwise, followed by the addition of trifluoromethanesulfonic anhydride (710 µL, 4.20 mmol, 1.2 equivalents), and the mixture was stirred at this temperature for 30 minutes. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL) and extracted three times with dichloromethane (3 × 30 mL). The combined organic layers were washed with saturated brine (30 mL) to separate the organic layer, which was dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by silica gel column chromatography (eluent: 5% methanol / dichloromethane) to give 1.82 g of the target compound, 69%, as a white solid (TLC Rf = 0.3, developing solvent: 5% methanol / dichloromethane). The proton and carbon spectral data of the target compound are as follows: 1 H NMR(600 MHz, CDCl3) δ 8.40(d, J = 7.8 Hz, 2 H), 8.31 (d, J = 7.8 Hz, 2 H), 7.97 (t, J = 7.2 Hz, 2 H), 7.74(t, J = 7.8 Hz, 2 H), 7.69 (s, 1 H), 7.56 (s, 1 H), 7.43 (s, 1 H), 1.71 (s, 6H), 1.35 (s, 9 H), 1.06 (s, 9 H); 13 C NMR (150 MHz, CDCl3) δ 149.8, 149.3, 148.2, 143.3, 139.6, 135.2, 133.0, 131.9, 130.7, 130.4, 129.2, 128.7, 128.6, 125.4, 122.6, 122.0, 120.8, 119.8, 113.2, 110.0, 35.7, 35.2, 34.9, 32.6, 31.3, 31.1, 30.9. The specific synthesis route is shown below.

[0036] .

[0037] Example 2 The target compound obtained in Example 1 (264 mg, 0.360 mmol, 1.2 equivalents) was placed in a dry glass tube, followed by the addition of the photocatalyst 2,4,6-tris(diphenylamino)-3,5-difluorobenzyl nitrile (1.9 mg, 0.0030 mmol, 1%), phenol diphenylphosphite (83.4 mg, 0.300 mmol, 1.0 equivalent), N,N-diisopropylethylamine (DIPEA, 77.5 mg, 0.600 mmol, 2.0 equivalent), and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (114 mg, 0.450 mmol, 1.5 equivalent). The mixture was degassed under vacuum at room temperature and purged with argon, a process repeated three times. Then, ethyl acetate (3.0 mL) was added to the mixture, and the mixture was stirred and reacted under a blue LED lamp at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated and filtered through a short silica gel column, then washed with a 1% ethyl acetate / hexane solution. The filtrate was collected and concentrated, and the concentrated product was used directly in the next reaction. The specific synthetic route is shown below. .

[0038] Example 3 The concentrated product obtained in Example 2 was dissolved in tetrahydrofuran (4 mL) and cooled to -78°C. At this temperature, n-butyllithium (156 µL, 0.39 mmol, 1.3 equivalents, 2.5 M solution) was added dropwise, and the mixture was stirred at -78°C for 30 minutes after the addition was complete. Then, bis(3,5-bis(trifluoromethylphenyl)phosphine chloride (177 mg, 0.36 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated product was purified by silica gel column chromatography (eluent: 2% ethyl acetate / hexane) to give 179 mg of the target compound, a yield of 62%, as a white gel (TLC showed an Rf value of 0.3, developing solvent: 2% ethyl acetate / hexane). The 1H and 1C spectral data of the target compound are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.36 (s, 2 H), 7.25-7.14 (m, 20 H), 6.52 (s, 2 H), 1.66 (s, 6 H), 1.09 (s, 18 H); 13C NMR (150 MHz, CDCl3) δ 150.5, 150.44, 150.38, 145.2, 137.72, 137.68, 137.64, 134.0, 133.9, 133.8, 129.4, 128.8, 128.05, 127.97, 124.7, 124.64, 124.62, 124.57, 122.9,34.8, 34.4, 32.1, 31.2; 31 P NMR (243 MHz, CDCl3) δ -16.7. The specific synthetic route is shown below.

[0039] .

[0040] Example 4 The procedure was the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl)phosphine chloride) was replaced with an equivalent amount of bis(3,5-dimethylphenyl)phosphine chloride. 179 mg of the target compound was obtained, in 62% yield, as a white gel (TLC Rf=0.3, developing solvent: 2% ethyl acetate / hexane). The 1H and 1C spectral data of the target compound are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.79 (s, 2 H), 7.58 (d, J = 6.0 Hz, 4 H), 7.52 (s, 2H), 3.76 (s, 1 H), 7.41 (s, 1 H), 7.23-7.09 (m, 10 H), 6.44 (s, 1 H), 6.34(s, 1 H), 1.70 (s, 6 H), 1.10 (d, J = 5.4 Hz, 18 H); 13C NMR(150 MHz, CDCl3) δ151.2, 151.1, 150.2, 150.1, 146.7, 146.2, 140.2, 140.0, 136.8, 136.7, 133.7,133.6, 133.4, 133.3, 131.72, 131.68, 131.50, 131.46, 131.3, 130.8, 129.2,128.4, 128.2, 128.1, 128.0, 125.8, 124.6, 124.2, 124.1, 124.0, 122.8, 122.7, 122.2, 120.4, 120.0, 119.9, 35.1, 34.6, 31.2, 31.14, 31.07. The structure of the target compound is as follows: .

[0041] Example 5 The operation was the same as in Example 2, except that the diphenylphosphite ester in Example 2 was replaced with an equivalent amount of phenyl di-p-methylphenylphosphite. The target product was obtained, and its chemical structure is as follows: .

[0042] Example 6 The concentrated product obtained in Example 5 was dissolved in tetrahydrofuran (4 mL) and cooled to -78°C. At this temperature, n-butyllithium (156 µL, 0.39 mmol, 1.3 equivalents, 2.5 M solution) was added dropwise, and the mixture was stirred at -78°C for 30 minutes after the addition was complete. Then, bis(3,5-bis(trifluoromethylphenyl)phosphine chloride (177 mg, 0.36 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted three times with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated product was purified by silica gel column chromatography (eluent: 2% ethyl acetate / hexane) to give 145 mg of the target compound, 65% yield, as a white gel (TLC showed an Rf value of 0.3, developing solvent: 2% ethyl acetate / hexane). The 1H and 1C spectral data of the target compound are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 10.8 Hz, 2H), 7.24-7.15 (m, 10 H), 6.83 (d, J= 5.4 Hz, 6 H), 6.60 (s, 1 H), 6.53 (s, 1H), 2.19 (s, 12 H), 1.67 (s, 6 H), 1.11 (d, J = 10.2 Hz, 18 H); 13 C NMR (150 MHz, CDCl3) δ 150.9, 150.8, 145.1, 145.0, 137.83, 137.78, 137.75, 137.51, 137.47,137.4, 137.0, 133.9, 133.81, 133.75, 131.65, 133.59, 131.5, 129.8, 129.5,129.2, 129.1, 128.9, 128.0, 127.80, 127.78, 127.76, 122.6, 122.4, 34.9, 34.4,31.6, 31.27, 31.26, 21.3. The structural formula of the target compound is: .

[0043] Example 7 The operation described herein is consistent with that in Example 3, except that bis(3,5-bistrifluoromethylphenyl)chlorine is replaced with an equivalent amount of bis(p-trifluoromethylphenyl)chlorine, resulting in a product with the following structure: The yield was 60%.

[0044] Example 8 The operation described herein is consistent with that in Example 3, except that bis(3,5-bistrifluoromethylphenyl)phosphine chloride is replaced with an equivalent amount of di-p-vinylphenylphosphine chloride, resulting in a product with the following structure: The yield was 62%.

[0045] Example 9 The operation described herein is consistent with that in Example 3, except that bis(3,5-bis(trifluoromethylphenyl)phosphine chloride) is replaced with an equivalent amount of di-p-fluorophenylphosphine chloride, resulting in a product with the following structure: The yield was 58%.

[0046] Example 10 The reaction in Example 6 was carried out on a gram scale (2.65 mmol) to give 1.05 g of the target product, with a yield of 53%.

[0047] The above examples mainly demonstrate that the synthesis method provided by the present invention can attach different types of aryl substituents to the two P-positions of the bidentate phosphine ligand pair, all of which can achieve good yields. Furthermore, by appropriately scaling up the reaction scale, good yields can also be obtained.

[0048] Example 11 The operation described is consistent with that in Example 1, except that an equivalent amount is used. replace The product obtained is The product obtained is then used to replace the corresponding substance obtained in the original Example 1 in Example 2, with other steps remaining the same as in the original Example 2. The concentrated solution obtained in the previous step is then used to replace the corresponding concentrated solution obtained in the original Example 2 in Example 3, with other steps remaining the same as in the original Example 3. The final product has the following structural formula: The yield was 71%.

[0049] Example 12 The operation is the same as in Example 11, except that an equal amount of Replace the one in Example 11 The final product structure is as follows: The yield was 68%.

[0050] Example 13 The operation is the same as in Example 11, except that an equal amount of Replace the one in Example 11 The final product structure is as follows: The yield was 69%.

[0051] Examples 11-13 demonstrate that different types of alkyl substituents can be attached to the backbone of bidentate phosphine ligands.

[0052] Example 14 The procedure is the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl)chlorine is replaced with an equivalent amount of dimethylphosphine chloride, and the final product is... The yield was 66%.

[0053] Example 15 The procedure is the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl)phosphine chloride is replaced with an equivalent amount of diethylphosphine chloride, and the final product is... The yield was 64%.

[0054] Example 16 The procedure is the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl))chlorine is replaced with an equivalent amount of di-tert-butylphosphine chloride, and the final product is... The yield was 56%.

[0055] Example 17 The procedure is the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl))chlorine is replaced with an equivalent amount of dihexylphosphine chloride, and the final product is... The yield was 53%.

[0056] Example 18 The procedure is the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl))chlorine is replaced with an equivalent amount of dimethoxyphosphine chloride, and the final product is... The yield was 66%.

[0057] Example 19 The procedure is the same as in Example 3, except that bis(3,5-bis(trifluoromethylphenyl)chloride) is replaced with an equivalent amount of bis(1-naphthyl)phosphine chloride, and the final product is... The yield was 56%.

[0058] Examples 14-19 demonstrate the flexibility of attaching alkyl, alkoxy, and naphthyl groups to one end of a phosphorus chloride compound by using different disubstituted phosphine chloride compounds.

[0059] Example 20 The procedure is the same as in Example 2, except that an equivalent amount of diphenylethoxyphosphine (CAS No. 719-80-2, structural formula: Replacing diphenylphosphite with phenol ester, the resulting product was identical to that in Example 2. The product was further subjected to the operation described in Example 3, and the resulting target product was identical to that in Example 3, with a yield of 58%.

[0060] Example 21 The procedure is the same as in Example 2, except that an equivalent amount of diphenylphosphine chloride (CAS No. 719-80-2, structural formula: Replacing diphenylphosphite with phenol ester, the resulting product was identical to that in Example 2. The product was further subjected to the operation described in Example 3, and the resulting target product was identical to that in Example 3, with a yield of 55%.

[0061] Example 22 The procedure was the same as in Example 2, except that diphenylphosphine was replaced with an equivalent amount of phenol diphenylphosphite. The resulting product was identical to that in Example 2. This product was then further processed as described in Example 3, yielding the same target product as in Example 3, with a yield of 43%. Example 23 The procedure is the same as in Example 2, except that an equivalent amount of N,N-diethyl-P,P-diphenylphosphineamide (structural formula: Replacing diphenylphosphite with phenol ester, the resulting product was identical to that in Example 2. The product was further subjected to the operation described in Example 3, and the resulting target product was identical to that in Example 3, with a yield of 45%.

[0062] Examples 3 and 20-23 demonstrate that disubstituted phosphorus chlorides, disubstituted phosphines, disubstituted aryl phosphites, disubstituted alkyl phosphites, and disubstituted phosphorous amides all exhibit good reactivity in this reaction. Based on this, those skilled in the art can reasonably expect that, for disubstituted aryl phosphites, the PO bond in common aryl esters can be broken, allowing the aryl group to leave; therefore, the aryl Ar group here can be expanded to C6-C. 12 Aryl groups, such as common phenyl, p-methylphenyl, p-tert-butylphenyl, 3,5-dimethylphenyl, etc.; for disubstituted alkyl phosphites and disubstituted phosphorous amides, the alkyl group on the alkyl group of the alkyl ester and the alkyl group on the N-terminus of the phosphorous amide can be selected from C1-C6 alkyl groups, such as methyl, ethyl, isopropyl, propyl, butyl, tert-butyl, pentyl, hexyl and cyclohexyl, etc., which causes the PO bond and PN bond to break.

[0063] Example 24 The operation described herein is consistent with that in Example 2, except that diphenylphosphite is replaced with an equivalent amount of diethylphosphite, resulting in the product being... The concentrated solution obtained in the previous step was used to further replace the corresponding concentrated solution obtained in the original Example 2 in Example 3, and di(3,5-bis(trifluoromethylphenyl)phosphine chloride) obtained in the original Example 3 was replaced with dimethoxyphosphine chloride. Other steps were performed in the same manner as in the original Example 3. The final product had the following structural formula: The yield was 65%.

[0064] Example 25 The operation is the same as in Example 19, except that diethylphosphite is replaced with di-tert-butylphosphite, and di(3,5-bis(trifluoromethylphenyl)phosphite is replaced with dihexylphosphite. The final product has the following structural formula: The yield was 42%.

[0065] Examples 24-25 illustrate the use of different alkyl or alkoxy groups at the bidentate P-position, expanding the types of bidentate P-ligands. Those skilled in the art will understand that, through reasonable adjustments to the reactants, they can reasonably anticipate the substitution of various common C1-C6 alkyl or alkoxy groups, such as methyl, propyl, isopropyl, tert-butyl, pentyl, hexyl, cyclohexyl, methoxy, ethoxy, and tert-butoxy groups, at the bidentate P-position.

[0066] Example 26 The operation described is consistent with that in Example 1, except that an equivalent amount is used. replace The product obtained is The product obtained is further replaced with the corresponding substance obtained in the original Example 1 in Example 2, and the other steps are the same as those in the original Example 2. The concentrated solution obtained in the above step is further replaced with the corresponding concentrated solution obtained in the original Example 2 in Example 3, and the other steps are the same as those in the original Example 3. The final product has the same structural formula as the product in Example 3, and the yield is 65%.

[0067] Example 27 The operation described is consistent with that in Example 1, except that an equivalent amount is used. replace The product obtained is The product obtained is further replaced with the corresponding substance obtained in the original Example 1 in Example 2, and the other steps are the same as those in the original Example 2. The concentrated solution obtained in the above step is further replaced with the corresponding concentrated solution obtained in the original Example 2 in Example 3, and the other steps are the same as those in the original Example 3. The final product has the same structural formula as the product in Example 3, and the yield is 74%.

[0068] As can be seen from Examples 3 and 26-27, the halogen substituents on the Xantphos skeleton can be Cl, Br, and I.

[0069] Example 28 The operation described is consistent with that in Example 1, except that an equivalent amount is used. replace The product obtained is The product obtained is then used to replace the corresponding substance obtained in the original Example 1 in Example 2, and the other steps are the same as those in the original Example 2. The concentrated solution obtained in the above step is then used to replace the corresponding concentrated solution obtained in the original Example 2 in Example 3, and the other steps are the same as those in the original Example 3. The final product has the same structural formula as the product in Example 3, and the yield is 60%.

[0070] Example 29 The operation described is consistent with that in Example 1, except that an equivalent amount is used. replace The product obtained is The product obtained is then used to replace the corresponding substance obtained in the original Example 1 in Example 2, and the other steps are the same as those in the original Example 2. The concentrated product obtained in the above step is then used to replace the corresponding concentrated product obtained in the original Example 2 in Example 3, and the other steps are the same as those in the original Example 3. The final product has the same structural formula as the product in Example 3, and the yield is 56%.

[0071] As can be seen from Examples 3 and 28-29, dibenzohexacyclic sulfoxide compounds with different heterocyclic structures can all be adapted to this synthetic method.

[0072] Application examples In an inert reaction environment, 0.5 mol% of tris(dibenzylacetone)palladium (Pd2(dba)3), 1.0 mol% of the Xantphos ligand prepared in Example 6, and 1.5 mmol of sodium tert-butoxide (NaOtBu) were added to the reactor. After sealing, the reactor was removed, and then, under argon protection, 1.0 mmol of p-bromotoluene, 1.2 mmol of piperidine, and 3 mL of anhydrous toluene were added to the reactor via syringe. The solids were completely dissolved by ultrasonic vibration. The reaction tube was then refluxed in an oil bath at 110 °C for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reactor was cooled to room temperature, and 5 mL of deionized water was added to quench the reaction. The reactor was extracted three times with ethyl acetate (5 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Finally, the crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate). With a ratio of 10:1, the target product N-p-tolylpiperidine can be obtained efficiently, and the yield of the Buchwald-Hartwig arylation reaction catalyzed by this palladium / Xantphos ligand can reach 92%.

[0073] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, all of which will fall within the protection scope of the present invention.

Claims

1. An asymmetric bidentate phosphine ligand, characterized in that, It has the structure shown in Equation I: ； R1 and R2 are independently selected from H, C1-C6 alkyl groups; R3 and R4 are different substituents.

2. The asymmetric bidentate phosphine ligand as described in claim 1, characterized in that, The C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and cyclohexyl.

3. The asymmetric bidentate phosphine ligand as described in claim 1, characterized in that, R3 and R4 are selected from C1-C6 alkyl, C1-C6 alkoxy, and C6-C6 alkyl groups. 15 One of the aryl substituents.

4. The asymmetric bidentate phosphine ligand as described in claim 3, characterized in that, The C1-C6 alkyl group is selected from one of methyl, ethyl, isopropyl, propyl, butyl, tert-butyl, pentyl, hexyl, and cyclohexyl; the C1-C6 alkoxy group is selected from one of methoxy, ethoxy, and tert-butoxy; the C6-C... 15 Aryl groups are selected from , and One of them, wherein R5 and R6 are independently selected from one of H, Cl, F, methyl, methoxy, trifluoromethyl, vinyl and tert-butyl.

5. A method for synthesizing the asymmetric bidentate phosphine ligand as described in any one of claims 1-4, characterized in that, Includes the following steps: S1. Place the organic solvent in the reactor and cool it to -50--90℃. Add halooxane and dibenzohexacyclic sulfoxide compounds to the reactor respectively. Add trifluoromethanesulfonic anhydride dropwise to the reactor. After the addition is completed, continue the reaction for a certain time. After post-processing, obtain compound II. ， In the compound of formula II, X is a halogen, and Y in the compound of formula II is selected from one of 0, O and S. When Y is 0, it means that the heterocycle containing Y is a five-membered thiophene heterocycle; when Y is 0, it means that the heterocycle containing Y is a six-membered oxygen-sulfur heterocycle; when Y is S, it means that the heterocycle containing Y is a six-membered disulfur heterocycle. S2. Place the compound of formula II into a reactor, add a certain amount of 2,4,6-tris(diphenylamino)-3,5-difluorobenzyl nitrile, a disubstituted phosphine compound, N-ethyl diisopropylamine and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate to the reactor, remove the air in the reactor to make the reactor an inert reaction environment, add a certain amount of organic solvent to the reactor, and stir the reaction under blue LED irradiation at room temperature for a certain period of time to obtain the compound of formula III; The Q is one of H, Cl, R7O-, ArO-, and (R7)2N-, where R7 is a C1-C6 alkyl group and Ar is a C6-C6 alkyl group. 12 Aryl; S3. Place the compound of formula III into a reactor, add an organic solvent and cool down to -50--90℃. At this temperature, add a certain amount of n-butyllithium dropwise and react for a certain time. After adding a certain amount of disubstituted phosphine halide compound, raise the reaction temperature to room temperature and react for a certain time. After the reaction is completed, the reaction solution is post-processed to obtain the compound of formula I. Wherein, T is a halogen.

6. The synthesis method as described in claim 5, characterized in that, In the compound of formula II, X is selected from chlorine, bromine, and iodine.

7. The synthesis method as described in claim 5, characterized in that, In the disubstituted phosphine halide compound, T is selected from one of chlorine, bromine, and iodine.

8. The synthesis method as described in claim 5, characterized in that, R7 is selected from one of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and cyclohexyl; Ar is... R8 is selected from one of H, Cl, methyl, ethyl, methoxy, trifluoromethyl and tert-butyl.

9. The synthesis method as described in claim 5, characterized in that, In step S1, the post-processing includes the following operations: pouring the reaction solution into a saturated sodium bicarbonate solution, extracting the saturated sodium bicarbonate solution with an organic solvent; and washing, drying and removing the organic solvent from the organic layer to obtain compound of formula II.

10. The synthesis method according to claim 5, characterized in that, In step S3, the post-processing includes the following operations: pouring the reaction solution into water and extracting it multiple times with an organic solvent; washing the combined organic phases with saturated brine, drying them with an anhydrous desiccant and removing the organic solvent to obtain compound I.

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