A pyridine-derived chiral sulfoxide monophosphine ligand, its preparation method and application

Abstract

The application discloses a pyridine-derived chiral sulfoxide monophosphine ligand, a preparation method and application thereof, and a structure of the pyridine-derived chiral sulfoxide monophosphine ligand is shown in the following formula; the preparation method comprises the following steps: obtaining an intermediate 1 by directly lithiumating a polysubstituted pyridine, obtaining an intermediate 2 by respectively reacting the intermediate 1 with a chiral sulfur reagent or a phosphorus reagent, further obtaining an intermediate 3 by lithiumating the different intermediate 2 with a lithium reagent, and obtaining the pyridine-derived chiral sulfoxide monophosphine ligand by respectively reacting the intermediate 3 with the phosphorus reagent or the chiral sulfur reagent. The method has a simple synthesis route, raw materials are easy to obtain, and a series of pyridine-derived chiral sulfoxide monophosphine ligands can be obtained in a good yield and excellent diastereoselectivity. The pyridine-derived chiral sulfoxide monophosphine ligand prepared by the application can be used for preparing a cyclic aliphatic ketone, and a target product can be obtained in a high yield and enantioselectivity, and has a wide application prospect in the field of organic synthesis.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry, specifically relating to a pyridine-derived chiral sulfoxide monophosphine ligand, its preparation method, and its application. Background Technology

[0002] Chirality is widespread in nature and is one of its fundamental properties. In living organisms, the vast majority of proteins, nucleotides, sugars, and other biomolecules are chiral. In our daily lives, some common drug molecules and food additives are also chiral. Two seemingly similar enantiomers often possess different optical properties, physicochemical properties, and different, even diametrically opposed, biological activities. For example, the use of racemic thalidomide led to the tragic birth of numerous fetuses with phocomelia. This is because (R)-thalidomide can be used as a sedative to alleviate pregnancy symptoms, while (S)-thalidomide has teratogenic side effects. Such examples highlight the importance of synthesizing optically pure molecules in synthetic chemistry, medicinal chemistry, materials science, and life sciences. The main methods for obtaining optically pure compounds generally include: asymmetric catalysis, chiral compound derivatization, separation of natural products, and resolution of racemic compounds. Among these, asymmetric catalysis has a unique advantage: it can obtain a large number of optically active products using only a small amount of catalyst. Therefore, asymmetric catalysis has been extensively studied. Asymmetric catalysis includes two main methods: chemical catalysis and bioenzymatic catalysis. Chemical asymmetric catalysis is more well-developed and widely used. Chemical asymmetric catalysis can be further divided into organometallic catalysis and small organic molecule catalysis. Small organic molecule catalysis has become a current research hotspot due to its advantages such as high reactivity, mild conditions, good selectivity, and broad substrate range.

[0003] The core issue in organometallic catalysis is the matching of metals and ligands to achieve highly efficient, active, and selective catalytic reactions. The induced transfer of chiral ligands is the source of chirality in catalytic reactions. In particular, phosphorus-containing chiral compounds are widely used in transition metal-catalyzed asymmetric transformation reactions. In 1977, Knowles et al. first reported asymmetric hydrogenation reaction catalyzed by metal / phosphorus chiral bisphosphine ligands, ushering in a new era of rapid development for chiral phosphine ligands. After long-term research and development by organic chemists, phosphine ligands with axial chirality, facial chirality, carbon-centered chirality, or spirochirality have become the most widely used. Due to the difficulties in preparation and separation, phosphorus chiral ligands are relatively expensive. Therefore, research on the synthesis and application of chiral organophosphine ligands is extremely important and urgent.

[0004] For nearly half a century, due to the diversity and unique effects of carbon skeletons, carbon chirality has been introduced into phosphine ligands. Currently, chiral carbon phosphine ligands with central chiral, axial chiral, planar chiral, and spirocyclic skeletons have been developed, achieving significant research results in asymmetric catalysis. In the last two decades, sulfur chirality has been introduced into phosphine ligands, leading to the development of various types of novel sulfur-chiral phosphine ligands. However, chiral sulfoxide monophosphine ligands containing aromatic heterocycles such as pyridine have not yet been reported. This may be related to the strong coordination ability of pyridine and its susceptibility to nucleophilic attack by organometallic reagents during synthesis.

[0005] Therefore, it is still of great significance to develop a pyridine-derived chiral sulfoxide monophosphine ligand that is inexpensive and readily available, easy to modify in structure, convenient for efficient synthesis, and has good application prospects. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing technologies by providing a pyridine-derived chiral sulfoxide monophosphine ligand, its preparation method, and its applications. This novel chiral sulfoxide monophosphine ligand can be used as a chiral catalyst for the preparation of cyclic aliphatic ketone compounds, and the cyclic aliphatic ketone compounds prepared by this system exhibit high yields and high ee (enantiomeric excess) values.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0008] In a first aspect, the present invention provides a pyridine-derived chiral sulfoxide monophosphine ligand with the following structural formula:

[0009]

[0010] Among them, R 1 R 2 Each is independently selected from aryl, alkyl, or naphthyl; R 3 Selected from hydrogen, halogen, alkyl, aryl, silyl, or thio; R 4 It is an alkyl group.

[0011] As a preferred option, R 1 Selected from phenyl, cyclohexyl, or isopropyl; R 2 Selected from tert-butyl, 4-methylphenyl, or naphthyl; R 3 Selected from hydrogen, halogen (chlorine or bromine), methyl, phenyl, p-toluenesulfinyl, tert-butylsulfinyl, silyl (trimethylsilyl, triphenylsilyl, or dimethylphenylsilyl); R 4 It is selected from one of methyl, ethyl or isopropyl.

[0012] Furthermore, the pyridine-derived chiral sulfoxide monophosphine ligand has a structural formula of one of the following L1 to L9:

[0013]

[0014] Secondly, the present invention provides a method for preparing a pyridine-derived chiral sulfoxide monophosphine ligand, the method comprising Scheme 1 and Scheme 2, wherein:

[0015] Option 1 involves introducing sulfoxide first, followed by phosphine, and includes the following steps:

[0016] (1) 3-bromo-2,6-dimethoxypyridine was reacted with a lithium reagent in a solvent to obtain lithium pyridine intermediate 1;

[0017] 1

[0019] (2) Reaction of lithium pyridinium intermediate 1 with a chiral sulfur reagent yields intermediate 2-1;

[0020]

[0021] (3) The lithium reagent is reacted with diisopropylamine to obtain the new base diisopropylaminolithium, and then reacted with intermediate 2-1 in solvent to obtain intermediate 3-1;

[0022]

[0023] (4) Intermediate 3-1 is reacted with a phosphorus reagent to obtain the pyridine-derived chiral sulfoxide monophosphine ligand;

[0024] The chiral sulfur reagent is (-)-menthol (S)-p-toluenesulfinate, (-)-menthol (S)-1-naphthalenesulfinate, or (S)-tert-butylsulfinate thiotert-butyl ester; the phosphorus reagent is diphenylphosphine chloride, diisopropylphosphine chloride, or dicyclohexylphosphine chloride.

[0025] Option 2 involves introducing phosphine first, followed by sulfoxide, and includes the following steps:

[0026] (1) 3-bromo-2,6-dimethoxypyridine was reacted with a lithium reagent in a solvent to obtain lithium pyridine intermediate 1;

[0027] 1

[0029] (2) Reaction of lithium pyridinium intermediate 1 with phosphorus reagent yields intermediate 2-2;

[0030]

[0031] (3) Intermediate 2-2 was reacted with lithium reagent in a solvent to obtain intermediate 3-2;

[0032]

[0033] (4) Intermediate 3-2 is reacted with a chiral sulfur reagent to obtain the pyridine-derived chiral sulfoxide monophosphine ligand;

[0034] The phosphorus reagent is diphenylphosphine chloride, diisopropylphosphine chloride, or dicyclohexylphosphine chloride; the chiral sulfur reagent is (-)-menthol (S)-p-toluenesulfinyl ester, (-)-menthol (S)-1-naphthalenesulfinyl ester, or (S)-tert-butylsulfinyl thiotert-butyl ester.

[0035] Further, in step (1), polysubstituted pyridine is added to the lithium reagent to carry out a substitution reaction to obtain intermediate 1.

[0036] Furthermore, the lithium reagent mentioned above is butyllithium, including one of n-butyllithium, sec-butyllithium, and tert-butyllithium, preferably n-butyllithium; the reaction temperature of butyllithium with polysubstituted pyridine is preferably -78 to 0 °C, more preferably -78 to -40 °C, and the reaction time is preferably 1 to 10 h. The reaction temperature of diisopropylaminolithium with polysubstituted pyridine is preferably -78 to 0 °C, more preferably -78 to -40 °C, and the reaction time is preferably 1 to 10 h.

[0037] Further, in step (1), the molar ratio of the substituted pyridine to the lithium reagent is preferably 1:0.9 to 1.2, for example 1:1.1.

[0038] Further, in step (1), the solvent is preferably one or more of the following: dry diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, and chlorobenzene, more preferably dry tetrahydrofuran.

[0039] Further, in step (2), the molar ratio of intermediate 1 to chiral sulfur reagent is preferably 1:1 to 2, for example 1:1.3; the molar ratio of intermediate 1 to phosphorus reagent is preferably 1:1 to 2, for example 1:1.2.

[0040] Furthermore, the reaction temperature in step (2) is preferably -78 to 30 °C, more preferably 20 to 30 °C; and the reaction time is preferably 12 to 24 h.

[0041] Further, in step (4), intermediate 3-1 reacts with a phosphorus reagent; intermediate 3-2 reacts with a chiral sulfur reagent.

[0042] Further, in step (4), the molar ratio of intermediate 3-1 to phosphorus reagent is preferably 1:2 to 4, for example 1:2; the molar ratio of intermediate 3-2 to chiral sulfur reagent is preferably 1:1 to 2, for example 1:1.3.

[0043] Furthermore, the reaction temperature in step (4) is preferably -78 to 30 °C, more preferably 20 to 30 °C; the reaction time is preferably 12 to 24 h.

[0044] Thirdly, the present invention provides the application of the above-mentioned pyridine-derived chiral sulfoxide monophosphine ligand as a chiral catalyst.

[0045] Furthermore, the specific application is as follows: the use of the above-mentioned pyridine-derived chiral sulfoxide monophosphine ligand as a chiral catalyst in the preparation of cyclic aliphatic ketone compounds. Cyclic aliphatic ketone compounds often serve as key intermediates in organic synthesis, especially for constructing drug molecules, natural products, and chiral compounds containing aryl-substituted cyclohexane skeletons. Among them, 3-phenylcyclohexanone, due to its simultaneous presence of an enolized ketone group and a phenyl-substituted ring structure, frequently participates in α-functionalization, reductive amination, Michael addition, and asymmetric synthesis.

[0046] Furthermore, the cyclic aliphatic ketone compound has the following general structural formula:

[0047]

[0048] R is preferably phenyl.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] This invention integrates the pyridine skeleton, chiral sulfoxide group, and phosphine group into a single molecule, providing a novel class of pyridine-derived chiral sulfoxide monophosphine ligands. By introducing different substituents onto the pyridine ring, the steric hindrance and electronic effects of the ligands can be systematically controlled, thereby modulating the catalytic activity and chiral induction ability of the metal complex, providing a novel ligand tool with broad tunability for asymmetric catalytic reactions.

[0051] The preparation method of the present invention has few synthesis steps, uses inexpensive and readily available raw materials, and has a high yield. It can obtain a series of pyridine-derived chiral sulfoxide monophosphine ligands with good yield and excellent diastereoselectivity.

[0052] The pyridine-derived chiral sulfoxide monophosphine ligand prepared in this invention, after coordination with rhodium metal, exhibits excellent catalytic performance in the asymmetric 1,4-addition reaction of arylboronic acid to cyclohexenone, and can obtain cyclic aliphatic ketones such as 3-phenylcyclohexanone in high yield and with high enantiomeric excess (ee value). This has important scientific significance and application value for the development of chiral cyclic aliphatic ketone synthesis methods. Attached Figure Description

[0053] Figure 1 The image shows the proton NMR spectrum of ligand L1.

[0054] Figure 2 The image shows the carbon NMR spectrum of ligand L1.

[0055] Figure 3 This is a single-crystal structure diagram of ligand L1.

[0056] Figure 4 This is a single-crystal structure diagram of ligand L3.

[0057] Figure 5 This is a single-crystal structure diagram of ligand L4.

[0058] Figure 6 The results are from the synthesis of cyclic aliphatic ketone compounds catalyzed by ligands. Detailed Implementation

[0059] As mentioned above, in view of the shortcomings of the prior art, the inventors, through long-term research and extensive practice, have proposed the technical solution of this invention. 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. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. Modifications or equivalent substitutions made by those skilled in the art based on their understanding of the technical solution of this invention, without departing from the spirit and scope of the technical solution of this invention, should all be covered within the protection scope of this invention.

[0060] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0061] This embodiment relates to the preparation of pyridine-derived chiral sulfoxide monophosphine ligands L1-L9, the structures of which are shown in the following formulas:

[0062]

[0063] Example 1: Preparation of Intermediate 1

[0064]

[0065] Under a nitrogen atmosphere, 3-bromo-2,6-dimethoxypyridine (2.17 g, 10 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), cooled to -78 °C, and added dropwise to LDA (11 mmol). After addition, the mixture was stirred at this temperature for 1 hour, and intermediate 1 could be obtained directly without further purification.

[0066] Example 2: Preparation of ligand L1

[0067]

[0068] Under a nitrogen atmosphere, intermediate 1 (4.0136 g, 18 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -78 °C, and diphenylphosphine chloride (4.897 g, 22 mmol) was slowly added dropwise. After addition, the mixture was stirred at this temperature for 1 hour, then the temperature was increased to 30 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and methanol was added to precipitate a white precipitate. After filtration, a white solid (3.948 g, 10 mmol) was obtained, which was intermediate 2, with a yield of 56%.

[0069] Intermediate 2 (2.00 g, 5 mmol) was added sequentially to a 100 mL reaction flask, followed by drying of tetrahydrofuran (15 mL). The mixture was cooled to -78 °C, and a 2.5 M solution of n-BuLi hexane (2.2 mL, 5.5 mmol) was added using a syringe. Stirring continued for 1 hour after the addition was complete. A 0.36 M solution of (-)-menthol (S)-p-toluenesulfinic acid ester in tetrahydrofuran (18 mL, 6.5 mmol) was added using a syringe. The mixture was stirred at this temperature for 0.5 hours, then the temperature was increased to 25 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white solid (1.67 g, 4.5 mmol), which was ligand L1, in 70% yield. The proton NMR spectrum, carbon NMR spectrum, and single crystal structure diagram of ligand L1 are shown below. Figure 1-3 As shown. 1 H NMR (400 MHz, CDCl3)δ7.45-7.38 (m, 10H), 7.03 (q,J = 8.3Hz,4H), 5.83(d,J = 3.2Hz, 1H), 3.81 (s,3H), 3.74 (s,3H), 2.31 (s, 3H).

[0070] Example 3: Preparation of ligand L2

[0071]

[0072] The first two reaction steps followed the synthesis procedure for L1 in Example 2. A 2.4 M tetrahydrofuran solution (1 mL, 2.4 mmol) of (S)-tert-butyl sulfinate thiotert-butyl ester was slowly added using a syringe. After stirring at this temperature for 0.5 hours, the temperature was increased to 25 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (0.49 g, 1.15 mmol), which was ligand L2, in 57% yield. 1 HNMR (400 MHz, CDCl3) δ7.26-7.17 (m, 10H), 5.73 (s,1H), 3.90 (s, 3H), 3.78 (s,3H), 1.27 (s, 9H).

[0073] Example 4: Preparation of ligand L3

[0074]

[0075] Under a nitrogen atmosphere, intermediate 1 (1.0 equivalent) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -78 °C, and dicyclohexylphosphorus chloride (1.2 equivalent) was slowly added dropwise. After addition, the mixture was stirred at this temperature for 1 hour, then the temperature was increased to 25 °C, and the reaction was monitored by TLC. After the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and methanol was added to precipitate a white precipitate. After filtration, a white solid (1.67 g, 4 mmol) was obtained, which was intermediate 2, with a yield of 60%.

[0076] Intermediate 2 (0.60 g, 1.45 mmol) was added sequentially to a 100 mL reaction flask, followed by drying tetrahydrofuran (5 mL). The mixture was cooled to -78 °C, and a 2.5 M n-BuLi hexane solution (0.64 mL, 1.60 mmol) was added using a syringe. Stirring continued for 1 hour after the addition was complete. A 0.31 M tetrahydrofuran solution of (-)-menthol (S)-p-toluenesulfinic acid ester (6 mL, 1.9 mmol) was added using a syringe. The mixture was stirred at this temperature for 0.5 hours, then the temperature was increased to 30 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white solid (0.49 g, 1.3 mmol), which was ligand L3, in 88% yield. The single-crystal structure diagram of ligand L3 is shown below. Figure 4 As shown. 1 H NMR (400 MHz, CDCl3)δ7.42 (d,J = 7.9Hz, 2H), 7.14 (d,J = 7.9Hz, 2H), 6.36(s, 1H), 3.84 (s,3H),3.68 (s,3H), 2.29 (s, 3H),1.66-1.05 (m, 22H).

[0077] Example 5: Preparation of ligand L4

[0078]

[0079] The first two reaction steps followed the synthesis procedure for L3 in Example 4. A 2.4 M tetrahydrofuran solution (2 mL, 4.8 mmol) of (S)-tert-butylsulfinic acid thiotert-butyl ester was slowly added using a syringe. After stirring at this temperature for 0.5 hours, the temperature was increased to 28 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (1.03 g, 2.36 mmol), which was ligand L4, with a yield of 59%. The single-crystal structure of ligand L4 is shown below. Figure 5 As shown. 1 H NMR (400 MHz, CDCl3) δ6.34 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 1.62-1.09 (m, 31H).

[0080] Example 6: Preparation of ligand L5

[0081]

[0082] Under a nitrogen atmosphere, intermediate 1 (1.0 equivalent) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to -78 °C, and a 0.13 M tetrahydrofuran solution of (-)-menthol (S)-p-toluenesulfinate (10 mL, 1.3 mmol) was added using a syringe. After addition, the mixture was stirred at this temperature for 0.5 hours, then the temperature was increased to 28 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white solid, which was intermediate 2.

[0083] Intermediate 2 (0.99 g, 2.78 mmol) was added sequentially to a 100 mL reaction flask, followed by 4.5 mL of dried tetrahydrofuran. The mixture was cooled to -78 °C, and a 0.56 M LDA tetrahydrofuran / n-heptane mixed solution (6 mL, 3.34 mmol) was added using a syringe. Stirring continued for 1 hour after the addition was complete. Diphenylphosphine chloride was slowly added using a syringe, and the mixture was stirred at this temperature for 0.5 hours. The temperature was then increased to 30 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid (0.902 g, 1.668 mmol), which was ligand L5, in 60% yield. 1 H NMR (400 MHz, CDCl3)δ7.28-6.89 (m, 8H),6.71 (d,J = 8.0Hz, 2H),6.72-6.47(m, 8H),3.94(s, 3H), 3.70 (s,3H),2.06 (s, 3H).

[0084] Example 7: Preparation of ligand L6

[0085]

[0086] Under a nitrogen atmosphere, 2,6-dimethoxypyridine (1.39 g, 10 mmol) was dissolved in anhydrous acetonitrile (15 mL). N-bromosuccinimide (4.44 g, 25 mmol) was slowly added at 30 °C. The reaction was monitored by TLC. After the reaction was completed, aqueous solution (20 mL) and ethyl acetate (20 mL) were added and the mixture was stirred for another 20 minutes. The organic phase was then separated, washed with dilute hydrochloric acid, and the combined organic phases were dried over anhydrous sodium sulfate. After concentration, the mixture was purified by rapid column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 3,5-dibromo-2,6-dimethoxypyridine solid (2.17 g, 7.30 mmol).

[0087] Under a nitrogen atmosphere, 3,5-dibromo-2,6-dimethoxypyridine (0.91 g, 3 mmol) was dissolved in anhydrous tetrahydrofuran (9 mL), cooled to -78 °C, and added dropwise to LDA (3.6 mmol). After addition, the mixture was stirred at this temperature for 1 hour, then transferred to a temperature of 30 °C for continued stirring. The reaction was monitored by TLC. After the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and methanol was added to precipitate a white solid, 3,5-dibromo-4-(diphenylphosphino)-2,6-dimethoxypyridine (1.59 g, 3.31 mmol).

[0088] Under a nitrogen atmosphere, 1.92 g (4 mmol) of 3,5-dibromo-4-(diphenylphosphino)-2,6-dimethoxypyridine was dissolved in 12 mL of anhydrous tetrahydrofuran and cooled to -78 °C. A 2.5 M solution of n-BuLi hexane (1.76 mL, 4.4 mmol) was added using a syringe, followed by stirring for 1 hour. Then, a 0.3 M solution of trimethylchlorosilane in tetrahydrofuran (20 mL, 6 mmol) was added using a syringe. After stirring at this temperature for 0.5 hours, the temperature was increased to 30 °C, and the reaction was monitored by TLC. Once the reaction was complete, an aqueous solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by rapid column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain solid 3-bromo-4-(diphenylphosphino)-2,6-dimethoxy-5-(trimethylsilyl)pyridine (1.38 g, 2.9 mmol).

[0089] Under a nitrogen atmosphere, 1.40 g (3 mmol) of 3-bromo-4-(diphenylphosphino)-2,6-dimethoxy-5-(trimethylsilyl)pyridine was dissolved in 10 mL of anhydrous tetrahydrofuran and cooled to -78 °C. A 2.5 M solution of n-BuLi hexane (1.28 mL, 3.2 mmol) was added using a syringe, followed by stirring for 1 hour. A 2.18 M solution of (-)-menthol (S)-p-toluenesulfinic acid ester in tetrahydrofuran (2 mL, 4.4 mmol) was slowly added using a syringe. After stirring at this temperature for 0.5 hours, the temperature was increased to 25 °C with stirring. The reaction was monitored by TLC. Once the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (0.75 g, 1.5 mmol), which is ligand L6, in 50% yield. 1 H NMR (400 MHz, CDCl3)δ7.46-7.33 (m, 6H),7.26-7.14 (m,4H), 3.93(s, 3H),3.87(s, 3H), 0.71 (s,9H),0.32(d,J = 2.7Hz 9H).

[0090] Example 8: Preparation of ligand L7

[0091]

[0092] The synthesis steps for 3,5-dibromo-4-(diphenylphosphino)-2,6-dimethoxypyridine are the same as those for L6 in Example 7.

[0093] Under a nitrogen atmosphere, 1.92 g (4 mmol) of 3,5-dibromo-4-(diphenylphosphino)-2,6-dimethoxypyridine was dissolved in 10 mL of anhydrous tetrahydrofuran and cooled to -78 °C. A 2.5 M solution of n-BuLi hexane (3.52 mL, 8.8 mmol) was added using a syringe, followed by stirring for 1 hour. A 2 M solution of (S)-tert-butyl sulfinyl thiotert-butyl ester in tetrahydrofuran (5 mL, 10 mmol) was then slowly added using a syringe. After stirring at this temperature for 0.5 hours, the temperature was increased to 35 °C, and the reaction was monitored by TLC. Once the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (0.71 g, 1.3 mmol), which was ligand L7, with a yield of 33%.1 HNMR (400 MHz, CDCl3) δ7.28-7.21 (m, 8H), 7.20-7.13 (m,2H), 3.91 (s, 3H), 3.79 (s,3H), 1.17 (s,18H).

[0094] Example 9: Preparation of ligand L8

[0095]

[0096] The synthesis steps for 3,5-dibromo-4-(diphenylphosphino)-2,6-dimethoxypyridine are the same as those for L6 in Example 7.

[0097] Under a nitrogen atmosphere, 0.97 g (2 mmol) of 3,5-dibromo-4-(diphenylphosphino)-2,6-dimethoxypyridine was dissolved in anhydrous tetrahydrofuran (6 mL). The solution was cooled to -78 °C, and a 2.5 M solution of n-BuLi hexane (0.88 mL, 2.2 mmol) was added using a syringe. After the addition was complete, the mixture was stirred for 1 hour. A 1.5 M solution of (S)-tert-butyl sulfinate in tetrahydrofuran (2 mL, 3 mmol) was slowly added using a syringe. The mixture was stirred at this temperature for 0.5 hours, then the temperature was increased to 35 °C. The reaction was monitored by TLC. After the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by rapid column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (0.37 g, 0.74 mmol), which is ligand L8, with a yield of 37%. 1 H NMR (400 MHz, CDCl3) δ7.39-7.34 (m, 2H), 7.29-7.21 (m, 8H), 3.98 (s, 3H), 3.94 (s, 3H), 1.26 (s, 9H).

[0098] Example 10: Preparation of ligand L9

[0099]

[0100] The first two reaction steps followed the synthesis procedure for L6 in Example 7. A 0.23 M tetrahydrofuran solution (2 mL, 0.65 mmol) of (-)-menthol (S)-p-toluenesulfinate was slowly added using a syringe. After stirring at this temperature for 0.5 hours, the temperature was increased to 35 °C with stirring. The reaction was monitored by TLC. After the reaction was complete, a salt solution was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by rapid column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a white solid (0.14 g, 0.26 mmol), which was ligand L9, in 48% yield. 1 H NMR (400 MHz, CDCl3)δ7.52-7.45(m, 2H),7.43-7.32 (m,5H), 7.30-7.20 (m,3H),6.97(d,J =8.1Hz 2H), 6.89 (d,J =8.2Hz 2H),3.90(s, 3H), 3.64(s, 3H), 2.23(s, 3H).

[0101] Example 11:

[0102] The above-mentioned pyridine-derived chiral sulfoxide monophosphine ligands L1-L9 were used to prepare cyclic aliphatic ketones, and the specific implementation process is as follows:

[0103]

[0104] At 25 °C, ligands L1-L4 (0.012 mmol) and [Rh(C2H4)2Cl]2 (1.9 mg, 0.005 mmol) were added to a 25 mL high-pressure tube. After purging with nitrogen, dried deoxytoluene (1 mL) was added. The mixture was stirred for half an hour, and then phenylboronic acid (0.12 g, 1 mmol) was added. The temperature was raised to 40 °C, and then cyclohexenone (48 mg, 0.5 mmol) was added via syringe, followed by degassed 0.25 M KOH (1.0 mL, 0.25 mmol). The reaction mixture was stirred at 40 °C. The reaction was monitored by TLC, and quenched with aqueous solution. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the mixture was concentrated and purified by rapid column chromatography to obtain a pale yellow oily liquid, which was the target product. The ee (enantiomer excess) value was determined by HPLC: Chiralcel AD-H (hexane / 2-propanol = 99:1, 1.0 mL / min, λ = 254 nm). The results are as follows. Figure 6 As shown, by Figure 6It is known that the chiral pyridine-derived chiral sulfoxide monophosphine ligand provided by the present invention exhibits high yield and stereoselectivity when used as a catalyst.

[0105]

[0106] At 30°C, 0.024 mmol of any one of ligands L5-L7 and 1.9 mg (0.005 mmol) of [Rh(C2H4)2Cl]2 were added to a 25 mL high-pressure tube. After purging with nitrogen, 1 mL of dried deoxytoluene was added. The mixture was stirred for half an hour, and then 0.12 g (1 mmol) of phenylboronic acid was added. The temperature was raised to 35°C, and then 48 mg (0.5 mmol) of cyclohexenone was added via syringe, followed by 1.0 mL (0.25 mmol) of degassed 0.25 M KOH. The reaction mixture was stirred at 35°C. The reaction was monitored by TLC, and quenched with aqueous solution. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the mixture was concentrated and purified by rapid column chromatography to obtain a pale yellow oily liquid, which was the target product. The ee (enantiomer excess) value was determined by HPLC: Chiralcel AD-H (hexane / 2-propanol = 99:1, 1.0 mL / min, λ = 254 nm). The results are as follows. Figure 6 As shown, by Figure 6 It is known that the chiral pyridine-derived chiral sulfoxide monophosphine ligand provided by the present invention exhibits high yield and stereoselectivity when used as a catalyst.

[0107]

[0108] At 25 °C, one of the ligands L8-L9 (0.030 mmol) and [Rh(C2H4)2Cl]2 (1.9 mg, 0.005 mmol) were added to a 25 mL high-pressure tube. After purging with nitrogen, dried deoxytoluene (1 mL) was added. The mixture was stirred for half an hour, and then phenylboronic acid (0.12 g, 1 mmol) was added. The temperature was raised to 35 °C, and then cyclohexenone (48 mg, 0.5 mmol) was added via syringe, followed by degassed 0.25 M KOH (1.0 mL, 0.25 mmol). The reaction mixture was stirred at 35 °C. The reaction was monitored by TLC, and quenched with aqueous solution. The organic phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the mixture was concentrated and purified by rapid column chromatography to obtain a pale yellow oily liquid, which was the target product. The ee (enantiomer excess) value was determined by HPLC: Chiralcel AD-H (hexane / 2-propanol = 99:1, 1.0 mL / min, λ = 254 nm). The results are as follows. Figure 6 As shown, by Figure 6 It is known that the chiral pyridine-derived chiral sulfoxide monophosphine ligand provided by the present invention exhibits high yield and stereoselectivity when used as a catalyst. 1 H NMR (300 MHz, CDCl3)δ7.36-7.31 (m, 2H), 7.26-7.21 (m, 3H), 3.01-3.00(m, 1H), 2.59-2.53 (m, 2H),2.44-2.37 (m, 2H), 2.16-2.07 (m, 2H), 1.89-1.80 (m, 2H).

[0109] The above description of the present invention is illustrative and not restrictive. Those skilled in the art will understand that many modifications, variations or equivalents may be made within the spirit and scope defined by the claims, but all of them will fall within the protection scope of the present invention.

Claims

1. A pyridine-derived chiral sulfoxide monophosphine ligand, characterized in that, Its structural formula is: Among them, R 1 R 2 Each is independently selected from aryl, alkyl, or naphthyl; R 3 Selected from hydrogen, halogen, alkyl, aryl, silyl, or thio; R 4 It is an alkyl group.

2. The pyridine-derived chiral sulfoxide monophosphine ligand according to claim 1, characterized in that, R 1 Selected from phenyl, cyclohexyl, or isopropyl; R 2 Selected from tert-butyl, 4-methylphenyl, or naphthyl; R 3 Selected from one of hydrogen, halogen, methyl, phenyl, p-toluenesulfinyl, tert-butylsulfinyl, or silyl; R 4 It is selected from one of methyl, ethyl or isopropyl.

3. The pyridine-derived chiral sulfoxide monophosphine ligand according to claim 1, characterized in that, The pyridine-derived chiral sulfoxide monophosphine ligand has a structural formula of one of the following L1 to L9:

4. A method for preparing a pyridine-derived chiral sulfoxide monophosphine ligand as described in any one of claims 1-3, characterized in that, Includes the following steps: (1) 3-bromo-2,6-dimethoxypyridine was reacted with a lithium reagent in a solvent to obtain lithium pyridine intermediate 1; 1 (2) Reaction of lithium pyridinium intermediate 1 with a chiral sulfur reagent yields intermediate 2-1; (3) The lithium reagent is reacted with diisopropylamine to obtain the new base diisopropylaminolithium, and then reacted with intermediate 2-1 in solvent to obtain intermediate 3-1; (4) Intermediate 3-1 is reacted with a phosphorus reagent to obtain the pyridine-derived chiral sulfoxide monophosphine ligand; The chiral sulfur reagent is (-)-menthol (S)-p-toluenesulfinate, (-)-menthol (S)-1-naphthalenesulfinate, or (S)-tert-butylsulfinate thiotert-butyl ester; the phosphorus reagent is diphenylphosphine chloride, diisopropylphosphine chloride, or dicyclohexylphosphine chloride.

5. A method for preparing a pyridine-derived chiral sulfoxide monophosphine ligand as described in any one of claims 1-3, characterized in that, Includes the following steps: (1) 3-bromo-2,6-dimethoxypyridine was reacted with a lithium reagent in a solvent to obtain lithium pyridine intermediate 1; 1 (2) Reaction of lithium pyridinium intermediate 1 with phosphorus reagent yields intermediate 2-2; (3) Intermediate 2-2 was reacted with lithium reagent in a solvent to obtain intermediate 3-2; (4) Intermediate 3-2 is reacted with a chiral sulfur reagent to obtain the pyridine-derived chiral sulfoxide monophosphine ligand; The phosphorus reagent is diphenylphosphine chloride, diisopropylphosphine chloride, or dicyclohexylphosphine chloride; the chiral sulfur reagent is (-)-menthol (S)-p-toluenesulfinyl ester, (-)-menthol (S)-1-naphthalenesulfinyl ester, or (S)-tert-butylsulfinyl thiotert-butyl ester.

6. The preparation method according to claim 4 or 5, characterized in that, The lithium reagent is butyllithium; the reaction temperature of 3-bromo-2,6-dimethoxypyridine with the lithium reagent is -78 to 0 °C, and the reaction time is 1 to 10 h; the molar ratio of 3-bromo-2,6-dimethoxypyridine to the lithium reagent is 1:0.9 to 1.

2.

7. The preparation method according to claim 4 or 5, characterized in that, The solvent is selected from one or more of the following: dry diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, and n-hexane.

8. The preparation method according to claim 4, characterized in that, In step (2), the molar ratio of lithium pyridine intermediate 1 to chiral sulfur reagent is 1:1 to 2; the reaction temperature is -78 to 30 °C; and the reaction time is 12 to 24 h. In step (4), the molar ratio of intermediate 3-1 to phosphorus reagent is 1:2 to 4; the reaction temperature is -78 to 30 °C; and the reaction time is 12 to 24 h.

9. The preparation method according to claim 5, characterized in that, In step (2), the molar ratio of lithium pyridine intermediate 1 to phosphorus reagent is 1:1 to 2; the reaction temperature is -78 to 30 ℃; and the reaction time is 12 to 24 h. In step (4), the molar ratio of intermediate 3-2 to chiral sulfur reagent is 1:1 to 2; the reaction temperature is -78 to 30 ℃; and the reaction time is 12 to 24 h.

10. The use of the pyridine-derived chiral sulfoxide monophosphine ligand as described in any one of claims 1-3 as a chiral catalyst in the preparation of cyclic aliphatic ketone compounds.

Images