Chiral sulfonamide monophosphine ligand modified by non-coordinated pyridine as well as preparation method and application of chiral sulfonamide monophosphine ligand

Abstract

The invention discloses a non-coordinated pyridine modified chiral sulfonamide monophosphine ligand as well as a preparation method and application thereof. The structural formula of the non-coordinated pyridine modified chiral sulfonamide monophosphine ligand is shown in the specification. The preparation method comprises the following steps: carrying out direct lithiation on polysubstituted pyridine to obtain an intermediate 1, carrying out dehydration condensation on o-diphenylphosphinobenzaldehyde and chiral tert-butyl sulfinamide in the presence of Lewis acid to obtain an intermediate 2, and adding the intermediate 1 into the solution of the intermediate 2 to react to obtain the chiral sulfinamide monophosphine ligand. The method is simple in synthetic route, raw materials are easy to obtain, and a series of chiral sulfonamide monophosphine ligands can be obtained with good yield and excellent diastereoselectivity. The chiral sulfonamide monophosphine ligand prepared by the method can be used for preparing an axial chiral biaryl compound, can obtain a target product with high yield and enantioselectivity, and has a wide application prospect in the field of organic synthesis. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry, and particularly relates to a non-coordinating pyridine-modified chiral sulfinamide monophosphine ligand, a preparation method thereof, and an application thereof. Background Art

[0002] Chirality is one of the basic properties of substances in nature. Chiral compounds are widely used in the fields of synthetic chemistry, pharmaceutical chemistry, materials science, and life science. Therefore, the synthesis research of chiral compounds with specific functions has attracted much attention in recent years. Although chiral compounds can be obtained through chemical resolution, chiral substrate or reagent-induced synthesis, etc., these methods have more or less disadvantages such as cumbersome steps and poor economy, and at the same time, they cannot play the role of chiral amplification. In contrast, the advantage of asymmetric catalytic synthesis is that a large amount of a single isomer can be synthesized only under the chiral induction of a small amount of chiral catalyst. Therefore, the research on asymmetric catalytic methods has always been a frontier topic in the field of chiral synthesis.

[0003] Chiral ligands or catalysts play a crucial role in the construction of chiral compounds. Especially chiral compounds containing phosphorus are widely used in transition metal-catalyzed asymmetric transformation reactions. One of the main problems faced in the application of chiral organophosphine / metal complex catalysts is that the synthesis methods of chiral organophosphine ligands are very limited and often involve multiple steps, resulting in a high cost of using chiral ligands and hindering their large-scale industrial applications. Therefore, it is extremely important and urgent to carry out research on the synthesis and application of chiral organophosphine ligands.

[0004] Since the first synthesis and isolation of optically pure chiral tert-butylsulfinamide by the Ellman research group in 1997, chiral tert-butylsulfinamide has been widely used in the synthesis of chiral phosphine ligands due to its low price, easy modification, diverse coordination modes, and strong stereoselective induction. It has been reported in the literature that the stereoselective nucleophilic addition reaction of organometallic reagents to sulfinimides containing phosphorus substituents can efficiently construct chiral organophosphorus compounds with corresponding structures. For example, Junliang Zhang (Z.M. Zhang, P. Chen, W. Li, Y. Niu, X.L. Zhao, J. Zhang, Angew. Chem. Int. Ed. 2014, 53, 4350 - 4354), Liwen Xu (X.-F. Bai, T. Song, Z. Xu, C.-G. X., W.-S. Huang, L.-W. Xu, Angew. Chem. Int. Ed. 2015, 54, 5255 - 5259), etc. successfully prepared multi-centered chiral and organophosphorus compounds with both central chirality and axial chirality using Grignard reagents or lithium reagents, respectively. It is worth noting that arylmetal reagents containing phenyl groups were used in the above studies, and chiral sulfinamide monophosphine ligands containing aromatic heterocycles such as pyridine have not been reported, which may be related to the strong coordination ability of pyridine and the susceptibility to nucleophilic attack by organometallic reagents during the synthesis process.

[0005] Therefore, it is still of great significance to develop a chiral sulfinamide monophosphine ligand derived from pyridine with low-cost and easily accessible raw materials, easy structural modification, convenient for efficient synthesis, and good application prospects. Summary of the Invention

[0006] The object of the present invention is to provide a novel chiral sulfinamide monophosphine ligand modified with non-coordinating pyridine, its preparation method and application in view of the deficiencies of the prior art. This novel chiral sulfinamide monophosphine ligand can be used as a chiral catalyst for the preparation of axially chiral biaryl compounds, and the axially chiral biaryl compounds prepared by this system have the characteristics of high yield and high ee value.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0008] In the first aspect, the present invention provides a chiral sulfinamide monophosphine ligand modified with non-coordinating pyridine, and its structural formula general formula is:

[0009]

[0010] Wherein, R 1 is selected from C1-C3 alkyl; R 2 is selected from one of hydrogen or halogen; Ph is phenyl, and t-Bu is tert-butyl.

[0011] Furthermore, R 1is methyl, ethyl or isopropyl; R 2 is H, Cl or Br.

[0012] Furthermore, the structural formula of the non-coordinating pyridine-modified chiral sulfinamide monophosphine ligand is selected from one of the following L1-L4:

[0013]

[0014] In a second aspect, the present invention provides a preparation method of a non-coordinating pyridine-modified chiral sulfinamide monophosphine ligand, comprising the following steps:

[0015] Step (1), dissolving a polysubstituted pyridine and a lithium reagent in a solvent and lithiating to obtain a pyridine lithium intermediate 1 shown in formula (I); wherein, the polysubstituted pyridine is 2,6-disubstituted pyridine or 2,3,6-trisubstituted pyridine;

[0016]

[0017] Step (2), dehydrating and condensing 2-diphenylphosphinobenzaldehyde and chiral tert-butylsulfinamide in the presence of a Lewis acid to obtain an intermediate 2 shown in formula (II);

[0018]

[0019] Step (3), adding the intermediate 1 into the solution of the intermediate 2 and reacting to obtain the chiral sulfinamide monophosphine ligand.

[0020] Furthermore, in step (1), when lithiating at the 3-position of pyridine, the substitution reaction can be directly carried out with a lithium reagent to obtain the intermediate 1; when lithiating at the 4-position of pyridine, the lithium reagent needs to react with diisopropylamine first to obtain a new base lithium diisopropylamide, and then add the polysubstituted pyridine, and the substitution reaction is carried out under the action of the new base to obtain the intermediate 1.

[0021] Furthermore, the above lithium reagent uses butyllithium, including one of n-butyllithium, sec-butyllithium, tert-butyllithium, preferably n-butyllithium; the reaction temperature of butyllithium and polysubstituted pyridine is preferably -78 to 25 °C, more preferably -40 to -0 °C, and the reaction time is preferably 1-10 h, more preferably 2-5 h. The reaction temperature of lithium diisopropylamide and polysubstituted pyridine is preferably -78 to 25 °C, more preferably -78 to -40 °C, and the reaction time is preferably 1-10 h, more preferably 2-4 h.

[0022] Furthermore, in step (1), the molar ratio of the substituted pyridine to the lithium reagent is preferably 1:0.9-1.2, for example 1:1.1.

[0023] Further, in step (1), the solvent is preferably one or more of dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, n-hexane, and more preferably dry tetrahydrofuran.

[0024] Further, in step (2), the molar ratio of 2-diphenylphosphinobenzaldehyde to chiral tert-butylsulfinamide and Lewis acid is preferably 1:1 to 10:1 to 10, such as 1:2:3; the Lewis acid is preferably tetramethyl titanate, tetraethyl titanate, or tetraisopropyl titanate.

[0025] Further, the reaction temperature of the dehydration condensation reaction is preferably 25 to 70 °C, more preferably 50 to 60 °C; the reaction time is preferably 1 to 10 h, more preferably 3 to 5 h.

[0026] Further, in step (3), the molar ratio of intermediate 2 to intermediate 1 is preferably 1:1.0 to 2.0, such as 1:1.5; the reaction is an addition reaction, and its reaction temperature is preferably -78 to 25 °C, more preferably -78 to -40 °C; the reaction time is 1 to 10 h, more preferably 3 to 5 h.

[0027] In a third aspect, the present invention provides the use of the above non-coordinating pyridine-modified chiral sulfinamide monophosphine ligand as a chiral catalyst.

[0028] Further, the use is specifically: the use of the above non-coordinating pyridine-modified chiral sulfinamide monophosphine ligand as a chiral catalyst in the preparation of axially chiral biaryl compounds.

[0029] Further, the axially chiral biaryl compounds have the following general structural formula:

[0030]

[0031] Among them, R is selected from alkoxy, benzyloxy, or aryloxy.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] (1) The chiral sulfinamide monophosphine ligand prepared by the present invention utilizes the unique steric, electronic effects, and basicity of 2,6-disubstituted pyridine, making it easy to derivatize and modify in the reaction, not participating in coordination, and facilitating salt separation under acidic conditions; it can be used as a chiral catalyst to synthesize axially chiral biaryl compounds with high yield and enantioselectivity, and has broad application prospects in the field of organic synthesis.

[0034] (2) The preparation method of the present invention has few synthesis steps, uses inexpensive and readily available raw materials, and has a high yield. A series of chiral sulfinamide monophosphine ligands can be obtained with good yields and excellent diastereoselectivity. The introduction of non-coordinating pyridine can not only regulate the steric and electronic effects of the ligand to adjust the activity and chiral induction ability of the catalyst, but also form a salt and enter the aqueous phase under acidic conditions, and the ligand can be recovered from the organic phase by simple extraction. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 1H NMR spectrum of ligand L1.

[0036] Figure 2 13C NMR spectrum of ligand L1.

[0037] Figure 3 31P NMR spectrum of ligand L1.

[0038] Figure 4 Results of using ligands L1-L4 for the catalytic synthesis of axially chiral biaryl compounds. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0039] As described above, in view of the deficiencies of the prior art, the inventors have proposed the technical solution of the present invention through long-term research and a large number of practices. In order to make the purpose, technical solution and advantages of the present invention clearer, the following examples are used to further elaborate on the present invention. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items. Those skilled in the art who make modifications or equivalent substitutions on the basis of understanding the technical solution of the present invention, without departing from the spirit and scope of the technical solution of the present invention, shall be covered by the protection scope of the present invention.

[0040] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods.

[0041] This example relates to the preparation of novel chiral sulfinamide monophosphine ligands L1-L4 modified with non-coordinating pyridine. The structures of the ligands are shown in the following formula:

[0042]

[0043] Example 1: Preparation of Intermediate 2

[0044]

[0045] At room temperature, 2-(diphenylphosphino)benzaldehyde (5.80 g, 20 mmol) and (R)-2-methylpropane-2-sulfonamide (3.64 g, 30 mmol) were successively added to a 100 mL reaction flask. After purging with nitrogen, dry tetrahydrofuran (30 mL) was added using a syringe. Tetraisopropyl titanate (17.8 mL, 60 mmol) was added dropwise to the above mixed solution using a syringe. The reaction flask was transferred to an oil bath at 50 °C and reacted for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and saturated brine was added with stirring. It was filtered through a sintered funnel, the filter cake was washed with ethyl acetate (20 mL), the organic phase was separated, dried over anhydrous sodium sulfate, and purified by flash column chromatography to obtain a yellow viscous substance (7.08 g, 18 mmol), which was Intermediate 2 with a yield of 90%.

[0046] 1 H NMR (400 MHz): δ 9.11 (d, J = 4.8 Hz, 1H), 8.02 - 7.98 (m, 1H), 7.48 - 7.23 (m, 12H), 6.98 - 6.94 (m, 1H), 1.08 (s, 9H). 31 P NMR (162 MHz): δ -11.7.

[0047] Example 2: Preparation of Ligand L1

[0048]

[0049] 2,6-Dimethoxypyridine (2.78 g, 20 mmol) and dry tetrahydrofuran (30 mL) were successively added to a 100 mL reaction flask. It was cooled to -40 °C, and a 2.5 M n-BuLi hexane solution (8.8 mL, 22 mmol) was added thereto using a syringe. After addition, stirring was continued for 4 hours. The resulting solution was transferred to a 1 mol / L toluene solution (10 mL, 10 mmol) of Intermediate 2. The reaction progress was monitored by TLC. After the reaction was completed, saturated aqueous ammonium chloride was added to quench the reaction. The organic phase was extracted with ethyl acetate (20 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a white solid (8.52 g, 16 mmol), which was Ligand L1 with a yield of 80%. The 1H NMR, 13C NMR, and 31P NMR spectra of Ligand L1 are shown as follows Figures 1 - 3 shown.

[0050] 11H NMR (400 MHz, CDCl3) δ 7.64 - 7.61 (m, 1H), 7.35 - 7.31 (m, 1H), 7.23 - 7.22 (m, 3H), 7.16 - 7.05 (m, 6H), 6.92 - 6.88 (m, 3H), 6.64 - 6.61 (m, 1H), 5.91 (d, J = 8.0 Hz, 1H), 3.80 (d, J = 4.8 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 1.11 (s, 9H). 13 13C NMR (100 MHz, CDCl3) δ 162.1, 159.7, 146.6, 146.4, 140.7, 137.4, 135.5 135.3, 135.0 133.8 133.6, 129.2, 128.5, 128.4, 128.3, 128.0, 127.8, 127.6, 127.0, 114.2, 100.2, 56.2, 54.5, 53.2, 27.0, 22.6. 31 31P NMR (162 MHz, CDCl3) δ -18.02.

[0051] Example 3: Preparation of Ligand L2

[0052]

[0053] 2,6 - Dimethoxypyridine (6.96 g, 50 mmol) and acetonitrile (100 mL) were successively added to a 250 mL reaction flask. N - Bromosuccinimide (8.90 g, 50 mmol) was added to the above - mentioned mixture in batches. The mixture was heated to 80 °C and stirred for 16 h. The solvent was concentrated and removed, and the product was purified by flash column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain a colorless liquid (10.47 g, 48 mmol) with a yield of 96%. 1 1H NMR (400 MHz): δ 7.62 (d, J = 8.3 Hz, 1H), 6.22 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.89 (s, 3H).

[0054] To a 100 mL reaction flask, 2,6-dimethoxy-3-bromopyridine (4.36 g, 20 mmol) and dry tetrahydrofuran (30 mL) were added successively. The mixture was cooled to -78 °C, and a 2 M solution of LDA in tetrahydrofuran / n-heptane (11 mL, 22 mmol) was added thereto using a syringe. After the addition, the mixture was stirred for an additional 2 hours. The resulting solution was transferred to a 1 mol / L toluene solution (10 mL, 10 mmol) of Intermediate 2. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched by adding saturated aqueous ammonium chloride solution. The organic phase was extracted with ethyl acetate (20 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a white solid (4.28 g, 7.0 mmol), which was ligand L2 with a yield of 70%.

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.51 (m, 1H), 7.43 - 7.39 (m, 1H), 7.33 - 7.31 (m, 3H), 7.26 - 7.17 (m, 6H), 7.14 - 7.07 (m, 3H), 6.89 - 6.85 (m, 1H), 6.16 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.74 (d, J = 6.0 Hz, 1H), 1.19 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 161.4, 158.9, 153.4, 144.6, 144.3, 136.9, 136.8 136.4, 136.2, 135.4 135.3, 133.9, 133.7, 129.4, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 103.4, 98.0, 60.0, 56.6, 54.4, 53.6, 22.7. 31 P NMR (162 MHz, CDCl3) δ -18.79.

[0056] Example 4: Preparation of Ligand L3

[0057]

[0058] To a 100 mL reaction flask, 2,6-dimethoxy-3-chloropyridine (3.47 g, 20 mmol) and dry tetrahydrofuran (30 mL) were added successively. It was cooled to -78 °C, and a 2 M solution of LDA in tetrahydrofuran / n-heptane mixture (10.5 mL, 21 mmol) was added thereto with a syringe. After the addition, stirring was continued for 2 hours. The resulting solution was transferred to a 1 mol / L toluene solution of intermediate 2 (10 mL, 10 mmol). The reaction process was monitored by TLC. After the reaction was completed, it was quenched with saturated aqueous ammonium chloride solution. 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 flash column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a white solid (4.25 g, 7.5 mmol), which was ligand L3 with a yield of 75%.

[0059] Example 5: Preparation of Ligand L4

[0060]

[0061] The first two reaction steps were carried out with reference to the synthesis procedure of L2 in Example 3. To a 100 mL reaction flask, 2,6-dimethoxy-3-bromopyridine (4.36 g, 20 mmol) and dry tetrahydrofuran (30 mL) were added successively. It was cooled to -78 °C, and a 2 M solution of LDA in tetrahydrofuran / n-heptane mixture (11 mL, 22 mmol) was added thereto with a syringe. After the addition, stirring was continued for 2 hours. The resulting solution was transferred to a 1 mol / L toluene solution of intermediate 2 (10 mL, 10 mmol). The reaction process was monitored by TLC. After the complete conversion of intermediate 2, a 2.5 M solution of n-BuLi in hexane (4.4 mL, 11 mmol) was added, and after 30 minutes, it was quenched with saturated aqueous ammonium chloride solution. 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 flash column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a white solid (3.83 g, 7.2 mmol), which was ligand L4 with a yield of 72%.

[0062] Example 6:

[0063] The chiral non-coordinating pyridine-modified chiral sulfinamide monophosphine ligands L1-L4 were respectively used for the preparation of axially chiral biaryl phosphates, and the specific preparation process was as follows:

[0064]

[0065] Add 2-methoxyphenylboronic acid (30.4 mg, 0.2 mmol), diethyl 1-bromo-2-naphthylphosphonate (34.3 mg, 0.6 mmol), palladium acetate (1.8 mg, 0.008 mmol), ligand L1-L4 (0.016 mmol), K3PO4 (63.7 mg, 0.3 mmol) into a 25 mL high-pressure tube. After purging with nitrogen, add dry and deoxygenated DME (2 mL). Transfer the high-pressure tube to an oil bath at 50 °C and react for 24 hours. After the reaction is completed, cool the mixture to room temperature, dilute it with water, extract twice with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate the mixture, and purify it by flash column chromatography to obtain the target product as a pale yellow oily liquid, and determine the ee (enantiomeric excess) value by HPLC. The results are as Figure 4 shown. It can be seen from Figure 4 that when the chiral non-coordinating pyridine-modified chiral sulfinamide monophosphine ligand provided by the present invention is used as a catalyst, the reaction has a high yield and stereoselectivity.

[0066] 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 11.8, 8.8 Hz, 1H), 7.94 (dd, J = 8.5, 3.5 Hz, 1H), 7.89 (s, 1H), 7.55 (t, J = 7.1 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.40 (q, J = 8.5 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.05–3.78 (m, 4H), 3.67 (s, 3H), 1.21 (td, J = 6.9, 2.6 Hz, 6H).

[0067] The above description of the present invention is illustrative and not restrictive. Those skilled in the art understand that many modifications, variations or equivalents can be made within the spirit and scope defined by the claims, but they all fall within the protection scope of the present invention.

Claims

1. A non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand, characterized in that: The structural formula of the non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand is: Among them, R 1 is selected from C1-C3 alkyl; R 2 Selected from one of hydrogen and halogen.

2. The non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand according to claim 1, characterized in that: R 1 is methyl, ethyl or isopropyl; R 2 is H, Cl or Br.

3. The non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand according to claim 2, characterized in that: The structural formula of the non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand is selected from one of the following L1 to L4:

4. A method for preparing a non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand as claimed in any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: Step (1), dissolving a polysubstituted pyridine and a lithium reagent in a solvent, and performing lithiation to obtain a lithium pyridine intermediate 1 represented by formula (I); wherein the polysubstituted pyridine is a 2,6-disubstituted pyridine or a 2,3,6-trisubstituted pyridine; Step (2), dehydrating and condensing 2-diphenylphosphobenzaldehyde with chiral tert-butylsulfenamide in the presence of Lewis acid to obtain intermediate 2 represented by formula (II); Step (3), adding intermediate 1 to the solution of intermediate 2 to react and obtain the chiral sulfenamide monophosphine ligand.

5. The preparation method according to claim 4, characterized in that: In step (1), the molar ratio of the substituted pyridine to the lithium reagent is 1:0.9-1.

2.

6. The preparation method according to claim 4, characterized in that: In step (1), the solvent is a dry organic solvent, including one or more of dichloromethane, ethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, and n-hexane.

7. The preparation method according to claim 4, characterized in that: In step (2), the molar ratio of the 2-diphenylphosphobenzaldehyde to the chiral tert-butylsulfenamide and the Lewis acid is 1:1-10:1-10; and the Lewis acid is one of tetramethyl titanate, tetraethyl titanate, and tetraisopropyl titanate.

8. The preparation method according to claim 4, characterized in that: In step (3), the molar ratio of intermediate 2 to intermediate 1 is 1:1.0-2.0; the reaction temperature of step (3) is -78-25°C, and the reaction time is 1-10h.

9. Use of the non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand as claimed in any one of claims 1 to 3 as a chiral catalyst.

10. The use according to claim 9, characterized in that: The application is specifically: application of non-coordinating pyridine-modified chiral sulfenamide monophosphine ligand as a chiral catalyst in the preparation of axially chiral biaryl compounds.

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