Novel C2 symmetric chiral bisamide ligand as well as preparation method and application thereof

Abstract

The invention discloses a novel C2 symmetric chiral bisamide ligand and a preparation method and application thereof, the ligand has a structure as shown in # imgabs0 #, Ar is aryl, the relative positions of two sulfur in the general formula are different, * represents a chiral center, R is 4-methylbenzyl, 4-bromobenzyl, 2, 6-dimethylbenzyl, methyl or benzyl, and n represents 1 or 2. Dithiophenol and (2S, 3S)-2, 3-diphenylaziridine react to obtain an intermediate, and the intermediate and nitrogen-substituted chiral cyclic amino acid or 2-diphenylphosphinobenzoic acid are subjected to dehydration condensation to obtain various ligands with novel structures. A catalyst formed by complexing the ligand and an allyl palladium chloride dimer can be used as a chiral ligand for efficiently catalyzing an asymmetric allyl alkylation reaction.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis. More specifically, the present invention relates to a novel class of C2-symmetric chiral bisamide ligands and their preparation methods and applications. Background Art

[0002] In recent decades, a series of C2-symmetric chiral ligands have been developed and applied in the synthesis of important compounds, providing a very diverse synthetic route for the asymmetric synthesis of a variety of high-value-added compounds. However, in the catalytic synthesis of chiral drugs or their chiral intermediates, there is still a great demand for efficient and novel chiral ligands, and the development and application of ligands remain a challenging task. Summary of the Invention

[0003] An object of the present invention is to solve at least the above problems and provide at least the advantages described hereinafter.

[0004] The present invention provides a novel class of C2-symmetric chiral bisamide ligands having the structures shown in General Formula I or II:

[0005]

[0006] Wherein: Ar is an aryl group; * represents a chiral center; R is 4-methylbenzyl, 4-bromobenzyl, 2,6-dimethylbenzyl, methyl or benzyl; n represents 1 or 2.

[0007] The present invention also provides a preparation method for the above novel C2-symmetric chiral bisamide ligands, which includes: reacting dithiol with (2S,3S)-2,3-diphenylaziridine to obtain an intermediate, and dehydrating and condensing the intermediate with a nitrogen-substituted chiral cyclic amino acid to obtain the target ligand of General Formula I; or dehydrating and condensing the intermediate with 2-diphenylphosphinobenzoic acid to obtain the target ligand of General Formula II;

[0008] The dithiol of General Formula III is:

[0009] (2S,3S)-2,3-Diphenylaziridine of General Formula IV is:

[0010] The intermediate of General Formula V is:

[0011] The nitrogen-substituted chiral cyclic amino acid of General Formula VI is:

[0012] 2-Diphenylphosphinobenzoic acid of General Formula VII is:

[0013] Wherein, Ar is an aryl group; * represents a chiral center; R is 4-methylbenzyl, 4-bromobenzyl, 2,6-dimethylbenzyl, methyl or benzyl; n represents 1 or 2.

[0014] Preferably, for the preparation method of the above novel C2-symmetric chiral bisamide ligand, under nitrogen protection, dissolve (2S,3S)-2,3-diphenylaziridine in methanol, then add dithiols, heat up to 65 °C, stir until the raw materials disappear and then cool to room temperature. Stir the reaction solution with silica gel powder, remove the solvent under reduced pressure, pass through a silica gel column, and perform column chromatography separation with petroleum ether / ethyl acetate / dichloromethane volume ratio = 2:1:1 as the eluent. After removing the chromatography solution under reduced pressure, the intermediate of formula V is obtained; wherein, the dithiols are o-benzenedithiol, m-benzenedithiol or p-benzenedithiol; the molar ratio of o-benzenedithiol, m-benzenedithiol or p-benzenedithiol to (2S,3S)-2,3-diphenylaziridine is 5:11 - 5:15.

[0015] Preferably, the intermediate is dehydrated and condensed with a nitrogen-substituted chiral cyclic amino acid to obtain the target ligand of formula I, specifically:

[0016] Dissolve the nitrogen-substituted chiral cyclic amino acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine in dichloromethane, then add the intermediate to the reaction system, and continue to react at room temperature. After the reaction is completed, stir the reaction solution with silica gel powder, remove the solvent under reduced pressure, pass through a silica gel column, and perform column chromatography separation with petroleum ether / ethyl acetate / dichloromethane volume ratio = 5:1:5 as the eluent to obtain the target ligand of formula I; wherein the molar ratio of the nitrogen-substituted chiral cyclic amino acid: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 4-dimethylaminopyridine: intermediate is 1.5:1.5:0.1:0.5; the nitrogen-substituted chiral cyclic amino acid is L-nitromethylproline, L-nitrobenzylproline, D-nitrobenzylproline or L-nitrobenzylindolinecarboxylic acid.

[0017] Preferably, the intermediate is dehydrated and condensed with 2-diphenylphosphinobenzoic acid to obtain the target ligand of formula II, specifically:

[0018] Dissolve 2-diphenylphosphinobenzoic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine in dichloromethane, then add the intermediate to the reaction system, and continue to react at room temperature. After the reaction is completed, stir the reaction solution with silica gel powder, remove the solvent under reduced pressure, pass through a silica gel column, and perform column chromatography separation with petroleum ether / ethyl acetate / dichloromethane volume ratio = 8:1:1 as the eluent to obtain the target ligand of formula II; wherein, the molar ratio of 2-diphenylphosphinobenzoic acid: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 4-dimethylaminopyridine: intermediate is 6:6:0.1:2.

[0019] The present invention provides a class of complexes, which are complexes formed based on the above-mentioned novel C2-symmetric chiral bisamide ligand and allyl palladium chloride dimer.

[0020] The preparation method of the above-mentioned class of complexes includes mixing allyl palladium chloride dimer and the ligand in a molar ratio of 1:2, dissolving them in an organic solvent, and stirring and reacting to form a complex.

[0021] The application of the above complex in a catalyst for catalytic asymmetric allylation reaction.

[0022] The present invention has at least the following beneficial effects: The present invention utilizes the structural diversity and coordination ability of chiral diamines to synthesize ideal chiral compound catalysts. A chiral diamine is constructed by the strategy of modular combination, and then a chiral ligand library is constructed by using an amide reaction. This strategy has a simple, efficient and mild synthetic route, providing a new idea for the development and application of ligands.

[0023] The ligand synthesized by the present invention is a C2-symmetric chiral bisamide compound, with a stable, novel, flexible and diverse structure. The complex formed by the ligand provided by the present invention and palladium has good catalytic activity for nucleophilic addition reactions. In particular, the catalyst formed by the complexation of ligand II-1 and allyl palladium chloride dimer can efficiently catalyze the asymmetric allylation reaction, obtaining the product in a short time, with the yield and ee value reaching as high as 96% and 95% respectively, providing an option for the synthesis of high-value-added compounds with high requirements in the fields of medicine, materials science, etc.

[0024] Other advantages, objectives and features of the present invention will be partially reflected by the following description, and partially will also be understood by those skilled in the art through the research and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a schematic diagram of the synthesis process of the ligand of the present invention, where R 1 and R 2 are both phenyl groups, or other aromatic rings;

[0026] Figure 2 It is a schematic diagram of the asymmetric allyl alkylation reaction process of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0027] The following further detailed description of the present invention is made in conjunction with embodiments, so that those skilled in the art can implement it with reference to the text of the specification.

[0028] It should be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0029] The present invention provides a novel class of C2-symmetric chiral bisamide ligands with structures shown in General Formula I or II:

[0030]

[0031] In the formula: Ar is an aryl group; * represents a chiral center; R is 4-methylbenzyl, 4-bromobenzyl, 2,6-dimethylbenzyl, methyl or benzyl, etc.; n represents 1 or 2.

[0032] For the preparation method of the above novel C2-symmetric chiral bisamide ligands, refer to Figure 1 the synthesis process, which includes: dithiols of Formula III react with (2S,3S)-2,3-diphenylaziridine of Formula IV to obtain intermediate of Formula V, and the intermediate of Formula V undergoes dehydration condensation with nitrogen-substituted chiral cyclic amino acids of Formula VI to obtain the target ligand of Formula I; or, the intermediate of Formula V undergoes dehydration condensation with 2-diphenylphosphinobenzoic acid of Formula VII to obtain the target ligand of Formula II.

[0033] Example 1

[0034] Ligand I-1

[0035]

[0036] Under the protection of nitrogen, dissolve (2S,3S)-2,3-diphenylaziridine IV (2.44 g, 12.5 mmol) in 20 mL of methanol, then add o-phenylenedithiol III-1 (0.71 g, 5 mmol), heat up to 65 °C, and stir until the raw materials disappear. The reaction system is cooled to room temperature, the reaction solution is mixed with silica gel powder, the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, intermediate V-1, a white solid, is obtained with a yield of 83%.

[0037] Dissolve L-n-methylproline VI-1 (193.7 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in 20 mL of dichloromethane, then add intermediate V-1 (266 mg, 0.5 mmol) to the reaction system, continue to react at room temperature. After the reaction is completed, the reaction solution is mixed with silica gel powder, the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by Formula I-1, a white solid, with a yield of 72%.

[0038] 11H NMR (400 MHz, CDCl3) δ 8.13 - 7.94 (m, 2H), 7.31 – 7.19 (m, 4H), 7.17 – 7.12 (m, 6H), 7.11 – 7.09 (m, 8H), 7.0 - 6.95 (m, 2H), 6.85 - 6.78 (m, 2H), 5.54 (dd, J=9.4, 6.7 Hz, 2H), 4.74 (d, J=6.6 Hz, 2H), 3.04 (dt, J=8.2, 4.2 Hz, 2H), 2.79 (dd, J=10.1, 4.3 Hz, 2H), 2.33 – 2.23 (m, 2H), 2.25 – 2.02 (m, 9H), 1.80 – 1.56 (m, 5H). 13 13C NMR (101 MHz, CDCl3) δ 173.32, 139.59, 137.87, 136.95, 132.64, 128.75, 128.17, 128.08, 128.01, 127.53, 127.44, 127.23, 127.18, 68.80, 57.44, 56.54, 56.21, 41.42, 30.72, 26.94, 24.29. HRMS m / z: anal. calcd for C 46 H 51 N4O2S2 [M + H] + : 755.3448, found: 755.3443. (c=0.1, CHCl3); m.p. 164.1 - 165.2 °C

[0039] Example 2

[0040] Ligand I - 2

[0041] Preparation:

[0042] Under nitrogen protection, (2S,3S)-2,3 - diphenylaziridine IV (2.44 g, 12.5 mmol) was dissolved in 20 mL of methanol, then o - benzenedithiol III - 1 (0.71 g, 5 mmol) was added. The temperature was raised to 65 °C and stirred until the raw materials disappeared. The reaction system was cooled to room temperature. After the reaction solution was stirred with silica gel powder and the solvent was removed under reduced pressure, it was passed through a silica gel column, and column chromatography separation was carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the eluent under reduced pressure, intermediate V - 1, a white solid, was obtained with a yield of 83%.

[0043] L-N-benzylproline VI-2 (307.9 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) were dissolved in 20 mL of dichloromethane. Then, intermediate V-1 (266 mg, 0.5 mmol) was added to the reaction system, and the reaction continued at room temperature. After the reaction was completed, the reaction system was stirred with silica gel powder, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by formula I-2 as a white solid with a yield of 60%.

[0044] 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 9.2 Hz, 2H), 7.33–7.24 (m, 7H), 7.23 - 7.15 (m, 10H), 7.13–6.97 (m, 11H), 6.92 - 6.85 (m, 2H), 6.80–6.74 (m, 2H), 5.56 (dd, J = 9.2, 6.7 Hz, 2H), 4.72 (d, J = 6.7 Hz, 2H), 3.66 (d, J = 13.1 Hz, 2H), 3.26 (d, J = 13.2 Hz, 2H), 3.12 (dd, J = 10.0, 5.0 Hz, 2H), 3.02 - 2.89 (m, 2H), 2.25 (td, J = 9.6, 6.3 Hz, 2H), 2.15–2.01 (m, 2H), 1.78–1.53 (m, 6H). 13 C NMR (100 MHz, CDCl3) δ 173.36, 139.18, 138.20, 137.92, 136.66, 132.04, 128.75, 128.73, 128.28, 128.24, 128.15, 128.01, 127.66, 127.40, 127.35, 127.08, 127.03, 67.16, 59.31, 56.93, 56.59, 53.39, 30.36, 23.96. HRMS m / z: anal. calcd for C 58 H 59 N4O2S2 [M + H] + : 907.4074, found: 907.4288. (c = 0.1, CHCl3); m.p. 72.8 - 73.7 °C

[0045] Example 3

[0046] Ligand I-3

[0047] Preparation:

[0048] Under nitrogen protection, dissolve (2S,3S)-2,3-diphenylaziridine IV (2.44 g, 12.5 mmol) in 20 mL of methanol, then add o-benzenedithiol III-1 (0.71 g, 5 mmol), heat to 65 °C, and stir until the raw materials disappear. After the reaction system cools to room temperature, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, the intermediate V-1, a white solid, is obtained with a yield of 83%.

[0049] Dissolve D-nitrobenzylproline VI-3 (307.9 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in 20 mL of dichloromethane, then add the intermediate V-1 (266 mg, 0.5 mmol) to the reaction system, and continue to react at room temperature. After the reaction is completed, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by formula I-3, a white solid, with a yield of 59%.

[0050] 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.8 Hz, 2H), 7.24–7.11 (m, 18H), 7.10-7.07 (m, 4H), 7.06-6.96 (m, 10H), 6.88–6.81 (m, 2H), 5.56 (dd, J = 9.8, 6.4 Hz, 2H), 4.76 (d, J = 6.5 Hz, 2H), 3.71 (d, J = 13.1 Hz, 2H), 3.34 (d, J = 13.0 Hz, 2H), 3.24–3.11 (m, 2H), 3.08–2.89 (m, 2H), 235-2.21 (m, 2H), 2.13–1.97 (m, 3H), 1.75–1.53 (m, 5H). 1313C NMR (100 MHz, CDCl3) δ 173.45, 139.58, 138.52, 137.57, 136.81, 132.54, 128.92, 128.52, 128.39, 128.26, 128.10, 128.02, 127.56, 127.47, 127.23, 127.21, 127.07, 67.42, 59.91, 57.30, 55.98, 53.96, 30.50, 24.30. HRMS m / z: anal. calcd for C 58 H 59 N4O2S2 [M+H] + : 907.4074, found: 907.4289. (c = 0.1, CHCl3); m.p. 72.2 - 73.0 °C

[0051] Example 4

[0052] Ligand I-4

[0053] Preparation:

[0054] Under nitrogen protection, (2S,3S)-2,3-diphenylaziridine IV (2.44 g, 12.5 mmol) was dissolved in 20 mL of methanol, then o-phenylenedithiol III-1 (0.71 g, 5 mmol) was added, and the temperature was raised to 65 °C and stirred until the raw materials disappeared. The reaction system was cooled to room temperature, and the reaction solution was mixed with silica gel powder and the solvent was removed under reduced pressure, then passed through a silica gel column, and column chromatography was carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, intermediate V-1, a white solid, was obtained with a yield of 83%.

[0055] L-N-benzylindolinecarboxylic acid VI-4 (389 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) were dissolved in 20 mL of dichloromethane, and then intermediate V-1 (266 mg, 0.5 mmol) was added to the reaction system. The reaction was continued at room temperature. After the reaction was completed, the system was mixed with silica gel powder and the solvent was removed under reduced pressure, then passed through a silica gel column, and column chromatography was carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by formula I-4, a white solid, with a yield of 65%.

[0056] 11H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.9 Hz, 2H), 7.33–7.25 (m, 6H), 7.24–7.13 (m, 11H), 7.12–7.03 (m, 13H), 6.93 - 6.86 (m, 2H), 6.82 - 6.77 (m, 2H), 5.46 (dd, J = 9.0, 7.0 Hz, 2H), 4.65 (d, J = 7.1 Hz, 2H), 3.61 (d, J = 14.0 Hz, 2H), 3.47 (d, J = 13.9 Hz, 2H), 3.25 (dd, J = 10.6, 4.8 Hz, 2H), 2.84 - 2.73 (m, 2H), 2.10–1.94 (m, 2H), 1.92–1.81 (m, 3H), 1.79–1.61 (m, 4H), 1.55–1.20 (m, 10H), 1.17 - 1.03 (m, 5H). 13 13C NMR (100 MHz, CDCl3) δ 173.66, 139.11, 138.15, 136.62, 136.56, 131.69, 129.78, 128.80, 128.25, 128.19, 128.10, 128.02, 127.67, 127.47, 127.46, 127.17, 126.87, 65.05, 60.82, 56.95, 56.66, 55.92, 36.81, 34.59, 27.92, 27.26, 24.10, 21.30. HRMS m / z: anal. calcd for C 66 H 71 N4O2S2 [M + H] + : 1015.5013, found: 1015.5128. (c = 0.1, CHCl3); m.p. 100.5 - 100.9 °C

[0057] Example 5

[0058] Ligand I - 5

[0059] Preparation:

[0060] (2S,3S)-2,3-Diphenylaziridine IV (2.44 g, 12.5 mmol) was dissolved in 10 mL of methanol, then 3-benzenedithiol III-2 (0.71 g, 5 mmol) was added. The temperature was raised to 65 °C and stirred until the raw materials disappeared. After the reaction system was cooled to room temperature, the reaction solution was mixed with silica gel powder and the solvent was removed under reduced pressure, then passed through a silica gel column. Column chromatography was carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent, and after removing the chromatography solution under reduced pressure, intermediate V-2, a white solid, was obtained with a yield of 88%.

[0061] L-N-benzylproline VI-2 (307.9 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) were dissolved in 20 mL of dichloromethane. Then intermediate V-2 (266 mg, 0.5 mmol) was added to the reaction system, and the reaction continued at room temperature. After the reaction was completed, the system was mixed with silica gel powder and the solvent was removed under reduced pressure, then passed through a silica gel column. Column chromatography was carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by formula I-5, a white solid, with a yield of 68%.

[0062] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 9.2 Hz, 2H), 7.30 - 7.15 (m, 15H), 7.13–6.97 (m, 14H), 6.93 (s, 1H), 6.8 - 6.79 (m, 2H), 5.44 (dd, J = 9.2, 6.5 Hz, 2H), 4.45 (d, J = 6.5 Hz, 2H), 3.72 (d, J = 13.1 Hz, 2H), 3.28 (d, J = 13.2 Hz, 2H), 3.13 (dd, J = 10.1, 4.8 Hz, 2H), 2.96 (ddd, J = 9.5, 6.9, 2.1 Hz, 2H), 2.25 (td, J = 9.6, 6.2 Hz, 2H), 2.18–2.02 (m, 2H), 1.81–1.54 (m, 6H). 1313C NMR (100 MHz, CDCl3) δ 173.31, 138.83, 138.27, 138.11, 135.24, 133.93, 129.89, 128.82, 128.70, 128.65, 128.61, 128.35, 128.31, 128.19, 128.14, 128.09, 127.65, 127.55, 127.33, 127.12, 67.26, 59.42, 58.83, 56.54, 53.44, 30.36, 23.96. HRMS m / z: anal. calcd for C 58 H 59 N4O2S2 [M + H] + : 907.4074, found: 907.4170. (c = 0.1, CHCl3); m.p. 74.5 - 75 °C

[0063] Example 6

[0064] Ligand I - 6

[0065] Preparation:

[0066] Dissolve (2S,3S)-2,3 - diphenylaziridine IV (2.44 g, 12.5 mmol) in 10 mL of methanol, then add p - benzenedithiol III - 3 (0.71 g, 5 mmol), heat up to 65 °C, and stir until the raw materials disappear. After the reaction system cools to room temperature, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, then passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, the intermediate V - 3, a white solid, is obtained with a yield of 92%.

[0067] Dissolve L - N - benzylproline VI - 2 (307.9 mg, 1.5 mmol), 1 - (3 - dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4 - dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in 20 mL of dichloromethane, then add the intermediate V - 3 (266 mg, 0.5 mmol) to the reaction system, continue to react at room temperature. After the reaction is completed, the system is mixed with silica gel powder and the solvent is removed under reduced pressure, then passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by formula I - 6, a white solid, with a yield of 66%.

[0068] 11H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 9.1 Hz, 2H), 7.27 - 7.18 (m, 14H), 7.16–6.92 (m, 14H), 6.81 (s, 4H), 5.44 (dd, J = 9.1, 6.3 Hz, 2H), 4.52 (d, J = 6.3 Hz, 2H), 3.73 (d, J = 13.2 Hz, 2H), 3.29 (d, J = 13.2 Hz, 2H), 3.14 (dd, J = 10.1, 5.0 Hz, 2H), 2.97 (ddd, J = 9.4, 6.9, 2.2 Hz, 2H), 2.44–2.22 (m, 2H), 2.16–2.00 (m, 2H), 1.82–1.56 (m, 4H), 1.36–1.13 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 173.45, 139.58, 138.52, 137.57, 136.81, 132.54, 128.92, 128.52, 128.39, 128.26, 128.10, 128.02, 127.56, 127.47, 127.23, 127.21, 127.07, 67.42, 59.91, 57.30, 55.98, 53.96, 30.50, 24.30. HRMS m / z: anal. calcd for C 58 H 59 N4O2S2 [M + H] + : 907.4074, found: 907.4152. (c = 0.5, CH3CN); m.p. 152.2 - 153.5 °C

[0069] Example 7

[0070] Ligand I-7

[0071] Preparation:

[0072] (2S,3S)-2,3-Diphenylaziridine IV (2.44 g, 12.5 mmol) was dissolved in 10 mL of methanol, then p - benzenedithiol III-3 (0.71 g, 5 mmol) was added. The temperature was raised to 65 °C and stirred until the raw materials disappeared. The reaction system was cooled to room temperature. After the reaction solution was mixed with silica gel powder and the solvent was removed under reduced pressure, it was passed through a silica gel column, and column chromatography separation was carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After the eluent was removed under reduced pressure, the intermediate V-3, a white solid, was obtained with a yield of 92%.

[0073] L-N-methylproline VI-1 (193.7 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (288 mg, 1.5 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) were dissolved in 20 mL of dichloromethane. Then, intermediate V-3 (266 mg, 0.5 mmol) was added to the reaction system, and the reaction continued at room temperature. After completion of the reaction, the reaction mixture was stirred with silica gel powder, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 5:1:5) as the eluent to obtain the target compound represented by formula I-7 as a white solid in a yield of 59%.

[0074] 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 9.4 Hz, 2H), 7.25 - 7.15 (m, 12H), 7.10 - 7.03 (m, 4H), 7.03 - 6.94 (m, 8H), 5.44 (dd, J = 9.4, 6.1 Hz, 2H), 4.50 (d, J = 6.1 Hz, 2H), 3.17–2.98 (m, 2H), 2.88 - 2.77 (m, 2H), 2.35 - 2.26 (m, 2H), 2.26 - 2.18 (s, 6H) 2.17–2.00 (m, 3H), 1.83–1.59 (m, 5H). 13 C NMR (100 MHz, CDCl3) δ 173.44, 139.31, 137.85, 133.85, 132.18, 128.67, 128.16, 128.13, 127.62, 127.53, 127.10, 68.82, 59.67, 56.61, 55.95, 41.59, 30.78, 24.35. HRMS m / z: anal.calcd for C 46 H 51 N4O2S2 [M + H] + : 755.3448, found: 755.3501. (c = 0.1, CHCl3); m.p. 222.7 - 223.4 °C

[0075] Example 8

[0076] Ligand II-1

[0077] Preparation:

[0078] Under nitrogen protection, dissolve (2S,3S)-2,3-diphenylaziridine IV (2.44 g, 12.5 mmol) in 20 mL of methanol, then add o-benzenedithiol III-1 (0.71 g, 5 mmol), heat up to 65 °C, and stir until the raw materials disappear. After the reaction system cools to room temperature, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, then passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, intermediate V-1, a white solid, is obtained with a yield of 83%.

[0079] Dissolve 2-diphenylphosphinobenzoic acid VII (1.84 g, 6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.15 g, 6 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in 20 mL of dichloromethane, then add intermediate V-1 (1.06 g, 2.0 mmol) to the reaction system, and continue to react at room temperature. After the reaction is completed, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, then passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 8:1:1) as the eluent to obtain the target compound represented by formula II-1, a white solid, with a yield of 83%.

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.29 - 7.01 (m, 2H), 7.30 - 7.01 (m, 40H), 7.0 - 6.87 (m, 10H), 6.87 - 6.80 (m, 2H), 5.60 (d, J = 5.3 Hz, 2H), 4.71 (d, J = 5.2 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 167.78, 140.99, 140.74, 138.11, 137.73, 137.01, 136.89, 136.24, 136.03, 134.04, 133.89, 133.76, 133.69, 133.56, 131.50, 130.12, 128.77, 128.69, 128.60, 128.57, 128.44, 128.37, 128.31, 128.04, 127.92, 127.74, 127.60, 127.42, 127.10, 58.03. 31 P NMR (162 MHz, CDCl3) δ -10.07. HRMS m / z: anal. calcd for C 72 H 58 N2O2P2S2 [M + H] +: 1109.3228, found: 1109.3487. (c = 0.1, CHCl3); m.p. 116.2 - 117.1 °C

[0081] Example 9

[0082] Ligand II-2

[0083] Preparation:

[0084] Dissolve (2S,3S)-2,3-diphenylaziridine IV (2.44 g, 12.5 mmol) in 10 mL of methanol, then add m-benzenedithiol III-2 (0.71 g, 5 mmol), heat up to 65 °C, and stir until the raw materials disappear. The reaction system is cooled to room temperature. After the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, it is passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, the intermediate V-2, a white solid, is obtained with a yield of 88%.

[0085] Dissolve 2-diphenylphosphinobenzoic acid VII (1.84 g, 6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.15 g, 6 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in 20 mL of dichloromethane, and then add the intermediate V-2 (1.06 g, 2.0 mmol) to the reaction system. Continue to react at room temperature. After the reaction is completed, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 8:1:1) as the eluent to obtain the target compound represented by formula II-2, a white solid, with a yield of 71%.

[0086] 1 H NMR (400 MHz, CDCl3) δ 7.54–7.39 (m, 2H), 7.34–7.08 (m, 40H), 7.08–7.00 (m, 5H), 6.97–6.82 (m, 7H), 5.51 (d, J = 5.8 Hz, 2H), 4.55 (d, J = 5.7 Hz, 2H). 1313C NMR (100 MHz, CDCl3) δ 167.83, 141.19, 140.94, 138.02, 137.94, 136.94, 136.83, 136.73, 136.09, 135.87, 135.50, 134.55, 134.16, 133.96, 133.76, 133.56, 130.17, 129.02, 128.72, 128.67, 128.49, 128.42, 128.21, 127.93, 127.61, 127.53, 59.22, 57.69. 31 31P NMR (162 MHz, CDCl3) δ -10.39. HRMS m / z: anal. calcd for C 72 H 58 N2O2P2S2 [M + H] + : 1109.3488, found: 1109.3595. (c = 0.1, CHCl3); m.p. 122.4 - 123.5 °C

[0087] Example 10

[0088] Ligand II - 3

[0089] Preparation:

[0090] Dissolve (2S,3S)-2,3-diphenylaziridine IV (2.44 g, 12.5 mmol) in 10 mL of methanol, then add p-benzenedithiol III - 3 (0.71 g, 5 mmol), heat to 65 °C, and stir until the raw materials disappear. After the reaction system cools to room temperature, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, then passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 2:1:1) as the eluent. After removing the chromatography solution under reduced pressure, the intermediate V - 3, a white solid, is obtained with a yield of 92%.

[0091] Dissolve 2-diphenylphosphinobenzoic acid VII (1.84 g, 6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.15 g, 6 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in 20 mL of dichloromethane, then add the intermediate V - 3 (1.06 g, 2.0 mmol) to the reaction system, and continue to react at room temperature. After the reaction is completed, the reaction solution is mixed with silica gel powder and the solvent is removed under reduced pressure, then passed through a silica gel column, and column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane (volume ratio = 8:1:1) as the eluent to obtain the target compound represented by formula II - 3, a white solid, with a yield of 75%.

[0092] 1 1H NMR (400 MHz, CDCl3) δ 7.55 - 7.47 (m, 2H), 7.39–7.11 (m, 37H), 7.08 - 7.02 (m, 4H), 6.98–6.91 (m, 7H), 6.89–6.83 (m, 4H), 5.51 (d, J=5.4 Hz, 2H), 4.57 (d, J=5.2 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 167.85, 141.25, 141.00, 137.94, 137.63, 136.84, 135.88, 134.20, 133.90, 133.79, 133.69, 133.59, 131.57, 130.25, 128.74, 128.54, 128.47, 128.18, 127.93, 127.57, 59.32, 57.82. 31 31P NMR (162 MHz, CDCl3) δ -10.43. HRMS m / z: anal. calcd for C 72 H 58 N2O2P2S2 [M + H] + : 1109.3488, found: 1109.3562. (c=0.1, CHCl3); m.p. 171.6 - 172.6 °C

[0093] Comparative Example 1

[0094] Existing ligand D-1

[0095]

[0096] Comparative Example 2

[0097] Existing ligand D-2

[0098]

[0099] <Catalytic verification test> Asymmetric allylation reaction:

[0100] Under nitrogen protection, 0.01 mmol of allylpalladium chloride dimer and 0.02 mmol of ligand were dissolved in 2 mL of acetonitrile and stirred at room temperature for one hour. Then, 0.2 mmol of allyl acetate and 0.6 mmol of cesium carbonate were added to the system. The temperature was raised to 80 °C or 40 °C or other suitable temperature, and then 0.3 mmol of dimethyl malonate was added. Stir until the reaction was complete. The reaction system was cooled to room temperature, and the reaction solution was directly mixed with silica gel powder, concentrated by solvent evaporation. The sample was separated by column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1), and the chromatography solution was removed under reduced pressure to obtain the allyl alkylation product. Table 1 shows the results of the ligand in the palladium-catalyzed asymmetric allylation reaction. The reaction process is referred to Figure 2 as shown. In Table 1, a, d, and e show the reaction conditions. It can be seen from the experimental results that the complexes formed by the compounds represented by Formula I and II of the ligand of the present invention and allylpalladium chloride dimer have good catalytic activity for the catalytic asymmetric allyl alkylation reaction, and among them, ligand II-1 has the best effect.

[0101] Table 1 Influence of ligand effect on allylation reaction

[0102]

[0103]

[0104] It can be seen from the above experiments that the complex formed by the compound of the present invention and allylpalladium chloride dimer has good catalytic activity for the catalytic asymmetric allyl alkylation reaction, can be used as a ligand for the palladium-catalyzed asymmetric allyl alkylation reaction, and can be directly used to prepare various allyl alkylation compounds. Although ligands I-1 to I-7 and ligands II-2 and II-3 have no catalytic activity at 40 °C, they have good catalytic activity at 80 °C, and ligand II-1 can achieve high catalytic activity at 40 °C. It can be seen that in the catalytic asymmetric allylation reaction of the catalyst formed by the complexation of ligand II-1 and allylpalladium chloride dimer, the product can be obtained in a short time, significantly improving the efficiency, and the separation yield and ee value of the product are high in a short time. The yield and ee value are as high as 96% and 95%, 99% respectively, and it has high application prospects, providing a choice for the high-demand synthesis of high-value-added compounds in the fields of medicine, materials science, etc.

[0105] Although the embodiments of the present invention have been disclosed as above, it is not limited to only the applications listed in the specification and embodiments. It can be fully applied to various fields suitable for the present invention. For those skilled in the art, additional modifications can be easily made. Therefore, without departing from the general concept defined by the claims and the equivalent scope, the present invention is not limited to the specific details and the embodiments shown and described herein.

Claims

1. A novel class of C2-symmetric chiral bisamide ligands, characterized in that, It has the structure shown in General Formula I or II: In the formula: Ar is an aryl group; * represents a chiral center; R is 4-methylbenzyl, 4-bromobenzyl, 2,6-dimethylbenzyl, methyl or benzyl; n represents 1 or 2.

2. The preparation method of the novel C2-symmetric chiral bisamide ligand according to claim 1, characterized in that, It includes: Dithiols react with (2S,3S)-2,3-diphenylaziridine to obtain an intermediate, and the intermediate undergoes dehydration condensation with a nitrogen-substituted chiral cyclic amino acid to obtain the target ligand of Formula I; or, the intermediate undergoes dehydration condensation with 2-diphenylphosphinobenzoic acid to obtain the target ligand of Formula II; The dithiol type III is as follows: (2S,3S)-2,3-diphenylaziridine of formula IV is: The intermediate of formula V is as follows: The nitrogen-substituted chiral cyclic amino acid of formula VI is as follows: 2-Diphenylphosphine benzoic acid of formula VII is: Among them, Ar is an aryl group; * represents a chiral center; R is 4-methylbenzyl, 4-bromobenzyl, 2,6-dimethylbenzyl, methyl or benzyl; n represents 1 or 2.

3. The preparation method of the novel C2-symmetric chiral bisamide ligand according to claim 2, characterized in that Under nitrogen protection, dissolve (2S,3S)-2,3-diphenylaziridine in methanol, then add dithiols, heat up to 65 °C, stir until the raw materials disappear and then cool to room temperature. The reaction solution is mixed with silica gel powder, the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane with a volume ratio of 2:1:1 as the eluent, and the intermediate of Formula V is obtained after removing the chromatography solution under reduced pressure; among them, the dithiols are o-benzenedithiol, m-benzenedithiol or p-benzenedithiol; the molar ratio of o-benzenedithiol, m-benzenedithiol or p-benzenedithiol to (2S,3S)-2,3-diphenylaziridine is 5:11 - 5:

15.

4. The preparation method of the novel C2-symmetric chiral bisamide ligand according to claim 3, characterized in that The intermediate undergoes dehydration condensation with a nitrogen-substituted chiral cyclic amino acid to obtain the target ligand of Formula I, specifically: Dissolve the nitrogen-substituted chiral cyclic amino acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine in dichloromethane, then add the intermediate to the reaction system, continue to react at room temperature. After the reaction is completed, the reaction solution is mixed with silica gel powder, the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography separation is carried out using petroleum ether / ethyl acetate / dichloromethane with a volume ratio of 5:1:5 as the eluent to obtain the target ligand of Formula I; among them, the molar ratio of the nitrogen-substituted chiral cyclic amino acid: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 4-dimethylaminopyridine: intermediate is 1.5:1.5:0.1:0.5; the nitrogen-substituted chiral cyclic amino acid is L-n-methylproline, L-n-benzylproline, D-n-benzylproline or L-n-benzylindolinecarboxylic acid.

5. The preparation method of the novel C2-symmetric chiral bisamide ligand according to claim 3, characterized in that The intermediate undergoes dehydration condensation with 2-diphenylphosphinobenzoic acid to obtain the target ligand of Formula II, specifically: 2-Diphenylphosphinobenzoic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine are dissolved in dichloromethane, and then the intermediate is added to the reaction system. The reaction continues at room temperature. After the reaction is completed, the reaction solution is stirred with silica gel powder, the solvent is removed under reduced pressure, and then passed through a silica gel column. Column chromatography is carried out using petroleum ether / ethyl acetate / dichloromethane with a volume ratio of 8:1:1 as the eluent to obtain the target ligand of formula II; wherein, the molar ratio of 2-diphenylphosphinobenzoic acid: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 4-dimethylaminopyridine: intermediate is 6:6:0.1:

2.

6. A class of complexes, characterized in that, A complex formed by the novel C2-symmetric chiral bisamide ligand according to claim 1 and allylpalladium chloride dimer.

7. The preparation method of a class of complexes according to claim 6, characterized in that, The allylpalladium chloride dimer and the ligand are mixed in a molar ratio of 1:2, dissolved in an organic solvent, and stirred to react to form a complex.

8. Use of the complex according to claim 7 as a catalyst in the catalytic asymmetric allylation reaction.

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