Preparation method of axially chiral bidentate sulfur ligand

Abstract

The invention discloses a preparation method of an axially chiral bidentate sulfur ligand, which comprises the following steps: by taking biaryl sulfonium salt 1 and a compound 2 as raw materials, simultaneously adding a catalyst, a ligand, alkali and a solvent, and carrying out asymmetric ring-opening reaction to generate the axially chiral bidentate sulfur ligand 3. Wherein the structural formula of the compound 2 is R-YH, and Y is heteroatoms containing lone pair electrons, such as S, N and the like. The enantiomer-enriched axially chiral 2, 2 '-dithio binaphthyl ligand and the axially chiral 2, 2'-sulfur and nitrogen binaphthyl ligand can be obtained through one-step reaction under the action of the chiral ligand / catalyst, and the bidentate axially chiral sulfur ligand can be obtained without subsequent chemical conversion. The method has the advantages of cheap and easily available raw materials, mild reaction conditions, simple preparation process, high yield, high enantioselectivity, less pollution and environmental friendliness, and has wide application prospects.

Description

Technical Field

[0001] The invention relates to the technical field of organic asymmetric catalytic synthesis, and in particular to a method for preparing an axially chiral bidentate sulfur ligand (including an axially chiral 2,2'-dithiobinaphthyl ligand and an axially chiral 2,2'-thio, nitrogenbinaphthyl ligand). Background Art

[0002] Chiral ligands / catalysts are tools for making chiral molecules and are the key to achieving efficient asymmetric catalysis. Chiral sulfur-containing compounds not only have strong coordination ability with many transition metals such as copper, palladium, nickel, rhodium, etc., but also have stable structures, are easy to obtain, store and handle. Therefore, chiral sulfur-containing compounds can be used as chiral ligands in asymmetric catalytic synthesis. Sulfur ligands are different from other heteroatom ligands such as phosphine and nitrogen in electronic effects, steric effects, coordination properties and abilities, which endow chiral sulfur ligands with unique properties. Axial chiral sulfur ligands based on the binaphthyl skeleton, such as axially chiral 2,2'-dithiobinaphthyl ligands (I) and axially chiral 2,2'-thio, nitrogenbinaphthyl ligands (II), have excellent bidentate ligand structures and controllable capabilities, which can be adjusted by adjusting the group R as needed. 1 , R 2 , R 3 …to adjust the electronic effect and steric hindrance of the ligand, thereby achieving high activity and high enantioselectivity in certain catalytic reactions. Therefore, chiral sulfur ligands have important scientific value and application prospects.

[0003] The traditional method for preparing 2,2'-dithiobinaphthyl ligands and 2,2'-thio, nitrogenbinaphthyl ligands is to use a binaphthyl halide with a thiol, a disulfide or an amine to prepare a racemic 2,2'-dithiobinaphthyl ligand (by constructing a double CS bond) and a 2,2'-thio, nitrogenbinaphthyl ligand (by constructing a CS and CN bond) (see reference: CN118271216A). After the racemic 2,2'-dithiobinaphthyl ligand and 2,2'-thio, nitrogenbinaphthyl ligand are prepared, the corresponding axial chiral 2,2'-dithiobinaphthyl ligand and axial chiral 2,2'-thio, nitrogenbinaphthyl ligand are prepared by chiral resolution. However, the chiral resolution of sulfur ligands is very difficult.

[0004] In order to solve the splitting problem, researchers first oxidized the sulfur ligand into sulfoxide, then split it, and finally reduced it to the sulfur ligand (see references: Tetrahedron Lett. 1989, 30, 2575-2576; Chem. Eur. J.2010, 16, 14335 -14347), which not only led to a complicated process route, but also greatly increased waste emissions and costs. Patent CN201911341904.X reported a method for synthesizing monodentate axial chiral sulfides using copper acetate and chiral oxazoline as catalysts, but to obtain bidentate axial chiral sulfur ligands, subsequent corresponding chemical conversions are still required. Summary of the invention

[0005] The purpose of the present invention is to provide a novel method for preparing bidentate sulfur ligands with axial chirality (including axially chiral 2,2'-dithiobinaphthyl ligands and axially chiral 2,2'-sulfur, nitrogen-binaphthyl ligands) in view of the deficiencies in the prior art. The method uses a five-membered cyclic biaryl sulfonium salt as a raw material, a 2-thiol heterocyclic compound and an aromatic amine as a nucleophilic reagent, and in the presence of a chiral catalyst, an asymmetric ring-opening reaction is performed to obtain axially chiral 2,2'-dithiobinaphthyl ligands and axially chiral 2,2'-sulfur, nitrogen-binaphthyl ligands. The preparation method synthesizes axially chiral bidentate sulfur ligands in one step without the need for a chiral resolution process, and the reaction conditions involved are mild, the reaction activity is high, the selectivity is good, the operation is convenient, the pollution is low, and the environment is friendly.

[0006] The present invention relates to a method for preparing an axially chiral bidentate sulfur ligand, specifically: Using biaryl sulfonium salt 1 and compound 2 (R-YH) as raw materials, a catalyst, a ligand, a base and a solvent are added simultaneously to carry out an asymmetric ring-opening reaction to generate the axially chiral bidentate sulfur ligand 3; wherein Y is a heteroatom containing a lone pair of electrons, such as S, N, etc.; Among them, RY is selected from or .

[0007] When RY is When RY is When the asymmetric ring-opening reaction is an asymmetric amination ring-opening reaction.

[0008] Preferably, the catalyst is a metal catalyst, specifically a copper salt catalyst or a palladium salt catalyst. The copper salt is tetraacetonitrile copper hexafluorophosphate Cu(NCMe)4PF6, CuCl, CuI, etc.; the palladium salt is Pd(OAc)2, Pd2(dba)3, [Pd(C2H5)Cl]2, Pd(PPh3)4.

[0009] More preferably, the catalyst is Pd2(dba)3.

[0010] Preferably, the selected ligands include chiral Binap, chiral Segphos, chiral F2-Segphos, chiral Josiphos and the like.

[0011] More preferably, for the asymmetric sulfurization ring-opening reaction, the ligand is chiral F2-Segphos; for the asymmetric amination ring-opening reaction, the ligand is (R)-Binap.

[0012] Preferably, the base selected is an organic base or an inorganic base, specifically including triethylamine, DBU, TMEDA, Barton base, Cs2CO3, K2CO3, Na2CO3, t BuOK, K3PO 4， At least one of CsF.

[0013] More preferably, for the asymmetric sulfidation ring-opening reaction, the base is CsF; for the asymmetric amination ring-opening reaction, the base is K3PO4.

[0014] Preferably, the selected solvent is an organic solvent, specifically including at least one of tetrahydrofuran, methyl tert-butyl ether, ethyl ether, toluene, dichloromethane and dichloroethane.

[0015] More preferably, for the asymmetric sulfidation ring-opening reaction, the solvent is dichloromethane; for the asymmetric amination ring-opening reaction, the solvent is toluene.

[0016] Preferably, the reaction temperature is 0°C-80°C.

[0017] More preferably, the temperature for the asymmetric sulfurization ring-opening reaction is 25°C; and the temperature for the asymmetric amination ring-opening reaction is 60°C.

[0018] Preferably, the molar ratio of the biarylsulfonium salt 1 to the compound 2 is 1:(1-3).

[0019] More preferably, for the asymmetric sulfidation ring-opening reaction, the molar ratio of the biaryl sulfonium salt 1 to the compound 2 is 1.1:1, and for the asymmetric amination ring-opening reaction, the molar ratio of the biaryl sulfonium salt 1 to the compound 2 is 1:2.

[0020] Preferably, for the asymmetric sulfidation ring-opening reaction, the molar ratio of the selected base to compound 2 is (10-1):1, more preferably 1:1; for the asymmetric amination ring-opening reaction, the molar ratio of the selected base to the biaryl sulfonium salt 1 is (10-1):1, more preferably 2:1.

[0021] Preferably, the molar ratio of the catalyst to the biarylsulfonium salt 1 is (0.1-0.01):1, more preferably 0.05:1; the molar ratio of the ligand to the catalyst is (1-10):1, more preferably 1.1:1.

[0022] Preferably, the reaction time is 1-24 hours, more preferably 13 hours.

[0023] Preferably, the reaction further comprises: after the reaction is completed, recrystallizing and purifying the axially chiral bidentate sulfur ligand; the solvent used for recrystallization is one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, ether, toluene, pentane, etc., more preferably a dual solvent of chloroform and pentane.

[0024] The beneficial effects of the present invention are: The present invention provides a method of using a biaryl sulfonium salt 1 as a raw material, reacting with 2-mercaptobenzothiazole 2-1 or aromatic amine 2-2, adding a catalyst, a chiral ligand, a base, and a solvent to a reaction container, and performing an asymmetric sulfurization or amination ring-opening reaction at a certain temperature to generate an axial chiral ligand. The reaction raw materials involved in the present invention are cheap and easy to obtain. Under the action of a chiral ligand / catalyst, an axial chiral 2,2'-dithiobinaphthyl ligand 3-1 and an axial chiral 2,2'-sulfur, nitrogenbinaphthyl ligand 3-2 enriched in enantiomers can be obtained by a one-step reaction. After recrystallization, a corresponding optically pure product can be obtained. The bidentate axial chiral sulfur ligand can be obtained without chiral separation or subsequent chemical conversion. The present invention has mild reaction conditions (room temperature), a simple preparation process, a high yield, a high enantioselectivity, less pollution (no harmful compounds in the reaction byproducts), and is environmentally friendly. DETAILED DESCRIPTION

[0025] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements may be made without departing from the concept of the present invention.

[0026] The preparation method of the axial chiral 2,2'-dithiobinaphthyl ligand 3 of the present invention is carried out in a specific embodiment according to the following reaction formula and steps: S1: Place the catalyst, ligand and solvent in a reaction vessel at room temperature (25 °C) and stir the mixture at room temperature for 0.5 hours.

[0027] S2: At room temperature (25 °C), biarylsulfonium salt 1, 2-mercaptobenzothiazole 2-1 and base were added to the reaction solvent and the mixture was stirred at room temperature for 13 hours.

[0028] S3: After the reaction is completed, the solvent is removed and the crude product is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product.

[0029] The preparation method of the axial chiral 2,2'-thioxanthracene ligand 3-2 of the present invention is carried out in the specific embodiment as follows: S1: Place the catalyst, ligand and solvent in a reaction vessel at room temperature (25 °C) and stir the mixture at room temperature for 0.5 hours.

[0030] S2: At room temperature (25 °C), biarylsulfonium salt 1, aromatic amine 2-2 and base were added to the reaction solvent and the mixture was stirred at room temperature for 13 hours.

[0031] S3: After the reaction is completed, the solvent is removed and the crude product is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product.

[0032] Embodiment 1: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in dichloromethane (4.0 mL) was added (R)-F2-Segphos (9.8 mg, 0.014 mmol, 12 mol%) in a Schlenk tube under nitrogen. The solution was stirred at room temperature for 30 min, and then sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), CsF (18.3 mg, 0.120 mmol, 1.00 equiv) and 2-mercaptobenzothiazole 2-1a (20 mg, 0.120 mmol, 1.00 equiv) were added. The mixture was stirred at 25°C for 13 h. After completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was subjected to silica gel chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain a white solid 3-1aa (33.7 mg, 52%, 68% ee). The product was recrystallized from chloroform / pentane to obtain optically pure 2,2'-dithiobinaphthyl ligand 3-1aa (recrystallization yield 45%, 99% ee).

[0033] NMR analysis data 3-1aa: 1H NMR (500 MHz, CDCl3)δ7.96 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz,1H), 7.87 (d, J = 8.7 Hz, 1H), 7.75-7.70 (m, 3H), 7.52-7.46 (m, 2H), 7.29-7.25 (m, 3H), 7.21 (d, J = 8.8 Hz, 1H), 7.18-7.08 (m, 5H), 7.04 (d, J = 8.5Hz, 1H), 6.91 (d, J = 7.9 Hz, 2H), 2.18 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ167.8, 153.5, 140.2, 137.9, 136.5, 136.0, 133.8, 133.4, 133.0, 131.8, 131.0,130.7, 130.0, 129.6, HRMS (ESI-TOF) m / z: [M+H] + Calcd for C34H23NS3H+: 542.1056; Found: 542.1053. Embodiment 2: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed THF (2.0 mL) in a Schlenk tube was added (R)-F2-Segphos (9.8 mg, 0.014 mmol, 12 mol%) under nitrogen. The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), K2CO3 (33.1 mg, 0.240 mmol, 2.00 equiv) and 2-mercaptobenzothiazole 2-1a (20 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 10°C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was chromatographed on silica gel (ethyl acetate / petroleum ether = 1 / 10) to give 3-1aa (60.4 mg, 93%, 20% ee) as a white solid.

[0034] Embodiment 3: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed DCM (4.0 mL) in a Schlenk tube was added (R)-F2-Segphos (9.8 mg, 0.014 mmol, 12 mol%) under nitrogen. The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), K2CO3 (33.1 mg, 0.240 mmol, 2.00 equiv) and 2-mercaptobenzothiazole 2-1a (20 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 0°C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was subjected to silica gel chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain a white solid 3-1aa (12.9 mg, 20%, 89% ee). The product was recrystallized according to the method of Example 1 to obtain an optically pure 2,2'-dithiobinaphthyl ligand.

[0035] Embodiment 4: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed THF (2.0 mL) in a Schlenk tube was added (R)-F2-Segphos (9.8 mg, 0.014 mmol, 12 mol%) under nitrogen. The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), K3PO4 (25.5 mg, 0.120 mmol, 1.00 equiv) and 2-mercaptobenzothiazole 2-1a (20 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 25°C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was chromatographed on silica gel (ethyl acetate / petroleum ether = 1 / 10) to give 3-1aa (62.9 mg, 97%, 45% ee) as a white solid.

[0036] Embodiment 5: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed DCM (2.0 mL) in a Schlenk tube was added (R, Rp)-Taniaphos (9.6 mg, 0.014 mmol, 12 mol%) under nitrogen. The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), K2CO3 (33.1 mg, 0.240 mmol, 2.00 equiv) and 2-mercaptobenzothiazole 2-1a (20 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 25°C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was chromatographed on silica gel (ethyl acetate / petroleum ether = 1 / 10) to give 3aa-1 as a white solid (46.7 mg, 72%, 14% ee).

[0037] Embodiment 6: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed DCM (2.0 mL) in a Schlenk tube was added (R)-Segphos (8.5 mg, 0.014 mmol, 12 mol%) under nitrogen. The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), K2CO3 (33.1 mg, 0.240 mmol, 2.00 equiv) and 2-mercaptobenzothiazole 2-1a (20 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 25°C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was chromatographed on silica gel (ethyl acetate / petroleum ether = 1 / 10) to give 3-1aa (51.3 mg, 79%, 16% ee) as a white solid.

[0038] Embodiment 7: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed Toluene (2.0 mL) in a Schlenk tube under nitrogen was added (R)-Binap (9.0 mg, 0.0142 mmol, 12 mol%). The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), K3PO4 (50.9 mg, 0.240 mmol, 2.00 equiv) and p-methylaniline 2-2a (12.9 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 60 °C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was subjected to silica gel chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain a white solid 3-2aa (13.3 mg, 23%, 66% ee). The product was recrystallized from chloroform / pentane to obtain optically pure 2,2'-thio, nitrogen-binaphthyl ligand 3-2aa (recrystallization yield 35%, 99% ee).

[0039] NMR analysis data 3-2aa: 1H NMR (500 MHz, CDCl3)δ7.89-7.94 (m, 3H), 7.85 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.50-7.47 (m, 1H), 7.38-7.27 (m, 8H), 7.15 (d, J =7.9 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 7.06-7.03 (m, 3H), 2.40 (s, 3H), 2.35(s, 3H). 13 C NMR (126 MHz, CDCl3) δ140.4, 140.2, 18.2, 138.1, 134.1, 133.8,133.2, 132.2, 131.8, 131.2, 130.3, 130.1, 129.7, 129.2, HRMS (ESI-TOF) m / z: [M+H] + Calcd for C34H27NSH + : 482.1937; Found:482.1939. Embodiment 8: In a Schlenk tube, to a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed Toluene (2.0 mL) under nitrogen was added (R)-Binap (9.0 mg, 0.0142 mmol, 12 mol%). The solution was stirred at room temperature for 30 min, and then sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), t BuOK (26.9 mg, 0.240 mmol, 2.00 equiv) and p-methylaniline 2-2a (12.9 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 60 °C for 13 hours. After completion, the reaction mixture was passed through a short silica gel column with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator and the residue was subjected to silica gel chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain a white solid 3-2aa (54.8 mg, 95%, 0% ee).

[0040] Embodiment 9: To a solution of Pd2(dba)3 (5.5 mg, 0.006 mmol, 5 mol%) in degassed Toluene (2.0 mL) in a Schlenk tube under nitrogen was added (R)-Binap (9.0 mg, 0.0142 mmol, 12 mol%). The solution was stirred at room temperature for 30 min, followed by the addition of sulfonium salt 1a (69.4 mg, 0.132 mmol, 1.10 equiv), DBU (36.5 mg, 0.240 mmol, 2.00 equiv) and p-methylaniline 2-2a (12.9 mg, 0.120 mmol, 1.00 equiv). The mixture was stirred at 60°C for 13 h. Upon completion, the reaction mixture was passed through a short column of silica gel with ethyl acetate as the eluent. The solvent was removed on a rotary evaporator, and the residue was chromatographed on silica gel (ethyl acetate / petroleum ether = 1 / 10) to give 3-2aa (25.4 mg, 44%, 0% ee) as a white solid.

[0041] The above embodiments are not limitations of the present invention, and the present invention is not limited to the above embodiments. As long as the requirements of the present invention are met, they belong to the protection scope of the present invention.

Claims

1. A method for preparing an axially chiral bidentate sulfur ligand, characterized in that: The preparation method comprises the following steps: Using biaryl sulfonium salt 1 and compound 2 as raw materials, a catalyst, a ligand, a base and a solvent are added simultaneously to carry out an asymmetric ring-opening reaction to generate the axially chiral bidentate sulfur ligand 3; Among them, RY is selected from or .

2. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The molar ratio of the biarylsulfonium salt 1 and the compound 2 is 1:(1-3).

3. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: When RY is When RY is When the molar ratio of the base to the biarylsulfonium salt 1 is (10-1):

1.

4. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The molar ratio of the catalyst to the biarylsulfonium salt 1 is (0.1-0.01):1, and the molar ratio of the ligand to the catalyst is (1-10):

1.

5. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The catalyst is a copper salt catalyst or a palladium salt catalyst, wherein the copper salt catalyst is selected from one of tetraacetonitrile copper hexafluorophosphate Cu(NCMe)4PF6, CuCl, and CuI; the palladium salt catalyst is selected from one of Pd(OAc)2, Pd2(dba)3, [Pd(C2H5)Cl]2, and Pd(PPh3)4.

6. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The ligand is selected from one of chiral Binap, chiral Segphos, chiral F2-Segphos and chiral Josiphos.

7. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The base is selected from triethylamine, DBU, TMEDA, Barton base, Cs2CO3, K2CO3, Na2CO3, t At least one of BuOK, K3PO4, and CsF.

8. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The solvent is selected from at least one of tetrahydrofuran, methyl tert-butyl ether, ethyl ether, toluene, dichloromethane and dichloroethane.

9. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The reaction temperature is 0°C-80°C.

10. The method for preparing an axially chiral bidentate sulfur ligand according to claim 1, characterized in that: The reaction time is 1-24 hours.

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