Monophosphine ligand oEPCP containing [2.2] paracyclophane skeleton structure as well as preparation method and application of monophosphine ligand oEPCP

Abstract

The invention discloses a monophosphine ligand oEPCP containing a [2.2] paracyclophane alkane skeleton structure as well as a preparation method and application of the monophosphine ligand oEPCP, and relates to the technical field of organic synthesis and chiral catalysis. The structural formula I of the monophosphine ligand oEPCP is as follows: # imgabs0 #. The chiral ligand oEPCP provided by the invention is mainly structurally characterized by having a [2.2] para-cyclophane alkane planar chiral rigid skeleton and an electron-donating phosphine ligand substituted by an isocyclic ortho-oxa; wherein the [2.2] paracyclophane is a minimum cyclophane compound containing a trans-ring pi electron system, which is formed by connecting two benzene rings at para-positions through two ethylidene groups. The chiral monophosphine ligand oEPCP provided by the invention can be directly used for palladium-catalyzed asymmetric Suzuki-Miyaura reaction and gold-catalyzed asymmetric [3 + 2] cycloaddition reaction, can obtain excellent reaction activity and stereoselectivity, and has economic practicability and industrial application prospects. Meanwhile, the structure enriches the family types of chiral phosphine ligands, and provides a new ligand choice for chiral catalytic synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis and chiral catalysis, and more specifically, to a monophosphine ligand oEPCP containing a [2.2]-p-cyclophane skeleton structure, and a preparation method and application thereof. Background Art

[0002] Chiral phosphine ligands have been widely used as chiral ligands, serving the precise and efficient creation of chiral drugs and chiral material molecules. Therefore, the development of new chiral phosphine ligands has always been one of the hot and cutting-edge research areas in the field of asymmetric catalysis (Fu, X.-F.; Zhou, Q.-L. CCS Chem. 2023, 5, 2685; Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.). However, most of these phosphine ligands reported in the literature are axially chiral, and there are fewer types of phosphine ligands developed based on planar chiral aromatic skeletons (CN101003549B; CN100379747C; Felder, S.; Wu, S.; Brom, J.; Micouin, L.; Benedetti, E. Chirality. 2021, 33, 506;), as shown in the following structures:

[0003]

[0004] Therefore, the present invention aims to provide a type of monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure and a preparation method and application thereof, by synthesizing a new type of non-C2-symmetric, planar chiral, sterically hindered, electron-donating ortho-oxaphosphine ligand oEPCP containing a [2.2]-cyclophane skeleton, and successfully applying it to palladium-catalyzed asymmetric Suzuki-Miyaura reaction and gold-catalyzed asymmetric [3+2] cycloaddition reaction. Summary of the invention

[0005] The purpose of the present invention is to provide a type of monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure and a preparation method and application thereof. The present invention starts from the enantiomer and racemate of o-bromo-4-hydroxy[2.2]-cyclophane synthesized by commercializing 4-hydroxy[2.2]-cyclophane as a starting material, and designs and synthesizes the corresponding monophosphine ligand oEPCP having a [2.2]-cyclophane skeleton. The skeleton is stable, easy to modify, has the characteristics of electron donation and large steric hindrance, and the synthesis route is simple, which will enrich and develop the types of chiral phosphine ligands and has important academic value and application value.

[0006] The above technical objectives of the present invention are achieved through the following technical solutions: a class of monophosphine ligands oEPCP containing a [2.2]-cyclophane skeleton structure, including racemates or enantiomers, and the structural formula-I of the monophosphine ligand oEPCP is as follows:

[0007]

[0008] Wherein, R is a substituted or unsubstituted phenyl or alkyl group, the substituents of the substituted phenyl group are each independently selected from C1-C6 alkyl, C1-C6 alkoxy or halogen, the number of the substituents is 1, 2 or 3, and the alkyl group is C1-C10 alkyl;

[0009] R 1 It is any one of hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 alkylsilyl, substituted or unsubstituted C6-C20 arylsilyl, one or more hydrogen atoms in the substituted group may be substituted by C1-C6 alkyl, C1-C6 alkoxy or halogen, and the number of substituents is 1, 2 or 3.

[0010] The present invention is further configured as follows: in the structural formula-Ⅰ of the monophosphine ligand oEPCP, R is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dipropylphenyl, 3,5-di-tert-butylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,4,5-trimethylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl or 3,5-di-tert-butyl-4-methylphenyl and methyl, ethyl, isopropyl, tert-butyl, cyclohexyl or 1-adamantyl.

[0011] The present invention is further configured as follows: In the structural formula-Ⅰ of the monophosphine ligand oEPCP, R 1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C5-C12 straight or branched alkyl, cyclopropyl, cyclobutyl, C5-C20 cycloalkyl, benzyl, naphthyl, methoxymethyl, trifluoromethyl, C2-C6 fluoroalkyl, trimethylsilyl, triethylsilyl, triphenylsilyl, C7-C9 silyl.

[0012] The present invention also provides a method for preparing a type of monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure, which is characterized by comprising the following steps:

[0013] S1, using a chiral or racemic compound ortho-halogenated 4-hydroxy [2.2] p-cyclophane 1 as a starting material, and subjecting it to an electrophilic substitution reaction with a halogenated compound R1-X of R1 under alkaline conditions, so that the phenolic hydroxyl group is introduced into the substituent group R1 to obtain compound 2;

[0014] S2, exchanging the obtained compound 2 with butyl lithium for lithium bromide to obtain an aryl lithium compound intermediate 3;

[0015] S3. Adding a di-R-substituted chlorophosphine R2PCl into the reaction system to cause electrophilic substitution to generate a planar chiral or racemic phosphine ligand compound oEPCP.

[0016] The present invention is further configured as follows: the reaction temperature in step S1 is -20 to 40°C, the reaction time is 0.5 to 12 hours, the reaction is carried out in the presence of a base, the reaction environment is an organic solvent environment, and the protective atmosphere of the reaction is nitrogen or argon inert gas;

[0017] The reaction temperature in step S2 is -80 to 60°C, the reaction time is 0.5 to 24 hours, the reaction is carried out in the presence of butyl lithium, the reaction environment is an anhydrous organic solvent environment, and the protective atmosphere of the reaction is nitrogen or argon inert gas;

[0018] The reaction temperature in step S3 is -80 to 60°C, the reaction time is 0.5 to 24 hours, the reaction is carried out in the presence of a di-R substituted chlorophosphine R2PCl, the reaction environment is an anhydrous organic solvent environment, and the reaction protective atmosphere is nitrogen or argon inert gas.

[0019] The present invention is further configured as follows: the reaction equation of the monophosphine ligand oEPCP is:

[0020]

[0021] The present invention also provides a type of monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure and its application in asymmetric catalysis.

[0022] In summary, the present invention has the following beneficial effects:

[0023] 1. The monophosphine ligand oEPCP with a [2.2]-cyclophane skeleton of the present invention has a simple synthesis method, and has unique planar chirality, large steric hindrance, electron donation, and rigid skeleton characteristics. By introducing different types of substituents on the ortho-phenolic hydroxyl group, the electron cloud density of the aromatic ring is increased, and the steric hindrance is changed. At the same time, the ortho-ether substituent can also serve as a weak coordination group to participate in adjusting the dihedral angle of the ligand chelation. This allows the ligand, metal, and substrate to form the most suitable coordination environment during the catalytic process, thereby showing excellent catalytic activity and enantioselectivity control ability;

[0024] 2. The present invention starts from the enantiomers and racemates of o-bromo-4-hydroxy[2.2]-cyclophane synthesized from commercial 4-hydroxy[2.2]-cyclophane as the starting material, and designs and synthesizes the corresponding monophosphine ligand oEPCP having a [2.2]-cyclophane skeleton. This type of skeleton is stable, easy to modify, has the characteristics of electron donation and large steric hindrance, and the synthetic route is simple. It will enrich and develop the types of chiral phosphine ligands and has important academic and application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a single crystal image of (Sp)-oEPCP-L1 in Example 1 of the present invention;

[0026] Figure 2 This is the synthesis route of the (Sp)-oEPCP-L1 compound in Example 1 of the present invention. DETAILED DESCRIPTION

[0027] The following is combined with Figure 1-2 The present invention is described in further detail.

[0028] Example 1: Preparation of a planar chiral monophosphine ligand (Sp)-oEPCP-L1 having a [2.2]-cyclophane skeleton, the structural formula of which is as follows:

[0029]

[0030] The preparation method of (Sp)-oEPCP-L1 compound in this embodiment, the synthetic route is as follows Figure 2 As shown, the following steps are included:

[0031] 1) Under nitrogen protection, a planar chiral o-iodo-5-hydroxy[2.2]-p-cyclophane (Sp)-1 compound (35 g, 100 mmol) and anhydrous DMF 100 mL were added to a dry 500 mL three-necked flask in sequence, and the reaction system was then transferred to an ice bath and stirred for 10 min. NaH (250 mmol, 2.5 eq., 10 g, 60% wt) was added in batches and continued to stir in the ice bath for 10 min. MeI (200 mmol, 2.0 eq., 12.5 mL) was then slowly added dropwise to the reaction system, the ice bath was removed, and stirring was continued for 1 h. The plate was sampled and tested. After the reaction was completed, saturated NH4Cl 20 mL was added to quench the reaction, and EA was extracted 3 times. The organic phases were combined and washed with saturated NaCl, dried over anhydrous Na2SO4, and evaporated under reduced pressure. After removing the solvent, the crude product was purified by silica gel column chromatography to obtain 33.1 g of (Sp)-2 compound with a yield of 91%.

[0032] 2) Under nitrogen protection, (Sp)-2 (10 mmol, 3.64 g) and 50 mL of anhydrous THF were added in sequence to a dry 250 mL single-mouth eggplant-shaped reaction bottle, and the reaction system was then transferred to -50 °C and stirred for 10 min. Then n-BuLi (30 mmol, 3.0 eq., 18.8 mL, 1.6 M n-hexane solution) was added dropwise to the reaction system and stirring was continued for 1 h to obtain the active intermediate lithium reagent 4.

[0033] 3) PPh2Cl (20 mmol, 2.0 eq., 3.6 mL) was then added dropwise to the reaction system, the refrigeration was turned off, and the mixture was stirred overnight; the plate was sampled for detection, and after the reaction was completed, 10 mL of saturated NH4Cl was added to quench the reaction, and the mixture was extracted with EA three times. The organic phases were combined and washed with saturated NaCl, dried over anhydrous Na2SO4, and evaporated under reduced pressure. After the solvent was removed, the crude product was purified by silica gel column chromatography (PE:DCM=2:1) ​​to obtain 2.65 g of a white solid (Sp)-L1 product with a yield of 63%.

[0034] Ligand (Sp)-L1 Characterization: 1 H NMR (400MHz, Chloroform-d) δ7.48–7.36(m,5H),7.26–7.19(m,5H),7.04(dd,J=8.0,2.0Hz,1H),6.73(dd,J=8.0,2. 0Hz,1H),6.48(dd,J=7.8,2.0Hz,1H),6.08(dd,J=8.0,2.0Hz,1H),5.70(dd,J=13.2,5.8Hz,2H),3.71(s,3H),3.63( ddt,J=12.8,10.4,2.2Hz,1H),3.45(ddd,J=12.5,10.4,5.0Hz,1H),3.27(ddd,J=13.0,8.8,2.5Hz,1H),3.03(ddd,J =12.8,10.5,2.5Hz,1H),2.99–2.86(m,2H),2.73(tdd,J=11.0,5.2,2.5Hz,1H),2.24(ddd,J=13.0,10.0,7.0Hz,1H); 13C NMR(101MHz,Chloroform-d)δ158.4,146.6,146.4,139.8,138.8,138.6,138.5,137.9,137.2,137.1,135.2,135.0,133.0,132.9 ,132.8,131.6,131.5,131.2,129.0,128.6,128.5,128.3,128.2,128.1,127.1,118.1,118.1,54.2,34.6,34.4,34.3,33.3,31.3; 31 PNMR(162MHz,Chloroform-d)δ-7.65; HRMS(ESI)m / z calcd.for423.1878,found:423.1876.

[0035] Example 2: According to the preparation method of Example 1, a series of planar chiral phosphine ligand compounds oEPCP-L1 to oEPCP-L14 were synthesized by conventional techniques in the art, and the structural formulas are shown below:

[0036]

[0037] Example 3: Experiment on the palladium-catalyzed asymmetric Suzuki-Miyaura reaction of the monophosphine ligand oEPCP having a [2.2]-cyclophane skeleton

[0038] In this embodiment [2.2], the reaction equation for the palladium-catalyzed asymmetric Suzuki-Miyaura reaction of the monophosphine ligand oEPCP of the cyclophane skeleton is as follows:

[0039]

[0040] By taking 25mL sealed tube, under argon atmosphere, add bromophosphine oxide (0.1mmol, 1.0eq.), 2-methoxynaphthalene-1-boric acid (0.15mmol, 1.5eq.), Pd(OAc)2 (5mol%), ligand L* (12mol%), potassium carbonate (2.0eq.), evacuate three times, add 2mL ultra-dry toluene under nitrogen atmosphere, and react at 50°C for 36h. Purify by silica gel column chromatography and analyze by HPLC to obtain the yield and ee value of the product. Catalytic reactions were carried out with ligands different from the present invention and commercially available well-known chiral ligands L1-L8, and their structural formulas are shown below:

[0041]

[0042] The results are shown in Table 1:

[0043] Table 1 Results of catalytic reactions of chiral ligands L1-L8

[0044]

[0045]

[0046] Example 4: Under the same experimental conditions and operation as Example 3, different types of substrates were replaced to carry out asymmetric palladium-catalyzed asymmetric Suzuki-Miyaura reaction. The reaction equation is shown below:

[0047]

[0048] The reaction results are shown in Table 2:

[0049] Table 2 Asymmetric Suzuki-Miyaura reaction catalyzed by asymmetric palladium on different types of substrates

[0050]

[0051]

[0052] As can be seen from Table 1 and Table 2, the monophosphine ligand oEPCP having a [2.2] paracyclophane skeleton of the present invention has excellent catalytic activity and enantioselectivity for the palladium-catalyzed asymmetric Suzuki-Miyaura reaction of bromophosphine oxide with aryl boronic acid, and the result is better than other related types of chiral phosphine ligands available at present; and the result obtained in ortho-alkyl substituted aryl boronic acid compounds is significantly better than that of other related types of chiral phosphine ligands.

[0053] The monophosphine ligand oEPCP having a [2.2]-cyclophane skeleton of the present invention also has good catalytic activity and enantioselectivity in a gold-catalyzed asymmetric [3+2] cycloaddition reaction.

[0054] Example 5: Application of the monophosphine ligand oEPCP having a [2.2]-cyclophane skeleton in a gold-catalyzed asymmetric [3+2] cycloaddition reaction, the reaction equation of which is shown below:

[0055]

[0056] Take a 25mL dry reaction tube, under an argon atmosphere, add AuCl(SMe)2 (5mol%), ligand L* (5.5mol% or 2.5mol%), and 1mL of 1,2-dichloroethane in sequence, stir at room temperature for 2h, then add counter anion silver salt (5mol%) and stir at room temperature for 10min, then add enynone (0.1mmol, 1.0eq.), nitrone (0.2mmol, 2.0eq.) in sequence, and stir at room temperature for 24h. Purify by silica gel column chromatography and analyze by HPLC to obtain the yield and ee value of the product. Catalytic reactions were carried out with ligands different from the present invention and commercially available well-known chiral ligands L1-L8, and the results are shown in Table 3:

[0057] Table 3 Results of catalytic reactions of chiral ligands L1-L8

[0058]

[0059]

[0060] As can be seen from Table 3, the monophosphine ligand oEPCP having a [2.2] paracyclophane skeleton of the present invention has good catalytic activity and enantioselectivity in the gold-catalyzed asymmetric [3+2] cycloaddition reaction of enynone and nitrone, and its results are significantly better than those of other related types and chiral phosphine ligands with similar structures.

[0061] Example 6: Under the same experimental conditions and operation as Example 5, different types of substrates were replaced to carry out an asymmetric [3+2] cycloaddition reaction. The reaction equation is shown below:

[0062]

[0063] The reaction results are shown in Table 4:

[0064] Table 4 Results of asymmetric [3+2] cycloaddition reactions of different types of substrates

[0065]

[0066]

[0067] As can be seen from Tables 3 and 4, the monophosphine ligand oEPCP having a [2.2]cyclophane skeleton of the present invention has excellent catalytic activity and enantioselectivity for the asymmetric gold-catalyzed asymmetric [3+2] cycloaddition reaction involving enynone and nitrone, and the results are better than those of other related types of chiral phosphine ligands available at present; significantly better results than those of other related types of chiral phosphine ligands are also obtained in nitrone compounds derived from alkyl aldehydes and ketones.

[0068] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A type of monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure, characterized in that: Including racemates or enantiomers, the structural formula-Ⅰ of the monophosphine ligand oEPCP is as follows: Wherein, R is a substituted or unsubstituted phenyl or alkyl group, the substituents of the substituted phenyl group are each independently selected from C1-C6 alkyl, C1-C6 alkoxy or halogen, the number of the substituents is 1, 2 or 3, and the alkyl group is C1-C10 alkyl; R 1 It is any one of hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 alkylsilyl, substituted or unsubstituted C6-C20 arylsilyl, one or more hydrogen atoms in the substituted group may be substituted by C1-C6 alkyl, C1-C6 alkoxy or halogen, and the number of substituents is 1, 2 or 3.

2. The monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure according to claim 1, characterized in that: In the structural formula-Ⅰ of the monophosphine ligand oEPCP, R is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-diethylphenyl, 3,5-dipropylphenyl, 3,5-di-tert-butylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,4,5-trimethylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl or 3,5-di-tert-butyl-4-methylphenyl and methyl, ethyl, isopropyl, tert-butyl, cyclohexyl or 1-adamantyl.

3. The monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure according to claim 1, characterized in that: In the structural formula-Ⅰ of the monophosphine ligand oEPCP, R 1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C5-C12 straight or branched alkyl, cyclopropyl, cyclobutyl, C5-C20 cycloalkyl, benzyl, naphthyl, methoxymethyl, trifluoromethyl, C2-C6 fluoroalkyl, trimethylsilyl, triethylsilyl, triphenylsilyl, C7-C9 silyl.

4. A method for preparing a monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1, using a chiral or racemic compound ortho-halogenated 4-hydroxy [2.2] p-cyclophane 1 as a starting material, and subjecting it to an electrophilic substitution reaction with a halogenated compound R1-X of R1 under alkaline conditions, so that the phenolic hydroxyl group is introduced into the substituent group R1 to obtain compound 2; S2, exchanging the obtained compound 2 with butyl lithium for lithium bromide to obtain an aryl lithium compound intermediate 3; S3. Adding a di-R-substituted chlorophosphine R2PCl into the reaction system to cause electrophilic substitution to generate a planar chiral or racemic phosphine ligand compound oEPCP.

5. The method for preparing a monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure according to claim 4, characterized in that: The reaction temperature in step S1 is -20 to 40°C, the reaction time is 0.5 to 12 hours, the reaction is carried out in the presence of a base, the reaction environment is an organic solvent environment, and the protective atmosphere of the reaction is nitrogen or argon inert gas; The reaction temperature in step S2 is -80 to 60°C, the reaction time is 0.5 to 24 hours, the reaction is carried out in the presence of butyl lithium, the reaction environment is an anhydrous organic solvent environment, and the protective atmosphere of the reaction is nitrogen or argon inert gas; The reaction temperature in step S3 is -80 to 60°C, the reaction time is 0.5 to 24 hours, the reaction is carried out in the presence of a di-R substituted chlorophosphine R2PCl, the reaction environment is an anhydrous organic solvent environment, and the reaction protective atmosphere is nitrogen or argon inert gas.

6. The method for preparing a monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure according to claim 5, characterized in that: The reaction equation of the monophosphine ligand oEPCP is:

7. Use of a monophosphine ligand oEPCP containing a [2.2]-cyclophane skeleton structure according to any one of claims 1 to 3 in asymmetric catalysis.

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