A method for constructing axial chiral compounds by rhodium-catalyzed hydrogenation and desymmetrization of anthracene
The hydrogenation reaction of 9-aryl substituted anthracene was catalyzed by rhodium chiral bisphosphine ligand catalyst, which solved the problem of slow development of asymmetric hydrogenation of aromatic carbocyclic compounds, and achieved the synthesis of axial chiral compounds with high enantioselectivity and high yields , has environmentally friendly and practical value.
Patent Information
- Application Number
- CN202210411469.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-04-19
- Publication Date
- 2024-12-10
- Estimated Expiration
- 2042-04-19
AI Technical Summary
The development of asymmetric hydrogenation of aromatic carbocyclic compounds is relatively slow, and lacks an efficient catalytic system, making it difficult to achieve high enantioselective synthesis of axial chiral compounds.
Using rhodium chiral bisphosphine ligand catalyst, the hydrogenation reaction of 9-aryl-substituted anthracene is catalyzed by the chiral bisphosphine complex of rhodium to achieve high enantioselective synthesis of axial chiral 1-aryl-substituted naphthalene derivatives .
High enantioselectivity (enantiomer excess can reach 89%), high yield, easy operation, environmentally friendly axial chiral compound synthesis, with potential practical value and green atomic economy.
Smart Images
Figure BDA0003603884920000021 
Figure BDA0003603884920000051 
Figure BDA0003603884920000052
Abstract
Description
Technical Field
[0001] The invention belongs to the field of asymmetric catalytic synthesis, relates to a method for constructing an axial chiral compound by hydrogenation desymmetrization of anthracene catalyzed by rhodium, and provides a method for synthesizing the axial chiral compound with high enantioselectivity. Technical Background
[0002] Asymmetric hydrogenation of aromatic compounds provides a simple and efficient way to synthesize chiral cyclic compounds. Although asymmetric hydrogenation of aromatic heterocyclic compounds has achieved a series of excellent research results, the development of asymmetric hydrogenation of aromatic carbocyclic compounds is very slow. At present, there are only a few reports on asymmetric hydrogenation of aromatic carbocyclic compounds. In 2011, Professor Glorius of the University of Münster in Germany used electron-rich chiral carbene as ligand to achieve ruthenium-catalyzed regioselective asymmetric hydrogenation of aromatic carbocyclic 2,3-diphenylquinoxaline. In 2012, the Kuwano research group of Kyushu University in Japan used the complex of trans-chelated ferrocene diphosphine ligand Ph-TRAP and transition metal ruthenium as catalyst to achieve asymmetric hydrogenation of 2-naphthyl ether compounds. Subsequently, the catalytic system was extended to the highly regioselective asymmetric hydrogenation of aromatic carbocyclic 8-substituted quinoline and 6-substituted isoquinoline. Recently, Researcher Zhou Yonggui of Dalian Institute of Chemical Physics used chiral bisphosphine complex catalyst of ruthenium to achieve asymmetric hydrogenation of 9-phenanthranamine. This catalytic system is not only effective for monosubstituted phenanthrenamine substrates, but also suitable for the asymmetric hydrogenation of 9,10-disubstituted phenanthrenamines to construct alkylamine compounds with two adjacent chiral centers. (Reference 1: (a) Urban, S.; Ortega, N.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 3803-3806. (b) Kuwano, R.; Morioka, R.; Kashiwabara, M.; Kameyama, N. Angew. Chem. Int. Ed. 2012, 51, 4136-4139. (c) Kuwano, R.; Ikeda, R.; Hirasada, K. Chem. Commun. 2015, 51, 7558-7561. (d) Jin, Y.; Makida, Y.; Uchida, T.; Kuwano, RJ Org. Che m. 2018, 83, 3829-3839. (e) Yan, Z.; Xie, H.-P.; Shen, H.-Q.; Zhou, Y.-G. Org. Lett. 2018, 20, 1094-1097.).
[0003] Axially chiral biaryl compounds are widely present in natural products, drugs, and materials, and are widely used in asymmetric reactions as axially chiral ligands or catalysts. (Reference 2: (a) Bringmann, G.; Gulder, T.; Gulder, TAM; Breuning, M. Chem. Rev. 2011, 111, 563-639. (b) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029-3069. (c) Terada, M. Synthesis 2010, 12, 1929-1982. (d) Rueping, M.; Kuenkel, A.; Atodiresei, L. Chem. Soc. Rev. 2011, 40, 4539-4549. (e) Chen, Y.; Yekta, S.; Yudin, AK Chem. Rev. 2003, 103, 3155-3212.) Desymmetrization is one of the strategies for efficiently constructing chiral compounds. (Reference 3: (a) Willis, MC Enantioselective desymmetrisation. J. Chem. Soc., Perkin Trans. 1999, 1, 1765. (b) García-Urdiales, E.; Alfonso, I.; Gotor, V. Enantioselective enzymatic desymmetrizations in organic synthesis. Chem. Rev. 2005, 105, 313. (c) Borissov, A.; Davies, TQ; Ellis, SR; Fleming, TA; Richardson, MSW; Dixon, DJ Organocatalytic enantioselective desymmetrisation. Chem. Soc. Rev. 2016, 45, 5474.) Therefore, the development of efficient catalytic systems to achieve asymmetric hydrogenation of aromatic carbocyclic compounds remains one of the challenging frontier scientific issues facing synthetic chemistry. Based on this, the present invention provides the first asymmetric hydrogenation of 9-aryl substituted anthracene compounds catalyzed by rhodium and chiral bisphosphine ligands, and provides axial chiral biaryl compounds with high enantioselectivity through a desymmetrization strategy. Summary of the invention
[0004] The invention provides a method for constructing an axial chiral compound by rhodium-catalyzed hydrogenation and desymmetrization of anthracene. The method is simple and practical to operate, the raw materials are readily available, the enantioselectivity is good, the yield is high, and the reaction has the advantages of green atom economy, environmental friendliness, potential practical value, etc.
[0005] The technical solution of the present invention is as follows:
[0006] A method for constructing an axial chiral compound by hydrogenation and desymmetrization of anthracene catalyzed by rhodium, characterized in that the method uses a chiral diphosphine complex of rhodium as a catalyst and a 9-aryl substituted anthracene compound as a substrate to synthesize a 1-aryl substituted naphthalene derivative having axial chirality by hydrogenation and desymmetrization;
[0007] The reaction formula is as follows:
[0008]
[0009] Where:
[0010] R is C1-C 10 Alkyl or aryl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0011] Or R=N(R1)SO2R2, wherein R1 and R2 are independently hydrogen or C1-C 10 Alkyl or aryl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0012] Or R=N(R1)COR2, wherein R1 and R2 are independently hydrogen or C1-C 10 Alkyl or aryl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0013] Or R=OR1, wherein R1 is hydrogen, or C1-C 10 Alkyl or aryl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0014] Or R=OSO2R1, where R1 is C1-C 10 Alkyl or aryl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0015] Or R=OCOR1, where R1 is C1-C 10 Alkyl or aryl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0016] Or R = PR1 2 , where R1 is C1-C 10 Alkyl or aryl, C1-C 10Alkyl includes one or more substituents of methoxy and halogen;
[0017] Ar is a benzene ring or an aromatic ring containing a substituent, wherein the substituent is C1-C 10 Alkyl, C1-C 10 Alkyl includes one or more substituents of methoxy and halogen;
[0018] The catalyst is a complex of a metal rhodium precursor and a chiral diphosphine ligand.
[0019] Based on the above technical solution, preferably, the reaction solvent is an organic solvent, and the organic solvent is one or more of 1,2-dichloroethane, dichloromethane, tetrahydrofuran, toluene, and chloroform; preferably dichloromethane.
[0020] Based on the above technical scheme, preferably, the reaction temperature is: 25-70°C, preferably 30°C; the reaction time is: 45 minutes-60 hours, preferably 5 hours; the hydrogen pressure is: 400-1000psi, preferably 600psi.
[0021] Based on the above technical scheme, preferably, the molar ratio of the 9-aryl substituted anthracene compound, the metal rhodium precursor and the chiral diphosphine ligand is 1:0.01:0.011-1:0.1:0.11, preferably 1:0.05:0.055 or 1:0.02:0.022; the amount of the organic solvent is 0.5-6mL, preferably 6mL; the amount of the 9-aryl substituted anthracene compound is 0.05-0.4mmol, preferably 0.15mmol.
[0022] Based on the above technical scheme, preferably, the metal rhodium precursor is one of bis(1,5-cyclooctadiene)rhodium(I) antimony hexafluoride salt and bis(dicyclopentadiene)rhodium tetrafluoroborate; preferably bis(1,5-cyclooctadiene)rhodium(I) antimony hexafluoride salt.
[0023] Based on the above technical scheme, preferably, the chiral bisphosphine ligand is (S)-(-)-[(5,6),(5',6')-bis(ethylenedioxy)biphenyl-2,2'-yl]diphenylphosphine, (R)-(+)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine), (+)-1,2-bis((2S,5S)-2,5-dimethylphosphine)benzene, (S,S,R ax)-C3*-TunePhos, [(2S,2'S,3S,3'S)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-4,4'-dimethoxy-2,2'-bis-1,3-benzooxaphosphorene], (2R,2'R,3R,3'R)-4,4'-bis(2,6-dimethoxyphenyl)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'-bis-1,3-benzooxaphosphorene One of pentadiene, (2R,2'R,3R,3'R)-4,4'-di(9-anthryl)-3,3'-di(tert-butyl)-2,2',3,3'-tetrahydro-2,2'-dibenzo[D][1,3]oxy, phosphine pentane conjugated, preferably (2R,2'R,3R,3'R)-4,4'-di(9-anthryl)-3,3'-di(tert-butyl)-2,2',3,3'-tetrahydro-2,2'-dibenzo[D][1,3]oxy, phosphine pentane conjugated.
[0024] Based on the above technical scheme, preferably, the preparation method of the catalyst is: under nitrogen protection, the metal rhodium precursor and the chiral diphosphine ligand are stirred in a solvent at room temperature for 10 minutes to 60 minutes, and the solvent used for the preparation of the catalyst is selected from one or more of trifluoroethanol, 1,2-dichloroethane, dichloromethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, toluene, benzene, trifluorotoluene, chlorobenzene, and methanol, preferably dichloromethane.
[0025] Based on the above technical scheme, preferably, the specific reaction steps of the method are: adding a 9-aryl substituted anthracene compound, an in-situ prepared catalyst and a solvent into a reaction bottle, placing the reaction bottle into an autoclave, introducing H2 to react to obtain a hydrogenated product, and purifying to obtain a pure product.
[0026] Based on the above technical scheme, preferably, the purification step is: after releasing hydrogen, the solvent is dried and separated by column chromatography to obtain a pure product.
[0027] The method of the present invention can realize the rhodium-catalyzed hydrogenation desymmetrization reaction of 9-aryl substituted anthracene, and obtain axial chiral compounds with high yield and high enantioselectivity (enantiomeric excess can reach 89%). The present invention has high enantioselectivity, simple and practical operation, easy to obtain raw materials, commercially available catalysts, mild reaction conditions, low energy consumption, environmental friendliness and potential practical value.
[0028] Beneficial Effects
[0029] 1. The raw materials are simple and easy to obtain, the catalyst is easy to prepare, and the reaction operation is simple and practical.
[0030] 2. High reaction activity, complete conversion of raw materials, easy separation, and high-purity products can be obtained.
[0031] 3. Good stereoselectivity, and can obtain enantiomers with high enantioselectivity.
[0032] 4. The reaction conditions are mild and environmentally friendly. DETAILED DESCRIPTION
[0033] The present invention is described in detail below by examples, but the present invention is not limited to the following examples.
[0034] References for the synthesis of 9-aryl substituted anthracenes in the following examples: (a) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; Kockritz, A.; Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008,64,1316-1322.(b)St-Gelais,A.;Alsarraf,J.;Legault,J.;Gauthier,C.;Pichette,A.Org.Lett.2018,20,7424-7428.(c)Ha n, B.; Ma, P.; Cong, X.; Chen, H.; Zeng, 4-55. (e) Hu, R.-B.; Zhang, H; Zhang, X.-Y; Yang, S.-D. Chem. Commun.2014,50,2193-2195. (f) -F;Fan,B.-M.;Duan,H.-F;Zhou,Q.-LJAm.Chem.Soc.2003,125,4404-4405.(g)Agrawal,T.;Cook,SPOrg.Lett.2014,16,5080-5083.
[0035] Examples 1-14
[0036] Condition optimization: changing the types of organic solvent, catalyst precursor and chiral ligand
[0037] Rhodium precursor (5.0 mol%) and chiral ligand (5.5 mol%) were added to the reaction bottle, and 1 mL of solvent was added after nitrogen replacement. The reaction bottle was stirred at room temperature for 10 minutes to prepare the catalyst in situ. The reaction bottle containing substrate 9-aryl substituted anthracene 1a (0.05 mmol) was added with the prepared catalyst and 1 mL of solvent in the glove box, and then placed in a high-pressure reactor, and hydrogen (600 psi) was introduced to react at 30°C for 22 hours. Hydrogen was slowly released, the solvent was removed by rotary evaporation, and the pure product was separated by column chromatography.
[0038] Types of organic solvent, catalyst precursor and chiral ligand. Specific results are shown in Table 1; ee is enantioselectivity.
[0039]
[0040] Table 1. Optimization of asymmetric hydrogenation conditions for 9-aryl substituted anthracene 1a
[0041]
[0042] Embodiment 15-42
[0043] Asymmetric hydrogenation of 9-aryl substituted anthracenes.
[0044] In a reaction flask, add bis(1,5-cyclooctadiene)rhodium(I) antimony hexafluoride salt (5.0 mol%) and (2R,2'R,3R,3'R)-4,4'-di(9-anthryl)-3,3'-di(tert-butyl)-2,2',3,3'-tetrahydro-2,2'-dibenzo[D][1,3]oxy,phosphine pentane conjugate (5.5 mol%), add 1 mL of dichloromethane after nitrogen replacement, stir at room temperature for 10 minutes, and prepare the catalyst in situ. In a glove box, add the catalyst prepared in advance and 5 mL of dichloromethane to the reaction flask containing the substrate 9-aryl substituted anthracene (0.15 mmol), put it in a high-pressure reactor, pass hydrogen (600 psi), and react at 30°C for 5 hours. Slowly release hydrogen, remove the solvent by rotary evaporation, and separate by column chromatography to obtain a pure product.
[0045] The 9-aryl substituted anthracene compound containing a nitrogen atom is 1, and 14 different examples of 1-aryl substituted naphthalene derivatives 2 are obtained by simply changing the type of 1 in the reaction. The specific types of changes are as follows:
[0046]
[0047] The reaction time of 2b was 12 hours, and the reaction time of 2c-n was 45 minutes.
[0048] The absolute configuration of 2a was determined to be R by X-ray diffraction. The CCDC number is 2095168.
[0049] In order to expand the applicable scope of asymmetric hydrogenation substrates of 9-aryl substituted anthracene compounds, raw materials containing ester groups, sulfonyl groups, and alkyl groups in the substrates can also obtain 1-aryl substituted naphthalene derivatives with high yield and high enantioselectivity. The compound is 3. Only by changing the type of 3 in the reaction, 12 different examples of 1-aryl substituted naphthalene derivatives 4 are obtained. The specific types of changes are as follows:
[0050]
[0051] The catalyst dosage of 4i-k is 5 mol%.
[0052] The absolute configuration of 4c was determined to be R by X-ray diffraction. The CCDC number is 2080871.
[0053] In order to further expand the scope of application of asymmetric hydrogenation substrates of 9-aryl substituted anthracene compounds and explore their application value, the phosphorus raw materials in the substrate can also obtain axially chiral phosphine oxide compounds with high yield and high enantioselectivity. This type of compound is 5. Only by changing the type of 5 in the reaction, two phosphine oxide compounds 6 with different axial chirality are obtained. Compound 6 can be treated with simple treatment to obtain monophosphine ligand 7 with axial chirality. The specific types of changes are as follows:
[0054]
[0055] The reaction time of 6a was 5 hours, and the reaction time of 6b was 48 hours.
[0056] The absolute configuration of 6a was determined to be R by X-ray diffraction. The CCDC number is 2044557. The compound 7 obtained by simple reduction of product 6 can be used as a monophosphine ligand with axial chirality in organic synthesis.
[0057]
[0058]
[0059]
[0060]
[0061]
[0062]
[0063]
[0064]
[0065]
Claims
1. A method for constructing axial chiral compounds by rhodium-catalyzed hydrogenation and desymmetrization of anthracene compounds, It is characterized in that The method uses a chiral diphosphine complex of rhodium as a catalyst and a 9-aryl substituted anthracene compound as a substrate, and synthesizes a 1-aryl substituted naphthalene derivative with axial chirality through hydrogenation and desymmetrization. The reaction formula is as follows: Where: R is C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; Or R=N(R 1 )SO 2 R 2 , where R 1 , R 2 are independently hydrogen or C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; Or R=N(R 1 )COR 2 , where R 1 , R 2 are independently hydrogen or C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; R=OR 1 , where R 1 is hydrogen, or C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; Or R = OSO 2 R 1 , where R 1 C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; Or R = OCOR 1 , where R 1 C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; Or R = PR 1 2 , where R 1 C 1 -C 10 Alkyl or aryl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; Ar is a benzene ring or an aromatic ring containing a substituent, wherein the substituent is C 1 -C 10 Alkyl, C 1 -C 10 Alkyl includes one or more substituents of methoxy and halogen; The catalyst is a complex of a metal rhodium precursor and a chiral diphosphine ligand; The reaction solvent is an organic solvent, and the organic solvent is one or more of 1,2-dichloroethane, dichloromethane, and chloroform; The metal rhodium precursor is one of bis(1,5-cyclooctadiene)rhodium(I) antimony hexafluoride salt and bis(dicyclopentadiene)rhodium tetrafluoroborate; the chiral diphosphine ligand is (2R,2'R,3R,3'R)-4,4'-di(9-anthryl)-3,3'-di(tert-butyl)-2,2',3,3'-tetrahydro-2,2'-dibenzo[D][1,3]oxy, phosphine pentane conjugate.
2. The method according to claim 1, It is characterized in that Reaction temperature: 25-70°C; reaction time: 45 minutes-60 hours; hydrogen pressure: 400-1000 psi.
3. The method according to claim 1, Features: The molar ratio of the 9-aryl substituted anthracene compound, the metal rhodium precursor and the chiral diphosphine ligand is 1:0.01:0.011-1:0.1:0.11, and the amount of the organic solvent used is 0.5-6 mL per 0.05-0.4 mmol of the 9-aryl substituted anthracene compound.
4. The method according to claim 1, Features: The preparation method of the catalyst is as follows: under the protection of nitrogen or argon, a metal rhodium precursor and a chiral diphosphine ligand are stirred in a solvent at room temperature for 10 minutes to 60 minutes, and the solvent used for preparing the catalyst is selected from 1,2-dichloroethane and dichloromethane.
5. The method according to claim 1, It is characterized in that The specific reaction steps of the method are: adding a 9-aryl substituted anthracene compound, an in-situ prepared catalyst and a solvent into a reaction bottle, placing the reaction bottle into an autoclave, and introducing H 2 The reaction yields a hydrogenated product, which is then purified to obtain a pure product.
6. The method according to claim 5, It is characterized in that The purification step is: after releasing hydrogen, the solvent is dried by spin drying, and the pure product is separated by column chromatography.