Phosphorus-containing nitrogen oxide compound based on cycloarane skeleton and ferrocene skeleton, and preparation method and application thereof
By synthesizing phosphorus-containing nitrogen oxides based on cycloarane and ferrocene skeletons, the problem of insufficient research on chiral PNO ligands was solved, and high catalytic activity and enantioselectivity control were achieved in asymmetric catalysis.
Patent Information
- Application Number
- CN202410974570.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-07-19
- Publication Date
- 2026-01-20
AI Technical Summary
There is limited research on chiral PNO ligands in the current technology, which limits the types and effects of asymmetric catalysis.
A class of phosphorus-containing nitrogen oxide compounds based on cycloaryl and ferrocene skeletons were designed. By reducing and amination of cycloaryl and diarylphosphine-ferrocene formaldehyde with optically pure 5-hydroxy-4-amino[2.2], a tridentate phosphine nitrogen oxide ligand with facial chirality was synthesized for the asymmetric hydrogenation of simple ketone compounds catalyzed by iridium.
The synthesized phosphorus-containing nitrogen oxides exhibit excellent catalytic activity and enantioselectivity control, and have been applied to the asymmetric hydrogenation of N-arylindolones and heteroaryl ketones, achieving highly efficient catalytic effects.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a class of phosphorus-nitrogen-oxygen compounds based on cycloaralkane skeleton and ferrocene skeleton, and a preparation method and application thereof, and belongs to the technical field of organic synthesis. BACKGROUND
[0002] Due to the excellent atom economy and high efficiency of asymmetric hydrogenation reaction, the asymmetric hydrogenation of prochiral ketones is an effective means to obtain chiral alcohols. In the past few decades, many tridentate ligands for asymmetric hydrogenation have been synthesized and reported, such as NNN, PNN, PNS ligands (Literature: a) Zhang, F.-H.;Wang, C.;Xie, J.-H.;Zhou, Q.-L. Adv. Synth. Catal. 2019, 361, 2832;b) Chen, G.-Q.;Lin, B.-J.;Huang, J.-M.;Zhao, L.-Y.;Chen, Q.-S.;Jia, S.-P.;Yin, Q.;Zhang, X. J. Am. Chem. Soc. 2018, 140, 8064;c) Yamamura, T.;Nakatsuka, H.;Tanaka, S.;Kitamura, M. Angew. Chem. Int. Ed. 2013, 52, 9313;d) Bao, D.-H.;Wu, H.-L.;Liu, C.-L.;Xie, J.-H.;Zhou, Q.-L. Angew. Chem. Int. Ed. 2015, 54, 8791;e) Enthaler, S.;Hagemann, B.;Bhor, S.;Anilkumar, G.;Tse, M.K.;Bitterlich, B.;Junge, K.;Erre, G.;Beller, M. Adv. Synth. Catal. 2007, 349, 853;f) Monfette, S.;Turner, Z.R.;Semproni, S.P.;Chirik, P.J. J. Am. Chem. Soc. 2012, 134, 4561.) Although much progress has been made in tridentate ligands, the research on chiral PNO ligands is relatively less. SUMMARY
[0003] The purpose of the present application is to provide a class of phosphorus-nitrogen-oxygen compounds based on cycloaralkane skeleton and ferrocene skeleton, and a preparation method and application thereof.
[0004] In order to expand the types of chiral phosphorus aza-oxazolane ligands and explore more possibilities in asymmetric catalysis, the present application designs a series of phosphorus aza-oxazolane ligands with two facial chiralities based on cycloparacycloalkane skeleton and ferrocene skeleton, which is a kind of phosphorus aza-oxazolane compounds based on cycloparacycloalkane skeleton and ferrocene skeleton. The synthesis uses optically pure 5-hydroxy-4-amino[2.2]paracyclophane as a raw material, and the compound can be obtained by reductive amination of the compound with diaryl phosphine ferrocene formaldehyde. The compound as a ligand shows excellent catalytic activity and enantioselective control ability in the asymmetric hydrogenation of simple ketone compounds catalyzed by iridium.
[0005] According to one aspect of the present application, a kind of phosphorus aza-oxazolane compounds based on cycloparacycloalkane skeleton and ferrocene skeleton is provided, and the phosphorus aza-oxazolane compound based on cycloparacycloalkane skeleton and ferrocene skeleton is selected from at least one of the compounds with formula I, formula II:
[0006]
[0007] Wherein, Ar is independently selected from phenyl, C7-C 15 Substituted aryl;
[0008] The substituent group of the substituted aryl is selected from one of C1-C4 alkyl, methoxy.
[0009] Optionally, the cycloparacycloalkane skeleton phosphorus aza-oxazolane compound is one of the following: racemic cycloparacycloalkane skeleton and ferrocene skeleton phosphorus aza-oxazolane compound, (R p )-cycloparacycloalkane skeleton and (S FC )-ferrocene skeleton phosphorus aza-oxazolane compound, (R p )-cycloparacycloalkane skeleton and (R FC )-ferrocene skeleton phosphorus aza-oxazolane compound, (S p )-cycloparacycloalkane skeleton and (S FC )-ferrocene skeleton phosphorus aza-oxazolane compound, (S p )-cycloparacycloalkane skeleton and (R FC )-ferrocene skeleton phosphorus aza-oxazolane compound.
[0010] According to another aspect of the present application, a preparation method of the above-mentioned cycloparacycloalkane skeleton and ferrocene phosphorus aza-oxazolane compound is provided, and the preparation method at least includes:
[0011] Under a non-active atmosphere, a mixture containing 5-hydroxy-4-amino[2.2]paracyclophane, a compound shown in formula III, a reducing agent, is reacted to obtain a cycloparacycloalkane skeleton and ferrocene skeleton phosphorus aza-oxazolane compound shown in formula I, formula II;
[0012] The structure of the compound shown in formula III is as follows:
[0013]
[0014] Ar is independently selected from phenyl, C7-C6. 15 Substitution of aryl groups;
[0015] The substituents of the substituted aryl group are selected from one of C1 to C4 alkyl and methoxy groups;
[0016] 5-Hydroxy-4-amino[2.2] at least one of the compounds containing cycloarylanes with structures as shown in Formula IV and Formula V;
[0017]
[0018] Optionally, the reducing agent is selected from at least one of sodium borohydride and sodium cyanoborohydride.
[0019] Optionally, the molar ratio of 5-hydroxy-4-amino[2.2] to cycloarane to the compound shown in Formula II is 1:1 to 1:1.2, and the molar ratio of 5-hydroxy-4-amino[2.2] to cycloarane to the reducing agent is 1:6 to 1:8.
[0020] Optionally, the mixture further contains a solvent selected from at least one of methanol, dichloromethane, ethanol, and chloroform, preferably a mixed solvent of methanol and dichloromethane; for example, the volume ratio of methanol to dichloromethane in the mixed solvent of methanol and dichloromethane is 1:1.
[0021] Optionally, the reaction temperature is 25–40°C.
[0022] Optionally, the temperature of the reaction is selected from any value of 25°C, 30°C, 35°C, 40°C, or a range between any two of the above.
[0023] Optionally, the reaction time is 3 to 6 hours.
[0024] Optionally, the reaction time is selected from any value of 3 hours, 4 hours, 5 hours, 6 hours, or a range between any two of the above points.
[0025] Optionally, the inactive atmosphere is selected from at least one of nitrogen atmosphere and argon atmosphere.
[0026] Optionally, a mixture containing 5-hydroxy-4-amino[2.2]-cycloarane and the compound shown in Formula III is first reacted at 40°C for 7 hours, and then a reducing agent is added and reacted at 25-40°C for 3-6 hours to obtain a phosphorus-containing nitrogen oxide compound containing a cycloarane skeleton and a ferrocene skeleton as shown in Formula I.
[0027] According to another aspect of the present application, there is provided an application of at least one of the above-mentioned cycloaralkane skeleton phosphorus-nitrogen-oxygen compound and the cycloaralkane skeleton phosphorus-nitrogen-oxygen compound prepared by the above-mentioned preparation method as a ligand in asymmetric hydrogenation of an N-aryl indolinone compound or a hetero-biaryl ketone compound catalyzed by iridium.
[0028] Optionally, the iridium precursor is [Ir(COD)Cl]2, the N-aryl indolinone compound is compound 5 in Example 3, and the hetero-biaryl ketone compound is compound 7 in Example 4.
[0029] As a specific embodiment, the present application is implemented by the following technical solutions:
[0030] A kind of phosphorus-nitrogen-oxygen compound based on cycloaralkane skeleton and ferrocene skeleton, the compound can be racemic or optically active, the structural formula of the phosphorus-nitrogen-oxygen compound based on cycloaralkane skeleton and ferrocene skeleton is as follows formula I or formula II compound structure:
[0031]
[0032] Wherein:
[0033] Ar represents phenyl or other aryl with substituents on benzene ring.
[0034] Using optically pure 5-hydroxy-4-amino[2.2]paracyclophane as raw material, it can be obtained by reductive amination reaction with ferrocenyl phosphine benzaldehyde to obtain phosphorus-nitrogen-oxygen compound based on cycloaralkane skeleton and ferrocene skeleton with facial chirality.
[0035] The present application provides a design and synthesis of a kind of phosphorus-nitrogen-oxygen compound based on cycloaralkane skeleton and ferrocene skeleton, and its synthesis route is as follows:
[0036]
[0037] Reaction steps:
[0038] Reductive amination: under nitrogen protection, compound 1, compound 2, methanol and dichloromethane are added to the reaction bottle, and reacted at 40 DEG C for 7 hours, and then the reaction is stopped, compound 3 can be obtained, sodium borohydride is added to the residue, and reacted at room temperature for 3 hours to obtain compound 4.
[0039] In the present application, C1-C4, C7-C 15 All refer to the number of carbon atoms contained in the group.
[0040] In the present application, "alkyl" is a group formed by losing any one hydrogen atom from an alkane compound molecule. The alkane compound includes straight-chain alkane, branched-chain alkane, cycloalkane and branched-chain cycloalkane.
[0041] In the present application, "aryl" is a group formed by removing a hydrogen atom from an aromatic ring of an aromatic compound; the aromatic compound includes a compound containing an aromatic ring, and a compound in which at least one hydrogen atom on the aromatic ring is substituted with an alkyl group.
[0042] In the present application, "phenyl" is a phenyl group formed by removing a hydrogen atom from a benzene ring of toluene.
[0043] The advantageous effects that can be produced by the present application include:
[0044] 1) The present application can effectively synthesize a new type of chiral phosphorus-nitrogen-oxygen compound based on a cycloaralkane skeleton and a ferrocene skeleton, and the synthesis route is short, and the target compound can be obtained at a high yield.
[0045] 2) The phosphorus-nitrogen-oxygen compound based on a cycloaralkane skeleton and a ferrocene skeleton synthesized by the present application is a relatively stable phosphine compound.
[0046] 3) The phosphorus-nitrogen-oxygen compound based on a cycloaralkane skeleton and a ferrocene skeleton synthesized by the present application can be used as a ligand in the asymmetric hydrogenation of N-aryl indole ketone compounds or hetero-linked aryl ketone compounds catalyzed by iridium, and has excellent catalytic activity and enantioselective control ability. DETAILED DESCRIPTION
[0047] The present application will be described in detail below with reference to examples, but the present application is not limited to these examples.
[0048] Unless otherwise specified, the raw materials in the examples of the present application are purchased through commercial channels.
[0049] The compounds 1a and 1b in the examples of the present application are prepared with reference to the following literature: (a) Cipiciani, A.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Ruzziconi, R. Asymmetric Diels-Alder, Michael, and Aldol Reactions Using a Planar Chiral 1,3-Oxazol-2(3H)-one Derived from (R)-(+)-4-Hydroxy[2.2]paracyclophane. J. Org. Chem. 2002, 67, 2665-2670. (b) Friedmann, C. J.; Ay, S.; S. Improved Synthesis of Enantiopure 4-Hydroxy[2.2]paracyclophane. J. Org. Chem. 2010, 75, 4612-4614. Compound 2 was prepared according to the literature: Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B., An Efficient Asymmetric Synthesis of 2-Substituted Ferrocenecarboxaldehydes. J. Org. Chem. 1997, 62, 6733-6745. Compound 7 was prepared according to the literature: Hornillos, V.; Carmona, J. A.; Ros, A.; Iglesias-Siguena, J.; Lopez-Serrano, J.; Fernandez, R.; Lassaletta, J. M., Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc-Catalyzed Asymmetric Hydrosilylation. Angew. Chem. Int. Ed. 2018, 57, 3777-3781.
[0050] The analytical methods in the embodiments of the present application are as follows:
[0051] NMR 1 H-NMR was determined on a Bruker 400 MHz NMR spectrometer.
[0052] The ee value in the embodiments of the present application was determined on an Agilent LC 1100 liquid chromatograph.
[0053] Room temperature in the embodiments of the present application refers to 25°C.
[0054] Example 1: Synthesis of compound 4a
[0055]
[0056] To a 50 mL reaction vial was added compound la (0.143 g, 0.6 mmol), compound 2 (0.239 g, 0.6 mmol), 6 mL methanol and 6 mL dichloromethane under nitrogen protection, and reacted at 40 °C for 7 h. Subsequently, NaBH4(0.136 g, 3.6 mmol) was added to the reaction vial and reacted at room temperature for 3 h. The reaction was quenched by adding 10 mL H2O. Dichloromethane extraction, dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to give a yellow oily liquid 0.135 g, yield 72%. 1 H NMR (400 MHz, CDC13) δ 7.67-7.60 (m, 2H), 7.59-7.26 (m, 9H), 6.40-6.32 (m, 3H), 6.25 (d, J = 7.9 Hz, 1H), 6.14 (d, J = 7.9 Hz, 1H), 5.67-5.62 (m, 1H), 4.45-4.41 (m, 1H), 4.35-4.30 (m, 1H), 3.98 (s, 5H), 3.91-3.88 (m, 1H), 3.53-3.47 (m, 1H), 3.38-3.30 (m, 1H), 3.01-2.88 (m, 3H), 2.87-2.77 (m, 1H), 2.68-2.47 (m, 3H). 13 C NMR (100 MHz, CDC13) δ 149.8, 139.3, 139.2, 138.5, 136.2, 136.1, 134.2, 134.0, 133.0, 132.4, 131.8, 131.5, 131.3, 130.9, 129.2, 128.2, 127.4, 127.30, 127.29, 127.2, 127.1, 126.2, 125.8, 125.6, 123.9, 89.7, 89.4, 75.3, 75.2, 71.24, 71.19, 71.0, 70.9, 68.6, 68.2, 47.7, 47.6, 32.7, 32.6, 29.7, 29.3. 31 P NMR (162 MHz, CDC13) δ -24.62. HRMS calculated for C 39 H 40 Fe N2OP[M+NH4] + 637.2269, found: 637.2275.
[0057] Example 2: Synthesis of compound 4b
[0058]
[0059] To a 50 mL reaction flask was added compound 1b (0.119 g, 0.5 mmol), compound 2 (0.196 g, 0.5 mmol), 5 mL methanol and 5 mL dichloromethane under nitrogen protection, and the reaction was carried out at 40 °C for 7 hours, followed by adding NaBH4(0.113 g, 3.0 mmol) to the reaction flask, and the reaction was carried out at room temperature for 3 hours. 10 mL H2O was added to quench the reaction. Dichloromethane extraction, anhydrous Na2SO4 drying, filtration, and column chromatography after solvent removal under reduced pressure to obtain 0.166 g of yellow oily liquid, with a yield of 53%. 1 H NMR (400 MHz, CDC13) δ 7.55-7.49 (m, 2H), 7.42-7.36 (m, 3H), 7.26-7.15 (m, 5H), 6.84-6.79 (m, 1H), 6.73-6.62 (m, 3H), 4.55-4.51 (m, 1H), 4.29-4.25 (m, 1H), 4.17-4.06 (m, 6H), 4.03-3.97 (m, 1H), 3.77-3.73 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 149.7, 139.5, 139.4, 138.4, 136.7, 135.8, 135.7, 134.0, 133.8, 133.6, 133.1, 131.9, 131.5, 131.3, 131.2, 130.0, 128.3, 127.84, 127.78, 127.6, 127.3, 127.2, 125.9, 125.4, 124.9, 123.9, 89.7, 89.5, 75.23, 75.17, 71.69, 71.65, 70.65, 70.60, 69.0, 68.6, 47.8, 47.7, 32.6, 32.3, 29.7, 29.6, 29.3. 31 PNMR (162 MHz, CDC13) δ -25.33. HRMS Calculated for C 39 H 40 Fe N2OP[M+NH4] + 637.2269, found: 637.2276.
[0060] Example 3: Asymmetric hydrogenation of N-aryl indolinones catalyzed by iridium
[0061]
[0062] In a glove box, compound 4b (1.4 mg, 0.0022 mmol) prepared in example 2, [Ir(COD)Cl]2(0.7 mg, 0.001 mmol) were dissolved in 1 mL of t-amyl alcohol, stirred at room temperature for 1 hour, then compound 5 (61.7 mg, 0.2 mmol), lithium tert-butoxide (0.8 mg, 0.01 mmol) were added in 1 mL of t-amyl alcohol, then the reaction system was transferred to a high-pressure reaction kettle and filled with hydrogen (600 psi). After stirring at 40 °C for 48 h, the remaining hydrogen was carefully released, and column chromatography gave compound 6, white solid 60.4 mg, yield 97%, 33.3:1 dr, 95% ee of the major diastereomer. 11 H NMR (400 MHz, CDC13) δ 7.69-7.56 (m, 1H), 7.18-7.05 (m, 4H), 7.03-6.96 (m, 1H), 6.94-6.86 (m, 1H), 6.61 (s, 1H), 5.69 (br s, 1H), 4.96 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 2.32 (s, 6H), 1.23 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 155.7, 143.8, 142.6, 138.9, 132.5, 127.8, 122.4, 120.6, 120.4, 120.3, 116.4, 114.8, 110.2, 102.7, 64.3, 55.7, 43.0, 22.5. HRMS Calculated for C 19 H 23 N2O2[M+H] + 311.1754, found: 311.1755. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min, retention time 10.3 min and 8.6 min (major peak).
[0063] Example 4: Iridium-catalyzed asymmetric hydrogenation of heterobiaryl ketones
[0064]
[0065] In a glove box, compound 4b (1.4 mg, 0.0022 mmol) prepared in Example 2, [Ir(COD)Cl]2(0.7 mg, 0.001 mmol) were dissolved in 1 mL of t-amyl alcohol, stirred at room temperature for 1 hour, then compound 7 (52.2 mg, 0.2 mmol), lithium tert-butoxide (0.8 mg, 0.01 mmol) were added in 1 mL of t-amyl alcohol, then the reaction system was transferred to a high-pressure reaction kettle and filled with hydrogen (600 psi). After stirring at 60 °C for 36 h, the remaining hydrogen was released carefully, and column chromatography gave compound 8, white solid 48.9 mg, yield 93%, 97% ee. 1 H NMR (400 MHz, CDC13) δ 8.62 (d, J = 5.7 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.73 - 7.66 (m, 2H), 7.58 - 7.51 (m, 2H), 7.50 - 7.40 (m, 2H), 7.27 - 7.24 (m, 1H), 4.29 (q, J = 6.5 Hz, 1H), 2.14 (br s, 1H), 1.87 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 160.5, 144.4, 142.3, 136.5, 136.23, 136.15, 130.5, 129.2, 129.0, 127.8, 127.7, 127.1, 126.6, 123.3, 120.1, 68.5, 24.9, 19.9. HPLC: Chiralpak AS-H column, 254 nm, 30 °C, n-hexane / isopropyl alcohol = 85 / 15, flow rate = 1.0 mL / min, retention time 4.8 min and 12.5 min (major peak).
[0066] The above is only a few embodiments of the present application, and does not limit the present application in any form. Although the present application is disclosed with preferred embodiments, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the disclosed technical content without departing from the scope of the technical solution of the present application, which are equivalent to equivalent embodiments and belong to the scope of the technical solution.
Claims
1. A class of phosphorus-nitrogen-oxygen compounds based on a cyclic aralkyl skeleton and a ferrocene skeleton, characterized in that, The phosphorus-nitrogen-oxygen compound based on the cycloparaffin skeleton and ferrocene skeleton is selected from at least one of the compounds having the structural formula of Formula I, Formula II: Ar is independently selected from phenyl, C7-C6. 15 Substitution of aryl groups; The substituent of the substituted aryl group is selected from one of C1-C4 alkyl group, methoxy group.
2. The phosphorus-containing oxynitrogen compound containing a cycloaromatic skeleton and a ferrocene skeleton according to claim 1, characterized by The phosphorus-nitrogen oxide compound based on the cycloaralkyl skeleton and the ferrocene skeleton is one of a racemic cycloaralkyl skeleton and ferrocene skeleton phosphorus-nitrogen oxide compound, an (R p )-cycloaralkyl skeleton and an (S FC )-ferrocene skeleton phosphorus-nitrogen oxide compound, an (R p )-cycloaralkyl skeleton and an (R FC )-ferrocene skeleton phosphorus-nitrogen oxide compound, an (S p )-cycloaralkyl skeleton and an (S FC )-ferrocene skeleton phosphorus-nitrogen oxide compound, an (S p )-cycloaralkyl skeleton and an (R FC )-ferrocene skeleton phosphorus-nitrogen oxide compound.
3. The process for producing a phosphorus-nitrogen-oxygen compound containing a cyclic aralkyl skeleton and a ferrocene skeleton according to any one of claims 1 to 2, characterized by, The preparation method at least comprises: under a non-active atmosphere, reacting a mixture containing 5-hydroxy-4-amino[2.2]paracyclophane, a compound shown in Formula III, a reducing agent, to obtain a cycloparaffin skeleton phosphorus-nitrogen-oxygen compound shown in Formula I, Formula II; The compound shown in Formula III has the following structure: wherein Ar is defined as in claim 1; 5-hydroxy-4-amino[2.2]paracyclophane has at least one of the structural formula shown in Formula IV, Formula V:
4. The production method according to claim 3, characterized by, The reducing agent is selected from at least one of sodium borohydride, sodium cyanoborohydride.
5. The preparation method according to claim 3, characterized in that, The molar ratio of 5-hydroxy-4-amino[2.2]paracyclophane to the compound shown in Formula II is 1:1-1:1.2, and the molar ratio of 5-hydroxy-4-amino[2.2]paracyclophane to the reducing agent is 1:6-1:
8.
6. The preparation method according to claim 3, characterized in that, The mixture further contains a solvent selected from at least one of methanol, dichloromethane, ethanol, and trichloromethane.
7. The preparation method according to claim 3, characterized in that, The reaction temperature is 25-40℃.
8. The preparation method according to claim 3, characterized in that, The reaction time is 3-6 hours.
9. The preparation method according to claim 3, characterized in that, The non-active atmosphere is selected from at least one of nitrogen atmosphere and argon atmosphere.
10. Use of at least one of the phosphorus-nitrogen-oxygen compound containing a cycloparaffin skeleton and a ferrocene skeleton according to any one of claims 1-2, or the phosphorus-nitrogen-oxygen compound containing a cycloparaffin skeleton and a ferrocene skeleton prepared by the preparation method according to any one of claims 3-9 as a ligand in the asymmetric hydrogenation of an iridium-catalyzed N-aryl indolinone or hetero-linked aryl ketone.