A method for constructing facially chiral [2,2]paracyclophanes by cobalt-catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution

Abstract

The application provides a method for constructing a planar chiral [2,2] paracyclophane by cobalt-catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution, which comprises the following steps: under the condition of direct current electrolysis, using a cobalt catalyst, a chiral ligand and an additive, taking a graphite felt electrode as an anode and a platinum electrode as a cathode, and allowing a racemic [2,2] paracyclophane formamide to undergo asymmetric carbon-hydrogen bond dehydrogenation coupling / kinetic resolution with an aryl acid, and after the reaction is completed, corresponding post-treatment is performed to obtain a planar chiral [2,2] paracyclophane formamide and a planar chiral oxo para-[2,2] paracyclophane. The application realizes electrochemical synthesis of the planar chiral oxo para-[2,2] paracyclophane by the method of crust-abundant transition metal catalyzed asymmetric carbon-hydrogen bond activation, the reaction substrate has wide universality, the stereoselectivity is excellent, and the product and the split-recovered raw material have excellent ee value (up to >99% ee) and a split factor (up to 1057).

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of compound synthesis, and in particular to a method for constructing facially chiral [2,2]paracyclophanes through electrochemical oxidation driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution. BACKGROUND

[0002] In recent years, the field of transition metal-catalyzed asymmetric carbon-hydrogen bond functionalization has developed rapidly, providing a new and revolutionary approach for the efficient and economical synthesis of chiral molecules (C.G.Newton,S.-G.Wang,C.C.Oliveira,N.Cramer,Chem.Rev.2017,117,8908). Among them, electrochemical oxidation driven transition metal-catalyzed asymmetric carbon-hydrogen bond oxidative coupling reactions have received widespread attention. Compared with traditional asymmetric carbon-hydrogen bond oxidative coupling reactions, this strategy uses anodic oxidation instead of equivalent chemical oxidants, and the protons in the reaction system are reduced to hydrogen at the cathode. The entire process uses electrons as a traceless redox agent, has the characteristics of atom economy and sustainable development, and is widely used in the stereospecific construction of central chirality, axial chirality, ferrocene-like facial chirality and other high-value chiral skeletons. For example: in 2020, Ackermann's group developed an electrochemical oxidation driven palladium-catalyzed asymmetric carbon-hydrogen bond activation olefination reaction to construct axially chiral compounds (U.Dhawa,C.Tian,T.Wdowik,J.C.A.Oliveira,J.Hao,L.Ackermann,Angew.Chem.Int.Ed.2020,59,13451); in 2023, Shi's group reported the first example of electrochemical oxidation driven 3d transition metal-catalyzed asymmetric carbon-hydrogen bond oxidative coupling reaction using inexpensive and readily available divalent cobalt salt as catalyst (Q.-J.Yao,F.-R.Huang,J.-H.Chen,M.-Y.Zhong,B.-F.Shi,Angew.Chem.,Int.Ed.2023,62,e202218533); in 2024, Shi and Yao research teams reported electrochemical oxidation driven copper-catalyzed asymmetric carbon-hydrogen bond alkinylization reaction to synthesize facially chiral ferrocene (Z.-Z.Zhang,G.Zhou,Q.Yue,Q.-J.Yao,B.-F.Shi,ACSCatal.2024,14,4030).

[0003] On the other hand, cyclophanes are cyclic compounds formed by one or more independent aromatic systems through bridging. Among them, [2,2] paracyclophane compounds with the smallest ring system are the most representative. Due to the structural rigidity of [2,2] paracyclophane molecules, when they lose structural symmetry, a variety of facial chirality structures are generated. In recent years, chiral [2,2] paracyclophanes, due to their unique structural characteristics, have been widely used in asymmetric catalysis, material science, and drug chemistry and many other fields, for example: Therefore, its asymmetric synthesis has also attracted the attention of chemists. The asymmetric synthesis strategies reported so far mainly include the following two (G. J. Rowlands, Org. Biomol. Chem. 2008, 6, 1527): 1) using an equivalent amount of chiral reagent or chiral auxiliary to realize chemical resolution of racemic [2,2] paracyclophane substrates; 2) asymmetric catalytic transformation to realize the kinetic resolution of racemic [2,2] paracyclophanes. Although the synthesis of chiral [2,2] paracyclophanes has achieved phased results, however, the above two categories of synthesis strategies have the following limitations: 1. Chemical resolution requires the introduction of an equivalent amount of chiral reagent, the resolution step is cumbersome, and the atom economy and step economy are poor; 2. The kinetic resolution strategy often requires specific side functional group substrates, and the strategy has poor universality; at the same time, the transformation form is single, and it is difficult to realize the structural diversity of the skeleton.

[0004] At present, based on asymmetric carbon-hydrogen bond catalytic transformation, the synthesis of diverse chiral [2,2] paracyclophane skeletons has only been reported in the research of chiral organic small molecule catalysts: In 2023, Yang's group used racemic 4-amino-[2,2] paracyclophane and azodicarboxylate as raw materials, and (S)-3,3'-di-9-phenyl-1,1'-binaphthyl phosphate as a chiral small molecule catalyst, to realize the kinetic resolution of 4-amino-[2,2] paracyclophane through asymmetric carbon-hydrogen bond amination reaction (S. Yu, H. Bao, D. Zhang, X. Yang, Nat. Commun. 2023, 14, 5239). The chiral small molecule catalyst used in this method is expensive, and the reaction substrate has low universality. Therefore, it is of important academic value and potential application value to develop new methods and new strategies for efficient asymmetric catalysis to realize the asymmetric and efficient construction of chiral [2,2] paracyclophane skeleton. SUMMARY

[0005] In view of the shortcomings of the existing asymmetric synthesis technology, the present application provides a method for cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution to construct facially chiral [2,2] paracyclophane, which uses inexpensive and readily available divalent cobalt as a catalyst and combines with electrochemical oxidation to further improve the efficiency and sustainability of synthesis.

[0006] The technical scheme of the present application is as follows: a method for constructing facially chiral [2,2]paracyclophanes by electrochemical oxidation driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution, comprising the following steps:

[0007] (1) dissolving racemic [2,2]paracyclophane formamide, carboxylic acid, cobalt catalyst, chiral ligand and conductive agent in a solvent, and heating and stirring to form a pre-reaction solution;

[0008] (2) adding an anode and a cathode to the pre-reaction solution obtained in step (1), and then passing direct current to perform asymmetric carbon-hydrogen bond dehydrogenation coupling / kinetic resolution, after the reaction is completed, after-treatment is performed to obtain facially chiral [2,2]paracyclophane formamide and facially chiral oxo para-[2,2]paracyclophane compound;

[0009] The reaction formula is as follows:

[0010]

[0011] wherein R is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted alkenyl;

[0012] The chiral ligand is a salicyl oxazoline ligand, and the structural formula is as follows:

[0013]

[0014] wherein R 1 ~ R 3 are independently selected from H, alkyl, alkoxy, halogen, trifluoromethyl, nitro or aryl;

[0015] R 4 is alkyl or aryl.

[0016] During the reaction process, by means of chiral ligand control, the asymmetric carbon-hydrogen bond acyloxylation product facially chiral para-oxo[2,2]paracyclophane compound P has a yield of 36% to 50% and an ee value of 95% to 99%, and the recovered chiral [2,2]paracyclophane formamide raw material S has a yield of 45% to 62% and an ee value of 54% to 99%.

[0017] Preferably, the racemic 4-formamide-[2,2]paracyclophane and carboxylic acid, and the cobalt catalyst, chiral ligand Chiral Ligand and additive are mixed, heated and stirred under an air atmosphere and at a specific reaction temperature T1, then the anode and the cathode are added, heated and stirred under an air atmosphere and at a specific reaction temperature T2, and direct current electrolysis CCE is powered on and the asymmetric carbon-hydrogen bond acyloxylation reaction occurs.

[0018] The additive is composed of a conductive agent and a solvent, and the reaction formula is as follows:

[0019]

[0020] In the formula, R is one of aryl, heterocyclic aryl, or alkenyl.

[0021] Preferably, the chiral ligand is a salicyl oxazoline ligand (Salox), and the structure formula is as follows:

[0022]

[0023] In the formula, R 1 ~R 3 are one or more of hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, and phenyl; and R 4 is n-propyl, iso-propyl, tert-butyl, cyclohexyl, or phenyl.

[0024] More preferably, the ligand is (S)-4-methoxy-2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenol.

[0025] Preferably, the cobalt catalyst is one of cobalt acetate tetrahydrate, cobalt nitrate hexahydrate, cobalt perchlorate hexahydrate, cobalt sulfate heptahydrate, cobalt thiocyanate, cobalt carbonate, and cobalt hydroxide.

[0026] More preferably, the cobalt catalyst is cobalt hydroxide.

[0027] Preferably, the conductive agent is one or a mixture of more than one of tetra(n-butyl)ammonium tetrafluoroborate, tetra(n-butyl)ammonium hexafluorophosphate, tetra(n-butyl)ammonium hexafluoroantimonate, tetra(n-butyl)ammonium hexafluorophosphate, tetra(n-butyl)ammonium triflate, and tetra(n-butyl)ammonium perchlorate.

[0028] More preferably, the conductive agent is tetra(n-butyl)ammonium hexafluorophosphate.

[0029] Preferably, the molar ratio of the racemic [2,2]paracyclophane formamide, carboxylic acid, cobalt catalyst, chiral ligand, and conductive agent is 1.0:1.0~1.2:0.1~0.2:0.12~0.15:1.0~1.2, and further preferably 1.0:1.0:0.1:0.12:1.0.

[0030] Preferably, the solvent is one or a mixture of more than one of methanol, ethanol, hexafluoroisopropanol, trifluoroethanol, water, and 1,2-dichloroethane.

[0031] More preferably, the solvent is a mixture of 2,2,2-trifluoroethanol, 1,2-dichloroethane and water, with a volume ratio of 2:4:0.1.

[0032] Preferably, the anode electrode is a carbon electrode.

[0033] More preferably, the anode electrode is a graphite felt (GF) electrode.

[0034] Preferably, the cathode electrode is a metal electrode.

[0035] More preferably, the cathode electrode is a platinum sheet (Pt) electrode.

[0036] Preferably, the electrolytic cell is an undivided cell.

[0037] Preferably, the temperature T1 of the stirring and mixing under an air atmosphere is 50 to 70°C, and the stirring time is 2 to 8 hours; the direct current electrolysis current is 1-3 mA, and is further preferably 1 mA; and during the electrolysis, the temperature T2 of the cobalt-catalyzed asymmetric carbon-hydrogen bond acyloxylation reaction is 50 to 70°C, and the reaction time is 12 to 16 hours.

[0038] Compared with the prior art, the present application has the following beneficial effects:

[0039] (1) The present application uses racemic 4-formamide-[2,2]paracyclane and carboxylic acid as raw materials, a cheap and readily available divalent cobalt salt as a catalyst, and a simple-to-synthesize salicyl oxazoline as a chiral ligand, to construct a facially chiral [2,2]paracyclane through cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution driven by electrochemical oxidation;

[0040] (2) The present application realizes the efficient synthesis of facially chiral [2,2]paracyclane through cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution driven by electrochemical oxidation, further develops the research technology of 3d transition metal-catalyzed asymmetric carbon-hydrogen bond activation, and expands the synthesis strategy of facially chiral [2,2]paracyclane.

[0041] (3) The present application uses an undivided electrolytic cell that is easy to operate, a cheap and readily available carbon electrode as an anode, and an anode electrochemical oxidation to drive the cyclic regeneration of the cobalt catalyst, and the entire process does not require the use of additional chemical oxidants, and has sustainable characteristics.

[0042] (4) The present application has wide adaptability to reaction substrates, strong stereoselectivity of products, and can make the products have a high ee value (95%-99% ee) through the control of chiral ligands, and at the same time, 54%-99% ee value of chiral [2,2]paracyclane formamide raw materials can be recovered;

[0043] (5) The present application synthesizes a variety of facially chiral [2,2]paracyclophanes, the synthesis method is simple, atom economy is good, green and sustainable, and the synthesis efficiency is high. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 HPLC chromatogram of compound 1 obtained from example 1 and its racemate, wherein the HPLC chromatogram conditions are: using a chiral chromatographic column of Daicel IA, the mobile phase is n-hexane / 2-propanol = 60 / 40, the flow rate is v = 1.5 mL·min -1 , and the detection wavelength is λ = 254 nm.

[0045] Figure 2 HPLC chromatogram of raw material compound S obtained from example 1 and its racemate, wherein the HPLC chromatogram conditions are: using a chiral chromatographic column of Daicel IA, the mobile phase is n-hexane / 2-propanol = 90 / 10, the flow rate is v = 1.5 mL·min -1 , and the detection wavelength is λ = 254 nm.

[0046] Figure 3 HPLC chromatogram of compound 22 obtained from example 22 and its racemate, wherein the HPLC chromatogram conditions are: using a chiral chromatographic column of Daicel IA, the mobile phase is n-hexane / 2-propanol = 65 / 35, the flow rate is v = 2.0 mL·min -1 , and the detection wavelength is λ = 254 nm; at the same time, the HPLC chromatogram of the recovered chiral 4-formamide-[2,2]paracyclophan raw material S, wherein the HPLC chromatogram conditions are: using a chiral chromatographic column of Daicel IA, the mobile phase is n-hexane / 2-propanol = 90 / 10, the flow rate is v = 1.5 mL·min -1 , and the detection wavelength is λ = 254 nm.

[0047] Figure 4 HPLC chromatogram of compound 23 obtained from example 23 and its racemate, wherein the HPLC chromatogram conditions are: using a chiral chromatographic column of Daicel IA, the mobile phase is n-hexane / 2-propanol = 65 / 35, the flow rate is v = 2.0 mL·min -1 , and the detection wavelength is λ = 254 nm; at the same time, the HPLC chromatogram of the recovered chiral 4-formamide-[2,2]paracyclophan raw material S, wherein the HPLC chromatogram conditions are: using a chiral chromatographic column of Daicel IA, the mobile phase is n-hexane / 2-propanol = 90 / 10, the flow rate is v = 1.5 mL·min -1 , and the detection wavelength is λ = 254 nm. Detailed Implementation

[0048] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings:

[0049] Example 1

[0050] In an integrated electrolytic cell, 0.20 mmol of 4-formamide-[2,2]-p-cyclophane feedstock S, 0.20 mmol of 4-methylbenzoic acid, 0.01 mmol of cobalt hydroxide catalyst, 0.012 mmol of (S)-4-methoxy-2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenol, 0.1 mmol of tetra(n-butyl)hexafluorophosphate, 4.0 mL of 1,2-dichloroethane (DCE), 2.0 mL of 2,2,2-trifluoroethanol (TFE), and 0.1 mL of water were added. After stirring and mixing at 70°C in air for 8 hours, a graphite felt GF electrode (size: 350mm*150mm*30mm) and a platinum electrode (size: 300mm*100mm*0.2mm) were added, and a 1.0 mA DC power supply was connected. Electrolysis was carried out at 50°C in air for 14 hours with stirring. Subsequently, the chiral para-oxo[2,2]-paracyclophane product 1, with structure of Formula 1, was obtained by silica gel column chromatography (eluent ratio: petroleum ether / dichloromethane / ethyl acetate = 70:40:10), with a yield of 46% and an ee value of 96%. The chiral 4-formamide-[2,2]-paracyclophane starting material S was recovered with a yield of 45% and an ee value of 96%. The HPLC chromatograms of compound 1 and its racemic mixture are shown in [Figure number missing]. Figure 1 The HPLC chromatograms of the recovered raw material S and its racemic mixture are shown in [reference needed]. Figure 2 .

[0051] The structure of compound 1 is as follows:

[0052]

[0053] The structural characterization data of product 1 are as follows:

[0054] 1 HNMR (400 MHz, CDC13) δ 9.99 (s, 1H), 8.85 (dd, J = 7.2, 1.2 Hz, 1H), 8.72 (dd, J = 4.4, 1.6 Hz, 1H), 8.06 (dd, J = 8.0, 1.6 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.4, 1.2 Hz, 1H), 7.36 (dd, J = 8.4, 4.4 Hz, 1H), 7.24 (dd, J = 8.0, 2.0 Hz, 1H), 7.11 (dd, J = 8.0, 2.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.74 - 6.68 (m, 2H), 6.63 (d, J = 8.0 Hz, 2H), 3.53 - 3.47 (m, 1H), 3.34 - 3.27 (m, 1H), 3.13 - 2.99 (m, 5H), 2.89 - 2.80 (m, 1H), 2.30 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 164.6, 164.6, 148.1, 146.0, 144.3, 141.5, 139.6, 139.6, 138.5, 136.9, 136.0, 134.7, 133.3, 132.9, 132.9, 132.6, 131.7, 130.2, 129.7, 129.5, 129.1, 127.9, 127.3, 126.3, 121.6, 121.5, 116.4, 35.3, 34.5, 33.7, 31.3, 21.7. HRMS (ESI-TOF) : Calculated for C 34 H 28 N2O3 + H + [M+H] +513.2173, found: 513.2173; The enantiomeric excess was determined by Daicel Chiralcel IA, n-hexane / 2-propanol = 60 / 40, 1.5 mL / min, λ = 254 nm, t (major) = 7.480 min, t (minor) = 13.189 min, 96% ee; The enantiomeric excess was determined by Daicel Chiralcel IA, n-hexane / 2-propanol = 90 / 10, 1.5 mL / min, λ = 254 nm, t (minor) = 5.932 min, t (major) = 6.967 min, 96% ee.

[0055] Examples 2-19

[0056] The operating procedures were the same as in Example 1, except that the coupling reagent carboxylic acid and electrolysis time were changed, and the eluent of column chromatography was changed in different proportions, and different facial chiral para-oxo[2,2]paracyclophane products 2-20 were obtained, and the chiral 4-formamide-[2,2]paracyclophane starting material S was recovered. The results are shown below:

[0057]

[0058]

[0059] Example 22

[0060] In a one-pot electrolysis cell, 0.20 mmol of 4-formamido-[2,2]paracyclophanes starting material S, 0.20 mmol of Tolfenamic Acid, 0.01 mmol of cobalt hydroxide catalyst, 0.012 mmol of (S)-4-methoxy-2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenol, 0.1 mmol of tetra(n-butyl)ammonium hexafluorophosphate, 4.0 mL of 1,2-dichloroethane (DCE), 2.0 mL of 2,2,2-trifluoroethanol (TFE) and 0.1 mL of water were stirred at 70 °C for 8 hours under air atmosphere. Then, a graphite felt GF electrode (specification: 350 mm*150 mm*30 mm) and a platinum electrode (specification: 300 mm*100 mm*0.2 mm) were added, and a 1.0 mA direct current power supply was connected. The mixture was stirred and electrolyzed at 50 °C for 12 hours under air atmosphere. Thereafter, the product 22 with the structure as shown in Formula 22 was obtained by silica gel column separation (eluent ratio: petroleum ether / dichloromethane / ethyl acetate = 70:40:15) in a yield of 38% and an ee value of 99%. The chiral 4-formamido-[2,2]paracyclophanes starting material S was recovered in a yield of 58% and an ee value of 66%. The HPLC chromatograms of compound 22 and its racemate are shown in Figure 3 A, and the HPLC chromatogram of the recovered starting material S is shown in Figure 3 B.

[0061] The structure of compound 22 is as follows:

[0062]

[0063] The structure characterization data of product 22 are as follows:

[0064] 1 HNMR (400 MHz, CDC13 ) δ 9.90 (s, 1H), 9.57 (s, 1H), 8.83 (dd, J = 7.6, 1.6 Hz, 1H), 8.58 (dd, J = 4.0, 1.6 Hz, 1H), 8.51 (dd, J = 8.0, 2.0 Hz, 1H), 8.18 (dd, J = 4.8, 2.0 Hz, 1H), 8.02 (dd, J = 8.0, 2.0 Hz, 1H), 7.55-7.43 (m, 3H), 7.27-7.21 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.08-7.01 (m, 2H), 6.78-6.64 (m, 4H), 6.56 (dd, J = 7.6, 4.8 Hz, 1H), 3.48 (td, J = 12.4, 2.0 Hz, 1H), 3.34 (td, J = 12.4, 4.0 Hz, 1H), 3.17-3.00 (m, 5H), 2.95-2.87 (m, 1H), 2.13 (s, 3H); 13 CNMR (101 MHz, CDC13) δ 166.0, 164.5, 156.6, 154.0, 148.0, 145.6, 141.8, 140.6, 139.7, 139.4, 138.7, 138.3, 137.0, 136.2, 134.8, 134.4, 133.3, 133.2, 132.8, 132.6, 131.9, 129.5, 129.4, 129.1, 127.9, 127.3, 126.5, 125.2, 122.1, 121.9, 121.5, 116.4, 113.5, 105.9, 35.3, 34.6, 33.6, 31.0, 15.0; HRMS (ESI-TOF) : Calculated for C 40 H 32 ClN3O3 + H + [M+H] + 638.2205, found: 638.2203; The enantiomeric excess of compound 22 was determined by Daicel Chiralcel IA, n-hexane / 2-propanol = 65 / 35, 2.0 mL / min, λ = 254 nm, t (major) = 3.146 min, t (minor) = 4.101 min, 99% ee; The enantiomeric excess of recovered starting material S was determined by Daicel Chiralcel IA, n-hexane / 2-propanol = 90 / 10, 1.5 mL / min, λ = 254 nm, t (minor) = 5.759 min, t (major) = 6.746 min, 66% ee.

[0065] Example 23

[0066] In a one-pot electrolysis, 0.20 mmol of 4-formamide-[2,2]paracyclophane starting material S, 0.20 mmol of Febuxostat (Nonsteroidal anti-inflammatory drug), 0.01 mmol of cobalt hydroxide catalyst, 0.012 mmol of (S)-4-methoxy-2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenol, 0.1 mmol of tetra(n-butyl)ammonium hexafluorophosphate, 4.0 mL of 1,2-dichloroethane (DCE), 2.0 mL of 2,2,2-trifluoroethanol (TFE) and 0.1 mL of water were stirred at 70 °C for 8 hours in air atmosphere. Then, a graphite felt electrode (specification: 350 mm*150 mm*30 mm) and a platinum electrode (specification: 300 mm*100 mm*0.2 mm) were added, and a 1.0 mA direct current power supply was connected. The mixture was stirred and electrolyzed at 50 °C for 14 hours in air atmosphere. After that, the product 23 with the structure as shown in Formula 3 was obtained by silica gel column separation (eluent ratio: petroleum ether / dichloromethane / ethyl acetate = 80:50:15) with a yield of 40% and an ee value of 99%. The chiral 4-formamide-[2,2]paracyclophane starting material S was recovered with a yield of 60% and an ee value of 64%. The HPLC chromatograms of compound 23 and its racemate are shown in Figure 4 A, and the HPLC chromatogram of the recovered starting material S is shown in Figure 4 B.

[0067] The structure of compound 23 is as follows:

[0068]

[0069] The structure characterization data of product 23 are as follows:

[0070] 1 HNMR (400 MHz, CDC13) δ 9.96 (s, 1H), 8.88 (d, J = 7.6 Hz, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 7.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.75 - 6.69 (m, 2H), 6.64 (d, J = 8.0 Hz, 2H), 3.88 (d, J = 6.8 Hz, 2H), 3.49 - 3.43 (m, 1H), 3.35 - 3.29 (m, 1H), 3.16 - 2.99 (m, 5H), 2.94 - 2.85 (m, 1H), 2.61 (s, 3H), 2.25 - 2.15 (m, 1H), 1.09 (d, J = 6.8 Hz, 6H); 13 CNMR (101 MHz, CDCI3) δ 168.0, 164.4, 163.2, 162.7, 159.6, 148.1, 145.2, 141.6, 139.7, 139.5, 138.5, 136.9, 136.3, 134.7, 133.4, 133.2, 132.9, 132.7, 132.7, 132.0, 131.6, 129.5, 127.9, 127.4, 125.7, 121.9, 121.8, 120.0, 116.4, 115.4, 112.6, 102.9, 75.8, 35.3, 34.4, 33.6, 31.3, 28.2, 19.1, 17.5; HRMS (ESI-TOF): Calculated for C 40 H 32 ClN3O3+H + [M+H] +638.2205, found: 638.2203; determination of the ee value of compound 23: The enantiomeric excess was determined by Daicel Chiralcel IA, n-hexane / 2-propanol = 65 / 35, 2.0 mL / min, λ = 254 nm, t (major) = 5.903 min, t (minor) = 8.600 min, 99% ee; determination of the ee value of the recovered starting material S: The enantiomeric excess was determined by Daicel Chiralcel IA, n-hexane / 2-propanol = 90 / 10, 1.5 mL / min, λ = 254 nm, t (minor) = 5.821 min, t (major) = 6.749 min, 64% ee.

[0071] The foregoing embodiments and description of the application only illustrate the principles of the application and the best mode of practicing it. Further modifications and improvements can be made without departing from the spirit and scope of the application, which is set forth in the following claims.

Claims

1. A method for electrochemically oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution to construct facially chiral [2,2]paracyclophanes, characterized in that, The method comprises the following steps: (1) dissolving racemic [2,2] para-cyclanamide, carboxylic acid, cobalt catalyst, chiral ligand and conductive agent in a solvent, and heating and stirring to form a pre-reaction solution; (2) adding an anode and a cathode to the pre-reaction solution obtained in step (1), and then passing direct current to perform asymmetric carbon-hydrogen bond dehydrogenation coupling / kinetic resolution, and after the reaction is completed, aftertreatment is performed to obtain a facially chiral [2,2] para-cyclanamide and a facially chiral oxo para-[2,2] para-cyclan compound; The reaction formula is as follows: wherein R is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl or substituted or unsubstituted alkenyl; The chiral ligand is a salicyl oxazoline ligand, and the structural formula is as follows: wherein R 1 ~R 3 is independently selected from H, alkyl, alkoxy, halogen, trifluoromethyl, nitro or aryl; R 4 R is H, alkyl, or aryl.

2. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclononanes according to claim 1, characterized in that, The reaction of step (1) and step (2) is performed in an air atmosphere; The electrolytic cell is an integrated electrolytic cell.

3. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclononanes according to claim 1, characterized in that, In R, the aryl is phenyl or naphthyl, and the substituents on the aryl are one or more of C1-C4 alkyl, C1-C4 alkoxy, methylenedioxy, halogen, C1-C4 alkoxyacyl, nitro, dipropyl sulfamoyl and 2-methyl-3-chloroanilino; The heterocyclic aryl is pyridyl, furanyl, benzothiophenyl, thiazolyl or phenylthiazolyl, and the substituents on the heterocyclic aryl are C1-C4 alkyl, C1-C4 alkoxy or cyano; The alkenyl is C2-C6 alkenyl, and the substituents on the alkenyl are phenyl.

4. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclononanes according to claim 1, characterized in that, R 1 ~R 3 one or more independently selected from the group consisting of hydrogen, methyl, tert-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro, phenyl; R 4 is n-propyl, i-propyl, t-butyl, cyclohexyl or phenyl.

5. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclonon by claim 1, characterized in that, The conductive agent is one or a mixture of multiple of tetrakis(n-butyl)ammonium tetrafluoroborate, tetrakis(n-butyl)ammonium hexafluorophosphate, tetrakis(n-butyl)ammonium hexafluoroantimonate, tetrakis(n-butyl)ammonium hexafluorophosphate, tetrakis(n-butyl)ammonium trifluoromethanesulfonate and tetrakis(n-butyl)ammonium perchlorate; The solvent is one or a mixture of multiple of methanol, ethanol, hexafluoroisopropanol, trifluoroethanol, water and 1,2-dichloroethane; The anode electrode is a carbon electrode; The cathode electrode is a metal electrode.

6. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclonon by claim 1, characterized in that, The cobalt catalyst is one of cobalt acetate tetrahydrate, cobalt nitrate hexahydrate, cobalt perchlorate hexahydrate, cobalt sulfate heptahydrate, cobalt thiocyanate, cobalt carbonate, cobalt hydroxide and bis(acetylacetone) cobalt; The chiral ligand is (S)-4-methoxy-2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenol.

7. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclonon by claim 1, characterized in that, The molar ratio of the racemic [2,2] para-cyclanamide, carboxylic acid, cobalt catalyst, chiral ligand and conductive agent is 1.0:1.0-1.2:0.1-0.2:0.12-0.15:1.0-1.

2.

8. The method of electrochemically oxidatively driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jump resolution to build facially chiral [2,2]paracyclononanes according to any one of claims 1 to 7, characterized in that, In step (1), the temperature of heating and stirring is 50-70°C, and the time of heating and stirring is 2-8 hours.

9. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclononanes according to any one of claims 1-7, characterized in that, In step (2), the direct current is 1-3 mA.

10. The method of electrochemical oxidation-driven cobalt catalyzed asymmetric carbon-hydrogen bond activation / jumpnical resolution to build facially chiral [2,2]paracyclononanes according to any one of claims 1-7, characterized in that, The temperature of heating and stirring is 50-70°C, and the reaction time is 12-16 hours.

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