Method for constructing planar chiral [2, 2] paracyclophane through cobalt-catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution

Abstract

The invention provides a method for constructing planar chiral [2, 2] paracyclophane by cobalt-catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution, which comprises the following steps: by using a cobalt catalyst, a chiral ligand and an additive, taking a graphite felt electrode as an anode and taking a platinum sheet electrode as a cathode, carrying out racemization on [2, 2] paracyclophane under the condition of direct-current electrolysis, so as to obtain the planar chiral paracyclophane. The preparation method comprises the following steps: carrying out asymmetric carbon-hydrogen bond dehydrogenation coupling / kinetic resolution on 2, 2] paracyclophane formamide and aryl acid, and after the reaction is finished, carrying out corresponding post-treatment to obtain planar chiral [2, 2] paracyclophane formamide and planar chiral oxopara-[2, 2] paracyclophane; according to the method, electrochemical synthesis of planar chiral oxara-[2, 2] paracyclophane is realized through a method for catalyzing asymmetric carbon-hydrogen bond activation by virtue of a crustal high-yield transition metal, a reaction substrate is wide in universality and excellent in stereoselectivity, and a product and a split and recycled raw material can have an excellent ee value (up to gt; 99% ee) and a splitting factor (up to 1057).

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, and in particular to a method for constructing a chiral [2,2] paracyclophane by cobalt catalysis driven by electrochemical oxidation and asymmetric carbon-hydrogen bond activation / kinetic resolution. Background Art

[0002] In recent years, the field of transition metal-catalyzed asymmetric carbon-hydrogen bond functionalization has developed rapidly, providing a new revolutionary idea for the efficient and economical synthesis of chiral molecules (CG Newton, S.-G. Wang, CC Liveira, N. Cramer, Chem. Rev. 2017, 117, 8908). Among them, the transition metal-catalyzed asymmetric carbon-hydrogen bond oxidative coupling reaction driven by electrochemical oxidation has received widespread attention. Compared with the traditional asymmetric carbon-hydrogen bond oxidative coupling reaction, this strategy replaces the equivalent chemical oxidant with anodic oxidation, and the protons in the reaction system undergo a reduction hydrogen evolution reaction at the cathode. The electrons in the whole process act as traceless redox agents, which has the characteristics of atom economy and sustainable development. It is widely used in the stereospecific construction of high-value-added chiral skeletons such as central chirality, axial chirality, and ferrocene-like face chirality. For example: In 2020, the Ackermann group developed an electrochemical oxidation-driven palladium-catalyzed asymmetric carbon-hydrogen bond activation olefination reaction to construct axial chiral compounds (U. Dhawa, C. Tian, ​​T. Wdowik, J. CAO Liveira, J. Hao, L. Ackermann, Angew. Chem. Int. Ed. 2020, 59, 13451); in 2023, the Shi group reported the first electrochemical oxidation-driven 3d transition metal-catalyzed asymmetric carbon-hydrogen bond oxidative coupling reaction using cheap and readily available divalent cobalt salts as catalysts. (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's research team reported the electrochemical oxidation-driven copper-catalyzed asymmetric carbon-hydrogen bond acetylation reaction to synthesize chiral ferrocene (Z.-Z.Zhang, G.Zhou, Q.Yue, Q.-J.Yao, B.-F.Shi, ACS Catal.2024, 14, 4030).

[0003] On the other hand, cyclophanes are cyclic compounds formed by bridging one or more independent aromatic systems. Among them, the [2,2]-cyclophane compounds with the smallest ring system are the most representative. Due to the structural rigidity of [2,2]-cyclophane molecules, when they lose their structural symmetry, they will produce a rich variety of chiral structural properties. In recent years, chiral [2,2]-cyclophanes have been widely used in many fields such as asymmetric catalysis, material science and medicinal chemistry due to their unique structural characteristics, such as:, so their asymmetric synthesis has also attracted the attention of chemists. The strategies for asymmetric synthesis reported so far mainly include the following two (GJ Rowlands, Org. Biomol. Chem. 2008, 6, 1527): 1) Chemical resolution of racemic [2,2]-cyclophane substrates using equivalent chiral reagents or chiral auxiliary groups; 2) Kinetic resolution of racemic [2,2]-cyclophanes by asymmetric catalytic transformation. Although the synthesis of chiral cyclophanes [2,2] has achieved some initial results, both of the above two types of synthetic strategies have the following limitations: 1. Chemical resolution requires the introduction of equivalent chiral reagents, the resolution steps are cumbersome, and the atom economy and step economy are poor; 2. Kinetic resolution strategies often require substrates with specific side functional groups, and the strategy has poor universality; at the same time, the transformation form is relatively single, making it difficult to achieve structural diversity of the skeleton.

[0004] At present, there are only reports on the catalytic research of chiral organic small molecules for the synthesis of diverse chiral [2,2]-cyclophane skeletons based on asymmetric carbon-hydrogen bond catalytic transformation: In 2023, Yang's research group used exo-rotatory 4-amino-[2,2]-cyclophane and azodicarbonate as raw materials, (S)-3,3'-di-9-phenanthrenyl-1,1'-binaphthol phosphate as a chiral small molecule catalyst, and achieved the kinetic resolution of 4-amino-[2,2]-cyclophane 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 universality of the reaction substrate is low. Therefore, the development of efficient new methods and strategies for asymmetric catalytic synthesis to achieve asymmetric and efficient construction of chiral [2,2]-cyclophane skeletons has important academic value and potential application value. Summary of the invention

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

[0006] The technical solution of the present invention is: a method for constructing a chiral [2,2]-cyclophane by cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution driven by electrochemical oxidation, comprising the following steps:

[0007] (1) dissolving racemic [2,2]-p-cyclophane carboxamide, carboxylic acid, a cobalt catalyst, a chiral ligand and a 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 splitting. After the reaction is completed, post-treatment is performed to obtain a chiral [2,2]-para-cyclophane carboxamide and a chiral oxo-para-[2,2]-para-cyclophane 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] Among them, R 1 ~R 3 independently selected from H, alkyl, alkoxy, halogen, trifluoromethyl, nitro or aryl;

[0015] R 4 is an alkyl group or an aryl group.

[0016] During the reaction, through the control of chiral ligands, the asymmetric carbon-hydrogen bond acyl oxidation product can be made to have a yield of 36% to 50% and an ee value of 95% to 99% for the chiral para-oxy [2,2] para-cyclophane compound P, while the recovered chiral [2,2] para-cyclophane carboxamide 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]cyclophane and carboxylic acid, as well as a cobalt catalyst, a chiral ligand and an additive are mixed, heated and stirred in an air atmosphere and a specific reaction temperature T1, and then an anode and a cathode are added, and heated and stirred in an air atmosphere and a specific reaction temperature T2, and direct current electrolysis CCE is energized to cause an asymmetric carbon-hydrogen bond acyl oxidation reaction.

[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 an aryl group, a heteroaryl group, or an alkenyl group.

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

[0022]

[0023] In the formula, R 1 ~R 3 R is one or more of hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, and phenyl; 4 It is n-propyl, isopropyl, 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 a mixture of one or more 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 trifluoromethanesulfonate, 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]-cyclophane carboxamide, 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 more preferably 1.0:1.0:0.1:0.12:1.0.

[0030] Preferably, the solvent Solvent is one or more mixed solvents of methanol, ethanol, hexafluoroisopropanol, trifluoroethanol, water and 1,2-dichloroethane.

[0031] More preferably, the solvent is a mixed solvent of 2,2,2-trifluoroethanol, 1,2-dichloroethane and water in 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 (Pt) electrode.

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

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

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

[0039] (1) The present invention uses racemic 4-formamide-[2,2]-cyclophane and carboxylic acid as raw materials, cheap and readily available divalent cobalt salt as catalyst, and simple synthetic salicyl oxazoline as chiral coordination, and constructs planar chiral [2,2]-cyclophane through cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution driven by electrochemical oxidation;

[0040] (2) The present invention achieves efficient synthesis of planar chiral [2,2]-cyclophanes 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 planar chiral [2,2]-cyclophanes.

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

[0042] (4) The reaction substrate of the present invention has wide adaptability and strong product stereoselectivity. Through the control of chiral ligands, the product can have a higher ee value (95% to 99% ee), and the chiral [2,2]-cyclopentanecarboxamide raw material with an ee value of 54% to 99% can be recovered;

[0043] (5) The present invention synthesizes a variety of planar chiral [2,2] para-cyclophane compounds, and the synthesis method is simple, has good atom economy, is green and sustainable, and has high synthesis efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0047] Figure 4 The HPLC spectrum of the compound 23 obtained in Example 23 and its racemate, wherein the conditions for the HPLC spectrum are: using a Daicel IA chiral chromatographic column, the mobile phase is n-hexane / 2-propanol=65 / 35, and the flow rate is v=2.0 mL·min -1 , the detection wavelength is λ=254nm; at the same time, the HPLC spectrum of the recovered chiral 4-carboxamide-[2,2]paracyclophane raw material S is obtained, wherein the conditions of the HPLC spectrum are: using a Daicel IA chiral chromatographic column, the mobile phase is n-hexane / 2-propanol=90 / 10, and the flow rate is v=1.5mL·min -1 , the detection wavelength is λ=254nm. DETAILED DESCRIPTION

[0048] The specific implementation of the present invention will be further described below in conjunction with the accompanying drawings:

[0049] Example 1

[0050] In an integrated electrolytic cell, 0.20 mmol of 4-formamide-[2,2]paracyclophane raw material 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)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 added, and after stirring and mixing at 70°C in an air atmosphere for 8 hours, 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 DC power supply was connected, and stirring and electrolysis was carried out at 50°C in an air atmosphere for 14 hours. Thereafter, the chiral para-oxo[2,2]-cyclophane product 1 having the structure of Formula 1 was obtained by separation on a silica gel column (eluent ratio: petroleum ether / dichloromethane / ethyl acetate = 70:40:10) with a yield of 46% and an ee value of 96%; the chiral 4-carboxamide-[2,2]-cyclophane raw material S was recovered with a yield of 45% and an ee value of 96%. The HPLC spectra of compound 1 and its racemate are shown in Figure 1 The HPLC spectrum of the recovered raw material S and its racemate is shown in 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(400MHz,CDCl3)δ9.99(s,1H),8.85(dd,J=7.2,1.2Hz,1H),8.72(dd,J=4.4,1.6Hz,1H),8.06(dd,J=8.0,1.6Hz,1H),8.02(d,J=8.4Hz,2H),7.51(t,J=8.0Hz,1H),7.44(dd,J=8.4,1.2Hz,1H),7.36(dd,J=8.4,4.4Hz,1H),7.24(dd,J=8.0,2.0Hz,1H),7.11(dd,J=8.0,2.0Hz,1H),7.06(d,J=8.0Hz,2H),6.74-6.68(m,2H),6.63(d,J=8.0Hz,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(101MHz,CDCl3)δ164.6,164.6,148.1,146.0,144.3,141.5,139.6,139.6,138.5,136.9,136.0,134.7,133.3,132.9,132.9,132.6,131.7,130.2,129.7,129.5,129.1,127.9,127.3,126.3,121.6,121.5,116.4,35.3,34.5,33.7,31.3,21.7. HRMS (ESI-TOF) :Calculated for C 34 H 28 N2O3+H + [M+H] +513.2173, found: 513.2173; Determination of the ee value of compound 1: 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; Determination of the ee value of the recovered raw 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) = 5.932 min, t (major) = 6.967 min, 96% ee.

[0055] Embodiments 2 to 19

[0056] The operation steps are the same as those in Example 1, except that by changing the coupling reagent carboxylic acid and the electrolysis time, as well as different proportions of the column chromatography eluent, different chiral para-oxo[2,2]paracyclophane products 2 to 20 can be obtained, and the chiral 4-carboxamide-[2,2]paracyclophane raw material S can be recovered. The results are shown below:

[0057]

[0058]

[0059] Embodiment 22

[0060] In an integrated electrolytic cell, 0.20 mmol of 4-formamide-[2,2]paracyclophane raw 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 added, and after stirring and mixing at 70°C in an air atmosphere for 8 hours, 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 DC power supply was connected, and stirring and electrolysis was carried out at 50°C in an air atmosphere for 12 hours. Thereafter, the chiral para-oxo[2,2]-cyclophane product 22 having a structure as shown in Formula 22 was obtained by separation on a silica gel column (eluent ratio: petroleum ether / dichloromethane / ethyl acetate = 70:40:15) with a yield of 38% and an ee value of 99%; the chiral 4-carboxamide-[2,2]-cyclophane raw material S was recovered with a yield of 58% and an ee value of 66%. The HPLC spectra of compound 22 and its racemate are shown in Figure 3 A, HPLC spectrum of recovered raw material S is shown in Figure 3 B.

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

[0062]

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

[0064] 1 HNMR(400MHz,CDCl3 )δ9.90(s,1H),9.57(s,1H),8.83(dd,J=7.6,1.6Hz,1H),8.58(dd,J=4.0,1.6Hz,1H),8.51(dd,J=8.0, 2.0Hz,1H),8.18(dd,J=4.8,2.0Hz,1H),8.02(dd,J=8.0,2.0Hz,1H),7.55-7.43(m,3H),7.27-7.21(m, 2H),7.13(d,J=8.4Hz,1H),7.08-7.01(m,2H),6.78-6.64(m,4H),6.56(dd,J=7.6,4.8Hz,1H),3.48(td ,J=12.4,2.0Hz,1H),3.34(td,J=12.4,4.0Hz,1H),3.17-3.00(m,5H),2.95-2.87(m,1H),2.13(s,3H); 13 CNMR(101MHz,CDCl3)δ166.0,164.5,156.6,154.0,148.0,145.6,141.8,140.6,139.7,139.4,138.7,138.3,137.0,136.2,134.8,134.4,133.3,133.2,132.8 ,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; Determination of the ee value of compound 22: The enantiomeric excess 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; Determination of the ee value of the recovered raw 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) = 5.759 min, t (major) = 6.746 min, 66% ee.

[0065] Embodiment 23

[0066] In an integrated electrolytic cell, 0.20 mmol of 4-formamide-[2,2]cyclophane raw material S, 0.20 mmol of Febuxostat, 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 added. After stirring and mixing at 70°C in an air atmosphere for 8 hours, 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 DC power supply was connected. The mixture was stirred and electrolyzed at 50°C in an air atmosphere for 14 hours. Thereafter, the chiral para-oxo[2,2]-cyclophane product 23 of 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-carboxamide-[2,2]-cyclophane raw material S was recovered with a yield of 60% and an ee value of 64%. The HPLC spectra of compound 23 and its racemate are shown in Figure 4 A, HPLC spectrum of recovered raw material S is shown in Figure 4 B.

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

[0068]

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

[0070] 1 HNMR(400MHz,CDCl3)δ9.96(s,1H),8.88(d,J=7.6Hz,1H),8.76(d,J=4.4Hz,1H),8.11(dd,J=8.4,1.6Hz,1H),7.93(dd,J=8.8,2.4Hz,1H),7.85(d,J=2.4Hz,1H),7.52(t,J=8.0Hz,1H),7.47-7.41(m,2H),7.25(dd,J=8.4,2.0Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),6.95(d,J=8.8Hz,1H),6.75-6.69(m,2H),6.64(d,J=8.0Hz,2H),3.88(d,J=6.8Hz,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=6.8Hz,6H); 13 CNMR(101 MHz,CDCl3) δ168.0,164.4,163.2,162.7,159.6,148.1,145.2,141.6,139.7,139.5,138.5,136.9,136.3,134.7,133.4,133.2,132.9,132.7,132.7,132.0,131.6,129.5,127.9,127.4,125.7,121.9,121.8,120.0,116.4,115.4,112.6,102.9,75.8,35.3,34.4,33.6,31.3,28.2,19.1,17.5;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 raw 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 above embodiments and descriptions are only for illustrating the principles and best embodiments of the present invention. Without departing from the spirit and scope of the present invention, the present invention may be subject to various changes and improvements, all of which fall within the scope of the present invention to be protected.

Claims

1. A method for constructing a chiral [2,2]-cyclophane by cobalt-catalyzed asymmetric carbon-hydrogen bond activation-kinetic resolution driven by electrochemical oxidation, characterized in that: The following steps are involved: (1) dissolving racemic [2,2]-p-cyclophane carboxamide, carboxylic acid, a cobalt catalyst, a chiral ligand and a 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 splitting. After the reaction is completed, post-treatment is performed to obtain a chiral [2,2]-para-cyclophane carboxamide and a chiral oxo-para-[2,2]-para-cyclophane 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: Among them, R 1 ~R 3 independently selected from H, alkyl, alkoxy, halogen, trifluoromethyl, nitro or aryl; R 4 is an alkyl group or an aryl group.

2. The method for constructing a chiral [2,2]-cyclophane by electrochemical oxidation-driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution according to claim 1, characterized in that: The reaction of step (1) and step (2) is carried out under air atmosphere; The electrolytic cell is an integrated electrolytic cell.

3. The method for constructing a chiral [2,2]-cyclophane by electrochemical oxidation-driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution according to claim 1, characterized in that: In R, the aryl group is phenyl or naphthyl, and the substituent on the aryl group is one or more of C1-C4 alkyl, C1-C4 alkoxy, methylenedioxy, halogen, C1-C4 alkoxyacyl, nitro, dipropylaminesulfonyl, and 2-methyl-3-chloroanilino; The heterocyclic aromatic group is pyridyl, furyl, benzothiophenyl, thiazolyl or phenylthiazolyl, and the substituent on the heterocyclic aromatic group is C1-C4 alkyl, C1-C4 alkoxy or cyano; The alkenyl group is a C2-C6 alkenyl group, and the substituent on the alkenyl group is a phenyl group.

4. The method for constructing a chiral [2,2]-cyclophane by electrochemical oxidation-driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution according to claim 1, characterized in that: R 1 ~R 3 Independently selected from one or more of hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, and phenyl; R 4 It is n-propyl, isopropyl, tert-butyl, cyclohexyl or phenyl.

5. The method for constructing a chiral [2,2]-cyclophane by electrochemical oxidation-driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution according to claim 1, characterized in that: The conductive agent is a mixture of one or more 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 trifluoromethanesulfonate, and tetra(n-butyl)ammonium perchlorate; The solvent is one or more mixed solvents 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 for constructing a chiral [2,2] paracyclophane by electrochemical oxidation driven cobalt catalysis asymmetric carbon-hydrogen bond activation / kinetic resolution according to 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 cobalt di(acetylacetonate); The chiral ligand is (S)-4-methoxy-2-(4-phenyl-4,5-dihydrooxazol-2-yl)phenol.

7. The method for constructing a chiral [2,2] paracyclophane by electrochemical oxidation driven cobalt catalysis asymmetric carbon-hydrogen bond activation / kinetic resolution according to claim 1, characterized in that: The molar ratio of the racemic [2,2] p-cyclophane carboxamide, 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 for constructing a chiral [2,2] paracyclophane by electrochemical oxidation driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution according to any one of claims 1 to 7, characterized in that: In step (1), the temperature of heating and stirring is 50 to 70° C., and the time of heating and stirring is 2 to 8 hours.

9. The method for constructing a chiral [2,2] paracyclophane by electrochemical oxidation driven cobalt-catalyzed asymmetric carbon-hydrogen bond activation / kinetic resolution according to any one of claims 1 to 7, characterized in that: In step (2), the direct current is 1 to 3 mA.

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

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