A chiral ferrocene P,N,N-ligand with side arms, a synthesis method thereof and applications thereof

Abstract

The present invention relates to a chiral ferrocene P,N,N-ligand with side arms, a synthesis method thereof and applications. Specifically: a ferrocenyl chiral amine and pyridine aldehyde (ketone) are reacted at room temperature in methanol, and then, NaBH 4 is added for reaction, and the chiral ferrocene amine-pyridine intermediate is obtained by column chromatography. Under nitrogen protection, the chiral ferrocene amine-pyridine intermediate is dissolved in anhydrous acetonitrile, a side arm substance such as benzyl bromide is added, and finally dry K 2 CO 3 is added, and the reaction is refluxed to obtain the chiral ferrocene P,N,N-ligand with side arms. The ligand synthesis method of the present invention has the characteristics of simple and easily available raw materials, mild reaction conditions, simple operation, etc. The catalyst prepared in-situ from the ligand and a copper metal precursor can efficiently and highly selectively catalyze the asymmetric cyclopropanation reaction of olefins, and is applicable to the asymmetric synthesis of chiral chrysanthemic acid, an important intermediate of the insecticide pyrethroid pesticides, with a yield of 80% and an enantioselectivity of 90%, and can be applied to industrial preparation.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a chiral ferrocene P,N,N-ligand with side arms and a synthesis method thereof. It also relates to the application of the chiral copper catalyst prepared from this ligand in the asymmetric cyclopropanation reaction of olefins and the asymmetric synthesis of chiral pyrethroid insecticide key intermediate - chiral chrysanthemic acid I. Background Art

[0002] Chiral synthesis methodology and its applications are the hotspots and frontiers in contemporary organic chemistry research, and also represent the development direction of organic synthetic chemistry in the 21st century. Currently, the asymmetric catalytic reaction using chiral ligands and metal catalysis is the most direct and efficient way to obtain highly optically active compounds, and it is also the method that best conforms to the concept of green chemistry. The key to asymmetric catalytic reaction is to design and synthesize catalysts with high catalytic activity and high enantioselectivity. Among them, the chiral ligand coordinated with metal is the root cause of the asymmetric induction and stereochemical control of chiral catalysts. Therefore, more and more scientific researchers have turned their research interests to the design and development of chiral ligands. So far, thousands of chiral ligands have been developed and applied in asymmetric catalytic reactions [(a) Xie, J.-H.; Zhou, Q.-L.; Acta Chimica Sinica 2014, 72, 778 - 797; (b) Yoon, T.P.; Jacobsen, E.N.; Science 2003, 299, 1691 - 1693; (c) Liu, Y.-Y.; Li, W.-B.; Zhang, J.-L.; Natl Sci Rev 2017, 4, 326 - 358; (d) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L.; Acc.Chem.Res.2003, 36, 659 - 667.].

[0003] The research group where the inventor belongs has been dedicated to the design, development, and application research of chiral ligands for many years. The self-developed asymmetric hybrid P,N,N-ligands have achieved many breakthroughs in asymmetric propargylation reactions and asymmetric hydrogenation reactions [(a) Zhang, C.; Hu, X.-H.; Wang, Y.-H.; Zheng, Z.; Xu, J.; X.-P. Hu. J. Am. Chem. Soc. 2012, 134, 9585-9588; (b) Zhu, F.-L.; Zou, Y.; Zhang, D.-Y.; Wang, Y.-H.; Hu, X.-H.; Chen, S.; Xu. J.; X.-P. Hu. Angew. Chem. Int. Ed. 2014, 53, 1410-1414; (c) Zhu, F.-L.; Wang, Y.-H.; Zhang, D.-Y.; Xu, J.; X.-P. Hu. Angew. Chem. Int. Ed. 2014, 53, 10223-10227; (d) Zhang, D.-Y.; Shao, L.; Xu, J.; X.-P. Hu. ACS Catal. 2015, 5, 5026-5030; (e) Shao, L.; Wang, Y.-H.; Zhang, D.-Y.; Xu, J.; X.-P. Hu. Angew. Chem. Int. Ed. 2016, 55, 5014-5018.]. However, the current chiral P,N,N-ligand-catalyzed reactions are relatively single, too rigid, and it is difficult to adjust the structure. Therefore, the applicant considers combining the dual advantages of asymmetric hybridization and side-arm effect, designing and developing a new type of chiral P,N,N-ligand with side arms, and exploring its application in asymmetric catalytic reactions.

[0004] The cyclopropane structure widely exists in carbocyclic and heterocyclic compounds with important biological activities, such as chiral pyrethroid insecticides. Additionally, cyclopropane is also a very important synthetic intermediate, for example, synthesizing medium-ring compounds and functionalized molecules through ring-opening or ring-expansion strategies [(a) R. Faust, Angew. Chem. Int. Ed. 2001, 40, 2251 - 2253; (b) H. Staudinger, L. Ruzicka, Helv. Chim. Acta 1924, 7, 177 - 235; (c) J. Pietruszka, Chem. Rev. 2003, 103, 1051 - 1070; (d) L. A. Wessjohann, W. Brandt, T. Thiemann, Chem. Rev. 2003, 103, 1625 - 1647; (e) P. Tang, Y. Qin, Synthesis 2012, 44, 2969 - 2984; (f) D. Y.-K. Chen, R. H. Pouwer, J.-A. Richard, Chem. Soc. Rev. 2012, 41, 4631 - 4642; (g) C. Ebner, E. M. Carreira, Chem. Rev. 2017, 117, 11651 - 11679; (h) F. Chem.Biodiversity 2014,11,1734-1751. Among various methods for synthesizing chiral cyclopropane structures, the transition-metal-catalyzed asymmetric cyclopropanation reaction is undoubtedly one of the most direct and effective strategies, featuring mild reaction conditions, wide application scope, high stereoselectivity, etc. The ligands mainly include nitrogen-containing ligands such as Schiff bases, semicorrins, bisoxazolines, and bipyridines [(a) R.E. Lowenthal, S. Masamune, Tetrahedron Lett. 1991, 32, 7373-7376; (b) K. Ito, T. Katsuki, Synlett 1993, 638-640; (c) H. Suematsu, S. Kanchiku, T. Uchida, T. Katsuki, J. Am. Chem. Soc. 2008, 130, 10327-10337; (d) H.M.L. Davies, M.G. Coleman, D.L. Ventura, Org. Lett. 2007, 9, 4971-4974.]. However, this method also has many limitations, such as narrow reaction substrate scope, low selectivity, and difficulty in industrial application. The present invention provides a novel chiral ferrocene P,N,N-ligand with side arms and a synthesis method. Such ligands exhibit excellent catalytic activity and stereoselectivity in the asymmetric cyclopropanation reaction of olefins and have been successfully applied to the industrial preparation of chiral chrysanthemic acid, an important intermediate of pyrethroid pesticides. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the present invention provides a chiral ferrocene P,N,N-ligand with side arms and a synthesis method thereof.

[0006] Another object of the present invention is to provide an application of the above-mentioned chiral P,N,N-ligand with side arms in asymmetric catalytic reactions, especially the application of the chiral copper catalyst in situ generated from such a ligand and a copper metal precursor in the asymmetric cyclopropanation reaction of olefins, which is applicable to the asymmetric synthesis of chiral chrysanthemic acid, an important intermediate of pyrethroid pesticides for insecticides, and can be applied to industrial preparation.

[0007] The structural general formula of the chiral P,N,N-ligand with side arms described in the present invention is as follows:

[0008]

[0009] In the formula: I and II are enantiomers, R 1 、R 2is one or more of an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a substituted cycloalkyl group having 3 to 6 carbon atoms, a phenyl group and a substituted phenyl group, a naphthyl group and a substituted naphthyl group, a benzyl group and a substituted benzyl group, a five- or six-membered heteroaromatic group containing one or more oxygen, sulfur or nitrogen atoms; the substituents on the C3-C6 cycloalkyl group, the phenyl group, the naphthyl group and the benzyl group are one or more of an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 3 to 6 carbon atoms, a halogen, a nitro group, an ester group or a cyano group, and the number of substituents is 1 to 5;

[0010] R 3 is one or more of H, a halogen, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group and a substituted phenyl group, an alkoxy group, a phenoxy group, an acyl group, a nitro group, an ester group or a cyano group.

[0011] R 4 、R 5 is one or more of H, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a substituted cycloalkyl group having 3 to 6 carbon atoms, a phenyl group and a substituted phenyl group, a naphthyl group and a substituted naphthyl group, a benzyl group and a substituted benzyl group, a five- or six-membered heteroaromatic group containing one or more oxygen, sulfur or nitrogen atoms; the substituents on the C3-C6 cycloalkyl group, the phenyl group, the naphthyl group and the benzyl group are one or more of an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 3 to 6 carbon atoms, a halogen, a nitro group, an ester group or a cyano group, and the number of substituents is 1 to 5;

[0012] For the preparation of the above chiral P,N,N-ligand with side arms, the specific technical solution is as follows:

[0013]

[0014] (1) The molar ratio of ferrocenyl chiral amine III or IV to pyridine aldehyde (ketone) is 1 to 2:1, and the reaction is carried out at room temperature in methanol for 12 - 24 hours. Then, 1.5 to 4 equivalents of NaBH 4 is added to the reaction solution, and the reaction is carried out at 25 - 40 °C for 4 - 8 hours. After the reaction is completed, it is quenched with saturated ammonium chloride, and part of the methanol is removed under reduced pressure. Dichloromethane is added for dilution, liquid separation is carried out, and it is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then treated by column chromatography to obtain the chiral ferroceneamine-pyridine intermediate V or VI.

[0015] (2) Under nitrogen protection, the chiral ferroceneamine-pyridine intermediate obtained in step (1) is dissolved in anhydrous acetonitrile, 1 to 2 equivalents of side arm substance benzyl bromide or chloromethyl oxazole is added, and finally 2 to 4 equivalents of dry K 2 CO 3 is added, and the reaction is refluxed for 2 - 4 hours, filtered, concentrated, and column chromatography is carried out to obtain the chiral ferrocene P,N,N-ligand I or II with side arms.

[0016] The structural formulas of the ferrocenyl chiral amine III or IV are as follows:

[0017]

[0018] In the formula: III and IV are enantiomers, and R 1 , R 2 are the same groups as those in I and II;

[0019] The structural formula of the pyridine aldehyde (ketone) is as follows:

[0020]

[0021] In the formula: R 3 , R 4 are the same groups as those in I and II;

[0022] The structural formulas of the chiral ferrocenylamine-pyridine intermediate V or VI are as follows:

[0023]

[0024] In the formula: V and VI are enantiomers, and R 1 , R 2 , R 3 , R 4 are the same groups as those in I and II.

[0025] The chiral ferrocene P,N,N-ligand with side arms in-situ forms a chiral copper catalyst with a copper metal precursor, and the chiral copper catalyst is used in the asymmetric cyclopropanation reaction of olefins.

[0026] The specific steps of the asymmetric cyclopropanation reaction of olefins catalyzed by the chiral copper catalyst are as follows:

[0027] (1) Preparation of the chiral copper catalyst: Under nitrogen protection, the copper metal precursor and the chiral ferrocene P,N,N-ligand with side arms are stirred in a reaction medium for 0.5 - 2 hours to in-situ coordinate to obtain the chiral copper catalyst;

[0028] (2) Asymmetric olefin cyclopropanation reaction of olefins catalyzed by the chiral copper catalyst: To the chiral copper catalyst solution obtained in step (1), olefin A and diazoacetate B are successively added, and the reaction is continued for 12 - 24 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, separated by silica gel column chromatography, concentrated under reduced pressure, and vacuum dried to obtain the cyclopropane compound C.

[0029] The cyclopropanation product C has the following structure:

[0030]

[0031] In the formula: R 6 , R 7 , R 8 is one or more of H, an alkyl group having 1 to 40 carbon atoms, a cycloalkyl group having 3 to 12 carbon atoms or a substituted cycloalkyl group having 3 to 12 carbon atoms, a phenyl group and a substituted phenyl group, a benzyl group and a substituted benzyl group, a five- or six-membered heteroaromatic group containing one or more oxygen, sulfur, or nitrogen atoms, and an ester group; the substituents on the cycloalkyl group having 3 to 12 carbon atoms, the substituents on the phenyl group, and the substituents on the benzyl group are one or more of an alkyl group having 1 to 40 carbon atoms, an alkoxy group having 1 to 40 carbon atoms, a halogen, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5; R 9 is one or more of an alkyl carboxylate having 1 to 10 carbon atoms, an alkyl carbonate having 1 to 10 carbon atoms, an alkyl sulfonate having 1 to 10 carbon atoms, an alkyl phosphate having 1 to 10 carbon atoms, a phenyl carboxylate and a substituted phenyl carboxylate, a phenyl carbonate and a substituted phenyl carbonate, a phenyl sulfonate and a substituted phenyl sulfonate, or a phenyl phosphate and a substituted phenyl phosphate; the substituents on the substituted phenyl group are one or more of an alkyl group having 1 to 40 carbon atoms, an alkoxy group having 1 to 40 carbon atoms, a halogen, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5.

[0032] The olefin A has the following structure:

[0033]

[0034] In the formula: R 6 , R 7 are the same groups as R 6 , R 7 in the structural formula C.

[0035] The diazo compound B has the following structure:

[0036]

[0037] In the formula: R 8 , R 9 are the same groups as R 8 , R 9 in the structural formula C.

[0038] The copper metal precursor is Cu(OAc) 2 ·H 2 O, CuSO 4 ·H 2 O, Cu(OAc) 2 , CuSO 4 , Cu(OTf) 2 , CuCl 2 , CuOAc, CuCl, CuI, CuClO 4, CuOTf·0.5C 6 H 6 , Cu(CH 3 CN) 4 BF 4 or Cu(CH 3 CN) 4 ClO 4 at least one of them, preferably Cu(OTf) 2 .

[0039] The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide, preferably at least one of methanol, ethanol or tetrahydrofuran, and preferably 1,2-dichloroethane.

[0040] In the present invention, the chiral copper catalyst in-situ generated from the chiral P,N,N-ligand with side arms and the copper metal precursor can catalyze the asymmetric cyclopropanation reaction of octene (2,5-dimethyl-2,4-hexadiene) with diazoacetate to obtain pyrethroid compounds, which are further saponified and acidified to obtain the important intermediate of pyrethroid insecticides - chiral chrysanthemic acid.

[0041] The specific technical solution is as follows:

[0042]

[0043] The beneficial effects of the present invention:

[0044] The synthesis method of the chiral P,N,N-ligand with side arms involved in the present invention has the characteristics of simple and easily available raw materials, mild reaction conditions, and simple operation. The ligand described in the present invention can be used in the asymmetric cyclopropanation reaction of copper-catalyzed olefins and is applicable to the asymmetric synthesis of the important intermediate of pyrethroid insecticides - chiral chrysanthemic acid, with a yield of 80% and an enantioselectivity of 90%, and can be applied to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The attached drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention and do not constitute an improper limitation of the present invention. Hereinafter, the embodiments of the present invention will be described in detail with reference to the drawings, wherein:

[0046] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the chiral ferrocenylamine-pyridine intermediate (R c ,S p )-Ⅴ-1 prepared in Example 1;

[0047] Figure 21H NMR spectrum of the chiral ferrocenylamine-pyridine intermediate (R c ,S p )-Ⅴ-1 prepared in Example 1;

[0048] Figure 3 1H NMR spectrum of the chiral P,N,N-ligand with side arms (R c ,S p )-I-1 prepared in Example 1;

[0049] Figure 4 13C NMR spectrum of the chiral P,N,N-ligand with side arms (R c ,S p )-I-1 prepared in Example 1. Detailed implementation manners

[0050] The following examples will further illustrate the present invention, but do not limit the present invention thereby. Nuclear magnetic resonance was measured by a Bruker nuclear magnetic resonance instrument, and high performance liquid chromatography (HPLC) was measured by an Agilent 1100 series high performance liquid chromatography.

[0051] Example 1

[0052] Synthesis steps of the chiral P,N,N-ligand with side arms:

[0053] (1) Chiral ferrocenylamine (R c ,S p )-III-1 (2 mmol, 826 mg) and 2-pyridinecarboxaldehyde (2.4 mmol, 257 mg) were reacted at room temperature in methanol for 12 hours. Then, 2 equivalents of NaBH 4 were added to the reaction solution, and the reaction was carried out at 40 °C for 4 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, the methanol was removed by rotary evaporation under reduced pressure, diluted with dichloromethane, separated by liquid separation, the organic phase was dried with anhydrous sodium sulfate, and rotary dried and column chromatographed (petroleum ether / ethyl acetate / triethylamine = 50:10:1) to obtain the chiral ferrocenylamine-pyridine intermediate (R c ,S p )-Ⅴ-1 with a yield of 97%. The 1H NMR and 13C NMR spectra are as shown in Figure 1 、 2 : 1 1H NMR (400 MHz, CDCl 3)δ8.33(d, J = 4.9Hz, 1H), 7.56 - 7.52(m, 2H), 7.37 - 7.30(m, 4H), 7.26 - 7.22(m, 2H), 7.17 - 7.14(m, 3H), 7.00 - 6.96(m, 1H), 6.56(d, J = 7.8Hz, 1H), 4.54(s, 1H), 4.31(t, J = 2.6Hz, 1H), 4.22 - 4.17(m, 1H), 4.02(s, 5H), 3.82(s, 1H), 3.63(d, J = 3.0Hz, 2H), 1.65(s, 1H), 1.56(d, J = 6.5Hz, 3H); 13 C NMR(101MHz, CDCl 3 )δ159.9, 148.7, 140.0(d, J = 9.6Hz), 137.3, 136.1, 135.0(d, J = 21.2Hz), 132.6(d, J = 18.7Hz), 129.1, 128.3, 128.2(d, J = 10.6Hz), 128.0, 121.5, 121.3, 97.7(d, J = 24.1Hz), 76.7, 75.1(d, J = 7.8Hz), 71.3(d, J = 3.9Hz), 69.6, 69.5(d, J = 4.0Hz), 69.1, 52.2, 51.3(d, J = 9.3Hz), 19.5.

[0054] (2) Under nitrogen protection, dissolve the chiral ferrocenylamine - pyridine intermediate (R c , S p ) - Ⅴ - 1 (0.5 mmol, 252 mg) in anhydrous acetonitrile, add 1.1 equivalents of benzyl bromide (0.55 mmol, 94 mg), and finally add 2.4 equivalents of dry K 2 CO 3 (1.2 mmol, 166 mg), reflux for 2 - 4 hours, filter, concentrate, and perform column chromatography (petroleum ether / ethyl acetate / triethylamine = 50:10:1) to obtain the chiral P,N,N - ligand (R c , S p ) - I - 1 with a yield of 86%. The proton nuclear magnetic resonance spectrum and carbon spectrum are as Figure 3 、 4 shown: 1 H NMR(400MHz, CDCl 3)δ8.35 - 8.33 (m, 1H), 7.57 - 7.53 (m, 2H), 7.36 - 7.29 (m, 5H), 7.27 - 7.21 (m, 4H), 7.17 - 7.06 (m, 4H), 7.02 - 7.00 (m, 2H), 6.95 - 6.92 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 4.49 (q, J = 2.1 Hz, 1H), 4.41 - 4.36 (m, 1H), 4.34 (t, J = 2.6 Hz, 1H), 4.09 - 4.01 (m, 1H), 3.82 (s, 5H), 3.67 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 14.6 Hz, 1H), 3.39 (d, J = 13.7 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )δ160.3, 148.0, 139.5, 135.8, 135.6, 135.4, 132.7, 132.6, 129.2 (d, J = 1.3 Hz), 128.9, 128.0, 127.9 (d, J = 1.3 Hz), 127.8, 127.7, 127.4, 126.4, 123.5 (d, J = 2.2 Hz), 121.2, 71.8 (d, J = 5.1 Hz), 70.4 (d, J = 4.7 Hz), 69.6, 69.3, 55.9, 54.7, 53.8, 53.7, 11.7.

[0055] (R c ,S p )-Ⅲ-1, (R c ,S p )-Ⅴ-1, (R c ,S p )-I-1 has the following structural formula:

[0056]

[0057] Example 2

[0058] The chiral P,N,N-ligand and copper metal precursor in-situ generate a chiral copper catalyst, and the chiral copper catalyst catalyzes the asymmetric cyclopropanation reaction of olefins:

[0059] Under nitrogen protection, copper salt Cu(OTf) 2 (5 mol%) and chiral P,N,N-ligand (R c ,S p)-I-1 (5.5 mol%) was placed in a 25 mL Schlenk tube, 1 mL of dichloroethane was added, and the mixture was stirred at room temperature for 2 h to prepare the chiral copper catalyst in situ. The substrate styrene A-1 was dissolved in 1 mL of dichloroethane and added to the above-mentioned well-stirred chiral copper catalyst solution. Methyl phenyldiazoacetate B-1 was slowly added using a syringe pump, and the addition was completed in 3 h. The reaction was continued for 12 h. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure until the solvent was almost gone, separated by silica gel column chromatography, concentrated under reduced pressure, and dried in vacuo to obtain the cyclopropanated product C-1 with a yield of 95%, dr > 19:1, and 90% ee. The ¹H NMR and HPLC detection data of the product are as follows: 1 ¹H NMR (400 MHz, CDCl 3 ) δ 7.11 - 7.09 (m, 3H), 7.04 - 7.00 (m, 5H), 6.76 - 6.74 (m, 2H), 3.63 (s, 3H), 3.11 (dd, J = 9.3, 7.3 Hz, 1H), 2.12 (dd, J = 9.3, 4.9 Hz, 1H), 1.86 (dd, J = 7.3, 4.9 Hz, 1H). HPLC (Chiralcel OJ-H, n-hexane / i-PrOH = 95 / 5, 0.8 mL / min, 254 nm, 40 °C): t R (minor) = 8.6 min, t R (major) = 12.3 min.

[0060] The structural formulas of A-1, B-1, C-1, and I-1 are as follows:

[0061]

[0062] Example 3

[0063] CuOTf·0.5C 6 H 6 and (R c ,S p )-I-1 catalyzed the reaction to produce the product C-1

[0064] Replace Cu(OTf) in Example 2 with CuOTf·0.5C 2 H 6 H 6 and the rest was the same as in Example 2. The reaction gave compound C-1 with a yield of 92%, dr > 20:1, and 87% ee.

[0065] Example 4

[0066] Replace dichloroethane in Example 2 with dichloromethane, and the rest was the same as in Example 2. The reaction gave compound C-1 with a yield of 84%, dr > 20:1, and 85% ee.

[0067] Example 5

[0068] The reaction temperature in Example 2 was raised to 40 °C, and the rest was the same as in Example 2. Compound C-1 was obtained by reaction with a yield of 87%, dr > 20:1, and 82% ee.

[0069] Example 6

[0070] A-2 and B-2 reacted as substrates to form product C-2

[0071] The styrene A-1 in Example 2 was replaced with cis-β-methylstyrene A-2, and methyl phenyl diazoacetate B-1 was replaced with B-2. The rest was the same as in Example 2 to obtain compound C-2 with a yield of 90%, dr > 20:1, and 93% ee. The detection data of the product by 1H NMR and HPLC were as follows: 1 H NMR(300MHz,CDCl 3 ):δ7.15(brs,4H),7.05(brs,3H),2.92(dd,J=10.0Hz,4.8Hz,1H),2.35(s,3H),2.17(s,6H),2.09(t,J=4.8Hz,1H),2.01-1.93(m,1H),1.01(d,J=6.4Hz,3H).HPLC(Chiralcel OJ-H,n-hexane / i-PrOH=99 / 1,0.3mL / min,230nm,40℃):t R (minor)=27.1min,t R (major)=31.2min.

[0072] The structural formulas of A-2, B-2, and C-2 are as follows:

[0073]

[0074] Example 7

[0075] A-3 and B-2 reacted as substrates to form product C-3

[0076] The cis-β-methylstyrene A-2 in Example 6 was replaced with cis-β-methyl-(4-methylphenyl)ethylene A-3, and the rest was the same as in Example 6 to obtain compound C-3 with a yield of 91%, dr > 20:1, and 87% ee. The detection data of the product by 1H NMR and HPLC were as follows: 1 H NMR(300MHz,CDCl 3): δ 7.15 (brs, 4H), 7.05 (brs, 3H), 2.92 (dd, J = 10.0 Hz, 4.8 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 6H), 2.09 (t, J = 4.8 Hz, 1H), 2.01 - 1.93 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H). HPLC (Chiralcel OJ-H, n-hexane / i-PrOH = 99 / 1, 0.3 mL / min, 230 nm, 40 °C): t R (minor) = 27.3 min, t R (major) = 31.2 min.

[0077] The structural formulas of A-3 and C-3 are as follows:

[0078]

[0079] Example 8

[0080] A-4 and B-2 react as substrates to form product C-4

[0081] Replace cis-β-methylstyrene A-2 in Example 6 with cis-β-methyl-(4-chlorophenyl)ethylene A-4, and the rest is the same as in Example 6, to obtain compound C-4 with a yield of 87%, dr > 20:1, and 91% ee. The nuclear magnetic resonance hydrogen spectrum and high performance liquid chromatography detection data of the product are as follows: 1 H NMR (300 MHz, CDCl 3 ): δ 7.15 (brs, 4H), 7.05 (brs, 3H), 2.92 (dd, J = 10.0 Hz, 4.8 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 6H), 2.09 (t, J = 4.8 Hz, 1H), 2.01 - 1.93 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H). HPLC (Chiralcel OD-H, n-hexane / i-PrOH = 99 / 1, 0.3 mL / min, 230 nm, 40 °C): t R (minor) = 10.7 min, t R (major) = 11.4 min.

[0082] The structural formulas of A-4 and C-4 are as follows:

[0083]

[0084] Example 9

[0085] A-5 and B-2 react as substrates to form product C-5

[0086] Replace cis-β-methylstyrene A-2 in Example 6 with trans-β-methyl-(4-methylphenyl)ethylene A-5, and the rest is the same as in Example 6 to obtain compound C-5 with a yield of 93%, dr > 20:1, and 95% ee. The nuclear magnetic resonance hydrogen spectrum and high performance liquid chromatography detection data of the product are as follows: 1 H NMR(300MHz,CDCl 3 ):δ7.14-7.12(m,2H),7.08-7.04(m,5H),2.53(dd,J=6.0Hz,5.2Hz,1H),2.34(s,3H),2.30(dd,J=8.8Hz,4.8Hz,1H),2.17(s,6H),1.88-1.80(m,1H),1.43(d,J=6.4Hz,3H).HPLC(Chiralcel AD-H,n-hexane / i-PrOH=98 / 2,0.5mL / min,254nm,40℃):t R (minor)=9.3min,t R (major)=10.0min.

[0087] The structural formulas of A-5 and C-5 are as follows:

[0088]

[0089] Example 10

[0090] React A-6 and B-3 as substrates to form product C-6

[0091] Replace styrene A-1 in Example 2 with octene (2,5-dimethyl-2,4-hexadiene) A-6, and methyl phenyl diazoacetate B-1 with ethyl diazoacetate B-3. The rest is the same as in Example 2 to obtain compound C-6 with a yield of 80%, dr = 7:1, and 87% ee. The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows: 1 H NMR(300MHz,CDCl 3 )δ4.88(d,J=9.44Hz,1H),4.17-4.07(m,2H),2.06-2.02(m,1H),1.73-1.67(m,6H),1.37(d,J=5.34Hz,1H),1.25(t,J=7.25Hz,6H),1.13(s,3H). 13 C NMR(126MHz,CDCl 3 )δ172.5,135.4,121.2,60.2,34.8,32.6,28.5,25.6,22.2,20.4,18.5,14.4.

[0092] The structural formulas of A-6, B-3, and C-6 are as follows:

[0093]

[0094] Example 11

[0095] A-6 and B-4 react as substrates to form product C-7

[0096] Replace styrene A-1 in Example 2 with octene (2,5-dimethyl-2,4-hexadiene) A-6, and methyl phenyldiazoacetate B-1 with tert-butyl diazoacetate B-4. The rest is the same as in Example 2 to obtain compound C-7 with a yield of 83%, dr = 9:1, and 90% ee. The proton nuclear magnetic resonance and carbon nuclear magnetic resonance data are as follows: 1 H NMR(600MHz,CDCl 3 )δ4.87(d,J = 6.6Hz,1H),1.96(br s,1H),1.70(s,6H),1.44(s,9H),1.30(d,J = 1.6Hz,1H),1.23(d,J = 1.9Hz,3H),1.11(d,J = 1.9Hz,3H); 13 C NMR(151MHz,CDCl 3 )δ171.8,135.1,121.6,80.0,36.0,31.8,28.3,27.9,25.6,22.3,20.4,18.5.

[0097] The structural formulas of B-4 and C-7 are as follows:

[0098]

[0099] The products C-6 and C-7 obtained in Examples 10 and 11 can be saponified and acidified to obtain chiral chrysanthemic acid. The proton nuclear magnetic resonance and carbon nuclear magnetic resonance data are as follows: 1 H NMR(500MHz,CDCl 3 ):δ11.59(brs,1H),4.81 - 4.91(m,1H),2.10(dd,1H,J = 5.7Hz,8.0Hz),1.72(s,3H),1.39(d,J = 5.2Hz,3H),1.30(s,3H),1.15(s,3H); 13 C NMR(125MHz,CDCl 3 ):δ179.4,135.8,120.7,34.6,33.6,29.8,25.5,22.2,20.4,18.5. The specific reaction process is as follows:

[0100]

Claims

1. A method for synthesizing a chiral ferrocene P,N,N-ligand with side arms, characterized in that: The chiral P,N,N-ligand with side arms has the following structure: ； In the formula: R1 is phenyl, R2 is methyl, R3 and R4 are H, and R5 is phenyl; (1) The molar ratio of ferrocenyl chiral amine III to pyridine aldehyde (ketone) is 1 - 2:1, and the reaction is carried out at room temperature in methanol for 12 - 24 hours. Then, 1.5 - 4 equivalents of NaBH 4 are added to the reaction solution, and the reaction is carried out at 25 - 40 °C for 4 - 8 hours. After the reaction is completed, it is quenched with saturated ammonium chloride, partially methanol is removed under reduced pressure, diluted with dichloromethane, separated by liquid separation, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and treated by column chromatography to obtain the chiral ferroceneamine-pyridine intermediate V; (2) Under nitrogen protection, dissolve the chiral ferrocenylamine-pyridine intermediate obtained in step (1) in anhydrous acetonitrile, add 1-2 equivalents of the side arm substance benzyl bromide or chloromethyl oxazole, and finally add 2-4 equivalents of dry K 2 CO 3 , reflux for 2-4 hours, filter, concentrate, and perform column chromatography to obtain the chiral ferrocene P,N,N-ligand I with side arms; The structural formula of the ferrocenyl chiral amine III is as follows: ； Wherein: R in III 1 , R 2 are the same groups as those in I; The structural formula of the pyridine aldehyde (ketone) is as follows: ； Wherein: R 3 , R 4 are the same groups as those in I; The structural formula of the chiral ferrocene amine-pyridine intermediate V is as follows: ； Wherein: R of V 1 , R 2 , R 3 , R 4 are the same groups as those in I.

2. A chiral ferrocene P,N,N-ligand with side arms prepared by the synthesis method according to claim 1.

3. An application of a chiral ferrocene P,N,N-ligand with side arms according to claim 1, characterized in that: The chiral ferrocene P,N,N-ligand with side arms forms a chiral copper catalyst in situ with a copper metal precursor, and the chiral copper catalyst is used in the asymmetric cyclopropanation reaction of olefins; The specific steps of the asymmetric cyclopropanation reaction of olefins catalyzed by the chiral copper catalyst are as follows: (1) Preparation of the chiral copper catalyst: Under nitrogen protection, the copper metal precursor and the chiral ferrocene P,N,N-ligand with side arms are stirred in a reaction medium for 0.5 - 2 hours to coordinate in situ to obtain the chiral copper catalyst; (2) Asymmetric olefin cyclopropanation reaction of olefins catalyzed by the chiral copper catalyst: To the chiral copper catalyst solution obtained in step (1), olefin A and diazoacetate B are added in sequence, and the reaction is continued for 12 - 24 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, separated by silica gel column chromatography, concentrated under reduced pressure, and dried in vacuo to obtain the cyclopropane compound C; The cyclopropanation product C has the following structure: ; wherein: R 6 is an alkyl group having 1 to 40 carbon atoms, a phenyl group or a substituted phenyl group, and the substituent on the substituted phenyl group is an alkyl group having 1 to 40 carbon atoms or a halogen; R 7 is an alkyl group having 1 to 40 carbon atoms, hydrogen; R 8 is hydrogen, a phenyl group; R 9 is one or more of an alkyl carboxylate having 1 to 10 carbon atoms, a phenyl carboxylate and a substituted phenyl carboxylate, and the substituent on the substituted phenyl group is an alkyl group having 1 to 40 carbon atoms; the number of substituents is 1 to 5; The olefin A has the following structure: ; Where: R 6 , R 7 is the same group as R 6 , R 7 in structural formula C; The diazo compound B has the following structure: ; wherein: R 8 , R 9 is the same group as R 8 , R 9 in the structural formula C; the copper metal precursor is Cu(OAc) 2 ·H 2 O, CuSO 4 ·H 2 O, Cu(OAc) 2 , CuSO 4 , Cu(OTf) 2 , CuCl 2 , CuOAc, CuCl, CuI, CuClO 4 , CuOTf·0.5C 6 H 6 , Cu(CH 3 CN) 4 BF 4 or Cu(CH 3 CN) 4 ClO 4 ; at least one of them The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, 1,2-dichloroethane, ether, tetrahydrofuran, dimethyl sulfoxide or N , N -dimethylformamide.

4. According to the application of the chiral ferrocene P,N,N-ligand with side arms described in claim 3, characterized in that: The reaction medium is at least one of methanol, ethanol or tetrahydrofuran.

5. An application of a chiral ferrocene P,N,N-ligand with side arms according to claim 1, characterized in that, A chiral P,N,N-ligand with side arms in-situ generates a chiral copper catalyst with a copper metal precursor. The chiral copper catalyst catalyzes the asymmetric cyclopropanation reaction of 2,5-dimethyl-2,4-hexadiene and diazoacetate to obtain a pyrethroid compound, and its structural formula is , and further through saponification and acidification, an important intermediate of pyrethroid insecticides is obtained. The intermediate is chiral chrysanthemic acid; The copper metal precursor is Cu(OAc) 2 ·H 2 O, CuSO 4 ·H 2 O, Cu(OAc) 2 , CuSO 4 , Cu(OTf) 2 , CuCl 2 , CuOAc, CuCl, CuI, CuClO 4 , CuOTf·0.5C 6 H 6 , Cu(CH 3 CN) 4 BF 4 or Cu(CH 3 CN) 4 ClO 4 or at least one of them.

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