阅读说明：本技术 铱催化亚胺不对称氢化制备手性胺的方法 (Method for preparing chiral amine by iridium-catalyzed asymmetric hydrogenation of imine ) 是由 胡向平 刘振婷 于 2019-11-21 设计创作，主要内容包括：本发明公开了一种铱催化亚胺不对称氢化制备手性胺的方法。方法采用的铱催化剂是由金属铱前驱体与手性双膦配体在各种极性和非极性溶剂中原位生成的,催化剂用量(以摩尔计)为：原料亚胺/催化剂(S/C)等于300000～1000000。本发明配体制备简单,催化剂用量低,操作简便,且可实现连续操作,适于大规模制备手性胺,产物的对映体过量值(ee值)达80％以上。本发明对于精异丙甲草胺关键中间体的合成催化剂用量低,2-乙基-6-甲基苯胺/催化剂(S/C)为500000,可达到95％收率,91％对映选择性,具有很好的工业化应用范围。(The invention discloses a method for preparing chiral amine by iridium-catalyzed asymmetric hydrogenation of imine. The iridium catalyst adopted by the method is generated in situ in various polar and nonpolar solvents by a metal iridium precursor and a chiral diphosphine ligand, and the dosage (by mol) of the catalyst is as follows: the raw material imine/catalyst (S/C) is equal to 300000-1000000. The ligand of the invention has simple preparation, low catalyst consumption and simple and convenient operation, can realize continuous operation, is suitable for preparing chiral amine on a large scale, and has an enantiomeric excess value (ee value) of the product of more than 80 percent. The invention has low consumption of the synthetic catalyst of the key intermediate of the metolachlor, the 2-ethyl-6-methylaniline/the catalyst (S/C) is 500000, the yield can reach 95 percent, the enantioselectivity is 91 percent, and the invention has good industrial application range.)

1. a method for preparing chiral amine by iridium-catalyzed asymmetric hydrogenation of imine is characterized by comprising the following steps: the method comprises the following steps: imine is taken as a substrate, and asymmetric hydrogenation is carried out on the imine in a reaction solvent under the action of a chiral iridium catalyst under certain hydrogen pressure and temperature to obtain a chiral amine compound.

2. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 1, wherein: the method comprises the following specific steps:

(1) preparation of chiral iridium catalyst: under the protection of nitrogen, stirring the iridium-cyclooctadiene complex and chiral diphosphine ligand in a reaction solvent for 2 hours to prepare a chiral iridium catalyst by in-situ coordination;

(2) preparation of chiral amine compound: dissolving substrate imine in a reaction solvent, adding the substrate imine into the stirred chiral iridium catalyst solution, placing the solution in a high-pressure reaction kettle, replacing the solution with hydrogen for 3 times, and then introducing hydrogen; after the reaction, slowly releasing hydrogen, concentrating under reduced pressure until no solvent exists, separating by silica gel column chromatography, concentrating under reduced pressure, and vacuum drying to obtain chiral amine compound.

3. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 2, wherein: the imine (1) and the chiral amine compound (2) have the following structures:

in the formula: r¹Is C₁～C₁₀Alkyl radicals such as CH₃、CH₃CH₂Etc. C₃～C₁₂Cycloalkyl radicals such as cyclopentyl, cyclohexyl, etc., or C containing one or more functional groups of N, S, O, P₁～C₁₀Alkyl such as methoxymethyl, ethoxymethyl, etc., or C containing one or more functional groups of N, S, O, P₃～C₁₀Cycloalkyl groups such as 2-tetrahydrofuryl, 4-tetrahydrofuryl, etc.; or aryl or the like C₆-C₃₀Aromatic groups such as phenyl, 4-methoxyphenyl, etc., which may or may not contain N, S, O, P, etc.; or ester groups such as COOCH₃、COOCH₂CH₃Etc.; r²Is H, C₁-C₄₀Alkyl or aryl within; ar is C such as phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl, etc₆-C₃₀Aromatic groups containing or not containing N, S, O, P functional groups such as 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-6-ethylphenyl, thiophene, etc.

4. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 2, wherein: the iridium-cyclooctadiene complex is [ Ir (COD) Cl]₂、Ir(COD)₂BARF or Ir (COD)₂BF₄One kind of (1).

5. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 2, wherein: the structural general formula of the chiral diphosphine ligand is as follows:

wherein: r is C1-C40 alkyl and C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms, and has 1-5 substituents of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano;

ar is one of phenyl or substituted phenyl, the substituent is one or more of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5.

6. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 1, wherein:

the solvent is at least one of dichloromethane, 1, 2-dichloroethane or toluene.

7. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 2, wherein:

the iridium concentration in the reaction solution is 0.0001-0.01 mol/L;

the molar ratio of the chiral diphosphine ligand to iridium is 1-5: 1;

the molar ratio of the imine substrate to the iridium catalyst is 300000-500000: 1.

8. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium according to claim 1 or 2, wherein: the reaction conditions were controlled as follows:

the hydrogen pressure is 20-100 bar;

the reaction temperature is 20-100 ℃;

the reaction time is 1-24 hours.

9. The method for preparing chiral amine by asymmetric hydrogenation of imine catalyzed by iridium as claimed in claim 1, wherein: the technical route of the invention is as follows:

in the above reaction formula, the general formula (1) represents a reaction substrate imine, and the general formula (2) represents a chiral amine compound.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing chiral amine by catalyzing asymmetric hydrogenation of imine with iridium/chiral diphosphine ligand.

Background

Chiral amine compounds are organic synthetic building blocks with important application values, and are widely applied to the synthesis of biology, agriculture and pharmaceutical preparations. The efficient preparation of highly optical homochiral amine compounds has also become a research hotspot for organic chemists. Among many synthetic strategies, the asymmetric hydrogenation reaction of imine is undoubtedly the simplest and most efficient method, and the catalytic system mainly includes three types of transition metal catalysis, organic catalysis and metal-organic concerted catalysis [ (a) Li, w ]; zhang, x.top.curr.chem.2013,343, 103-144; (b) verendel, j.j.; pamies, o.; di guez, M.; andersson, P.G.chem.Rev.2014,114, 2130-2169; (c) etayo, p.; Vidal-Ferran, A.chem.Soc.Rev.2013,42, 728-754; (d) xie, j. -h.; zhu, s. -f.; zhou, q. — l.chem.rev.2011,111, 1713-1760; (e) faisca Phillips, a.m.; pomberiro, a.j.l.org.biomol.chem.2017,15, 2307-; (f) rueping, m.; dufour, j.; schoepke, F.R.Green chem.2011,13, 1084-1105; (g) tang, w.; xiao, j.synthesis 2014,46, 1297-1302; (h) du, z.; shao, Z.chem.Soc.Rev.2013,42, 1337-1378; (i) stegbauer, l.; sladojevich, F.; dixon, d.j.chem.sci.2012,3,942-958 ]. However, these catalytic systems still have many disadvantages and limitations, such as large amount of catalyst, relatively low S/C, narrow substrate range, and harsh reaction conditions. The subject group of the inventors has been devoted for many years to the design and development of asymmetric hydrogenation catalytic systems and research of their application in the synthesis of the broad-spectrum herbicide (S) -metolachlor. The key step of the existing industrial production technology is to realize the oriented synthesis of the (S) -metolachlor intermediate by asymmetrically hydrogenating and reducing (2-methyl-6-ethyl aniline) -imine, but chiral amine with 76% ee can only be obtained, the synthesis of the used ligand is difficult, and the requirement of the reaction condition on equipment is high. Therefore, the development of novel, efficient and universal chiral catalysts becomes the key to solve the difficulties of chiral amine synthesis and practical application.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a method for preparing chiral amine by catalyzing asymmetric hydrogenation of imine by an iridium/chiral diphosphine ligand, and the method has the advantages of cheap and easily prepared catalyst, high activity, high stereoselectivity, greenness, simplicity and convenience and the like.

The technical scheme of the invention comprises the following specific steps:

(1) preparation of chiral iridium catalyst: under the protection of nitrogen, stirring the iridium-cyclooctadiene complex and chiral diphosphine ligand in a reaction medium for 2 hours to prepare a chiral iridium catalyst by in-situ coordination;

(2) preparation of chiral amine compound: dissolving substrate imine in a reaction medium, adding the substrate imine into the stirred chiral iridium catalyst solution, placing the solution in a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100 bar, and reacting for 1-24 hours at 20-100 ℃; after the reaction is finished, slowly releasing hydrogen, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography, concentrating under reduced pressure, and drying under vacuum to obtain chiral amine compound;

the imine (1) and the chiral amine compound (2) have the following structures:

in the formula: r¹Is C₁～C₁₀Alkyl radicals such as CH₃、CH₃CH₂Etc. C₃～C₁₂Cycloalkyl radicals such as cyclopentyl, cyclohexyl, etc., or C containing one or more functional groups of N, S, O, P₁～C₁₀Alkyl such as methoxymethyl, ethoxymethyl, etc., or C containing one or more functional groups of N, S, O, P₃～C₁₀Cycloalkyl groups such as 2-tetrahydrofuryl, 4-tetrahydrofuryl, etc.; or aryl or the like C₆～C₃₀Aromatic groups such as phenyl, 4-methoxyphenyl, etc., which may or may not contain N, S, O, P, etc.; or ester groups such as COOCH₃、COOCH₂CH₃Etc.; r²Is H, C₁～C₄₀Alkyl or aryl within; ar is C such as phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl, etc₆～C₃₀Aromatic groups containing or not containing N, S, O, P functional groups such as 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-6-ethylphenyl, thiophene, etc.

The iridium-cyclooctadiene complex is [ Ir (COD) Cl]₂、Ir(COD)₂BARF or Ir (COD)₂BF₄。

The structural general formula of the chiral diphosphine ligand is as follows:

wherein: r is C1-C40 alkyl and C3-C12 cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl, contains one or more than two five-membered or six-membered heterocyclic aromatic groups of oxygen, sulfur and nitrogen atoms, and has 1-5 substituents of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano;

ar is one of phenyl or substituted phenyl, the substituent is one or more of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituents is 1-5.

The concentration of iridium in the reaction system is 0.0001-0.01 mol/L, and the molar ratio of the chiral diphosphine ligand to iridium is 1-5: 1;

the molar ratio of the imine substrate to the iridium catalyst is 300000-500000: 1;

the solvent is at least one of dichloromethane, 1, 2-dichloroethane or toluene;

the hydrogen pressure is 20-100 bar;

the reaction temperature is 20-100 ℃;

the reaction time is 1-24 hours.

In order to achieve the purpose, the technical scheme of the invention is as follows:

in the above reaction formula, the general formula (1) represents a reaction substrate imine, and the general formula (2) represents a chiral amine compound.

The invention has the beneficial effects that:

compared with other methods for synthesizing chiral amine, the method has the advantages that the preparation of the ligand is simple, the dosage of the catalyst is low, and the dosage (by mol) of the catalyst is as follows: the imine/catalyst (S/C) as the raw material is equal to 300000-1000000, the operation is simple and convenient, the continuous operation can be realized, the method is suitable for preparing the chiral amine on a large scale, and the enantiomeric excess value (ee value) of the product reaches more than 80%. The invention has low consumption of the synthetic catalyst of the key intermediate of the metolachlor, the 2-ethyl-6-methylaniline/the catalyst (S/C) is 500000, the yield can reach 95 percent, the enantioselectivity is 91 percent, and the invention has good industrial application range.

Detailed Description

The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent1100 series HPLC. GC analysis conditions were as follows: SE-54, injection port temperature: 250 ℃, detector temperature: column temperature 250 ℃ initial temperature 50 ℃ held for 2 minutes, then 10 degrees/minute to 250 ℃, held for 5 minutes.

The ligand synthesis method related by the invention is shown as the following reaction equation:

example 1

Ligand (R)_c,S_p) Preparation of-L1

Under the protection of nitrogen, (R) is_c,S_p) -3a (3mmol) and benzimidazole (24mmol) were dissolved in 15mL dehydroacetic acid and heated to 80 ℃ for 8 hours. Cooling, neutralizing with excessive saturated sodium bicarbonate solution, extracting with dichloromethane (3 × 50mL), mixing organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to substantially no solvent, separating with silica gel column chromatography (n-hexane/ethyl acetate/triethylamine: 10/10/1), concentrating under reduced pressure, and vacuum drying to obtain brown crystal (R)_c,S_p)-4a。

Under the protection of nitrogen, (R) is_c,S_p) -4a (0.5mmol) was dissolved in 15mL of anhydrous ether, 0.47mL of n-BuLi (1.6M n-hexane solution) was slowly added dropwise, the reaction mixture gradually turned into a deep red clear solution, and the reaction was continued for one hour. Then continuously dropwise adding 0.13mL of diphenyl phosphine chloride, reacting for two hours, adding a saturated sodium bicarbonate solution, separating, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure until no solvent exists basically, separating by silica gel column chromatography (normal hexane/ethyl acetate: 10/1), and recrystallizing normal hexane to obtain an orange red crystal (R)_c,S_p) -L1, yield 50%.

Ligand (R)_c,S_p) Structural formula and nmr spectral data of L1 are as follows:

¹H NMR(400MHz,CD₂Cl₂):δ7.64(m,2H),7.38(m,2H),7.08(m,2H),6.95(m,10H),6.83(m,1H),6.61(m,2H),6.36(m,2H),6.06(m,2H),5.46(m,2H),4.58(s,1H),4.19(s,1H),3.66(m,6H),2.50(m,1H),1.12(d,J＝6.4Hz,3H),0.01(d,J＝6.4Hz,3H)；¹³C NMR(100MHz,CD₂Cl₂):δ136.3(d,J＝9Hz),135.9,135.5,134.3(dd,J＝15,21Hz),133.0(d,J＝21Hz),129.7(d,J＝11Hz),127.9,127.5(d,J＝13Hz),137.5(d,J＝10Hz),127.0(d,J＝8Hz),126.6(d,J＝8Hz),126.4(d,J＝8Hz),125.3(d,J＝6Hz),125.1,120.7,120.1,118.9,111.9,91.7(d,J＝27Hz),74.3(d,J＝15Hz),71.3(d,J＝4Hz),69.8,69.2,68.6,60.2(d,J＝20Hz),30.7,21.9,19.3；³¹P NMR(162MHz,CD₂Cl₂):δ-36.89(d,J＝62.0Hz),-27.94(d,J＝62.4Hz).

example 2

Ligand (R)_c,S_p) Preparation of-L2

The procedure of example 1 was repeated except that imidazole was used instead of benzimidazole and bis (3, 5-dimethylphenyl) phosphine chloride was used instead of diphenylphosphine chloride in example 1 to obtain an orange-colored solid (R)_c,S_p) -L2, yield 49%.

Ligand (R)_c,S_p) Structural formula and nmr spectral data of L2 are as follows:

¹H NMR(400MHz,CDCl₃):δ7.92(m,1H),7.56(s,2H),7.43(d,J＝8.4Hz,2H),7.35(s,3H),7.11(m,6H),6.91(d,J＝12.4Hz,4H),5.80(m,1H),4.57(s,1H),4.35(s,1H),4.00(s,1H),3.54(s,5H),2.41(m,1H),2.23(s,12H),0.67(d,J＝5.2Hz,3H),0.53(d,J＝6.4Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ138.4,138.0(d,J＝9Hz),137.5,135.2(d,J＝22Hz),132.7(t,J＝17Hz),131(d,J＝20Hz),130.3,129.1,128.0(d,J＝8Hz),127.8,127.6(d,J＝7Hz),121.6(d,J＝20Hz),95.44,73.8,73.5,72.6,70.0,69.1,62.3(d,J＝11Hz),34.4,21.7,21.4,20.3；³¹P NMR(162MHz,CDCl₃):δ-36.03,-25.34.

example 3

Ligand (R)_c,S_p) Preparation of-L3

Orange-colored crystals (R) were obtained in the same manner as in example 1 except that benzimidazole was used instead of benzimidazole and bis (3, 5-bistrifluoromethylphenyl) phosphine chloride was used instead of diphenylphosphine chloride in example 1_c,S_p) -L3, yield 47%.

Ligand (R)_c,S_p) Structural formula and nmr spectral data of L3 are as follows:

¹H NMR(400MHz,CDCl₃):δ8.17(m,1H),7.80(m,1H),7.75(m,2H),7.51(m,4H),7.41(m,1H),7.33(m,4H),7.22(m,1H),7.01(m,1H),6.93(m,3H),6.41(t,J＝7.4Hz,2H),6.15(m,1H),4.67(s,1H),4.34(s,1H),4.04(s,1H),3.79(s,5H),2.61(m,1H),0.98(d,J＝5.2Hz,3H),0.63(d,J＝6.6Hz,3H)；¹³C NMR(100MHz,CDCl₃):δ142.8,138.5(d,J＝8Hz),137.7(d,J＝8Hz),137.2,136.7(d,J＝16Hz),135.3(d,J＝23Hz),131.7(d,J＝18Hz),131.0,130.8(d,J＝9Hz),130.3(d,J＝12Hz),129.3,128.8(dd,J＝6,11Hz),128.1(d,J＝8Hz),127.4(d,J＝6Hz),126.0,125.5,122.7(d,J＝7Hz),121.8,75.3(d,J＝14Hz),72.6(d,J＝4Hz),71.1,70.1,69.8,61.7,33.4,22.5,20.1；³¹P NMR(162MHz,CDCl₃):δ-39.31(d,J＝33.5Hz),-25.49(d,J＝35.0Hz).

example 4

Iridium catalyzed asymmetric hydrogenation of imines: a metal precursor [ Ir (COD) Cl]₂Stirring the solution and chiral diphosphine ligand in 2L dichloromethane at room temperature for 2h to prepare the chiral iridium catalyst (10)^-3mol/L). A200 mL autoclave was replaced three times with nitrogen, the freshly prepared imine 1a was injected, and then the in situ prepared chiral iridium catalyst Ir-L1(S/C ═ 5X 10)⁵). The reaction mixture was replaced three times with hydrogen, the pressure was adjusted to 60bar and the reaction was carried out at room temperature for 24 hours. After the reaction, the pressure was released, the reaction conversion was greater than 99% by GC analysis, the hydrogenated product 2a was obtained in 99% yield by column chromatography separation, and 93% ee was obtained by HPLC analysis. The detection data of the product of the nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatography are as follows:¹H NMR(400MHz,CDCl₃):δ7.20–7.36(m,5H),7.05–7.09(m,2H),6.61–6.65(m,1H),6.48–6.50(m,2H),4.46(q,J＝8.0Hz,1H),4.02(br,1H),1.49(d,J＝8.0Hz,3H).HPLC(OJ-H,n-hexane/i-PrOH＝97/3,1.0mL/min,254nm,40℃):t_R(minor)＝20.9min,t_R(major)＝25.5min.

the structural formulas of 1a and 2a are as follows:

example 5

The chiral catalyst Ir-L1 in example 4 was replaced with Ir-L2, and the reaction was performed as in example 4 to obtain a reaction conversion of greater than 99% by GC analysis and 80% ee by HPLC analysis.

Example 6

The chiral catalyst Ir-L1 in example 4 was replaced with Ir-L3, and the reaction was carried out as in example 4 to obtain a reaction conversion of more than 99% by GC analysis and 75% ee by HPLC analysis.

Example 7

The reaction solvent dichloromethane in example 4 was replaced by tetrahydrofuran, and the rest of the example 4 was carried out, giving a reaction conversion of more than 99% by GC analysis and 90% ee by HPLC analysis.

Example 8

The reaction solvent dichloromethane in example 4 was replaced with ethyl acetate as in example 4, and the reaction gave a reaction conversion of greater than 99% by GC analysis and 86% ee by HPLC analysis.

Example 9

Imine 1a in example 4 was replaced with 1b, the remainder being as in example 4, the reaction was complete and 2b was isolated by column chromatography in 99% yield and 92% ee by HPLC. The detection data of the product of the nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatography are as follows:¹H NMR(400MHz,CDCl₃):δ7.33(d,J＝8.0Hz,2H),7.15(t,J＝8.0Hz,2H),6.90(d,J＝8.0Hz,2H),6.70(t,J＝8.0Hz,1H),6.56(d,J＝8.0Hz,2H),4.50(q,J＝8.0Hz,1H),4.09(br,1H),3.82(s,3H),1.54(d,J＝8.0Hz,3H).HPLC(OD-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):t_R(minor)＝7.4min,t_R(major)＝8.1min.

the structural formulas of 1b and 2b are as follows:

example 10

Imine 1a from example 4 was replaced with 1c, the remainder being as in example 4, and the reaction was completed and 2c was isolated by column chromatography in 98% yield and 93% ee by HPLC. The detection data of the product of the nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatography are as follows:¹H NMR(400MHz,CDCl₃):δ8.17(d,J＝8.0Hz,2H),7.54(d,J＝8.0Hz,2H),7.10(t,J＝8.0Hz,2H),6.70(t,J＝8.0Hz,1H),6.46(d,J＝8.0Hz,2H),4.57(q,J＝8.0Hz,1H),4.30(br,1H),1.55(d,J＝8.0Hz,3H).HPLC(OD-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):t_R(minor)＝25.7min,t_R(major)＝27.9min.

the structural formulae of 1c, 2c are as follows:

example 11

Imine 1a from example 4 was replaced with 1d, the remainder being as in example 4, and the reaction was completed and column chromatography gave 2d in 98% yield and 96% ee by HPLC. The detection data of the product of the nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatography are as follows:¹H NMR(400MHz,CDCl₃):δ7.31–7.32(m,4H),7.25–7.27(m,1H),6.97(d,J＝8.0Hz,2H),6.81(t,J＝8.0Hz,1H),4.34(q,J＝6.8Hz,1H),3.22(br,1H),2.19(s,6H),1.54(d,J＝8.0Hz,3H).HPLC(OJ-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):t_R(minor)＝4.9min,t_R(major)＝5.4min.

the structural formulae of 1d, 2d are as follows:

example 12

Imine 1a from example 4 was replaced with 1e, the rest of the same as example 4, reaction was complete, column chromatography gave 2e in 95% yield, and HPLC gave 95% ee. The detection data of the product of the nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatography are as follows:¹H NMR(400MHz,CDCl₃):δ7.28–7.35(m,4H),7.19–7.24(m,1H),6.78(t,J＝8.0Hz,2H),6.40–6.43(m,2H),4.40(q,J＝8.0Hz,1H),3.97(br,1H),1.49(d,J＝8.0Hz,3H).HPLC(OD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):t_R(minor)＝12.3min,t_R(major)＝15.5min.

the structural formulae of 1e, 2e are as follows:

example 13

The imine 1a from example 4 was replaced with the s-metolachlor key intermediate 1f (generated from 2-methyl-6-ethylaniline and methoxyacetone), the reaction solvent was dichloroethane, and the hydrogen pressure was 50bar, reaction temperature 80 ℃, the rest of the example 4, 2f obtained after the reaction is finished, yield 95% and 91% ee obtained after HPLC analysis. The detection data of the product of the nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatography are as follows:¹H NMR(400MHz,CDCl₃):δ7.02(dd,J＝7.6,15.2Hz,2H),6.89(t,J＝7.6Hz,1H),3.36-3.40(m,6H),2.67(q,J＝7.6Hz,2H),2.31(s,3H),1.25(t,J＝7.6Hz,3H),1.20(d,J＝5.6Hz,3H).HPLC(OJ-H,n-hexane/i-PrOH＝98/2,1.0mL/min,254nm,40℃):t_R(minor)＝3.9min,t_R(major)＝4.3min.

the structural formulas of 1f and 2f are as follows: