CN110551037B - Method for catalyzing asymmetric hydrogenation of imine by iridium/chiral diphosphine system - Google Patents
Method for catalyzing asymmetric hydrogenation of imine by iridium/chiral diphosphine system Download PDFInfo
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Abstract
The invention discloses an asymmetric hydrogenation method of imine catalyzed by an iridium/chiral diphosphine system, which takes chiral diphosphine ligand and metal iridium precursor to react to prepare a complex in situ as a catalyst, and imine is asymmetrically hydrogenated to prepare chiral amine. The ligand of the invention has simple preparation, low catalyst consumption, simple and convenient operation, can realize continuous operation, is suitable for preparing chiral amine on a large scale, has the enantiomeric excess value of more than 80 percent, has better result for 500000 of 2-ethyl-6-methylaniline/catalyst (S/C) in the synthesis of the metolachlor intermediate, achieves 95 percent of yield and 91 percent of enantioselectivity, and has good industrial practicability.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an asymmetric hydrogenation method for imine by using an iridium/chiral diphosphine system as a catalyst.
Background
Chiral amine compounds are important organic synthetic intermediates useful in the preparation of a variety of natural and unnatural compounds having biological activity. In recent years, the preparation of chiral amine compounds by asymmetric catalytic Hydrogenation of imines has been very successful [ (a) H. -U.Blaser, F.Spinder in Handbook of Homogeneous Hydrogenation (eds.: J.G.de Vries, C.J.Elsevier), Wiley-VCH, Weinheim,2007, pp.1193; (b) claver, e.fernandez in Morden Reduction Methods (eds.: p.anderson, i.munsell), Wiley-VCH, Weinheim,2008, pp.237; (c) U.Blaser, F.Spinder in Comprehensive asymmetry assay catalysts (eds.: E.Jacobsen, A.Pfaltz, H.Yamamoto), Springer, Berlin,1999, pp.247 ], but these catalytic systems have problems such as low reaction activity, narrow substrate range, harsh reaction conditions, and especially for the synthetic route of how to obtain the refined metolachlor by Asymmetric Catalysis, many different attempts have been made by some organic chemists at home and abroad to design and synthesize Asymmetric catalytic catalysts. The preparation of s-metolachlor intermediates by asymmetric hydrogenation of (2-methyl-6-ethylaniline) -imines was found to be a viable and efficient route.
In 1975, Levi et al reported a hydrogenation process for imines, but the enantiomeric excess (ee value) was only 22% (Levi A., Modena G., Scorano G.J.chem.Soc.Commun.1975,1, 6-7). In 1999 Hans-Peter Jalett et al used ferrocene bisphosphine ligand to catalyze asymmetric hydrogenation to increase ee value to 76% (Jalett H.P., Spindler F., Hanreich R.G.US5886225[ P ],1999), and achieved industrialization. The method is characterized in that { (R) -1- [ (S) -2-diphenylphosphine cyclopentadienyl iron group ] } ethyl-bis- (3, 5-dimethylphenyl) phosphine is used as a ligand and forms a catalyst precursor with an iridium complex in situ, and the asymmetric hydrogenation of 2-methyl-6-ethyl-N-methyleneaniline is catalyzed in the presence of acid and tetrabutylammonium iodide at 50 ℃ and 80 atmospheres of hydrogen pressure to obtain chiral amine with the highest ee of 76%. However, the synthesis of the ligand used in this reaction is difficult, and the hydrogenation system requires a large amount of acid and requires high equipment. Therefore, the development of the catalyst for preparing the chiral amine with high activity, high stereoselectivity and low cost has very important significance.
Disclosure of Invention
The invention aims to provide a method for catalyzing asymmetric hydrogenation of imine by an iridium/chiral diphosphine system.
In order to achieve the purpose, the technical scheme of the invention is as follows:
an asymmetric hydrogenation method of imine catalyzed by iridium/chiral diphosphine system, which adopts chiral catalyst Ir-L to prepare chiral amine by asymmetric hydrogenation of imine; the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and a chiral diphosphine ligand in a solvent.
An asymmetric hydrogenation method of imine catalyzed by an iridium/chiral diphosphine system comprises the following steps:
(1) adding an iridium-cyclooctadiene complex and a chiral diphosphine ligand into the solvent, stirring the mixture for 2 to 5 hours at room temperature, and carrying out in-situ coordination to generate a chiral catalyst Ir-L;
(2) under the protection of nitrogen, adding a substrate imine dissolved in a solvent, adding a chiral catalyst Ir-L, placing the mixture into a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting at 20-100 ℃ for 1-24 hours, slowly releasing the hydrogen, removing the solvent, and separating by using a silica gel column to obtain a product chiral amine;
the solvent is dichloromethane, 1, 2-dichloroethane or toluene;
the substrate imine is as follows:
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;
in order to achieve the purpose, the technical scheme of the invention is as follows:
the imines and the chiral amines produced according to the invention have the following structures:
in the formula:
R1is C1～C10Alkyl radicals such as CH3、CH3CH2Etc. C3～C12Cycloalkyl radicals such as cyclopentyl,Cyclohexyl, or C containing N, S, O, P one or more functional groups1～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 structural general formula of the chiral diphosphine ligand L is as follows:
wherein: r is one of phenyl, substituted phenyl, alkyl or cycloalkyl, and R' is one of phenyl, substituted phenyl, alkyl, hydrogen, halogen or cycloalkyl.
The iridium-cyclooctadiene complex is: [ Ir (COD) Cl]2、Ir(COD)2BF4Or Ir (COD)2BARF。
The iridium concentration in the reaction system is 0.0001-0.01mol/l, and the molar ratio of the ligand to the iridium is 1-5: 1.
the molar ratio of the imine substrate to the catalyst is 100-500000: 1.
the ligand synthesis method related by the invention is shown as the following reaction equation:
the preparation method of the chiral diphosphine ligand L comprises the following steps:
(1) introducing argon to react (R)c,Sp) -ppfa (i) and imidazole are dissolved in dehydroacetic acid and heated to 80 ℃ for 8 hours; (R)c,Sp) The molar ratio of PPFA (I) to imidazole is 1: 1.1-5;
cooling, neutralizing with excessive saturated sodium bicarbonate solution, extracting with dichloromethane (3 × 50ml), mixing organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, removing solvent, and subjecting the crude product to column chromatography (n-hexane/ethyl acetate/triethylamine: 10/10/1); brown crystals II;
(2) under the condition of introducing argon, dissolving the brown crystal II in diethyl ether, slowly dropwise adding n-BuLi, gradually changing the reaction mixture into a dark red clear solution, and continuously reacting for one hour; dropwise adding diphenyl phosphine chloride, wherein the molar ratio of the brown crystal II, the n-BuLi and the diphenyl phosphine chloride is 1: 1.2-5;
after reacting for two hours, a saturated sodium hydrogencarbonate solution was added, and the organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Desolventizing, column chromatography (n-hexane/ethyl acetate 10/1), and n-hexane recrystallization to give 0.24g of orange needle crystals IaNamely chiral diphosphine ligand L.
The invention has the beneficial effects that: compared with other methods for synthesizing chiral amine, the method for synthesizing chiral diphosphine ligand L by imine reductive hydrogenation is simple in synthesis, low in price and suitable for kilogram-level production, an iridium/chiral diphosphine system is high in catalytic activity and enantioselectivity, the enantiomeric excess value (ee value) of a product reaches more than 85%, the reductive amination reaction is simple to operate, mild in conditions and high in atom economy, and the method is suitable for industrial production, has a good result that 2-ethyl-6-methylaniline/a catalyst (S/C) is 500000 in the synthesis of the S-metolachlor intermediate, achieves 95% of yield and 91% of enantioselectivity, and has good industrial practicability.
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 degrees, detector temperature: initial temperature 50 ℃ for 2 minutes, then 10 ℃ per minute to 250 ℃ and then 5 minutes.
Example 1
The ligand synthesis method related by the invention is shown as the following reaction equation:
wherein (R)c,Sp)-Ia:R＝Me,R＇＝H；(Rc,Sp)-Ib:R＝Et,R＇＝H；(Rc,Sp)-Ic:R＝Ph,R＇＝H etc
1 preparation of ligand (R)c,Sp)-Ia
Introducing argon, adding 1.32g of (R)c,Sp) PPFA (I) and 1.63g imidazole were dissolved in 15ml dehydroacetic acid and heated to 80 ℃ for 8 hours. After cooling, the reaction mixture was neutralized with an excess of saturated sodium bicarbonate solution, extracted with dichloromethane (3 × 50ml), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, desolventized and the crude product was subjected to column chromatography (n-hexane/ethyl acetate/triethylamine ═ 10/10/1) to give 1.24g of brown crystals II in 89% yield.
0.23g of II was dissolved in 15ml of dry diethyl ether under argon and 0.47ml of n-BuLi was slowly added dropwise, the reaction mixture gradually turned into a deep red clear solution and the reaction was continued for one hour. 0.13ml of diphenylphosphine chloride was added dropwise thereto, the reaction was carried out for two hours, a saturated sodium hydrogencarbonate solution was added thereto, the organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Desolventizing, column chromatography (n-hexane/ethyl acetate 10/1), and n-hexane recrystallization to give 0.24g of orange needle crystals IaThe yield thereof was found to be 75%.
Nuclear magnetic resonance spectroscopy data for the ligands are as follows:
1H NMR(400MHz,CDCl3):δ7.53(m,4H),7.33-7.38(m,5H),7.25(s,1H),7.15(m,3H),7.07(m,3H),6.92(m,3H),6.78(d,J＝2.0Hz,4H),6.57(m,2H),6.43(m,1H),4.69(s,1H),4.43(s,1H),4.06(s,5H),3.91(s,1H),1.62(d,J＝6.8Hz,1H),ppm；31P NMR(162MHz，CDCl3):δ-24.12,-35.12ppm；13C NMR(100MHz,CDCl3):δ143.7,139.0,137.6,36.2,135.5,134.4,133.4,131.4,130.7,129.2,128.5,128.2,128.0,127.9,127.7,127.4,118.9,93.8,76.5,72.1,70.1,70.0,69.3,51.2,23.0ppm。
upon detection, the ligand (R)c,Sp)-IaThe structural formula of (A) is as follows:
2 preparation of ligand (R)c,Sp)-Ib
(Rc,Sp)-IbAccording to (R)c,Sp)-IaThe method of (1).
Nuclear magnetic resonance spectroscopy data for the ligands are as follows:
1H NMR(400MHz,CDCl3):δ7.57(m,4H),7.4(m,3H),7.20-7.27(m,5H),7.08-7.14(m,3H),7.00(t,J＝6.8Hz,2H),6.86-6.92(m,3H),6.37(t,J＝7.0Hz,2H),6.21(br,1H),4.66(br,1H),4.38(s,1H),3.98(s,5H),3.91(s,1H),2.52(m,1H),2.04(br,1H),0.62(m,3H)ppm；31P NMR(162MHz，CDCl3):δ-23.86,-37.95ppm；13C NMR(100MHz,CDCl3):δ144.8,139.6,138.0,137.0,136.6,135.8,135.5,134.5,134.3,133.8,133.6,131.3,131.2,129.4,128.7,128.3,128.2,128.1,128.0,127.9,127.6,127.1,119.0,94.9,76.3,72.2,70.0,57.1,29.6,11.6ppm。
detected, ligand IbThe structural formula of (A) is as follows:
3 preparation of ligand (R)c,Sp)-Ic
(Rc,Sp)-IcAccording to (R)c,Sp)-IaThe method of (1).
Nuclear magnetic resonance spectroscopy data for the ligands are as follows:
1H NMR(400MHz,CDCl3):δ7.60(m,2H),7.45(m,1H),7.36(m,5H),7.15(m,8H),7.04(m,2H),6.97(m,4H),6.89(m,3H),6.82(m,3H),4.42(s,1H),4.39(s,1H),4.05(s,1H),3.85(s,5H)ppm；31P NMR(162MHz，CDCl3):δ-25.30,-33.55ppm；13C NMR(100MHz,CDCl3):δ144.7,139.9,138.3,137.4,135.6,135.3,133.6,133.4,132.0,130.2,129.3,128.2,128.1,128.0,127.9,127.8,127.7 127.6,120.2,92.8,72.6,71.1,70.4,70.2,59.8,59.6ppm。
the structural formula of the ligand is detected as follows:
preparation of 4 catalyst Ir-I
0.6717g of a metal precursor [ Ir (COD) Cl was added]2And 1.690g of ligand I is stirred in 2L of dichloroethane at room temperature for 2h to generate the catalyst (10)-3mol/l)。
Example 2
The hydrogenation reaction was carried out in a 200ml autoclave. The reaction kettle is replaced by nitrogen for three times, then 52g of imine (generated by 2-methyl-6-ethyl aniline and methoxy acetone) is injected into the reaction kettle, and 0.5ml of catalyst Ir-I which is well coordinated in situ is injected into the reaction kettlea(S/C＝5×105). And then replacing with hydrogen for three times, introducing hydrogen, pressurizing to 50bar, heating to 80 ℃, reacting for 3 hours, cooling, relieving pressure, opening the kettle, performing GC analysis to obtain 50g of (S) -NAA, wherein the reaction conversion rate is more than 99%, and performing reduced pressure distillation to obtain 50g of (S) -NAA, the yield is 95%, and the ee value of HPLC analysis is 91%.
Liquid phase and nmr spectra data were as follows:
HPLC(OJ-H,n-hexane/i-PrOH＝98/2,1.0ml/min,254nm,40℃):tR(minor)＝3.9min,tR(major)＝4.3min.1H NMR(400MHz,CDCl3):7.02(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),δ＝1.20(d,J＝5.6Hz,3H)ppm。
the product was presumed to be (S) -2-ethyl-N- (1-methoxy-2-propyl) -6-methylaniline, and the structural formula was as follows:
example 3
Otherwise the catalyst Ir-I was identical to example 2aModified to Ir-IbThe reaction conversion rate was more than 99% by GC analysis and the ee value was 85% by HPLC analysis.
Example 4
Otherwise the catalyst Ir-I was identical to example 2aModified to Ir-IcThe reaction conversion rate was more than 99% by GC analysis and the ee value was 80% by HPLC analysis.
Example 5
Otherwise, the reaction pressure was 80bar, the reaction conversion was greater than 99% by GC analysis and the ee value by HPLC analysis was 90% as in example 2.
Example 6
Otherwise, the reaction pressure was 60bar, the reaction conversion was greater than 99% by GC analysis and the ee value by HPLC analysis was 91% as in example 2.
Example 7
Otherwise the reaction temperature was 100 ℃ and the reaction conversion was more than 99% by GC analysis and 88% by HPLC analysis under the same conditions as in example 2.
Example 8
Otherwise conditions were the same as in example 2, molar ratio of substrate to catalyst (S/C ═ 106) The reaction conversion was 90% by GC analysis and the ee value was 89% by HPLC analysis.
Example 9
Otherwise conditions were the same as in example 2, modified to ligand IbThe reaction conversion was 15% by GC analysis and the ee value was 10% by HPLC analysis.
Example 10
Other conditions andexample 2 same, modified to ligand IcThe reaction conversion was 99% by GC analysis and the ee value by HPLC analysis was 94%.
Example 11
The substrate in the example 2 is changed into 2- (2, 6-dimethylphenylimino) methyl propionate, and the reaction is carried out in the same way as the example 2 to obtain the product 2- (2, 6-dimethylphenylamino) methyl propionate. 96% yield.86% ee.
Liquid phase and nmr spectra data were as follows:
HPLC(chiralcel OD-H,n-hexane/i-PrOH＝99/1,1.0ml/min,254nm,40℃):tR(minor)＝6.9min,tR(major)＝7.7min.1H NMR(400MHz,CDCl3):δ＝6.97(d,J＝7.6Hz,2H),6.81(t,J＝7.6Hz,1H),4.00(q,J＝7.2Hz,1H),3.68(s,3H),2.31(s,6H)，1.38(d,J＝7.2Hz,3H)。
the product was presumed to be methyl 2- (2, 6-dimethylphenylamino) propionate, of the formula:
Claims (6)
1. an asymmetric hydrogenation method of imine catalyzed by an iridium/chiral diphosphine system is characterized in that: the method adopts a chiral catalyst Ir-L, and adopts imine asymmetric hydrogenation to prepare chiral amine; the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and a chiral diphosphine ligand in a solvent; the chiral diphosphine ligand L has the following structural general formula:
,
wherein: r is one of phenyl and alkyl, and R' is H;
the preparation method of the chiral diphosphine ligand L comprises the following steps:
(1) introducing argon to react (R)c,Sp) -ppfa (i) and imidazole are dissolved in dehydroacetic acid and heated to 80 ℃ for 8 hours; (R)c,Sp) The molar ratio of PPFA (I) to imidazole is 1: 1.1-5; after cooling, in excessNeutralizing with saturated sodium bicarbonate solution, extracting with dichloromethane 3 × 50ml, mixing organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, removing solvent, and subjecting the crude product to column chromatography with n-hexane/ethyl acetate/triethylamine 10/10/1 to obtain brown crystal II;
(2) under the condition of introducing argon, dissolving the brown crystal II in diethyl ether, slowly dropwise adding n-BuLi, gradually changing the reaction mixture into a dark red clear solution, and continuously reacting for one hour; dropwise adding diphenyl phosphine chloride, wherein the molar ratio of the brown crystal II, the n-BuLi and the diphenyl phosphine chloride is 1: 1.2-5; reacting for two hours, adding saturated sodium bicarbonate solution, separating an organic phase, washing with saturated saline, and drying with anhydrous sodium sulfate; removing solvent, separating n-hexane/ethyl acetate 10/1 by column chromatography, and recrystallizing n-hexane to obtain 0.24g orange needle crystal IaNamely chiral diphosphine ligand L;
the imine is as follows:
,
in the formula: r1Is C1～C10Alkyl radical, C3～C12Is cycloalkyl, or C containing one or more functional groups of N, S, O, P1～C10Alkyl, or C containing one or more functional groups of N, S, O, P3～C10A cycloalkyl group; or C6-C30Aromatic groups with or without N, S, O, P functional groups; or an ester group; r2Is H, C1-C40Alkyl or aryl within; ar is C6-C30Aromatic groups with or without N, S, O, P functional groups.
2. The method for the asymmetric hydrogenation of imine by using an iridium/chiral diphosphine system according to claim 1, wherein the reaction mixture comprises a mixture of iridium and chiral diphosphine; the imine and the resulting chiral amine have the following structures:
。
3. the method for the asymmetric hydrogenation of imines catalyzed by an iridium/chiral diphosphine system according to claim 1 or 2, wherein: the method specifically comprises the following steps:
(1) adding an iridium-cyclooctadiene complex and a chiral diphosphine ligand into the solvent, stirring the mixture for 2 to 5 hours at room temperature, and carrying out in-situ coordination to generate a chiral catalyst Ir-L;
(2) under the protection of nitrogen, adding a substrate imine dissolved in a solvent, adding a chiral catalyst Ir-L, placing the mixture into a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting at 20-100 ℃ for 1-24 hours, slowly releasing the hydrogen, removing the solvent, and separating by using a silica gel column to obtain a product chiral amine;
the solvent is dichloromethane, 1, 2-dichloroethane or toluene;
R1wherein C1-C10 alkyl is CH3、CH3CH2，C3～C12Cycloalkyl is cyclopentyl, cyclohexyl, or C containing one or more than two functional groups of N, S, O, P1～C10The alkyl is methoxymethyl, ethoxymethyl, or C containing one or more than two functional groups of N, S, O, P3～C10The cycloalkyl is 2-tetrahydrofuryl or 4-tetrahydrofuryl; or C6-C30The aromatic group containing or not containing N, S, O, P functional group is phenyl, 4-methoxyphenyl; or the ester group is COOCH3、COOCH2CH3；R2Is H, C1-C40Alkyl or aryl within; ar is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-6-ethylphenyl or thiophene.
4. The method for the asymmetric hydrogenation of imines catalyzed by an iridium/chiral diphosphine system according to claim 1 or 2, wherein: the iridium-cyclooctadiene complex is: [ Ir (COD) Cl]2、Ir(COD)2BF4Or Ir (COD)2BARF。
5. The method for the asymmetric hydrogenation of imine by using an iridium/chiral diphosphine system according to claim 2, wherein the method comprises the following steps: the iridium concentration in the reaction system is 0.0001-0.01mol/L, and the molar ratio of the ligand to the iridium is 1-5: 1.
6. the method for the asymmetric hydrogenation of imine by using an iridium/chiral diphosphine system according to claim 2, wherein the method comprises the following steps: the molar ratio of the imine substrate to the chiral catalyst Ir-L is 100-500000: 1.
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