CN111285774A - Asymmetric imine hydrogenation method based on chiral monodentate phosphine ligand derived from D-mannitol - Google Patents
Asymmetric imine hydrogenation method based on chiral monodentate phosphine ligand derived from D-mannitol Download PDFInfo
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- CN111285774A CN111285774A CN201811500419.8A CN201811500419A CN111285774A CN 111285774 A CN111285774 A CN 111285774A CN 201811500419 A CN201811500419 A CN 201811500419A CN 111285774 A CN111285774 A CN 111285774A
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- chiral
- mannitol
- phosphine ligand
- imine
- monodentate phosphine
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 title claims abstract description 68
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 239000003446 ligand Substances 0.000 title claims abstract description 43
- 235000010355 mannitol Nutrition 0.000 title claims abstract description 34
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 34
- 150000002466 imines Chemical class 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000005984 hydrogenation reaction Methods 0.000 title claims description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 8
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000011065 in-situ storage Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000000758 substrate Substances 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000000524 functional group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BXMJNGVLZAWGJH-UHFFFAOYSA-N [Ir].C1CCC=CC=CC1 Chemical compound [Ir].C1CCC=CC=CC1 BXMJNGVLZAWGJH-UHFFFAOYSA-N 0.000 claims description 6
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- WVQBLGZPHOPPFO-UHFFFAOYSA-N 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(1-methoxypropan-2-yl)acetamide Chemical compound CCC1=CC=CC(C)=C1N(C(C)COC)C(=O)CCl WVQBLGZPHOPPFO-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- XXPOATHRRKDYBT-UHFFFAOYSA-N 2,6-dimethyl-n-(1-phenylethyl)aniline Chemical compound C=1C=CC=CC=1C(C)NC1=C(C)C=CC=C1C XXPOATHRRKDYBT-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- -1 amine compounds Chemical class 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- WVQBLGZPHOPPFO-LBPRGKRZSA-N (S)-metolachlor Chemical compound CCC1=CC=CC(C)=C1N([C@@H](C)COC)C(=O)CCl WVQBLGZPHOPPFO-LBPRGKRZSA-N 0.000 description 1
- ARKIFHPFTHVKDT-UHFFFAOYSA-N 1-(3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1 ARKIFHPFTHVKDT-UHFFFAOYSA-N 0.000 description 1
- KAFLIVPUBWCPSR-UHFFFAOYSA-N 1-(4-nitrophenyl)-n-phenylethanimine Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C(C)=NC1=CC=CC=C1 KAFLIVPUBWCPSR-UHFFFAOYSA-N 0.000 description 1
- CUZLJOLBIRPEFB-UHFFFAOYSA-N 1-methoxypropan-2-one Chemical compound COCC(C)=O CUZLJOLBIRPEFB-UHFFFAOYSA-N 0.000 description 1
- CCLHADURFVJYCL-UHFFFAOYSA-N 2,6-dimethyl-N-(1-phenylpropyl)aniline Chemical compound CCC(Nc1c(C)cccc1C)c1ccccc1 CCLHADURFVJYCL-UHFFFAOYSA-N 0.000 description 1
- XQGGRWPSCZSBJJ-UHFFFAOYSA-N 2,6-dimethyl-N-(2-methylpropyl)aniline Chemical compound CC(C)CNC1=C(C)C=CC=C1C XQGGRWPSCZSBJJ-UHFFFAOYSA-N 0.000 description 1
- JJVKJJNCIILLRP-UHFFFAOYSA-N 2-ethyl-6-methylaniline Chemical compound CCC1=CC=CC(C)=C1N JJVKJJNCIILLRP-UHFFFAOYSA-N 0.000 description 1
- YXWIRQHVEQIJOV-NSHDSACASA-N 2-ethyl-n-[(2s)-1-methoxypropan-2-yl]-6-methylaniline Chemical compound CCC1=CC=CC(C)=C1N[C@@H](C)COC YXWIRQHVEQIJOV-NSHDSACASA-N 0.000 description 1
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 description 1
- HRVCQTUAMGZRRU-SAPNQHFASA-N C\C(=N/C1=C(C)C=CC=C1C)C1=CC=CC=C1 Chemical compound C\C(=N/C1=C(C)C=CC=C1C)C1=CC=CC=C1 HRVCQTUAMGZRRU-SAPNQHFASA-N 0.000 description 1
- 239000005808 Metalaxyl-M Substances 0.000 description 1
- NUENXZWEKMPKRV-UHFFFAOYSA-N N-[1-(3-nitrophenyl)ethyl]aniline Chemical compound C=1C=CC([N+]([O-])=O)=CC=1C(C)NC1=CC=CC=C1 NUENXZWEKMPKRV-UHFFFAOYSA-N 0.000 description 1
- 239000005617 S-Metolachlor Substances 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000009905 homogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- ZQEIXNIJLIKNTD-GFCCVEGCSA-N metalaxyl-M Chemical compound COCC(=O)N([C@H](C)C(=O)OC)C1=C(C)C=CC=C1C ZQEIXNIJLIKNTD-GFCCVEGCSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- QYJCGOLBBQDWFE-UHFFFAOYSA-N n-(1-methoxypropan-2-yl)-2,6-dimethylaniline Chemical compound COCC(C)NC1=C(C)C=CC=C1C QYJCGOLBBQDWFE-UHFFFAOYSA-N 0.000 description 1
- UUMWWWHCQIKRJM-UHFFFAOYSA-N n-(2-ethyl-6-methylphenyl)methanimine Chemical compound CCC1=CC=CC(C)=C1N=C UUMWWWHCQIKRJM-UHFFFAOYSA-N 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for asymmetrically hydrogenating imine based on a chiral monodentate phosphine ligand derived from D-mannitol, which comprises the following steps: chiral monodentate phosphine ligand derived from D-mannitol reacts with metal iridium precursor to prepare complex in situ as catalyst, and imine is asymmetrically hydrogenated to prepare chiral amine. Suitable amounts of catalyst (in moles) are: the starting imine/catalyst (S/C) is equal to 100-10000. The ligand of the invention has simple preparation, low catalyst consumption and simple and convenient operation, can realize continuous operation, is suitable for large-scale preparation of chiral amine, has an enantiomeric excess value (ee value) of the product of more than 75 percent, and can meet the requirement of being used as a pesticide intermediate. The invention obtains better result for the synthesis of the metolachlor intermediate and has good industrial practicability.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for asymmetrically hydrogenating imine based on a chiral monodentate phosphine ligand derived from D-mannitol, which is suitable for producing herbicide metolachlor intermediate and metalaxyl-M intermediate.
Background
In asymmetric synthesis reactions, asymmetric catalysis is one of the most efficient and economically valuable methods for obtaining chiral compounds. 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 catalysis catalysts (eds.: E.Jacobsen, A.Pfaltz, H.Yamamoto), Springer, Berlin,1999, pp.247 ], but the catalytic systems have the problems of low reaction activity, narrow substrate range, harsh reaction conditions and the like, and particularly, for the synthetic route of obtaining the refined metolachlor through asymmetric catalysis, a plurality of different attempts are made by organic chemists at home and abroad to design and synthesize a plurality of 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-PeterJalett et al catalyzed asymmetric hydrogenation with ferrocene bisphosphine ligand increased its 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 asymmetrically hydrogenating imine based on a chiral monodentate phosphine ligand derived from D-mannitol, which solves the technical problems that: the chiral monodentate phosphine ligand derived from the D-mannitol has simple synthesis, low cost and is suitable for kilogram-level production, the iridium/D-mannitol-derived chiral monodentate phosphine ligand system has high catalytic activity and high enantioselectivity, and the enantiomeric excess value (ee value) of the product reaches over 75 percent
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for asymmetrically hydrogenating imine based on a chiral monodentate phosphine ligand derived from D-mannitol adopts a chiral catalyst Ir-L to asymmetrically hydrogenate imine to prepare chiral amine; the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and a chiral monodentate phosphine ligand derived from D-mannitol in a solvent.
A method for asymmetric hydrogenation of imine based on a chiral monodentate phosphine ligand derived from D-mannitol comprises the following steps:
under the protection of nitrogen, dissolving an iridium-cyclooctadiene complex and a chiral monodentate phosphine ligand derived from D-mannitol in a solvent, stirring for 10 minutes at room temperature, adding a substrate imine dissolved in the solvent, placing the substrate imine in a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting for 1-24 hours at 20-100 ℃, slowly releasing the hydrogen, removing the solvent, and separating by using a silica gel column to obtain the product chiral amine.
The solvent is dichloromethane, 1, 2-dichloroethane or toluene;
the structural formula of the substrate imine is as follows:
wherein R is1Is C1～C10Alkyl radical, C3～C12Cycloalkyl radicals, or containing one or two of N, S, O, PC of the above functional group1～C10Alkyl, or C containing one or more functional groups of N, S, O, P3～C10A cycloalkyl group; or aryl or the like C6-C30Aromatic groups with or without functional groups such as N, S, O, P; or an ester group.
R2Is H, C1-C40Alkyl or aryl within;
ar is phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl C6-C30Aromatic groups with or without N, S, O, P functional groups.
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:
wherein R is1Is C1～C10Alkyl radical, C3～C12Cycloalkyl, 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 aryl or the like C6-C30Aromatic groups with or without functional groups such as N, S, O, P; or an ester group R2Is H, C1-C40Alkyl or aryl within;
ar is phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl C6-C30Aromatic groups with or without N, S, O, P functional groups.
The structural general formula of the chiral monodentate phosphine ligand derived from D-mannitol is as follows:
wherein: r is aromatic hydrocarbon or C1-C10An aliphatic group;
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 100-10000: 1.
the invention has the beneficial effects that: compared with other methods for synthesizing chiral amine, the method for synthesizing chiral monodentate phosphine ligand derived from D-mannitol for imine reduction hydrogenation is simple in synthesis, low in price and suitable for kilogram-level production, an iridium/D-mannitol-derived chiral monodentate phosphine ligand system is high in catalytic activity and enantioselectivity, the enantiomeric excess value (ee value) of a product reaches over 75%, the reaction operation is simple, the condition is mild, the atom economy is high, and the method is suitable for industrial production.
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
Under the protection of nitrogen gas, [ Ir (COD) Cl]2(0.0025mmol,0.5 mol%), D-mannitol-derived chiral monodentate phosphine ligand A (shown in the above formula) (0.0055mmol,1.1 mol%) was dissolved in dichloromethane (1.0mL), stirred at room temperature for 10 minutes, a solution of the substrate (E) -2, 6-dimethyl-N- (1-phenylethylidene) aniline (0.5mmol) in dichloromethane (1.0mL) was added, the mixture was placed in an autoclave, replaced with hydrogen gas for 3 times, and then hydrogen gas was introduced to 20 atmospheres, and reacted at room temperature for 24 hours. Slowly releasing hydrogen, removing solvent, and separating by using silica gel column to obtain the product 2, 6-dimethyl-N- (1-phenylethyl) aniline.
The product was analyzed and the NMR and HPLC data are as follows:
98％yield.76％ee(chiralcel OJ-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):tR(major)＝4.9min,tR(minor)＝5.4min.[α]D25＝-158(c＝1.42inCHCl3).1H NMR(400MHz,CDCl3):δ＝1.54(d,J＝6.8Hz,3H),2.19(s,6H),3.22(br,1H),4.34(q,J＝6.8Hz,1H),6.81(t,J＝7.2Hz,1H),6.97(d,J＝7.2Hz,2H),7.25-7.27(m,1H),7.31-7.32(m,4H)；13C NMR(100MHz,CDCl3):δ＝19.1,22.9,57.0,121.8,121.9,126.3,126.4,127.1,127.2,128.6,128.7,129.0,129.1,129.6,145.2,145.5。
example 2
The reaction conditions in example 1 were changed from D-mannitol-derived chiral monodentate phosphine ligand to B, and the reaction was performed as in example 1 to give 2, 6-dimethyl-N- (1-phenylethyl) aniline in a yield of 98% and an enantioselectivity of 50% ee.
Ligand B has the following structure:
example 3
The reaction conditions in example 1 were changed to C for the chiral monodentate phosphine ligand derived from D-mannitol, and the reaction was performed as in example 1 to give 2, 6-dimethyl-N- (1-phenylethyl) aniline in a yield of 98% and an enantioselectivity of 60% ee.
Ligand C has the structure:
example 4
The reaction conditions in example 1 were changed from D-mannitol-derived chiral monodentate phosphine ligand to D, and the reaction was performed as in example 1 to give 2, 6-dimethyl-N- (1-phenylethyl) aniline in a yield of 70% and an enantioselectivity of 60% ee.
Ligand D has the structure:
example 5
The reaction conditions in example 1 were changed from D-mannitol-derived chiral monodentate phosphine ligand to E, and the reaction was performed as in example 1 to give 2, 6-dimethyl-N- (1-phenylethyl) aniline in 58% yield and with an enantioselectivity of 30% ee.
Ligand E has the structure:
example 6
The reaction conditions H in example 1 were2The pressure was changed to 20 atmospheres, and the remainder was the same as in example 1, giving 2, 6-dimethyl-N- (1-phenylethyl) aniline in 90% yield and 80% ee enantioselectivity.
Example 7
The substrate to catalyst ratio in example 1 was changed to 1000S/C, i.e.: [ Ir (COD) Cl]2(0.00025mmol,0.05 mol%) and D-mannitol-derived chiral monodentate phosphine ligand (0.00055mmol,0.11 mol%) reacted to give the product 2, 6-dimethyl-N- (1-phenylethyl) aniline with an enantioselectivity of 74% ee.
Example 8
The substrate to catalyst ratio in example 1 was changed to S/C10000, i.e.: [ Ir (COD) Cl]2(0.000025mmol,0.005 mol%), D-mannitol-derived chiral monodentate phosphine ligand (0.000055mmol,0.011 mol%), reaction conditions H2A pressure ofThe same as in example 1 except that the reaction was carried out at 80 atm, 100 ℃ and 36 hours, the enantioselectivity of the product 2, 6-dimethyl-N- (1-phenylethyl) aniline was 73% ee.
Example 9
The substrate in the example 1 is changed into p-nitroacetophenone, and the reaction is carried out in the same way as the example 1 to obtain the product 2, 6-dimethyl-N- (1- (4-nitrophenyl) ethylideneaniline.
The product was analyzed and the NMR and HPLC data are as follows:
99％yield.77％ee(chiralpak AD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(major)＝5.4min,tR(minor)＝7.5min.[α]D 25＝-233(c＝1.90inCHCl3).1HNMR(400MHz,CDCl3):δ＝1.57(d,J＝6.8Hz,3H),2.16(s,6H),3.13(br,1H),4.40(q,J＝6.8Hz,1H),6.81(t,J＝7.2Hz,1H),6.96(d,J＝7.2Hz,2H),7.45(d,J＝8.8Hz,2H),8.15(d,J＝8.8Hz,2H)；13C NMR(100MHz,CDCl3):δ＝19.0,22.9,56.5,122.1,123.6,127.1,129.1,129.3,144.4,146.9,152.9。
example 10
The substrate in example 1 was changed to 3-nitroacetophenone, and the reaction was carried out in the same manner as in example 1 to give 2, 6-dimethyl-N- (1- (3-nitrophenyl) ethylaniline).
The product was analyzed and the NMR and HPLC data are as follows:
98％yield.78％ee(chiralpak AD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(minor)＝10.3min,tR(major)＝10.9min.[α]D 25＝-141(c＝1.88inCHCl3).1H NMR(400MHz,CDCl3):δ＝1.58(d,J＝6.8Hz,3H),2.19(s,6H),3.20(br,1H),4.43(q,J＝6.8Hz,1H),6.82(t,J＝7.6Hz,1H),6.97(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,1H),7.62(d,J＝7.6Hz,1H),8.10(d,J＝7.6Hz,1H),8.24(s,1H)；13C NMR(100MHz,CDCl3):δ＝19.0,23.0,56.3,121.0,122.0,122.2,129.1,129.3,129.4,132.7,144.3,147.5,148.3。
example 11
The substrate in the example 1 is changed into butanone, and the reaction is carried out in the same way as the example 1 to obtain the product N-isobutyl-2, 6-dimethylaniline.
The product was analyzed and the GC and NMR data are shown below:
94％yield.74％ee(chiralβ-DEX 120column(0.25mm x 30m),columntemp.:90℃,carrier gas:N2):tR(major)＝20.1min,tR(minor)＝20.8min.[α]D 25＝-41(c＝0.96inCHCl3).1HNMR(400MHz,CDCl3):δ＝0.98(t,J＝7.2Hz,3H),1.07(d,J＝6.4Hz,3H),1.37-1.44(m,1H),1.58-1.64(m,1H),2.28(s,6H),2.84(br,1H),3.21(q,J＝6.8Hz,1H),6.80(t,J＝7.2Hz,1H),6.99(d,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3):δ＝7.1,15.3,17.1,27.2,50.1,117.4,125.1,141.5。
example 12
The substrate in the example 1 is changed into methoxy acetone, and the reaction is carried out in the same way as the example 1 to obtain the product N- (1-methoxy-2-propyl) -2, 6-dimethylaniline.
The product was analyzed and the GC and NMR data are shown below:
95％yield.78％ee(chiralβ-DEX 120column,column temp.:85℃,carriergas:N2):tR(major)＝69.8min,tR(minor)＝71.4min.[α]D 25＝9.5(c＝1.31in CHCl3).1HNMR(400MHz,CDCl3):δ＝1.20(d,J＝6.0Hz,3H),2.30(s,6H),3.35-3.80(m,7H),6.82(t,J＝7.2Hz,1H),6.99(d,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3):δ＝18.6,18.7,52.4,59.0,76.3,121.5,128.8,129.4,145.0。
example 13
The substrate in the example 1 is changed into acetone methyl ester, and the reaction is carried out in the same way as the example 1 to obtain the product 2- (2, 6-dimethylphenylamino) methyl propionate.
The product was analyzed and the NMR and HPLC data are as follows:
96％yield.77％ee(chiralcel OD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(minor)＝6.9min,tR(major)＝7.7min.[α]D 25＝-16(c＝1.33inCHCl3).1HNMR(400MHz,CDCl3):δ＝1.38(d,J＝7.2Hz,3H),2.31(s,6H),3.68(s,3H),4.00(q,J＝7.2Hz,1H),6.81(t,J＝7.6Hz,1H),6.97(d,J＝7.6Hz,2H)。
example 14
The substrate in the example 1 is changed into propiophenone, and the rest is reacted with the substrate in the example 1 to obtain the product 2, 6-dimethyl-N- (1-phenylpropyl) aniline.
The product was analyzed and the NMR and HPLC data are as follows:
97％yield.72％ee(chiralcel OJ-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):tR(major)＝4.4min,tR(minor)＝4.8min.[α]D 25＝-116(c＝1.79inCHCl3).1HNMR(400MHz,CDCl3):δ＝0.91(d,J＝7.2Hz,3H),1.87-1.92(m,1H),2.02-2.05(m,1H),2.18(s,6H),3.30(br,1H),4.07(m,1H),6.78(t,J＝7.2Hz,1H),6.94(d,J＝7.2Hz,2H),7.20-7.31(m,5H)；13CNMR(100MHz,CDCl3):δ＝11.3,19.1,29.8,63.5,121.4,126.3,126.8,127.0,128.4,128.9,129.1,143.9,145.0。
example 15
Under the protection of nitrogen gas, [ Ir (COD) Cl]2(0.00125mmol,0.0005 mol%), D-mannitol-derived chiral monodentate phosphine ligand (0.00275mmol,0.0011 mol%) and n-Bu4NI (0.0125mmol,0.005 mol%) was dissolved in 1, 2-dichloroethane (10mL), stirred at room temperature for 10 minutes, a solution of the substrate 2-ethyl-N- (1-methoxy-2-propylene) -6-methylaniline (0.25mol) in 1, 2-dichloroethane (10mL) was added, the mixture was placed in an autoclave, replaced with hydrogen for 3 times, and then hydrogen was introduced to 80 atmospheres and reacted at 100 ℃ for 18 hours. Slowly releasing hydrogen, removing solvent, and separating with silica gel column to obtain the product (S) -2-ethyl-N- (1-methoxy-2-propyl) -6-methylaniline.
The product was analyzed and the NMR and HPLC data are as follows:
95％yield.75％ee(chiralcel OD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(minor)＝4.4min,tR(major)＝4.8min.[α]D 25＝8.8(c＝1.0in CHCl3).1HNMR(400MHz,CDCl3):δ＝1.18(d,J＝5.6Hz,3H),1.23(t,J＝7.6Hz,3H),2.29(s,3H),2.65(q,J＝7.6Hz,2H),3.34-3.38(m,6H),6.87(t,J＝7.6Hz,1H),7.00(dd,J＝7.6,15.2Hz,2H)。
Claims (7)
1. a method for asymmetrically hydrogenating imine based on a chiral monodentate phosphine ligand derived from D-mannitol is characterized by comprising the following steps: 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 monodentate phosphine ligand derived from D-mannitol.
2. The asymmetric imine hydrogenation process based on a chiral monodentate phosphine ligand derived from D-mannitol according to claim 1, wherein: the method specifically comprises the following steps:
under the protection of nitrogen, dissolving an iridium-cyclooctadiene complex and a chiral monodentate phosphine ligand derived from D-mannitol in a solvent, stirring for 10 minutes at room temperature, adding a substrate imine dissolved in the solvent, placing the substrate imine in a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting for 1-24 hours at 20-100 ℃, 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.
3. The asymmetric imine hydrogenation process based on a chiral monodentate phosphine ligand derived from D-mannitol according to claim 1 or 2, characterized in that; the substrate imine and the prepared chiral amine respectively have the following structures:
in the formula:
R1is C1～C10Alkyl radical, C3～C12Cycloalkyl, 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 aryl or the like C6～C30Aromatic groups with or without N, S, O, P functional groups, or ester groups;
R2is H, C1～C40Alkyl or aryl within;
ar is phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl; c6～C30Aromatic groups with or without N, S, O, P functional groups.
4. The asymmetric imine hydrogenation process based on a chiral monodentate phosphine ligand derived from D-mannitol according to claim 1 or 2, characterized in that: the structural general formula of the D-mannitol derived chiral monodentate phosphine ligand is as follows:
wherein R is aromatic hydrocarbon or C1～C10An aliphatic group.
5. The asymmetric imine hydrogenation process based on a chiral monodentate phosphine ligand derived from D-mannitol according to claim 1 or 2, characterized in that: the iridium-cyclooctadiene complex is: [ Ir (COD) Cl]2、Ir(COD)2BF4Or Ir (COD)2BARF。
6. The asymmetric imine hydrogenation process based on a chiral monodentate phosphine ligand derived from D-mannitol according to claim 2, characterized in that: the iridium concentration is 0.0001-0.01mol/L, and the molar ratio of the D-mannitol-derived chiral monodentate phosphine ligand to iridium is 1-5: 1.
7. the asymmetric imine hydrogenation process based on a chiral monodentate phosphine ligand derived from D-mannitol according to claim 2, characterized in that: the molar ratio of the imine substrate to the catalyst Ir-L is 100-10000: 1.
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| CN103570484A (en) * | 2012-08-07 | 2014-02-12 | 中国科学院大连化学物理研究所 | Asymmetric hydrogenation synthetic method of chiral aromatic amine compound with high steric hindrance |
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| CN1579627A (en) * | 2003-08-05 | 2005-02-16 | 中国科学院大连化学物理研究所 | Chiral ligand metal complex catalyst system, and its preparation method and use |
| CN103570484A (en) * | 2012-08-07 | 2014-02-12 | 中国科学院大连化学物理研究所 | Asymmetric hydrogenation synthetic method of chiral aromatic amine compound with high steric hindrance |
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