CN111233849A - Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof - Google Patents
Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof Download PDFInfo
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- CN111233849A CN111233849A CN201811469505.7A CN201811469505A CN111233849A CN 111233849 A CN111233849 A CN 111233849A CN 201811469505 A CN201811469505 A CN 201811469505A CN 111233849 A CN111233849 A CN 111233849A
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- isoquinoline
- oxazoline
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- 239000003446 ligand Substances 0.000 title claims abstract description 30
- IVSLFIDYOXEDCG-UHFFFAOYSA-N O1C=NCC1.C1=NC=CC2=CC=CC=C12 Chemical compound O1C=NCC1.C1=NC=CC2=CC=CC=C12 IVSLFIDYOXEDCG-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000006845 Michael addition reaction Methods 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract 4
- 238000006243 chemical reaction Methods 0.000 claims description 52
- NDMFETHQFUOIQX-UHFFFAOYSA-N 1-(3-chloropropyl)imidazolidin-2-one Chemical compound ClCCCN1CCNC1=O NDMFETHQFUOIQX-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- -1 hydroxymethylene Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 5
- BWKMGYQJPOAASG-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1 BWKMGYQJPOAASG-UHFFFAOYSA-N 0.000 claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000958 aryl methylene group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 3
- XIWMTQIUUWJNRP-UHFFFAOYSA-N amidol Chemical compound NC1=CC=C(O)C(N)=C1 XIWMTQIUUWJNRP-UHFFFAOYSA-N 0.000 claims 2
- 150000004696 coordination complex Chemical class 0.000 claims 2
- 239000010949 copper Substances 0.000 claims 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 238000006352 cycloaddition reaction Methods 0.000 claims 1
- 150000002466 imines Chemical class 0.000 claims 1
- 229910052759 nickel Inorganic materials 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract 1
- 239000004327 boric acid Substances 0.000 abstract 1
- 229910052763 palladium Inorganic materials 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 238000003756 stirring Methods 0.000 description 33
- 238000001704 evaporation Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 22
- 239000003480 eluent Substances 0.000 description 21
- 239000003208 petroleum Substances 0.000 description 21
- 238000005406 washing Methods 0.000 description 21
- 238000001035 drying Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- PZVKSFBOPQYWGM-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;pyridine Chemical compound C1CN=CO1.C1=CC=NC=C1 PZVKSFBOPQYWGM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- YZDXFUGIDTUCDA-UHFFFAOYSA-N isoquinoline-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NC=CC2=C1 YZDXFUGIDTUCDA-UHFFFAOYSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- JCBPETKZIGVZRE-SCSAIBSYSA-N (2r)-2-aminobutan-1-ol Chemical compound CC[C@@H](N)CO JCBPETKZIGVZRE-SCSAIBSYSA-N 0.000 description 1
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 description 1
- JBULSURVMXPBNA-RXMQYKEDSA-N (2s)-2-amino-3,3-dimethylbutan-1-ol Chemical compound CC(C)(C)[C@H](N)CO JBULSURVMXPBNA-RXMQYKEDSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- PIAOLBVUVDXHHL-UHFFFAOYSA-N 2-nitroethenylbenzene Chemical compound [O-][N+](=O)C=CC1=CC=CC=C1 PIAOLBVUVDXHHL-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/006—Palladium compounds
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- 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
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
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- 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
- B01J2531/824—Palladium
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- 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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Abstract
The invention relates to a novel isoquinoline-oxazoline chiral ligand and a preparation method and application thereof, the chemical structural formula of the compound is shown as the following formula,
substituent R in the general formula1And R2The steric configuration of the attached carbon atom is R or S; the isoquinoline-oxazoline chiral ligand is a compound with wide application, can be used as a ligand to form a complex or a composition with metal for asymmetric catalysis, and is particularly suitable for asymmetric catalysisThe isoquinoline-oxazoline ligand and metal palladium combination can effectively catalyze the asymmetric Michael addition of boric acid and nitroolefin, and has excellent stereoselectivity.
Description
Technical Field
The invention relates to a novel isoquinoline-oxazoline chiral ligand and preparation and application thereof, belonging to the field of catalytic asymmetric organic synthesis.
Background
Catalytic asymmetric organic synthesis has been a hotspot in the research field of organic synthetic chemistry, wherein asymmetric catalysis with metal complexes has been considered as an efficient way to prepare pure enantiomers due to high efficiency, good atom economy and low environmental impact (Vogel, P., et al, Springer Berlin Heidelberg: Berlin, Heidelberg, 2003; pp 3-44.). Since the discovery that organic ligands can affect the steric and electronic effects of metal catalysts, the development of novel and highly efficient chiral ligands has been at the heart of asymmetric catalysis (Desimoni, g., et ai., Chemical Reviews 2006, 106(9), 3561-3651.) metal catalyzed organic reactions in the presence of chiral ligands have increased reactivity, regioselectivity, and enantioselectivity by lowering the temperature and reducing the formation of by-products. In 1986, the Brunner group discovered the first oxazoline-containing ligand, the pyridine oxazoline ligand (PyoX) (Brunner, H., et al, Journal of Organometallic Chemistry 1987, 328(1), 71-80.). Since this pioneering work, many pyridine oxazoline ligands have been developed and exhibit excellent catalytic performance in many types of reactions. The availability of raw materials, the stability, is an important factor in asymmetric synthetic chemistry (Xi, t., et al, organic letters 2015, 17(24), 5939-. Thus chiral ligands of the pyridine-oxazoline type are rapidly gaining popularity in asymmetric catalysis, particularly in some novel and highly efficient asymmetric methodologies. Recent studies have found that pyridine-oxazoline type ligands can catalyze some very challenging classical asymmetric reactions such as: asymmetric Heck-type reactions, Asymmetric (aza) -Wacker-type, which indicate their properties as ligands and potential applications for the development of new catalytic methodologies (Yang, G., et al., Chemical society reviews 2018, 47(5), 1783-. The invention designs and synthesizes a novel isoquinoline-oxazoline chiral ligand, and finds that the ligand can be used for catalyzing asymmetric synthesis, and an addition product is obtained with higher yield and ee value in the Michael addition reaction.
Disclosure of Invention
The invention provides a novel isoquinoline-oxazoline chiral ligand and a preparation method and application thereof, wherein isoquinoline-3-carboxylic acid and chiral amino alcohol are condensed to cyclize and synthesize the isoquinoline-oxazoline chiral ligand, and the isoquinoline-oxazoline chiral ligand is used for Michael addition reaction to obtain higher catalytic activity and stereoselectivity.
The general formula of the novel isoquinoline-oxazoline chiral ligand is as follows:
in the general formula1And R2The steric configuration of the attached carbon atom is R or S;
wherein the substituent R1Represents: c1～C8A phenyl group, a substituted phenyl group (the substituent on the phenyl group is C)1～C6The number of the substituent is 1-5), benzyl, substituted benzyl (the substituent on the phenyl is C)1～C6The number of the substituents is 1 to 5), hydroxymethylene, carboxylic acid, and carboxylic acid alkyl ester (C)1～C6)，C1～C6Hydrocarbyl carbonyl, phenylcarbonyl, substituted phenylcarbonyl (substituent on phenyl is C)1～C6The number of the substituent is 1-5), and substituted hydroxymethyl (the ortho position of the hydroxyl is substituted by C)1～C6Phenyl, and substituted phenyl substitution),
substituent R2Respectively represent: methyl, ethyl, isopropyl, sec-butyl, isobutyl, hydroxymethylene, hydrocarbyl carboxylate (1-6 carbons), aryl and arylmethylene;
and
the compounds of the present invention can be chemically synthesized according to the following synthetic route, which comprises the following four steps:
step 1, adding L-phenylalanine, 37% formaldehyde and concentrated hydrochloric acid into a reaction system, heating to 95 ℃, stirring for 5 hours, cooling to room temperature, and filtering to obtain tetrahydroisoquinoline-3-carboxylic acid.
And 2, dissolving tetrahydroisoquinoline-3-carboxylic acid in N, N-Dimethylformamide (DMF), adding potassium permanganate (0.5 times in amount) under an ice bath condition, stirring at room temperature for 72 hours, tracking and monitoring by TLC, filtering after complete reaction, concentrating the filtrate under reduced pressure, and washing the obtained solid with distilled water for three times to obtain the isoquinoline-3-carboxylic acid.
And 3, dissolving isoquinoline-3-carboxylic acid (1 time of the amount) and amino alcohol compounds (1 time of the amount) in dichloromethane, adding 1-hydroxybenzotriazole (1.3 times of the amount) under an ice bath condition, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.3 times of the amount), stirring at room temperature for reaction, tracking and monitoring by TLC (thin layer chromatography), washing with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution respectively after the reaction is completed, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography to obtain the isoquinoline amidol.
And 4, dissolving isoquinoline amide in dichloromethane, dropwise adding thionyl chloride (3 times of the amount of the isoquinoline amide) in an ice bath, stirring at room temperature for reaction for 5 hours, concentrating under reduced pressure, then adding acetonitrile for dissolution, dropwise adding triethylamine (2 times of the amount of the isoquinoline amide), heating to 95 ℃, stirring for reaction, tracking and monitoring by TLC, after the reaction is completed, evaporating the solvent under reduced pressure, dissolving dichloromethane, respectively using water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution for washing, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and carrying out silica gel column chromatography to obtain a white solid L.
The synthesis of the isoquinoline-oxazoline chiral ligand provided by the invention has the characteristics of cheap and easily obtained raw materials, easy operation and the like.
The isoquinoline oxazoline chiral ligand related to the invention is preferably the following compound:
detailed description of the invention
The following is a detailed description of the practice of the invention: the present embodiment is implemented on the premise of the technical scheme of the present invention, and a specific operation process is given, but the protection scope of the present invention is not limited to the following reaction examples.
Example one
L-phenylalanine (10g, 60mmol), 37% formaldehyde 33mL and concentrated hydrochloric acid 87mL are added to the reaction system, heated to 95 ℃, stirred for 5 hours, cooled to room temperature, and filtered to obtain white solid I8.3 g with yield of 83%.
Adding an intermediate tetrahydroisoquinoline-3-carboxylic acid I (5.3g, 30mmol) and 80mLN, N-Dimethylformamide (DMF) into a reaction system, adding potassium permanganate (2.5g, 16mmol) under the ice bath condition, stirring at room temperature for 72 hours, filtering, concentrating the filtrate under reduced pressure, washing the obtained solid with distilled water for three times to obtain a yellow solid isoquinoline-3-carboxylic acid II 3.1g, and obtaining the yield of 62%.
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and S-2-aminopropanol (75mg, 1mmol) into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL x 2), saturated sodium bicarbonate solution (10mL x 2) and saturated sodium chloride solution (10mL x 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to obtain white solid III-1 with 76% yield.
Adding intermediate amide alcohol III-1(115mg, 0.5mmol) into the reaction system, dissolving in 10mL dichloromethane, dropping 110 μ L (1.5mmol) thionyl chloride, stirring at room temperature for 5 hours, concentrating under reduced pressure, then adding 10mL acetonitrile for dissolution, dropping 277 μ L triethylamine, heating to 95 deg.C, stirring for 4 hours, distilling off solvent under reduced pressure, dissolving dichloromethane, washing with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2), saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, distilling off solvent under reduced pressure, performing silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate2: 1, 5% triethylAmine) to give L1 as a white solid in 90% yield.
The structural identification data for compound L1 is as follows:
1H NMR(400MHz，CDCl3)δ9.31(s，1H)，8.42(s，1H)，8.02(d，J＝8.44Hz，1H)，7.90(d，J＝8.19Hz，1H)，7.78-7.65(m，2H)，4.62-4.68(m，1H)，4.44-4.54(m，1H)，4.08(td，J1＝1.23Hz，J2＝8.06Hz，1H)，1.43(d，J1＝1.08Hz，J2＝6.62Hz，3H).
13C NMR(100MHz，CDCl3)δ163.05，152.68，140.30，135.57，130.95，129.30，128.77，127.70，127.51，121.58，74.65，62.34，21.41.
ESI-HRMS，calcd for C13H13N2O[M+H]+213.0950，found 213.1098.
example two
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and S-2-aminobutanol (89mg, 1mmol) into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL x 2), saturated sodium bicarbonate solution (10mL x 2) and saturated sodium chloride solution (10mL x 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to give III-2 as a white solid in 68% yield.
Adding intermediate amide alcohol III-2(122mg, 0.5mmol) into the reaction system, dissolving in 10ml dichloromethane, dropwise adding 110. mu.L (1.5mmol) thionyl chloride, stirring and reacting at room temperature for 5 hours, concentrating under reduced pressure, subsequently adding 10ml acetonitrile to dissolve, dropwise adding 277. mu.L triethylamine, heating to 95 ℃, stirring and reacting for 4 hours, evaporating the solvent under reduced pressure, dissolving dichloromethane, washing with water (10ml × 2), saturated sodium bicarbonate solution (10ml × 2), saturated sodium chloride solution (10ml × 2), drying with anhydrous sodium sulfate, and evaporating under reduced pressureAfter removal of the solvent and column chromatography on silica gel (eluent: V)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L2 as a white solid in 87% yield.
The structural identification data for compound L2 is as follows:
1H NMR(400MHz，CDCl3)δ9.31(s，1H)，8.42(s，1H)，8.02(d，J＝8.51Hz，1H)，7.90(d，J＝8.33Hz，1H)，7.64-7.78(m，2H)，4.62(dd，J1＝8.21Hz，J2＝9.58Hz，1H)，4.31-4.40(m，1H)，4.17(t，J＝8.13Hz，1H)，1.87(m，1H)，1.64-1.74(m，1H)，1.05(t，J＝7.40Hz，3H).
13C NMR(100MHz，CDCl3)δ164.34，152.70，142.03，140.13，135.58，131.05，129.44，128.95，128.77，127.73，127.68，127.59，126.88，122.14，75.31，70.40.
ESI-HRMS，calcd for C14H15N2O[M+H]+227.1106，found 227.1264.
EXAMPLE III
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and R-2-aminobutanol (89mg, 1mmol) into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2) and saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V: 1)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to give III-3 as a white solid in 68% yield.
Adding intermediate amide alcohol III-3(122mg, 0.5mmol) into the reaction system, dissolving in 10ml dichloromethane, dropwise adding 110 mu L (1.5mmol) thionyl chloride, stirring at room temperature for reaction for 5 hours, concentrating under reduced pressure, subsequently adding 10ml acetonitrile for dissolution, dropwise adding 277 mu L triethylamine, heating to 95 ℃, stirring for reaction for 4 hours, evaporating under reduced pressure to remove solvent, and then adding dichlorohydrinDissolving in methane, washing with water (10 ml. times.2), saturated sodium bicarbonate solution (10 ml. times.2), and saturated sodium chloride solution (10 ml. times.2), drying with anhydrous sodium sulfate, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (eluent: V)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L3 as a white solid in 87% yield.
The structural identification data for compound L3 is as follows:
1H NMR(400MHz，CDCl3)δ9.30(s，1H)，8.41(s，1H)，8.01(d，J＝8.62Hz，1H)，7.89(d，J＝8.05Hz，1H)，7.70(m，2H)，4.60(dd，J1＝8.12Hz，J2＝9.57Hz，1H)，4.34(m，1H)，4.16(t，J＝8.19Hz，1H)，1.85(m，1H)，1.67(m，1H)，1.04(t，J＝7.50Hz，3H).
13C NMR(100MHz，CDCl3)δ163.08，152.69，140.30，135.57，130.96，129.28，128.77，127.71，127.52，121.61，72.75，68.40，28.61，10.23.
ESI-HRMS，calcd for C14H15N2O[M+H]+227.1106，found 227.1264.
example four
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and S-valinol into the reaction system, dissolving in 20ml dichloromethane, adding HoBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10ml × 2), saturated sodium bicarbonate solution (10ml × 2) and saturated sodium chloride solution (10ml × 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to obtain the product, i.e. white solid III-4 with 73% yield.
The intermediate amide alcohol III-4(129mg, 0.5mmol) was added to the reaction system and dissolved in 10ml of dichloromethane, 110. mu.L (1.5mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, followed by addition of 10Dissolving in acetonitrile ml, adding dropwise 277 μ L triethylamine, heating to 95 deg.C, stirring for reaction for 4 hr, distilling off solvent under reduced pressure, dissolving in dichloromethane, washing with water (10ml × 2), saturated sodium bicarbonate solution (10ml × 2), saturated sodium chloride solution (10ml × 2), drying with anhydrous sodium sulfate, distilling off solvent under reduced pressure, and performing silica gel column chromatography (eluent: V)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L4 as a white solid in 85% yield.
The structural identification data for compound L4 is as follows:
1H NMR(400MHz，CDCl3)δ9.32(s，1H)，8.44(s，1H)，8.02(d，J＝7.85Hz，1H)，7.91(d，J＝8.19Hz，1H)，7.71(m，2H)，4.55(td，J1＝1.20Hz，J2＝7.40Hz，1H)，4.16-4.30(m，2H)，1.95(m，1H)，1.09(d，J＝6.70Hz，3H)，0.97(d，J＝6.71Hz，3H).
13C NMR(100MHz，CDCl3)δ163.61，152.71，140.23，137.95，135.57，131.00，129.35，129.24，128.85，128.62，127.73，127.56，126.55，121.74，72.51，68.20，41.79.
ESI-HRMS，calcd for C15H17N2O[M+H]+241.1263，found 241.1427.
EXAMPLE five
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and S-phenylglycinol (137mg, 1mmol) into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL x 2), saturated sodium bicarbonate solution (10mL x 2) and saturated sodium chloride solution (10mL x 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V: chromatography)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to obtain the product, i.e. white solid III-5 with yield of 72%.
Adding intermediate acyl into the reaction systemAminoalcohol III-5(146mg, 0.5mmol) was dissolved in 10mL of dichloromethane, 110. mu.L (1.5mmol) of thionyl chloride was added dropwise, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, then dissolved in 10mL of acetonitrile, added dropwise with 277. mu.L of triethylamine, heated to 95 ℃ and stirred for 6 hours, the solvent was distilled off under reduced pressure, the dichloromethane was dissolved, washed with water (10 mL. times.2), a saturated sodium bicarbonate solution (10 mL. times.2), a saturated sodium chloride solution (10 mL. times.2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and after silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L5 as a white solid in 89% yield.
The structural identification data for compound L5 is as follows:
1H NMR(400MHz，CDCl3)δ9.35(s，1H)，8.57(s，1H)，8.04(d，J＝8.05Hz，1H)，7.92(d，J＝8.17Hz，1H)，7.67-7.80(m，2H)，7.28-7.42(m，5H)，5.51(dd，J＝8.54Hz，J＝10.33Hz，1H)，4.95(dd，J1＝8.55，J2＝10.30Hz，1H)，4.44(t，J＝8.55Hz，1H).
13C NMR(100MHz，CDCl3)δ163.05，152.68，140.30，135.57，130.95，129.30，128.77，127.70，127.51，121.58，74.65，62.34，21.41.
ESI-HRMS，calcd for C18H15N2O[M+H]+275.1106，found 275.1270.
EXAMPLE six
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and S-phenylalaninol (151mg, 1mmol) into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2) and saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to obtain the productThe product was obtained as a white solid III-6 with a yield of 73%.
Adding intermediate amide alcohol III-6(153mg, 0.5mmol) into the reaction system, dissolving in 10mL dichloromethane, dripping 110 μ L (1.5mmol) thionyl chloride, stirring and reacting at room temperature for 5 hours, concentrating under reduced pressure, then adding 10mL acetonitrile to dissolve, dripping 277 μ L triethylamine, heating to 95 ℃, stirring and reacting for 6 hours, evaporating the solvent under reduced pressure, dissolving dichloromethane, respectively using water (10mL x 2), saturated sodium bicarbonate solution (10mL x 2), saturated sodium chloride solution (10mL x 2), washing, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, performing silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L6 as a white solid in 85% yield.
The structural identification data for compound L6 is as follows:
1H NMR(400MHz，CDCl3)δ9.32(s，1H)，8.43(s，1H)，8.03(d，J＝8.14Hz，1H)，7.92(d，J＝8.03Hz，1H)，7.72(m，2H)，7.19-7.38(m，5H)，4.71(m，1H)，4.48(t，J＝9.01Hz，1H)，4.27(t，J＝8.17Hz，1H)，3.38(dd，J1＝4.91Hz，J2＝13.83Hz，1H)，2.80(dd，J1＝9.30Hz，J2＝13.91Hz，1H).
13C NMR(100MHz，CDCl3)δ163.01，152.67，140.37，135.60，130.94，129.30，128.74，127.70，127.52，121.64，73.05，70.69，32.79，19.20，18.19.
ESI-HRMS，calcd for C19H17N2O[M+H]+289.1263，found 289.1439.
EXAMPLE seven
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) into the reaction system, dissolving S-tert-leucinol in 20ml dichloromethane, adding HoBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, and respectively adding water (10ml × 2), saturated sodium bicarbonate solution (10ml × 2) and saturated sodium chloride solution (10m × 2) into the reaction systemlx2) and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the mixture was subjected to silica gel column chromatography (eluent: vPetroleum ether/VEthyl acetate4: 1, 5% triethylamine) to obtain white solid III-7 with 76% yield.
Adding intermediate amide alcohol III-7(136mg, 0.5mmol) into the reaction system, dissolving in 10ml dichloromethane, dripping 110 μ L (1.5mmol) thionyl chloride, stirring at room temperature for 5 hours, concentrating under reduced pressure, then adding 10ml acetonitrile for dissolution, dripping 277 μ L triethylamine, heating to 95 ℃, stirring for 4 hours, evaporating under reduced pressure to remove solvent, dissolving dichloromethane, washing with water (10ml × 2), saturated sodium bicarbonate solution (10ml × 2), saturated sodium chloride solution (10ml × 2), drying with anhydrous sodium sulfate, evaporating under reduced pressure to remove solvent, performing silica gel column chromatography (eluent: V: silica gel column chromatography)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L7 as a white solid in 81% yield.
The structural identification data for compound L7 is as follows:
1H NMR(400MHz，CDCl3)δ9.34(s，1H)，8.48(s，1H)，8.04(d，J＝8.04Hz，1H)，7.94(d，J＝8.15Hz，1H)，7.68-7.79(m，2H)，4.50(dd，J1＝8.60Hz，J2＝10.21Hz，1H)，4.37(t，J＝8.51Hz，1H)，4.19(dd，J1＝8.24Hz，J2＝10.09Hz，1H)，1.03(s，9H).
13C NMR(100MHz，CDCl3)δ163.08，152.69，140.36，135.59，130.95，129.30，128.75，127.71，127.52，121.60，72.75，68.42，28.61，10.21.
ESI-HRMS，calcd for C16H19N2O[M+H]+254.1419，found 255.1585.
example eight
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) into the reaction system, dissolving S-isoleucinol in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition,after stirring overnight at room temperature, the reaction mixture was washed with water (10 mL. times.2), saturated sodium bicarbonate solution (10 mL. times.2), and saturated sodium chloride solution (10 mL. times.2), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the mixture was subjected to silica gel column chromatography (eluent: V)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to obtain white solid III-8 with 74% yield.
Adding intermediate amide alcohol III-8(136mg, 0.5mmol) into the reaction system, dissolving in 10mL dichloromethane, dripping 110 μ L (1.5mmol) thionyl chloride, stirring at room temperature for reaction for 5 hours, concentrating under reduced pressure, then adding 10mL acetonitrile for dissolution, dripping 277 μ L triethylamine, heating to 95 ℃, stirring for reaction for 6 hours, evaporating the solvent under reduced pressure, dissolving dichloromethane, respectively washing with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2), saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, performing silica gel column chromatography (eluent: V: eluent: 1, and performing silica gel column chromatographyPetroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L8 as a white solid in 83% yield.
The structural identification data for compound L8 is as follows:
1H NMR(400MHz，CDCl3)δ9.32(s，1H)，8.44(s，1H)，8.02(d，J＝8.11Hz，1H)，7.91(d，J＝8.08Hz，1H)，7.72(m，2H)，4.53(dd，J1＝7.91Hz，J2＝9.48Hz，1H)，4.29-4.39(m，1H)，4.26(d，J＝8.25Hz，1H)，1.77-1.87(m，1H)，1.66-1.74(m，1H)，1.23-1.36(m，1H)，0.98(t，J＝7.43Hz，3H)，0.92(d，J＝6.84Hz，3H).
13C NMR(100MHz，CDCl3)δ161.78，152.63，140.14，135.59，130.92，129.29，128.73，127.71，127.52，121.60，72.60，71.03，38.86，26.45，12.89，11.66.
ESI-HRMS，calcd for C16H19N2O[M+H]+255.1419，found 255.1585.
example nine
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol) and S-leucinol into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol) and EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL x 2), saturated sodium bicarbonate solution (10mL x 2) and saturated sodium chloride solution (10mL x 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing silica gel column chromatography (eluent: V)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to give III-9 as a white solid in 72% yield.
Adding intermediate III-9(136mg, 0.5mmol) into reaction system, dissolving in 10mL dichloromethane, dripping 110 μ L (1.5mmol) thionyl chloride, stirring and reacting at room temperature for 5 hours, concentrating under reduced pressure, then adding 10mL acetonitrile to dissolve, dripping 277 μ L triethylamine, heating to 95 deg.C, stirring and reacting for 6 hours, evaporating solvent under reduced pressure, dissolving dichloromethane, washing with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2), saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure, and performing silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L9 as a white solid in 82% yield.
The structural identification data for compound L9 is as follows:
1H NMR(400MHz，CDCl3)δ9.31(s，1H)，8.41(s，1H)，8.01(d，J＝8.09Hz，1H)，7.90(d，J＝8.18Hz，1H)，7.65-7.80(m，2H)，4.64(dd，J1＝8.08Hz，J2＝9.36Hz，1H)，4.44(m，1H)，4.10(t，J＝8.28Hz，1H)，1.87-1.95(m，1H)，1.79-1.86(m，1H)，1.43(dt，J1＝7.72Hz，J2＝13.38Hz，1H)，0.99(dd，J1＝6.53Hz，J2＝8.97Hz，6H).
13C NMR(100MHz，CDCl3)δ162.92，152.68，140.40，135.59，130.94，129.28，128.74，127.71，127.52，121.59，73.71，65.46，45.56，25.45，22.80，22.76.
ESI-HRMS，calcdfor C16H19N2O[M+H]+255.1419，found 255.1580.
example ten
Adding intermediate isoquinoline-3-carboxylic acid II (173mg, 1mmol), (1S, 2R) - (-) -1-2-indanol (150mg, 1mmol) into the reaction system, dissolving in 20mL dichloromethane, adding HOBt (175mg, 1.3mmol), EDCi (250mg, 1.3mmol) under ice bath condition, stirring at room temperature overnight, washing the reaction system with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2), saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, performing silica gel column chromatography (eluent: V: silica gel column chromatography)Petroleum ether/VEthyl acetate4: 1, 5% triethylamine) to give white solid III-10 with a yield of 72%.
Adding intermediate III-10(152mg, 0.5mmol) into reaction system, dissolving in 10mL dichloromethane, dripping 110 μ L (1.5mmol) thionyl chloride, stirring and reacting at room temperature for 6 hours, concentrating under reduced pressure, then adding 10mL acetonitrile to dissolve, dripping 277 μ L triethylamine, heating to 95 deg.C, stirring and reacting for 6 hours, evaporating solvent under reduced pressure, dissolving dichloromethane, washing with water (10mL × 2), saturated sodium bicarbonate solution (10mL × 2), saturated sodium chloride solution (10mL × 2), drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure, performing silica gel column chromatography (eluent: V: 2)Petroleum ether/VEthyl acetate2: 1, 5% triethylamine) to give the product L10 as a white solid in 82% yield.
The structural identification data for compound L9 is as follows:
1H NMR(400MHz，CDCl3)δ9.29(s，1H)，8.43(s，1H)，8.00(d，J＝8.15Hz，1H)，7.89(d，J＝8.03Hz，1H)，7.60-7.77(m，3H)，7.26-7.29(m，3H)，5.86(d，J＝7.76Hz，1H)，5.66-5.57(m，1H)，3.53(dd，J1＝4.03Hz，J2＝10.00Hz，2H).
13C NMR(100MHz，CDCl3)δ163.64，152.62，141.76，140.34，139.82，135.51，130.96，129.28，128.81，128.56，127.69，127.51，125.84，125.32，121.90，83.93，39.83.
ESI-HRMS，calcd for C19H15N2O[M+H]+287.1184，found 287.1290.
EXAMPLE eleven
Asymmetric Michael addition reaction
Pd (TFA) was added to a 10mL reaction flask2(3.4mg, 0.01mmol), L7(3.8mg, 0.015mmol), 2mL methanol, stirred at 40 ℃ for half an hour. Followed by the addition of nitrostyrene (38mg, 0.25mmol), p-methoxyphenylboronic acid (76mg, 0.5 mmol). TLC follow-up to monitor completion of the reaction, concentration under reduced pressure, column chromatography (V)Petroleum ether∶VEthyl acetate30: 1). The ee value of the addition product was 93%.
The structure identification data is as follows:
1H NMR(400MHz，CDCl3)δ7.32(m，1H)，7.23(m，2H)，7.15(m，1H)，6.85(m，1H)，4.96(d，J＝2.43Hz，1H)，4.94(s，1H)，4.86(t，J＝8.05Hz，1H)，3.78(s，1H).
13C NMR(100MHz，CDCl3)δ158.92，139.65，131.27，129.04，128.71，127.62，127.52，114.40，79.55，55.36，48.35.
Claims (6)
1. a novel isoquinoline-oxazoline chiral ligand, characterized by having the following structural formula:
wherein the substituent R1Represents: c1～C8A phenyl group, a substituted phenyl group (the substituent on the phenyl group is C)1～C6The number of the substituent groups is 1-5), benzyl, substituted alkyl, alkoxy and halogenated alkylBenzyl (substituent on phenyl is C1～C6The number of the substituents is 1 to 5), hydroxymethylene, carboxylic acid, and carboxylic acid alkyl ester (C)1～C6)，C1～C6Hydrocarbyl carbonyl, phenylcarbonyl, substituted phenylcarbonyl (substituent on phenyl is C)1～C6The number of the substituent is 1-5), and substituted hydroxymethyl (the ortho position of the hydroxyl is substituted by C)1～C6Phenyl, and substituted phenyl substitution),
the substituents R2 represent respectively: methyl, ethyl, isopropyl, sec-butyl, isobutyl, hydroxymethylene, hydrocarbyl carboxylate (1-6 carbons), aryl and arylmethylene;
and
substituent R in the general formula1And R2The steric configuration of the attached carbon atom is R or S.
2. The compound of formula (I) according to claim 1, characterized in that it is selected from the following compounds:
3. the method for synthesizing the chiral isoquinoline oxazoline ligand of claim 1, which is derived from phenylalanine through the following four-step reaction:
and (3) preparing an isoquinoline oxazoline chiral ligand.
4. The method for synthesizing isoquinoline-oxazoline chiral ligand according to claim 1, wherein phenylalanine is used as a starting material, tetrahydroisoquinoline-3-carboxylic acid is obtained through Pictet-Spengler reaction, isoquinoline-3-carboxylic acid is obtained through oxidative dehydrogenation, chiral amidol is obtained through condensation with chiral β -amino alcohol, and finally the isoquinoline-oxazoline ligand is obtained through cyclization of the chiral amidol.
5. The metal complex of isoquinoline-oxazoline chiral ligand of claim 1 with metallic palladium (Pd), copper (Cu) and nickel (Ni).
6. The isoquinoline-oxazoline chiral ligand of claim 1 and the metal complex of claim 5 for use in asymmetric catalytic reactions, including Michael addition reactions, [2+3] cycloaddition reactions of imines and olefins, and asymmetric oxidation reactions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811469505.7A CN111233849A (en) | 2018-11-28 | 2018-11-28 | Novel isoquinoline-oxazoline chiral ligand and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111925356A (en) * | 2020-08-17 | 2020-11-13 | 华东理工大学 | Synthesis method and application of chiral quinoline-imidazoline ligand |
| CN115232115A (en) * | 2022-08-10 | 2022-10-25 | 贵州大学 | Quinclorazoline-quinazoline chiral ligand as well as preparation method and application thereof |
| CN115368350A (en) * | 2022-09-19 | 2022-11-22 | 兰州大学 | PyrOX ligand containing electron-rich group at 5-position of pyridine |
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2018
- 2018-11-28 CN CN201811469505.7A patent/CN111233849A/en active Pending
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| Title |
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| CHUN ZHANG，等: "Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 137, no. 50, 1 December 2015 (2015-12-01), pages 15668 - 15671 * |
| MEIQING ZHENG，等: "A class of novel N-isoquinoline-3-carbonyl-L-amino acid benzylesters: Synthesis, anti-tumor evaluation and 3D QSAR analysis", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 46, 22 February 2011 (2011-02-22), pages 1672 - 1681, XP028370934, DOI: 10.1016/j.ejmech.2011.02.017 * |
| QUN HE，等: "Palladium-Catalyzed Asymmetric Addition of Arylboronic Acids to Nitrostyrenes", 《ORGANIC LETTERS》, vol. 17, 16 April 2015 (2015-04-16), pages 2250 - 2253 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111925356A (en) * | 2020-08-17 | 2020-11-13 | 华东理工大学 | Synthesis method and application of chiral quinoline-imidazoline ligand |
| CN111925356B (en) * | 2020-08-17 | 2023-04-28 | 华东理工大学 | Synthesis method and application of chiral quinoline-imidazoline ligand |
| CN115232115A (en) * | 2022-08-10 | 2022-10-25 | 贵州大学 | Quinclorazoline-quinazoline chiral ligand as well as preparation method and application thereof |
| CN115232115B (en) * | 2022-08-10 | 2024-04-16 | 贵州大学 | Quinclorac-oxazoline chiral ligand and preparation method and application thereof |
| CN115368350A (en) * | 2022-09-19 | 2022-11-22 | 兰州大学 | PyrOX ligand containing electron-rich group at 5-position of pyridine |
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