CN114874140A - Cyclic imine derivative with acrylate structure and preparation method thereof - Google Patents

Cyclic imine derivative with acrylate structure and preparation method thereof Download PDF

Info

Publication number
CN114874140A
CN114874140A CN202210690233.3A CN202210690233A CN114874140A CN 114874140 A CN114874140 A CN 114874140A CN 202210690233 A CN202210690233 A CN 202210690233A CN 114874140 A CN114874140 A CN 114874140A
Authority
CN
China
Prior art keywords
cyclic imine
reaction
acrylate structure
compound
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210690233.3A
Other languages
Chinese (zh)
Inventor
郑连友
王思宇
项金宝
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jilin University
Original Assignee
Jilin University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jilin University filed Critical Jilin University
Priority to CN202210690233.3A priority Critical patent/CN114874140A/en
Publication of CN114874140A publication Critical patent/CN114874140A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a cyclic imine derivative with an acrylate structure and a preparation method thereof, belonging to the technical field of organic synthetic chemistry. The cyclic imine derivative with the acrylate structure has a structural general formula as follows:
Figure DDA0003699213610000011
the preparation method comprises the following steps: mixing a cyclic imine compound and MBH carbonate according to a molar ratio of 1: 1-3, dissolving in an organic solvent, and reacting at 20-160 ℃ for 30 minutes-24 hours in the air or nitrogen atmosphere to obtain the cyclic imine derivative with an acrylate structure. The invention has wide raw material source, and the synthesis method of the target product has simple and convenient operationThe method has the characteristics of environmental protection, good atom economy, high yield of target products, easy industrial production and the like.

Description

Cyclic imine derivative with acrylate structure and preparation method thereof
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and mainly relates to a cyclic imine compound with an acrylate structure and a preparation method thereof.
Background
The cyclic imine is an important nitrogen-containing heterocycle, can be used as a chemical intermediate for synthesizing medicaments and pesticides, and has wide application. Among them, aromatic six-membered cyclic imine (such as dihydroisoquinoline and derivatives thereof) is a core structure constituting many natural bioactive substances, and is also a key intermediate in the synthesis of various natural products, so that the development of structurally diverse cyclic imine derivatives and preparation methods thereof are of great significance.
Currently, chemical reaction studies for cyclic imines are mainly focused on the conversion of highly reactive C ═ N bonds, whereas less studies are made on the functionalization reactions of the cyclic ketimines α -Csp 3-H. In recent years, allylic alkylation reactions on the α -carbon of cyclic imines have been reported, but have focused mainly on highly active cyclic N-sulfonyl ketimine-based substrates (Guin, s.et al.chem.commun.,2021,57, 9010). In 2017, Kljajic et al used allyl alcohol acetate as an allyl alkylation reagent to react with cyclic imine containing alpha-Csp 3-H under the catalysis of Pd/Xantphos to realize the alpha-allyl alkylation of the cyclic imine (Kljajic, M.et al. org.Lett.2017, 19, 126-.
Morita-Baylis-Hillman carbonate (MBH carbonate for short) is an important allyl substitution reaction substrate, an ester group of the Morita-Baylis-Hillman carbonate is easy to leave, the Morita-Baylis-Hillman carbonate is easy to generate allylic substitution reaction with different nucleophiles, the reaction condition is mild, the atom economy is good, and a molecule with multiple functional groups is easy to construct. Currently, allyl alkylation reactions using MBH carbonate as a substrate have been reported (Guo, H.C. et al. chem. Commun, 2021,57, 8059; Han, J.H.et al. org.Biomol.chem.,2021,19, 1503; Riguet, E.et al. chem. Commun, 2020,56, 6640; Lu.Y.et al. org.Lett.2021,23, 1787-. However, these reported reactions usually need to be catalyzed by small organic molecular catalysts such as cinchona alkaloid derivatives, triethylene diamine, triphenylphosphine, etc., or reacted under the action of a catalytic system of metal and phosphine ligands such as iridium, palladium and monophosphine ligands and palladium and diphosphine ligands, and thus the development requirements of environmental protection are difficult to meet.
In view of the important application of the cyclic imine in the field of pharmaceutical chemicals, MBH carbonate is used as an allyl alkylation reagent, an acrylate structure is introduced into the cyclic imine, a high-efficiency, simple, green and environment-friendly synthesis method is developed, and the method has important significance and potential application value for constructing the cyclic imine derivative containing multiple functional groups.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides cyclic imine with an acrylate structure and a preparation method thereof.
The functional groups in the cyclic imine derivative with the acrylate structure provided by the invention have diversity, and the product skeleton structure contains imine, unsaturated carbon-carbon double bonds, electron-withdrawing carboxylic ester and other groups which can be further functionalized, and can be used as a synthetic intermediate of medicines or other chemical products.
The synthesis method of the invention uses cyclic imine compounds and Morita-Baylis-Hillman carbonate (MBH carbonate for short) as precursor raw materials, and finally obtains the cyclic imine derivatives with acrylate structures through allylation substitution reaction by using imine alpha-position carbon atoms as pre-nucleophilic reagents. Wherein, the cyclic imine compound can be prepared by Bischler-Napieralski cyclization and other reactions by taking aryl ethylamine and carboxylic acid as raw materials (the preparation method is shown in the literatures: Luu, H.T., et al, Org.Lett.2015,17, 2478-. The synthetic method has the advantages of simple and convenient operation, environmental protection, high yield and the like.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a cyclic imine derivative with an acrylate structure is characterized by having a general structural formula as follows:
Figure BDA0003699213590000021
wherein R is 1 Selected from phenyl, substituted aryl, alkyl, aralkyl, haloalkyl, alkoxySubstituted alkyl, allyl, cycloalkyl, or
Figure BDA0003699213590000022
R 2 Selected from methyl, ethyl, isopropyl, tert-butyl or benzyl; ar is phenyl, thiophene, furan, indole, benzofuran or benzothiophene containing substituent groups.
Further, the substituent group contained in Ar is preferably one or two selected from hydrogen, halogen, nitro, alkoxy, amino, alkyl, benzyl, cyano, trifluoromethyl, ester group, amide group and the like.
A preparation method of the cyclic imine derivative with the acrylate structure is characterized in that a cyclic imine compound and Morita-Baylis-Hillman carbonate (MBH carbonate for short) are mixed according to a molar ratio of 1: 1-3 and dissolved in an organic solvent, and the mixture is reacted for 30 minutes to 24 hours at 20 ℃ to 160 ℃ in the air or nitrogen atmosphere to obtain the cyclic imine derivative with the acrylate structure; the organic solvent is toluene, acetonitrile, N-dimethylformamide, ethyl acetate, 1, 4-dioxane or tetrahydrofuran, and the dosage of the solvent enables the molar concentration of the cyclic imine compound to be 0.01-1.0M;
the molecular structure general formula of the cyclic imine compound is as follows:
Figure BDA0003699213590000031
wherein R is 3 Is phenyl, substituted aryl, alkyl, aralkyl, haloalkyl, alkoxy-substituted alkyl, allyl, cycloalkyl or a hydrogen atom;
ar is any one of phenyl, thiophene, furan, indole, benzofuran or benzothiophene containing substituent groups, wherein the substituent groups are any one or two of hydrogen, halogen, nitro, alkoxy, amino, alkyl, benzyl, cyano, trifluoromethyl, ester group and amide group;
the molecular structure general formula of the MBH carbonate compound is as follows:
Figure BDA0003699213590000032
wherein R is 2 Is any one of methyl, ethyl, isopropyl, tertiary butyl or benzyl.
Preferably, the organic solvent is acetonitrile or toluene.
Preferably, the reaction temperature is 60 ℃ to 120 ℃.
Preferably, the organic solvent is used in an amount such that the cyclic imine compound has a molar concentration of 0.05 to 0.2M.
After the reaction is finished, the product is separated according to a conventional separation and purification method to obtain the cyclic imine derivative with the acrylate structure, and the structure of the obtained product contains derivatizationable functional groups such as imine, ester group, unsaturated carbon-carbon double bond and the like, and can be further converted into other functional molecules.
The invention regulates and controls Ar and R in the product 1 、R 2 And synthesizing a series of structurally diverse cyclic imine derivatives containing acrylate structural units.
The chemical reaction formula provided by the invention is as follows:
Figure BDA0003699213590000033
the reaction mechanism is as follows: first, a nitrogen atom containing a lone pair of electrons on a cyclic imine attacks MBH carbonate to produce an intermediate A. tBuO generated in situ - The imine alpha-hydrocarbon proton with acidity is removed as alkali to form an enamine intermediate B, and then the enamine intermediate B undergoes an aza-Cope rearrangement reaction to obtain a final product (I).
Figure BDA0003699213590000041
The invention has the beneficial effects that:
1. the cyclic imine and the MBH carbonate utilized in the preparation method are intermediates which are wide in raw material source and easy to prepare, and the raw materials are cheap and easy to obtain; the synthesis method of the target product is simple and convenient to operate, the target product can be generated only by mixing and heating the two raw materials without adding extra reagents or catalysts, and the method has the characteristics of environmental protection, good atom economy, high yield of the target product, easiness in industrial production and the like.
2. The functional groups in the product of the cyclic imine compound with acrylate have diversity, and the skeleton structure of the product contains imine, carbon-carbon double bonds, ester groups and other groups which can be further functionalized, so that the cyclic imine compound with acrylate can be used for preparing molecules with potential biological activity, such as quinolizidine and the like with various structures, and has wide application value in biological and pharmaceutical active molecules.
Description of the drawings:
FIG. 1 is a scheme showing that of Compound 3aa prepared in example 1 1 H NMR spectrum.
FIG. 2 is a photograph of Compound 3aa prepared in example 1 13 C NMR spectrum.
FIG. 3 is of compound 3ba prepared in example 2 1 H NMR spectrum.
FIG. 4 is a photograph of compound 3ba prepared in example 2 13 C NMR spectrum.
FIG. 5 is a drawing of Compound 3ca prepared in example 3 1 H NMR spectrum.
FIG. 6 is a drawing of Compound 3ca prepared in example 3 13 C NMR spectrum.
FIG. 7 is a photograph of Compound 3da prepared in example 4 1 H NMR spectrum.
FIG. 8 is a photograph of Compound 3da prepared in example 4 13 C NMR spectrum.
FIG. 9 is of Compound 3ea prepared in example 5 1 H NMR spectrum.
FIG. 10 is a photograph of Compound 3ea prepared in example 5 13 C NMR spectrum.
FIG. 11 is a photograph of Compound 3ha prepared in example 8 1 H NMR spectrum.
FIG. 12 is a photograph of Compound 3ha prepared in example 8 13 C NMR spectrum.
FIG. 13 is a photograph of Compound 3ka prepared in example 11 1 H NMR spectrum.
FIG. 14 is a photograph of Compound 3ka prepared in example 11 13 C NMR spectrum.
FIG. 15 is a photograph of Compound 3la prepared in example 12 1 H NMR spectrum.
FIG. 16 is a photograph of Compound 3la prepared in example 12 13 C NMR spectrum.
The specific implementation mode is as follows:
the technical solutions of the present invention will be clearly and accurately described below with reference to the accompanying drawings and embodiments, and it should be understood that the described embodiments are only a part of the present invention, and therefore do not limit the present invention within the scope of the described embodiments.
The solvent used in the present invention is purified and purified before use.
Preparation routes in the examples: cycloimine compounds 1 (see the literature: Luu, H.T., et al. org. Lett.2015,17, 2478-typed 2481; Xie, J.et al. ACS Catal.2012,2, 561-typed 564; Leipold, F.et al. ChemCAT Chem 2013,5, 3505-typed 3508) and MBH carbonate (prepared according to the literature: Yang, X.H.et al. Chem.Commun.2019,55, 9144-typed 9147; Pautigny, C.et al. adv.Synth. Catal.2008,350, 2525-2532) were mixed in an organic solvent in a certain proportion and reacted under stirring at a certain temperature in an air or nitrogen atmosphere. After the reaction is finished, the obtained crude product is separated by using a flash silica gel column chromatography to obtain the target product (I) (the reaction formula is shown in the specification).
Figure BDA0003699213590000051
Example 1: 4- (3, 4-dihydroisoquinolin-1-yl) -2, 6-dimethylidepimelic acid dimethyl ester (3aa)
Figure BDA0003699213590000052
1-methyl-3, 4-dihydroisoquinoline 1a (0.2mmol) and MBH carbonate 2a (0.6 mmol) are weighed separately and added to a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) is added, followed by addition of nitrogenAfter bubbling with gas for several minutes, the reaction tube was sealed with a cap and placed in an oil bath at 80 ℃ to heat and stir the reaction for 3 hours, and the completion of the reaction was monitored by TLC. After the reaction solution was cooled to room temperature, the reaction solution was transferred to a round-bottomed flask, the solvent was evaporated under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1, v/v) to give the desired product 3aa (50mg, yield 73%) as a pale yellow oil 1 H NMR and 13 the C NMR spectra are shown in FIG. 1 and FIG. 2, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.66–7.60(m,1H),7.36–7.28(m,2H),7.19– 7.13(m,1H),6.10(d,J＝1.2Hz,2H),5.56(s,2H),3.80–3.74(m,1H),3.72(s,6H), 3.71–3.63(m,2H),2.77(dd,J＝13.9,7.8Hz,2H),2.65–2.49(m,4H).
13 C NMR(75MHz,CDCl 3 )δ169.2,167.6,138.4,137.8,130.5,129.8,127.5, 127.1,127.1,124.7,51.9,51.8,46.8,38.9,36.4,26.5.
Example 2: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ba)
Figure BDA0003699213590000061
1-ethyl-3, 4-dihydroisoquinoline 1b (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively and added into a 10mL Schlenk reaction tube with a stirrer, anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, and the reaction is heated and stirred for 2 hours, and the reaction is monitored by TLC to be finished. After the reaction mixture was cooled to room temperature, the reaction mixture was transferred to a round-bottomed flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (8:1, v/v) to give the product 3ba (45mg, yield 87%), a colorless oil, a colorless oily product 1 H NMR and 13 the C NMR spectra are shown in FIG. 3 and FIG. 4, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.67–7.61(m,1H),7.38–7.29(m,2H),7.21–7.15(m,1H), 6.16(d,J＝1.5Hz,1H),5.57(br.,1H),3.76(s,3H),3.67(t,J＝7.5Hz,2H),3.51–3.39(m,1H), 2.86(dd,J＝13.5,5.5Hz,1H),2.70–2.60(m,2H),2.40–2.29(m,1H),1.17(d,J＝6.8Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ170.6,167.8,138.8,138.2,130.4,129.1,127.7,127.2,127.1, 124.9,51.9,46.9,38.2,35.3,26.5,18.3.
Example 3: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidyne-octanoic acid methyl ester (3ca)
Figure BDA0003699213590000071
1-pentyl-3, 4-dihydroisoquinoline 1c (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively, added to a 10mL Schlenk reaction tube with a stirrer, anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for several minutes, the reaction tube is capped and sealed, placed in an oil bath at 80 ℃, heated and stirred for 2 hours, and the reaction is monitored by TLC to be completed. After the reaction mixture was cooled to room temperature, the reaction mixture was transferred to a round-bottomed flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10:1, v/v) to give the product 3ca (46mg, 77% yield) as a colorless oil 1 H NMR and 13 the C NMR spectra are shown in FIGS. 5 and 6, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.58–7.52(m,1H),7.37–7.27(m,2H),7.20–7.14(m,1H), 6.07(d,J＝1.7Hz,1H),5.51(dd,J＝2.7,1.1Hz,1H),3.72(s,3H),3.70–3.55(m,2H),3.42– 3.30(m,1H),2.78–2.50(m,4H),1.69(s,2H),1.30–1.20(m,4H),0.86–0.79(m,3H).
13 C NMR(75MHz,CDCl 3 )δ170.1,167.8,138.8,138.0,130.3,130.1,127.5,127.0,127.0, 124.7,51.8,46.8,40.7,37.2,33.5,29.6,26.6,23.0,14.1.
Example 4: 4- (3, 4-dihydroisoquinolin-1-yl) -5-methyl-2-methylidene hexanoic acid methyl ester (3da)
Figure BDA0003699213590000072
1-isobutyl-3, 4-dihydroisoquinoline 1d (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively and added into a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, and the reaction is heated and stirred for 2 hours, and the reaction is monitored by TLC to be finished. After the reaction mixture was cooled to room temperature, the reaction mixture was transferred to a round-bottomed flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (3:1, v/v) to give the product 3da (45mg, yield 79%), a colorless oil, a colorless oily substance 1 H NMR and 13 the C NMR spectra are shown in FIGS. 7 and 8, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.41(dd,J＝7.5,1.4Hz,1H),7.35–7.22(m,2H),7.18– 7.13(m,1H),5.95(d,J＝1.7Hz,1H),5.48–5.43(m,1H),3.79–3.68(m,1H),3.67(s,3H), 3.64–3.52(m,1H),3.24–3.13(m,1H),2.79(ddd,J＝13.5,3.9,1.2Hz,1H),2.72–2.65(m, 1H),2.65–2.57(m,2H),2.00(m,1H),1.00(d,J＝6.7Hz,3H),0.92(d,J＝6.7Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ169.7,167.9,139.2,137.9,130.8,130.2,127.5,126.9,126.6, 124.7,51.7,47.3,46.7,33.5,32.4,26.6,21.4,19.9.
Example 5: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene-5-phenylpentanoic acid methyl ester (3ea)
Figure BDA0003699213590000081
1-phenethyl-3, 4-dihydroisoquinoline 1e (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively and added into a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, heated and stirred for reaction for 3 hours, and the reaction is monitored by TLC to be finished. Cooling the reaction solution to room temperature, transferring the reaction solution into a round-bottom flask, and reducing the reaction solution by using a rotary evaporatorThe solvent was evaporated under pressure and the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (8:1, v/v) to give 3ea (52mg, yield 78%), as a colorless oil, as the product 1 H NMR and 13 the C NMR spectra are shown in FIGS. 9 and 10, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.44–7.39(m,1H),7.31–7.06(m,8H),6.06(d,J＝1.6Hz, 1H),5.53(dd,J＝2.5,1.1Hz,1H),3.78–3.69(m,2H),3.68(s,3H),3.67–3.63(m,1H),3.10 (dd,J＝13.6,8.1Hz,1H),2.89–2.73(m,2H),2.64–2.53(m,3H).
13 C NMR(75MHz,CDCl 3 )δ169.5,167.7,140.5,138.6,137.9,130.3,130.0,129.2,128.2, 127.4,127.2,127.0,126.0,124.6,51.8,46.8,42.4,39.9,37.1,26.5.
Example 6: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene-4-phenylbutyric acid methyl ester (3fa)
Figure BDA0003699213590000082
1-benzyl-3, 4-dihydroisoquinoline 1f (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively and added into a 10mL Schlenk reaction tube with a stirrer, anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, and the reaction is heated and stirred for 3 hours, and the reaction is monitored by TLC to be finished. After the reaction solution was cooled to room temperature, the reaction solution was transferred to a round-bottomed flask, the solvent was distilled off under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with methylene chloride/ethyl acetate (40:1, v/v) to give the product 3fa (36mg, yield 56%) as a pale yellow oil.
1 H NMR(300MHz,CDCl 3 )δ7.46–7.41(m,1H),7.33–7.26(m,3H),7.25–7.21(m,2H), 7.18–7.09(m,3H),6.03(d,J＝1.6Hz,1H),5.28(d,J＝1.3Hz,1H),4.51(t,J＝7.3Hz,1H), 3.80(td,J＝7.4,0.6Hz,2H),3.73(s,3H),3.23(m,1H),2.80(m,1H),2.67(m,2H).
13 C NMR(75MHz,CDCl 3 )δ167.9,166.9,141.9,138.6,138.2,130.2,129.5,128.6,128.3, 127.5,127.5,126.9,126.7,125.3,51.9,48.5,47.1,38.0,26.3.
Example 7: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene-4-cyclohexyl-butyric acid methyl ester (3ga)
Figure BDA0003699213590000091
1-cyclohexylmethyl-3, 4-dihydroisoquinoline 1g (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively, added into a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction solution is covered and sealed and placed in an oil bath at 80 ℃, heated and stirred for reaction for 3 hours, and the reaction is monitored by TLC to be finished. After the reaction tube was cooled to room temperature, the reaction solution was transferred to a round-bottomed flask, the solvent was distilled off under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10:1, v/v) to give the product 3ga (54mg, yield 83%) as a pale yellow oil.
1 H NMR(300MHz,CDCl 3 )δ7.43–7.38(m,1H),7.35–7.28(m,1H),7.26–7.22(m,1H), 7.16(dd,J＝7.1,1.0Hz,1H),5.94(d,J＝1.7Hz,1H),5.45(s,1H),3.79–3.68(m,1H),3.66(s, 3H),3.64–3.55(m,1H),3.30–3.16(m,1H),2.84(dd,J＝13.4,3.0Hz,1H),2.71–2.54(m, 3H),2.01–1.89(m,1H),1.80–1.56(m,6H),1.23–1.03(m,4H).
13 C NMR(75MHz,CDCl 3 )δ169.9,167.9,139.2,137.8,131.0,130.2,127.5,126.9,126.6, 124.8,51.7,46.7,46.5,46.4,42.3,33.9,31.7,30.6,26.7,26.6,26.5.
Example 8: 4- (6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ha)
Figure BDA0003699213590000092
1-ethyl-6, 7-dimethoxy-3, 4-dihydroisoquinoline 1h (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively and added to a stirrerTo a 10mL Schlenk reaction tube, anhydrous acetonitrile (4.0mL) was added, and after bubbling with nitrogen gas for several minutes, the reaction tube was capped and sealed, placed in an oil bath at 80 ℃ and heated with stirring for 3 hours, and the reaction was monitored by TLC for completion. After the reaction mixture was cooled to room temperature, the reaction mixture was transferred to a round-bottomed flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, the residue was separated by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1, v/v) to give the product 3ha (44mg, 69% yield) as a yellow oil 1 H NMR and 13 the C NMR spectra are shown in FIGS. 11 and 12, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.33(s,1H),6.69(s,1H),6.15(d,J＝1.6Hz,1H),5.60(s, 1H),3.97(s,3H),3.92(s,3H),3.75(s,3H),3.69–3.62(m,2H),3.44–3.33(m,1H),2.88(m, 1H),2.59(td,J＝7.1,2.6Hz,2H),2.32–2.20(m,1H),1.17(d,J＝6.8Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ170.1,167.7,150.7,147.7,138.7,131.7,127.3,122.0,110.4, 109.1,56.5,56.1,51.9,47.1,39.0,35.4,26.2,17.8.
Example 9: 4- (6-chloro-3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ia)
Figure BDA0003699213590000101
1-ethyl-6-chloro-3, 4-dihydroisoquinoline 1i (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively, added into a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, heated and stirred for reaction for 2 hours, and the reaction is monitored by TLC to be finished. After the reaction was cooled to room temperature, the reaction was transferred to a round bottom flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (8:1, v/v) to give the product 3ia (51mg, 87% yield) as a colorless oil.
1 H NMR(300MHz,CDCl 3 )δ7.59(d,J＝8.4Hz,1H),7.29(dd,J＝8.3,2.2Hz,1H),7.19– 7.17(m,1H),6.17(d,J＝1.6Hz,1H),5.58(dd,J＝2.4,1.3Hz,1H),3.76(s,3H),3.71–3.63(m, 2H),3.44–3.32(m,1H),2.82(m,1H),2.63(t,J＝7.5Hz,2H),2.31(m,1H),1.15(d,J＝6.8Hz, 3H).
13 C NMR(75MHz,CDCl 3 )δ169.6,167.7,140.2,138.9,136.1,127.7,127.6,127.2,127.0, 126.3,51.8,46.7,38.3,35.6,26.4,18.3.
Example 10: 4- (7-Nitro-3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ja)
Figure BDA0003699213590000111
1-ethyl-7-nitro-3, 4-dihydroisoquinoline 1j (0.2mmol) and MBH carbonate 2a (0.24mmol) are weighed respectively and added into a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, the reaction is heated and stirred for 2 hours, and the reaction is monitored by TLC to be finished. After the reaction solution was cooled to room temperature, the reaction solution was transferred to a round-bottomed flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (3:1, v/v) to give the product 3ja (56mg, yield 93%) as a yellow oil.
1 H NMR(300MHz,CDCl 3 )δ8.50(d,J＝2.2Hz,1H),8.23(dd,J＝8.3,2.3Hz,1H),7.38 (d,J＝8.3Hz,1H),6.20(d,J＝1.6Hz,1H),5.58(d,J＝1.1Hz,1H),3.82(s,3H),3.75(t,J＝7.4 Hz,2H),3.54–3.43(m,1H),2.84(m,1H),2.80–2.73(m,2H),2.37(m,1H),1.21(d,J＝6.8 Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ168.9,167.5,147.4,145.5,138.3,129.7,128.7,127.7,125.1, 119.8,52.1,46.3,38.3,35.5,26.5,18.1.
Example 11: 4- (6, 7-Dihydrothieno [3,2-c ] pyridin-4-yl) -2-Methylenepentanoic acid methyl ester (3ka)
Figure BDA0003699213590000112
Compound 1k (0.2mmol) and MBH carbonate 2a (0.24mmol) were weighed separately and added to a 10mL Schlenk reaction tube with a stirrer, then anhydrous acetonitrile (4.0mL) was added, after bubbling with nitrogen for several minutes, the reaction tube was capped and sealed and placed in an oil bath at 80 ℃ and heated to stir for 1 hour, and the completion of the reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, the reaction mixture was transferred to a round-bottomed flask, the solvent was evaporated under reduced pressure using a rotary evaporator, the residue was separated by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (6:1, v/v) to give the product 3ka (33mg, yield 63%) as a pale yellow oil 1 H NMR and 13 the C NMR spectra are shown in FIGS. 13 and 14, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.28(d,J＝5.2Hz,1H),7.09(d,J＝5.2Hz,1H),6.17(d,J＝ 1.5Hz,1H),5.57(d,J＝1.0Hz,1H),3.81–3.77(m,1H),3.76(s,3H),3.75–3.70(m,1H),3.24 –3.10(m,1H),2.91–2.75(m,3H),2.30(m,1H),1.16(d,J＝6.9Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ167.7,167.3,143.4,138.6,131.6,127.3,124.2,122.0,51.9, 47.8,37.9,37.8,22.4,17.5.
Example 12: 4- (9-methyl-4, 9-dihydro-3H-pyrido [3,4-b ] indol-1-yl) -2-methylidene pentanoic acid methyl ester (3la)
Figure BDA0003699213590000121
1l (0.2mmol) of the compound and MBH carbonate 2a (0.24mmol) were weighed, added to a 10mL Schlenk reaction tube with a stirrer, followed by addition of anhydrous acetonitrile (4.0mL), bubbling with nitrogen gas for several minutes, the reaction tube was capped and sealed, placed in an oil bath at 80 ℃ and heated for stirring for 2 hours, and the completion of the reaction was monitored by TLC. After the reaction was cooled to room temperature, the reaction was transferred to a round-bottomed flask, the solvent was evaporated off under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (3:1, v/v) to give the product 3la (49mg, yield 79%) as a pale yellow oil, which was purified by filtration to give a white solidIs/are as follows 1 H NMR and 13 the C NMR spectra are shown in FIGS. 15 and 16, respectively.
1 H NMR(300MHz,CDCl 3 )δ7.58(dt,J＝8.0,1.0Hz,1H),7.34–7.30(m,2H),7.17– 7.10(m,1H),6.14(d,J＝1.6Hz,1H),5.60(d,J＝1.2Hz,1H),3.93(s,3H),3.85–3.70(m, 2H),3.69(s,3H),3.58–3.48(m,1H),2.87(m,1H),2.78–2.68(m,2H),2.43(m,1H),1.21(d,J ＝6.8Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ167.7,165.0,139.1,138.4,131.4,127.6,124.6,124.4,120.0, 120.0,119.4,110.3,51.9,48.0,38.2,36.5,32.7,20.0,18.4.
Example 13: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidenepentanoic acid tert-butyl ester (3bb)
Figure BDA0003699213590000122
1-ethyl-3, 4-dihydroisoquinoline 1b (0.2mmol) and MBH carbonate 2b (0.24mmol) are weighed respectively and added into a 10mL Schlenk reaction tube with a stirrer, anhydrous acetonitrile (4.0mL) is added, after bubbling with nitrogen for a plurality of minutes, the reaction tube is capped and sealed and placed in an oil bath at 80 ℃, and the reaction is heated and stirred for 5 hours, and the reaction is monitored by TLC to be finished. After the reaction solution was cooled to room temperature, the reaction solution was transferred to a round-bottomed flask, the solvent was evaporated under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10:1, v/v) to give the product 3bb (48mg, yield 80%) as a pale yellow oil.
1 H NMR(300MHz,CDCl 3 )δ7.64–7.59(m,1H),7.38–7.27(m,2H),7.21–7.16(m,1H), 6.04(d,J＝1.9Hz,1H),5.46(d,J＝1.6Hz,1H),3.72–3.63(m,2H),3.53–3.39(m,1H),2.81 (ddd,J＝13.6,6.1,0.9Hz,1H),2.65(dd,J＝8.7,6.1Hz,2H),2.34(m,1H),1.50(s,9H),1.17(d, J＝6.8Hz,3H).
13 C NMR(75MHz,CDCl 3 )δ170.8,166.7,140.5,138.2,130.4,129.3,127.6,127.1,126.0, 124.9,80.6,46.9,38.4,35.5,28.3,26.5,18.7.
Example 14: 4- (3, 4-dihydroisoquinolin-1-yl) -2, 6-dimethylidepimelic acid dimethyl ester (3aa)
The procedure was as described for the preparation of compound 3ba, example 1, except that:
the reaction solvent was changed to toluene at 110 ℃ for 21 hours under the same conditions as in example 1. The target product was obtained in 82% yield.
Example 15: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ba)
The procedure was as described for the preparation of compound 3ba, example 2, except that:
the reaction solvent was changed to toluene at 110 ℃ for 12 hours under the same conditions as in example 2. The target product was obtained in 85% yield.
Example 16: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ba)
The procedure was as described for the preparation of compound 3ba, example 2, except that:
the reaction solvent was changed to N, N-dimethylformamide at 80 ℃ for 2 hours under the same conditions as in example 2. The target product was obtained in 71% yield.
Example 17: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ba)
The procedure was as described for the preparation of compound 3ba, example 2, except that:
the reaction solvent was changed to tetrahydrofuran, the reaction temperature was 80 ℃ and the reaction time was 6 hours, and the other conditions were the same as in example 2. The target product was obtained in 60% yield.
Example 18: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ba)
The procedure was as described for the preparation of compound 3ba, example 2, except that:
the same conditions as in example 2 were changed to 1:1.5 with respect to the charged molar ratio of 1-ethyl-3, 4-dihydroisoquinoline 1b (0.2mmol) to carbonate 2 a. The target product was obtained in 85% yield.
Example 19: 4- (3, 4-dihydroisoquinolin-1-yl) -2-methylidene pentanoic acid methyl ester (3ba)
The procedure was as described for the preparation of compound 3ba, example 2, except that:
in the amplification experiment, the dosage of the 1-ethyl-3, 4-dihydroisoquinoline 1b is 5 mmol; the amount of carbonate 2a used was 6 mmol, the amount of acetonitrile as a solvent was 50mL, and the other conditions were the same as in example 2. The yield of the desired product was 1.03g, 82%.
Example 20: application examples
The dihydroisoquinoline derivative 3ba obtained in example 19 is used as an intermediate of a structure of a medicament and a chemical product for further reaction, and specifically comprises the following steps:
Figure BDA0003699213590000141
dihydroisoquinoline 3ba (128mg, 0.5mmol) is dissolved in 10mL of toluene and NaBH (OAc) is added portionwise at room temperature 3 (318mg, 1.5mmol) and the reaction was then stirred at room temperature for an additional 4 hours and monitored by TLC for completion. Diluting with ethyl acetate, washing with water, drying the organic layer with anhydrous sodium sulfate, spin-drying the solvent, separating the crude product with silica gel column chromatography, eluting with petroleum ether/ethyl acetate (4:1, v/v), and separating to obtain 2 isomer products 4 with total yield of 66%.
The less polar isomer: 43mg, light yellow oil, yield 19%. 1 H NMR(300MHz,CDCl 3 ) δ7.26–7.11(m,4H),6.37(t,J＝2.4Hz,1H),5.41–5.36(m,1H),5.12–5.03(m,1H),4.97(d,J ＝2.9Hz,1H),2.96–2.52(m,6H),0.58(d,J＝6.9Hz,3H). 13 C NMR(75MHz,CDCl 3 )δ163.8, 136.2,135.7,135.2,129.0,126.8,126.5,125.7,124.2,61.3,39.1,36.3,33.7,29.3,11.6.
The polar large isomer: 107mg of colorless oil, yield 47%. 1 H NMR(300MHz,CDCl 3 )δ 7.26–7.15(m,4H),6.17(dd,J＝3.0,1.4Hz,1H),5.28(q,J＝1.7Hz,1H),4.44(dt,J＝12.5,5.6 Hz,1H),4.36(d,J＝5.2Hz,1H),3.26–3.15(m,1H),3.13–3.00(m,1H),2.82(dt,J＝15.7,5.2 Hz,1H),2.68–2.50(m,2H),2.36(dd,J＝14.1,7.2Hz,1H),1.24(d,J＝6.7Hz,3H). 13 C NMR (75MHz,CDCl 3 )δ164.3,137.2,136.8,136.7,128.9,127.4,126.3,124.3,121.9,62.6,42.7,35.1, 30.7,28.8,19.5。

Claims (6)

1. A cyclic imine derivative with an acrylate structure is characterized by having a general structural formula as follows:
Figure FDA0003699213580000011
wherein R is 1 Selected from phenyl, substituted aryl, alkyl, aralkyl, haloalkyl, alkoxy-substituted alkyl, allyl, cycloalkyl, or
Figure FDA0003699213580000012
R 2 Selected from methyl, ethyl, isopropyl, tert-butyl or benzyl; ar is phenyl, thiophene, furan, indole, benzofuran or benzothiophene containing substituent groups.
2. The cyclic imine derivative having an acrylate structure according to claim 1, wherein the substituents contained in Ar are selected from one or two of hydrogen, halogen, nitro, alkoxy, amino, alkyl, benzyl, cyano, trifluoromethyl, ester, and amide.
3. A preparation method of cyclic imine derivatives with acrylate structure as claimed in claim 1, wherein the cyclic imine compounds and MBH carbonate are mixed and dissolved in organic solvent according to the molar ratio of 1: 1-3, and the mixture is reacted for 30 minutes-24 hours at 20-160 ℃ in air or nitrogen atmosphere to obtain the cyclic imine derivatives with acrylate structure; the organic solvent is toluene, acetonitrile, N-dimethylformamide, ethyl acetate, 1, 4-dioxane or tetrahydrofuran, and the dosage of the solvent enables the molar concentration of the cyclic imine compound to be 0.01-1.0M;
the molecular structure general formula of the cyclic imine compound is as follows:
Figure FDA0003699213580000013
wherein R is 3 Is phenyl, substituted aryl, alkyl, aralkyl, haloalkyl, alkoxy-substituted alkyl, allyl, cycloalkyl or a hydrogen atom;
ar is any one of phenyl, thiophene, furan, indole, benzofuran or benzothiophene containing substituent groups, wherein the substituent groups are any one or two of hydrogen, halogen, nitro, alkoxy, amino, alkyl, benzyl, cyano, trifluoromethyl, ester group and amide group;
the molecular structure general formula of the MBH carbonate compound is as follows:
Figure FDA0003699213580000014
wherein R is 2 Is any one of methyl, ethyl, isopropyl, tertiary butyl or benzyl.
4. The method for preparing the cyclic imine derivative having an acrylate structure according to claim 3, wherein the organic solvent is acetonitrile or toluene.
5. The method for preparing cyclic imine derivative with acrylate structure according to claim 3, wherein the reaction temperature is 60-120 ℃.
6. The method for preparing the cyclic imine derivative having an acrylate structure according to claim 3, wherein the amount of the organic solvent is such that the molar concentration of the cyclic imine compound is 0.05 to 0.2M.
CN202210690233.3A 2022-06-17 2022-06-17 Cyclic imine derivative with acrylate structure and preparation method thereof Pending CN114874140A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210690233.3A CN114874140A (en) 2022-06-17 2022-06-17 Cyclic imine derivative with acrylate structure and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210690233.3A CN114874140A (en) 2022-06-17 2022-06-17 Cyclic imine derivative with acrylate structure and preparation method thereof

Publications (1)

Publication Number Publication Date
CN114874140A true CN114874140A (en) 2022-08-09

Family

ID=82681473

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210690233.3A Pending CN114874140A (en) 2022-06-17 2022-06-17 Cyclic imine derivative with acrylate structure and preparation method thereof

Country Status (1)

Country Link
CN (1) CN114874140A (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA683457A (en) * 1964-03-31 Farbenfabriken Bayer Aktiengesellschaft Process for the production of polycyclic imines
US4443452A (en) * 1982-02-06 1984-04-17 Dr. Karl Thomae Gmbh Dibenzodiazepinones, pharmaceutical compositions thereof and method of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA683457A (en) * 1964-03-31 Farbenfabriken Bayer Aktiengesellschaft Process for the production of polycyclic imines
US4443452A (en) * 1982-02-06 1984-04-17 Dr. Karl Thomae Gmbh Dibenzodiazepinones, pharmaceutical compositions thereof and method of use thereof

Similar Documents

Publication Publication Date Title
Tietze et al. The domino multicomponent allylation reaction for the stereoselective synthesis of homoallylic alcohols
Li et al. Highly enantioselective phenylacetylene addition to aldehydes catalyzed by a chiral N, O-ferrocene ligand
CN111217848A (en) Spiro-dihydrobenzothiole diphenol compound, synthesis method and application thereof
WO2015102020A1 (en) Novel n-heterocyclic carbene compounds, their preparation and use
CN103408573B (en) Boric acid derivatives and its preparation method and application
CN113896674A (en) Synthetic method of apremilast
CN108658841A (en) A kind of carbazole compound and preparation method thereof
CN111925356A (en) Synthesis method and application of chiral quinoline-imidazoline ligand
CN109293700B (en) Chiral diphosphine ligand, preparation method, intermediate and application thereof
CN114874140A (en) Cyclic imine derivative with acrylate structure and preparation method thereof
CN113045530B (en) Method for preparing naphthopyran compounds by ruthenium catalysis
CN111848623A (en) Method for synthesizing fluorine-containing chiral ketal amine by catalysis of chiral phosphoric acid
CN111499542A (en) Preparation method of cycloenone compound containing α -cyano substituted quaternary carbon center
CN109503387B (en) Method for catalyzing asymmetric synthesis of binaphthyl diamine
Pandey et al. Organocatalytic dynamic kinetic resolution via conjugate addition: synthesis of chiral trans-2, 5-dialkylcyclohexanones
Szemes et al. Diastereoselective access to hexahydro-and octahydrofuro [f] indolizines analogues of phenanthro [f] indolizidines alkaloids
CN114591369B (en) Phosphoramidite ligand and preparation method and application thereof
CN110467613B (en) Reaction method for alkylation of imide cation intramolecular amide by nickel catalysis
CN111393437B (en) Trisubstituted indolizine compound and preparation method thereof
EP1233828A2 (en) Chiral catalysts for asymmetric acylation and related transformations
CN108440534B (en) Efficient synthesis of beta-chiral bicyclic or polycyclic imidazole derivatives
CN110467556B (en) Nucleophilic reaction method for catalyzing imine ions and acetophenone by nickel
CN113429323B (en) Preparation method of sulfonyl substituted styrene type axial chiral compound
CN113861238B (en) Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis
CN109180406B (en) Synthesis method of (4R, 5R) -5-benzyl-4-hydroxy-2-cyclopentene-1-ketone compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination