CN107488090B - Efficient catalytic asymmetric preparation method of N-cyclopropyl nitrone compound - Google Patents
Efficient catalytic asymmetric preparation method of N-cyclopropyl nitrone compound Download PDFInfo
- Publication number
- CN107488090B CN107488090B CN201710728856.4A CN201710728856A CN107488090B CN 107488090 B CN107488090 B CN 107488090B CN 201710728856 A CN201710728856 A CN 201710728856A CN 107488090 B CN107488090 B CN 107488090B
- Authority
- CN
- China
- Prior art keywords
- oxime
- reaction
- cyclopropyl
- compound
- catalytic asymmetric
- 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.)
- Expired - Fee Related
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
-
- 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
Abstract
The invention provides a high-efficiency catalytic asymmetric preparation method of an N-cyclopropyl nitrone compound, belonging to the technical field of organic synthetic chemistry. Adding an organic solvent into a reaction vessel, then sequentially adding a copper catalyst, a chiral ligand, alkali and oxime, and then adding a cyclopropene compound for reaction to obtain the N-cyclopropyl nitrone compound. The method has mild reaction conditions, the reaction is promoted because the chiral ligand is a bidentate phosphine ligand, and the ligand coordinated chiral metal catalyst causes a very compact substrate binding pocket, thereby being beneficial to realizing the control of high enantioselectivity and diastereoselectivity. Meanwhile, the catalyst and the raw material oxime used in the method are cheap and easy to obtain, the reaction mechanism is novel, the universality of the reacted functional group is good, a simple and efficient way is provided for the synthesis of the ketonitrone which is difficult to prepare at present, and the product obtained by the preparation method can be used as an important physiologically active compound for treating cancers, neurodegenerative diseases and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a high-efficiency catalytic asymmetric preparation method of an N-cyclopropyl nitrone compound.
Background
Nitrone is an important functional group, and has extremely important application value in the fields of organic synthesis, free radical chemistry, polymer production and biomedicine. For example, the catalytic asymmetric 1, 3-dipolar cycloaddition reaction in which various nitrone compounds are involved, which has been developed in the last twenty-three years, provides an efficient preparation method for various heterocyclic compounds with important physiological activities, and has important application in natural product synthesis. (chem.Rev.1998,98, 863-. In the field of polymer chemistry, nitrones can be used to regulate free radical polymerization. In addition, nitrone can also be directly used as a medicine for treating some serious diseases, such as tumors, neurodegenerative diseases and the like (Free Radic Biol Med 2008,45(10), 1361-74; Future Med Chem 2012,4, 1171-1207; Free Radic Biol Med 2013,62, 145-56; Biochim Biophys Acta 2014,1840(2), 722-9.).
The methods for synthesizing nitrones conventionally used at present are still limited to classical methods such as condensation of aldehydes, ketones with hydroxylamine, oxidation of amines, imines, hydroxylamines, etc., alkylation of oximes, etc. These reactions have many limitations, such as the preparation of ketonitrones, the poor atomic economy and selectivity of the oxidation reaction, and the like. Importantly, most of these reactions are not amenable to catalytic asymmetric synthesis. Although new strategies have recently emerged in nitrone synthesis, a general and efficient methodology suitable for catalyzing asymmetric reactions has not yet emerged, and thus highly enantioselective nitrone synthesis methodologies have not yet been reported. These limitations greatly limit the important applications of nitrones, especially chiral nitrone compounds, in various fields.
Disclosure of Invention
The invention aims to solve the problem that the existing methods for preparing nitrone compounds cannot carry out catalytic asymmetric synthesis, and provides a high-efficiency catalytic asymmetric preparation method of an N-cyclopropyl nitrone compound.
The invention provides a high-efficiency catalytic asymmetric preparation method of an N-cyclopropyl nitrone compound, which comprises the following steps:
adding an organic solvent into a reaction vessel, then sequentially adding a copper catalyst, a chiral ligand, alkali and oxime, and then adding a cyclopropene compound for reaction to obtain the N-cyclopropyl nitrone compound.
Preferably, the chiral ligand is a bidentate phosphine ligand, and the structure is shown as L1 or L2:
preferably, the oxime is benzophenone oxime, 4' -dimethylbenzophenone oxime, acetophenone oxime, phenylacetone oxime, 4-phenylbenzaldehyde oxime or 4-methoxybenzaldehyde oxime.
Preferably, the cyclopropene compound is 3-methyl-3-phenylcyclopropene, 3-methyl-3- (2-naphthyl) cyclopropene, 3-methyl-3- (4-trifluoromethyl) phenylcyclopropene, 3-ethyl-3-phenylcyclopropene, or 3-methyl-3- (2-phenylethyl) phenylcyclopropene, 3-diphenylcyclopropene, or 3-phenyl-3-isopropylcyclopropene.
Preferably, the organic solvent is toluene, tetrahydrofuran, dioxane, diethyl ether, n-hexane, cyclohexane or acetonitrile.
Preferably, the copper catalyst is CuCl, CuBr, CuI, Cu (OAc)2、CuOAc、Cu(OTf)2Or Cu (CH)3CN)4PF6。
Preferably, the base is sodium tert-butoxide, lithium tert-butoxide, potassium phenoxide or sodium phenoxide.
Preferably, the reaction temperature is-50-40 ℃, and the reaction time is 40-180 min.
Preferably, the mol ratio of the cyclopropene compound to the oxime to the chiral ligand is 1: 1.2: (0.25-0.3).
The invention has the advantages of
The invention provides a high-efficiency catalytic asymmetric preparation method of an N-cyclopropyl nitrone compound. Compared with the prior art, the method has mild reaction conditions, the reaction is promoted because the chiral ligand is a bidentate phosphine ligand, and the ligand-coordinated chiral metal catalyst causes a very compact substrate binding pocket, thereby being beneficial to realizing high enantioselectivity (up to 99% ee) and diastereoselectivity control. Meanwhile, the catalyst and the raw material oxime used in the method are cheap and easy to obtain, the reaction mechanism is novel, the universality of the reacted functional group is good, a simple and efficient way is provided for the synthesis of the ketonitrone which is difficult to prepare at present, and the product obtained by the preparation method can be used as an important physiologically active compound for treating cancers, neurodegenerative diseases and the like.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a product produced in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 3 is a high performance liquid chromatogram of the product prepared in example 1 of the present invention;
FIG. 4 is a nuclear magnetic hydrogen spectrum of a product produced in example 2 of the present invention;
FIG. 5 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 6 is a high performance liquid chromatogram of the product prepared in example 2 of the present invention;
FIG. 7 is a nuclear magnetic hydrogen spectrum of a product produced in example 3 of the present invention;
FIG. 8 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 9 is a high performance liquid chromatogram of the product prepared in example 3 of the present invention;
FIG. 10 is a nuclear magnetic hydrogen spectrum of a product produced in example 4 of the present invention;
FIG. 11 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 12 is a high performance liquid chromatogram of the product prepared in example 4 of the present invention;
FIG. 13 is a nuclear magnetic hydrogen spectrum of a product produced in example 5 of the present invention;
FIG. 14 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 15 is a high performance liquid chromatogram of the product prepared in example 5 of the present invention;
FIG. 16 is a nuclear magnetic hydrogen spectrum of a product produced in example 6 of the present invention;
FIG. 17 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 18 is a high performance liquid chromatogram of the product prepared in example 6 of the present invention;
FIG. 19 is a nuclear magnetic hydrogen spectrum of a product produced in example 7 of the present invention;
FIG. 20 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 21 is a high performance liquid chromatogram of the product prepared in example 7 of the present invention;
FIG. 22 is a nuclear magnetic hydrogen spectrum of a product produced in example 8 of the present invention;
FIG. 23 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 24 is a high performance liquid chromatogram of the product prepared in example 8 of the present invention;
FIG. 25 is a nuclear magnetic hydrogen spectrum of a product produced in example 9 of the present invention;
FIG. 26 is a high performance liquid chromatogram of a product of racemic structure;
FIG. 27 is a high performance liquid chromatogram of the product prepared in example 9 of the present invention;
FIG. 28 is a nuclear magnetic hydrogen spectrum of a product produced in example 10 of the present invention;
FIG. 29 is a high performance liquid chromatogram of a product of racemic structure.
FIG. 30 is a high performance liquid chromatogram of the product prepared in example 10 of the present invention;
FIG. 31 is a schematic structural diagram of a product prepared in example 2 of the present invention.
Detailed Description
The invention provides a high-efficiency catalytic asymmetric preparation method of an N-cyclopropyl nitrone compound, which comprises the following steps:
adding an organic solvent into a reaction vessel, then sequentially adding a copper catalyst, a chiral ligand, alkali and oxime, and then adding a cyclopropene compound for reaction to obtain the N-cyclopropyl nitrone compound.
According to the invention, the cyclopropene compound is synthesized according to the literature (Rubin, et al, Tetrahedron 2008,64, 8610-. Preferably 3-methyl-3-phenylcyclopropene, 3-methyl-3- (2-naphthyl) cyclopropene, 3-methyl-3- (4-trifluoromethyl) phenylcyclopropene, 3-ethyl-3-phenylcyclopropene or 3-methyl-3- (2-phenylethyl) phenylcyclopropene, 3-diphenylcyclopropene or 3-phenyl-3-isopropylcyclopropene.
According to the invention, the oxime is formed by condensation of an aldehyde or ketone with hydroxylamine according to the methods of the prior art. Preferably benzophenone oxime, 4' -dimethylbenzophenone oxime, acetophenone oxime, phenylacetone oxime, 4-phenylbenzaldehyde oxime or 4-methoxybenzaldehyde oxime.
According to the invention, the chiral ligand is a bidentate phosphine ligand, and the obtaining mode is commercial; the invention adopts the chiral ligand as the bidentate phosphine ligand, thus promoting the reaction, and the chiral metal catalyst coordinated by the ligand causes a very compact substrate binding pocket, thereby being beneficial to realizing the control of high enantioselectivity and diastereoselectivity. The bidentate phosphine ligand structure is shown as L1 or L2:
according to the invention, the copper catalyst is preferably monovalent or divalent copper, more preferably CuCl, CuBr, CuI, Cu (OAc)2、CuOAc、Cu(OTf)2Or Cu (CH)3CN)4PF6。
According to the present invention, the organic solvent used preferably includes toluene, tetrahydrofuran, dioxane, diethyl ether, n-hexane, cyclohexane or acetonitrile.
According to the invention, the base comprises the usual alkali metal salts of alkoxides or phenolates, preferably sodium tert-butoxide, lithium tert-butoxide or potassium tert-butoxide; the alkali metal phenolate is preferably potassium phenolate or sodium phenolate.
According to the invention, the reaction temperature is preferably-50 to 40 ℃ and the reaction time is preferably 40 to 180 min.
According to the present invention, the molar ratio of the cyclopropene compound, oxime, and chiral ligand is preferably 1: 1.2: (0.25-0.3), the addition amount of the copper catalyst is preferably 5% of that of the cyclopropene compound; the amount of the base added is preferably 30% of the amount of the cyclopropene compound added.
The catalyst copper catalyst and the raw material oxime used in the preparation method are cheap and easy to obtain, the reaction mechanism is novel, and a series of preliminary mechanism researches show that the reaction is carried out by CuIA catalytic process, which is quite different from the reports in the literature concerning copper and oxime derivatives concerning Single Electron Transfer (SET) processes and free radical processes. The formation of the C-N bond proceeds through a 5 and 3 membered ring copper heteroretro-Cope hydroamination transition state. The preliminary reaction mechanism is shown below:
the present invention is described in further detail below with reference to specific examples, in which the starting materials are all commercially available.
Example 1
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L1(14.2 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and benzophenone oxime (47.3 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; cooling the reaction system to-50 ℃, and slowly dropwise adding 3-methyl-3-phenyl cyclopropene (0.2 millimole); stirring the reaction system at-50 deg.C for 3h, monitoring by TLC plate, purifying by column chromatography to obtain white solid, and purifying by chromatography1H NMR (shown in FIG. 1),13C NMR technique, high resolution mass spectrometry detection, determining the structure as formula 1, weighing 62.2 mg, calculating the yield to 95%, fig. 2 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 2, and then obtaining a high performance liquid chromatogram of the product prepared in example 1 (as shown in fig. 3) with an enantioselectivity of 92%; the reaction can be represented by the following equation:
example 2
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L1(14.2 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and benzophenone oxime (47.3 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; cooling the reaction system to-50 ℃, and slowly dropwise adding 3-methyl-3- (2-naphthyl) cyclopropene (0.2 mmol); stirring the reaction system at-50 deg.C for 3h, monitoring by TLC plate, purifying by column chromatography to obtain white solid, and purifying by chromatography1H NMR (as shown in FIG. 4),13C NMR technique, high resolution mass spectrometric detection, determining the structure as formula 2, weighing 63.4 mg, calculating a yield of 84%, fig. 5 is a high performance liquid chromatogram of the racemic product, determining a control retention time by the structure of the racemic product of fig. 5, and then obtaining a high performance liquid chromatogram of the product prepared in example 2 (as shown in fig. 6) with an enantioselectivity of 95%; the reaction can be represented by the following equation:
inventive example 2 single crystal X-ray diffraction crystal data was received in cambridge crystal database (CCDC #1548526), the structure is shown in fig. 31, and the crystal structure data is shown in table 1.
TABLE 1
Example 3
Tetrahydrofuran (2 ml) was added to a 25 ml reaction tube, followed by cuprous chloride (0.0 ml)10 mmol), chiral ligand L1(14.2 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol) and benzophenone oxime (47.3 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate; cooling the reaction system to-50 ℃, and slowly adding 3-methyl-3- (4-trifluoromethyl) phenyl cyclopropene (0.2 mmol) dropwise; stirring the reaction system at-50 deg.C for 3h, monitoring by TLC plate, purifying by column chromatography to obtain white solid, and purifying by chromatography1H NMR (shown in FIG. 7),13C NMR technique, high resolution mass spectrometric detection, determining the structure as formula 3, weighing 50.6 mg, calculated yield of 64%, fig. 8 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 8, and then obtaining a high performance liquid chromatogram of the product prepared in example 3 (as shown in fig. 9) with an enantioselectivity of 96%; the reaction can be represented by the following equation:
example 4
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L1(14.2 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and benzophenone oxime (47.3 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; cooling the reaction system to-50 ℃, and slowly dropwise adding 3-ethyl-3-phenylcyclopropene (0.2 mmol); stirring the reaction system at-50 deg.C for 3h, monitoring by TLC plate, purifying by column chromatography to obtain white solid, and purifying by chromatography1H NMR (shown in FIG. 10),13C NMR technique, high resolution mass spectrometric detection, determining the structure as formula 4, weighing 45.6 mg, calculated yield 67%, fig. 11 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 11, and then obtaining a high performance liquid chromatogram of the product prepared in example 4 (as shown in fig. 12) with an enantioselectivity of 99%; the reaction can be represented by the following equation:
example 5
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L1(14.2 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and benzophenone oxime (47.3 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; cooling the reaction system to-50 ℃, and slowly adding 3-methyl-3- (2-phenethyl) phenyl cyclopropene (0.2 mmol) dropwise; stirring the reaction system at-50 deg.C for 3h, monitoring by TLC plate, purifying by column chromatography to obtain white solid, and purifying by chromatography1H NMR (shown in FIG. 13),13CNMR technique, high resolution mass spectrometry, determining the structure as formula 5, weighing 46.2 mg, calculating the yield to 65%, fig. 14 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 14, and then obtaining a high performance liquid chromatogram of the product prepared in example 5 (as shown in fig. 15) with an enantioselectivity of 96%; the reaction can be represented by the following equation:
example 6
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L1(14.2 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and 4, 4' -dimethylbenzophenone oxime (54.1 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; cooling the reaction system to-0 ℃, and slowly dropwise adding 3-methyl-3-phenyl cyclopropene (0.2 millimole); stirring the reaction system at-0 deg.C for 60min, monitoring by TLC, purifying by column chromatography to obtain white solid, and purifying by chromatography1H NMR (shown in FIG. 16),13C NMR technique, high resolution Mass Spectrometry detection, determined as formula 6, weighed 58.3 mg, calculated yield of 82%, FIG. 17 is the high racemic productA liquid chromatogram, wherein the retention time of the control is determined by the structure of the racemic product in FIG. 17, and then a liquid chromatogram of the product prepared in example 6 (shown in FIG. 18) is obtained, wherein the enantioselectivity is 90%; the reaction can be represented by the following equation:
example 7
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L2(11.7 mg, 0.06 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and acetophenone oxime (32.4 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; then 3-methyl-3-phenylcyclopropene (0.2 mmol) was slowly added dropwise; stirring the reaction system at room temperature for 40min, monitoring by TLC spot plate, after the reaction is completed, separating and purifying by column chromatography to obtain white solid, purifying by column chromatography1H NMR (as shown in FIG. 19),13C NMR technique, high resolution mass spectrometry detection, determining the structure as formula 7, weighing 47.8 mg, calculated yield of 90%, fig. 20 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 20, and then obtaining a high performance liquid chromatogram of the product prepared in example 7 (as shown in fig. 21) with an enantioselectivity of 94%; the reaction can be represented by the following equation:
example 8
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L2(9.7 mg, 0.05 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and propiophenone oxime (35.8 mg, 0.24 mmol) in an amount of 1.2 times the molar mass of the substrate were added in this order; then 3-methyl-3-phenylcyclopropene (0.2 mmol) was slowly added dropwise; stirring the reaction system at room temperature for 40min, monitoring by TLC spot plate, and purifying by column chromatography to obtain white solidBody, the solid warp1H NMR (shown in FIG. 22),13C NMR technique, high resolution mass spectrometry detection, determining the structure as formula 8, weighing 55.3 mg, calculated yield of 99%, fig. 23 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 23, and then obtaining a high performance liquid chromatogram of the product prepared in example 8 (as shown in fig. 24) with an enantioselectivity of 97%; the reaction can be represented by the following equation:
example 9
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L2(9.7 mg, 0.05 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and 4-phenylbenzaldoxime (47.3 mg, 0.24 mmol) in an amount 1.2 times the molar mass of the substrate were added in this order; then 3-methyl-3-phenylcyclopropene (0.2 mmol) was slowly added dropwise; stirring the reaction system at room temperature for 40min, monitoring by TLC spot plate, after the reaction is completed, separating and purifying by column chromatography to obtain white solid, purifying by column chromatography1H NMR (shown in FIG. 25),13C NMR technique, high resolution mass spectrometry detection, determining the structure as formula 9, weighing 64.8 mg, calculating the yield to 99%, fig. 26 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 26, and then obtaining a high performance liquid chromatogram of the product prepared in example 9 (as shown in fig. 27) with an enantioselectivity of 92%; the reaction can be represented by the following equation:
example 10
Tetrahydrofuran was added as a solvent (2 ml) to a 25 ml reaction tube, and cuprous chloride (0.010 mmol), chiral ligand L2(9.7 mg, 0.05 mmol), sodium tert-butoxide (5.8 mg, 0.06 mmol), and 4-methoxybenzene of 1.2 times the molar mass of the substrate were added in this orderFormaldoxime (36.3 mg, 0.24 mmol); then 3-methyl-3-phenylcyclopropene (0.2 mmol) was slowly added dropwise; stirring the reaction system at room temperature for 40min, monitoring by TLC spot plate, after the reaction is completed, separating and purifying by column chromatography to obtain white solid, purifying by column chromatography1H NMR (as shown in FIG. 28),13C NMR technique, high resolution mass spectrometry detection, determining the structure as formula 10, weighing 52.9 mg, calculated yield 94%, fig. 29 is a high performance liquid chromatogram of the racemic product, determining the control retention time by the structure of the racemic product of fig. 29, and then obtaining a high performance liquid chromatogram of the product prepared in example 10 (as shown in fig. 30) with an enantioselectivity of 92%; the reaction can be represented by the following equation:
Claims (6)
1. a catalytic asymmetric preparation method of N-cyclopropyl nitrone compounds is characterized by comprising the following steps:
adding an organic solvent into a reaction container, sequentially adding a copper catalyst, a chiral ligand, alkali and oxime, and adding a cyclopropene compound for reaction to obtain an N-cyclopropyl nitrone compound;
the chiral ligand is a bidentate phosphine ligand, and the structure is shown as L1 or L2:
the oxime is benzophenone oxime, 4' -dimethyl benzophenone oxime, acetophenone oxime, phenylacetone oxime, 4-phenylbenzaldehyde oxime or 4-methoxybenzaldehyde oxime;
the copper catalyst is CuCl.
2. The catalytic asymmetric preparation method of an N-cyclopropylnitrone compound according to claim 1, wherein the cyclopropene compound is 3-methyl-3-phenylcyclopropene, 3-methyl-3- (2-naphthyl) cyclopropene, 3-methyl-3- (4-trifluoromethyl) phenylcyclopropene, 3-ethyl-3-phenylcyclopropene, 3-methyl-3- (2-phenylethyl) phenylcyclopropene, 3-diphenylcyclopropene, or 3-phenyl-3-isopropylcyclopropene.
3. The catalytic asymmetric preparation method of N-cyclopropyl nitrone compound of claim 1, wherein said organic solvent is toluene, tetrahydrofuran, dioxane, diethyl ether, N-hexane, cyclohexane or acetonitrile.
4. The catalytic asymmetric preparation method of N-cyclopropyl nitrone compound of claim 1, wherein said base is sodium tert-butoxide, lithium tert-butoxide, potassium phenoxide or sodium phenoxide.
5. The catalytic asymmetric preparation method of N-cyclopropyl nitrone compound according to claim 1, wherein the reaction temperature is-50 to 40 ℃ and the reaction time is 40 to 180 min.
6. The catalytic asymmetric preparation method of N-cyclopropyl nitrone compound according to claim 1, wherein the molar ratio of cyclopropene compound, oxime and chiral ligand is 1: 1.2: (0.25-0.3).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017104782872 | 2017-06-22 | ||
| CN201710478287 | 2017-06-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107488090A CN107488090A (en) | 2017-12-19 |
| CN107488090B true CN107488090B (en) | 2020-06-02 |
Family
ID=60645539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710728856.4A Expired - Fee Related CN107488090B (en) | 2017-06-22 | 2017-08-23 | Efficient catalytic asymmetric preparation method of N-cyclopropyl nitrone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107488090B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530389B (en) * | 2018-05-22 | 2020-06-09 | 东北师范大学 | Preparation method of 2-aryl cyclopropylamine compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1281432A (en) * | 1997-10-17 | 2001-01-24 | 桑道药品有限公司 | Alpha-aryl-N-alkylnitrones and pharmaceutical compositions containing same |
| IL169774A (en) * | 2005-07-20 | 2011-06-30 | Rohm & Haas | Compositions with cyclopropenes and metal-complexing agents |
| WO2015149068A1 (en) * | 2014-03-28 | 2015-10-01 | The University Of Chicago | Chiral ligand-based metal-organic frameworks for broad-scope asymmetric catalysis |
| CN106565709A (en) * | 2016-11-10 | 2017-04-19 | 杭州市第人民医院 | Preparation method and application of copper-catalyzed tetrahydropyrroloquinoline derivative |
-
2017
- 2017-08-23 CN CN201710728856.4A patent/CN107488090B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1281432A (en) * | 1997-10-17 | 2001-01-24 | 桑道药品有限公司 | Alpha-aryl-N-alkylnitrones and pharmaceutical compositions containing same |
| IL169774A (en) * | 2005-07-20 | 2011-06-30 | Rohm & Haas | Compositions with cyclopropenes and metal-complexing agents |
| WO2015149068A1 (en) * | 2014-03-28 | 2015-10-01 | The University Of Chicago | Chiral ligand-based metal-organic frameworks for broad-scope asymmetric catalysis |
| CN106565709A (en) * | 2016-11-10 | 2017-04-19 | 杭州市第人民医院 | Preparation method and application of copper-catalyzed tetrahydropyrroloquinoline derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107488090A (en) | 2017-12-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106902880B (en) | 4,6- dimethyl -2- mercaptopyrimidine univalent copper complex prepares the application in alcohol in catalysis ketone or aldehyde hydrogen transfer reaction | |
| TW514634B (en) | Process to make chiral compounds | |
| WO2009144906A1 (en) | Aluminum complex and use thereof | |
| US20040106818A1 (en) | Process for the preparation of cyclohexanol derivatives | |
| Wang et al. | Chemo-, regio-, and enantioselective synthesis of allylic nitrones via rhodium-catalyzed addition of oximes to allenes | |
| CN107488090B (en) | Efficient catalytic asymmetric preparation method of N-cyclopropyl nitrone compound | |
| Wang et al. | Applications of conformational design: rational design of chiral ligands derived from a common chiral source for highly enantioselective preparations of (R)-and (S)-enantiomers of secondary alcohols | |
| CN110669023A (en) | Application of chiral oxazoline copper complex | |
| CN110615811B (en) | Method for preparing chiral sulfinamide monophosphine ligand in large scale | |
| EP2376411B1 (en) | Aluminium complexes and use thereof as a catalyst in intramolecular ring closure reactions | |
| CN110922420B (en) | 5-isonicotinamide pyridylisotitanium cadmium complex and preparation method and application thereof | |
| CN112300219B (en) | Novel ligand compound and synthesis method and application thereof | |
| CN107522635B (en) | N-cyclopropyl nitrone derivatives and preparation method thereof | |
| CN114478351B (en) | Method for synthesizing alpha-alkyl substituted indole-3-formaldehyde compound | |
| Błocka et al. | Structural and electronic effects of oxazolidine ligands derived from (1R, 2S)-ephedrine in the asymmetric addition of diethylzinc to aldehydes | |
| CN108530389B (en) | Preparation method of 2-aryl cyclopropylamine compound | |
| Gonsalves et al. | Pyrrolidine-based amino alcohols: novel ligands for the enantioselective alkylation of benzaldehyde | |
| Sha et al. | Catalytic intramolecular hydroamination of aminoallenes using titanium and tantalum complexes of sterically encumbered chiral sulfonamides | |
| Sviridova et al. | Synthesis of hydroxydiamines and triamines via reductive cleavage of N–N bond in substituted pyrazolidines | |
| Wally et al. | Ferrocene derivatives, LXXI; Stereochemistry of metallocenes, LVI Synthesis and structure of optically active ferrocenylaminoalcohols | |
| CN111377850A (en) | Chiral N-substituted-3, 3-difluoro-4-hydroxypiperidine derivative and preparation method thereof | |
| CN112939850B (en) | Method for synthesizing pyridine ring structure by utilizing serial reaction of aldehyde, arylboronic acid and acetonitrile | |
| CN103992243A (en) | Preparation method and application of chiral amide salt crystal | |
| Jaworska et al. | Imines derived from (1S, 2R)-norephedrine as catalysts in the enantioselective addition of diethylzinc to aldehydes | |
| JP2019077623A (en) | Chromium-nitrogen complex and nitrogen fixation method using the same |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200602 Termination date: 20210823 |