CN109096138B - Method for synthesizing alpha-aminoketone derivative - Google Patents

Method for synthesizing alpha-aminoketone derivative Download PDF

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CN109096138B
CN109096138B CN201811107560.1A CN201811107560A CN109096138B CN 109096138 B CN109096138 B CN 109096138B CN 201811107560 A CN201811107560 A CN 201811107560A CN 109096138 B CN109096138 B CN 109096138B
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aminoketone
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carboxylic acid
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CN109096138A (en
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徐粉
刘春森
靳清贤
宋媛媛
耿鹏飞
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Zhengzhou University of Light Industry
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/31—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/76—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a method for synthesizing an alpha-aminoketone derivative. The method comprises the following steps: providing a mixed reaction system containing 2H-aziridine, carboxylic acid compounds, a catalyst, an additive, alkali and a solvent, reacting the mixed reaction system at 80-110 ℃ for 12-18H, and promoting nucleophilic addition reaction of carboxylic acid to imine and intramolecular ring-opening rearrangement reaction by palladium to obtain a series of alpha-aminoketone derivatives. The invention realizes nucleophilic addition and ring-opening rearrangement tandem reaction of carboxylic acid on 2H-aziridine for the first time, and successfully constructs the alpha-aminoketone derivative in one step; the method disclosed by the invention is stable and insensitive to water and air, simple to operate, mild in reaction condition, high in reaction efficiency, wide in application range of the substrate, high in atom utilization rate, high in reaction regioselectivity and chemoselectivity, and the prepared alpha-aminoketone derivative is novel in structure and has potential application value.

Description

Method for synthesizing alpha-aminoketone derivative
Technical Field
The invention relates to a synthetic method of an alpha-aminoketone derivative, in particular to a novel method for synthesizing the alpha-aminoketone derivative by using Pd to catalyze nucleophilic addition and ring-opening rearrangement reaction of carboxylic acid and 2H-aziridine, belonging to the technical field of organic synthesis.
Background
The alpha-aminoketone derivative is a very important structural unit and is widely applied in the fields of medicines and natural products. As important synthetic intermediates, α -aminoketones can be used for the synthesis of various heterocyclic compounds, such as imidazoles, oxazoles, thiazoles and other fine chemicals. The presently reported methods for synthesizing α -aminoketone derivatives include: cope rearrangement, Neber rearrangement, intermolecular aldehyde-imine cross-coupling reaction, Dakin-West, etc., but these methods tend to have the following problems: the preparation of the starting raw materials is complex, the reaction conditions are harsh, and the substrate range is limited. Therefore, the development of a new method for synthesizing the alpha-aminoketone derivative has important significance.
The 2H-aziridine has large ring tension and high reaction activity, and mainly generates ring-opening reaction through three fracture modes: 1) breaking a C-N bond to generate alkenyl, 2) breaking the C-C bond by transition metal catalysis or photocatalysis to generate nitrile dipole, and 3) breaking the C-C bond and the C-N bond simultaneously to generate a carbene intermediate. However, the reaction of 2H-aziridine with carboxylic acid via nucleophilic addition reaction, intramolecular ring-opening rearrangement tandem reaction has not been reported.
According to the literature [ Yadav j.s., Reddy b.v.s., Sadashiv k., et al tetrahedron lett, 2002,43, 2099-; in Li x, Li g, Chang h.h., et al.rsc adv.,2014,4, 6490-:
Figure BDA0001808210740000011
the method utilizes the nucleophilicity of electron-rich oxygen on carboxyl in carboxylic acid to complete the ring-opening reaction of carboxylic acid on aziridine. The aziridine used in the method must be protected by using tosyl, has ring-opening capability due to the tension effect, but can only undergo nucleophilic ring-opening reaction, and has a single reaction type. The product obtained by the reaction is a p-toluenesulfonyl protected amino compound, and the regioselectivity of the reaction is poor.
According to literature [ Oh, b.; nakamura, i.; yamamoto, Y.J.org.chem.2004,69,2856-2858, the ring-opening reaction of methylene azetidine with carboxylic acid is described as follows:
Figure BDA0001808210740000021
although this method is said to produce alpha-aminoketone derivatives, the methylene azetidines used are complex to produce, the range of substrates is narrow, and only tertiary amide products are obtained. In view of the presence of phosphine ligands, strict oxygen-free conditions are required for the reaction, limiting its application.
Disclosure of Invention
The invention mainly aims to provide a method for synthesizing alpha-aminoketone derivatives, so as to overcome the defects of the prior art.
The embodiment of the invention provides application of 2H-aziridine as a synthon in synthesizing alpha-aminoketone derivatives.
Preferably, the structural formula of the 2H-aziridine is shown in the specification
Figure BDA0001808210740000022
Wherein R is1、R2Including substituted or unsubstituted aryl or heteroaryl.
The embodiment of the invention also provides application of carboxylic acid as a synthon in synthesizing alpha-aminoketone derivatives.
The embodiment of the invention also provides a method for synthesizing the alpha-aminoketone derivative, which comprises the following steps: reacting a mixed reaction system containing 2H-aziridine, carboxylic acid compounds, a catalyst, an additive, alkali and a solvent to obtain an alpha-aminoketone derivative;
wherein the structural formula of the 2H-aziridine is shown as the specification
Figure BDA0001808210740000023
Wherein R is1、R2Including substituted or unsubstituted aryl or heteroaryl; the structural formula of the carboxylic acid compounds is
Figure BDA0001808210740000024
Wherein R is3Including substituted or unsubstituted aryl, heteroaryl, or alkyl groups.
In some embodiments, the method specifically comprises: the preparation method comprises the steps of uniformly mixing 2H-aziridine, carboxylic acid compounds, a catalyst, an additive, alkali and a solvent to form a mixed reaction system, reacting at 80-110 ℃ for 12-18 hours, and carrying out nucleophilic addition reaction and ring-opening rearrangement reaction to obtain a series of alpha-aminoketone derivatives.
The embodiment of the invention also provides the alpha-aminoketone derivative prepared by the method.
Furthermore, the alpha-aminoketone derivative has an alpha-aminoketone structural unit with a structural formula
Figure BDA0001808210740000031
Wherein R is1、R2Including substituted or unsubstituted aryl or heteroaryl, R3Including substituted or unsubstituted aryl, heteroaryl, or alkyl groups.
Compared with the prior art, the invention has the beneficial effects that:
1) the method for synthesizing the alpha-aminoketone derivative provided by the invention successfully realizes the one-step construction of the alpha-aminoketone derivative by using 2H-aziridine as a synthon through nucleophilic addition reaction and ring-opening rearrangement reaction for the first time. Therefore, the invention realizes the nucleophilic addition/ring-opening tandem reaction of 2H-aziridine and carboxylic acid, and prepares a plurality of polysubstituted alpha-aminoketone derivatives with high yield;
2) the method for synthesizing the alpha-aminoketone derivative firstly uses the 2H-aziridine synthon for nucleophilic addition reaction and ring-opening rearrangement reaction. The method uses simple and easily obtained carboxylic acid as a synthon to undergo nucleophilic addition and ring-opening rearrangement reaction, and provides support for expanding the reaction type of 2H-aziridine;
3) the catalyst system selected by the method for synthesizing the alpha-aminoketone derivative simultaneously meets the requirements of nucleophilic addition reaction and ring-opening rearrangement reaction, greatly improves the atom utilization rate of the reaction, simplifies the reaction steps, and fully embodies the advantages of a convergent synthesis method;
4) the method for synthesizing the alpha-aminoketone derivative is stable and insensitive to water and air, the reaction does not need to be protected by inert gas and does not need to be carried out in the inert gas, the operation is simple, the reaction condition is mild, the reaction efficiency is high, the application range of the substrate is wide, the atom utilization rate is high, the reaction region selectivity and the chemical selectivity are high, and various functional groups are suitable for the reaction condition. For heterocyclic substrates, the method can also obtain good reaction effect;
5) the alpha-aminoketone derivative prepared by the invention has a novel structure and potential application value.
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FIG. 1 is a schematic diagram of the chemical reaction of a method for synthesizing an alpha-aminoketone derivative according to an exemplary embodiment of the present invention.
FIG. 2 is a hydrogen spectrum of NMR spectrum of alpha-aminoketone derivative 3aa obtained in example 1 of the present invention.
FIG. 3 is a carbon spectrum of NMR spectrum of alpha-aminoketone derivative 3aa obtained in example 1 of the present invention.
FIG. 4 is a hydrogen spectrum of a nuclear magnetic resonance spectrum of α -aminoketone derivative 3ba obtained in example 12 of the present invention.
FIG. 5 is a carbon spectrum of NMR spectrum of α -aminoketone derivative 3ba obtained in example 12 of the present invention.
FIG. 6 is a hydrogen spectrum of a nuclear magnetic resonance spectrum of α -aminoketone derivative 3ca obtained in example 13 of the present invention.
FIG. 7 is a carbon spectrum of NMR spectrum of alpha-aminoketone derivative 3ca obtained in example 13 of the present invention.
FIG. 8 is a hydrogen spectrum of a nuclear magnetic resonance spectrum of α -aminoketone derivative 3da obtained in example 14 of the present invention.
FIG. 9 is a carbon spectrum of NMR spectrum of alpha-aminoketone derivative 3da obtained in example 14 of the present invention.
FIG. 10 is a high resolution mass spectrum of α -aminoketone derivative 3aa obtained in example 1 of the present invention.
FIG. 11 is a high-resolution mass spectrum of α -aminoketone derivative 3ba obtained in example 12 of the present invention.
FIG. 12 is a high-resolution mass spectrum of alpha-aminoketone derivative 3ca obtained in example 13 of the present invention.
FIG. 13 is a high-resolution mass spectrum of α -aminoketone derivative 3da obtained in example 14 of the present invention.
Detailed Description
In view of the defects in the prior art, the inventor of the present invention provides a technical scheme of the present invention through long-term research and a great deal of practice, and mainly relates to a novel method for synthesizing alpha-aminoketone derivatives through Pd-catalyzed nucleophilic addition and ring-opening rearrangement tandem reaction, so as to realize the nucleophilic addition and ring-opening rearrangement tandem reaction and construct the alpha-aminoketone derivatives with various functional groups in one step. The technical solution, its implementation and principles, etc. will be further explained as follows.
2H-aziridine tends to undergo cyclization reactions with other unsaturated bonds, which in turn initiates ring-opening reactions, but few reagents are available that can undergo nucleophilic addition/ring-opening rearrangement reactions with imines in 2H-aziridine. The method uses simple and easily obtained carboxylic acid compounds as synthons to undergo nucleophilic addition and ring-opening rearrangement reactions, and provides support for expanding the reaction type of 2H-aziridine.
Different from aziridine, 2H-aziridine has the tension of a three-membered ring and also contains an imine group, so that the reaction activity is higher, and the reaction types are more abundant; compared with methylene azetidine, the preparation method of 2H-aziridine is simple. Therefore, the research for constructing the alpha-aminoketone derivative through the nucleophilic addition and ring-opening tandem reaction of 2H-aziridine and carboxylic acid is expected.
One aspect of the embodiments of the present invention provides an application of a class of 2H-aziridines as synthons in nucleophilic addition, ring-opening rearrangement tandem reactions.
Another aspect of the embodiments of the present invention provides an application of a class of 2H-aziridines as synthons in the synthesis of α -aminoketone derivatives.
Further, the structural formula of the 2H-aziridine is shown in the specification
Figure BDA0001808210740000041
Wherein R is1、R2Including substituted or unsubstituted aryl or heteroaryl.
Specifically, the R is1Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-, CF3-or-OMe, etc., but is not limited thereto) or heteroaryl (including thiophene, furan, pyridine, etc.), said R2Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-, CF3-、CO2Et-or-OMe, etc., but are not limited thereto) or heteroaryl (including thiophene, furan, pyridine, etc.).
In some embodiments, the application comprises: the 2H-aziridine is used as a synthon for synthesizing the alpha-aminoketone derivative through nucleophilic addition and ring-opening rearrangement tandem reaction.
The embodiment of the invention also provides application of the carboxylic acid compounds in synthesizing alpha-aminoketone derivatives.
Further, the carboxylic acid compounds have the structural formula
Figure BDA0001808210740000051
Wherein R is3Including substituted or unsubstituted aryl, heteroaryl, or alkyl groups.
Specifically, the R is3Wherein said aryl substituents include methyl, ethyl, Cl-, F-, Br-, I-, CF3-, MeO-, phenyl or CO2Et-and the like, but are not limited thereto; the heteroaryl group includes, but is not limited to, thiophene, furan, pyridine, and the like; the alkyl group includes methyl, ethyl, propyl, -CF3And the like, but not limited thereto.
In another aspect of the embodiments of the present invention, there is also provided a method of synthesizing an α -aminoketone derivative, including: reacting a mixed reaction system containing 2H-aziridine, carboxylic acid compounds, a catalyst, an additive, a base and a solvent to obtain the alpha-aminoketone derivative.
Wherein the structural formula of the 2H-aziridine is shown as the specification
Figure BDA0001808210740000052
Wherein R is1、R2Including substituted or unsubstituted aryl or heteroaryl, R1Including aryl radicals(the substituent group includes hydrogen atom, methyl group, ethyl group, Cl-, F-, Br-, I-, CF3-or-OMe etc., but not limited thereto) or heteroaryl (including thiophene, furan, pyridine etc.); the R is2Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-, CF3-、CO2Et-or-OMe, etc., but are not limited thereto) or heteroaryl (including thiophene, furan, pyridine, etc.).
Wherein the carboxylic acid compounds have the structural formula
Figure BDA0001808210740000053
Wherein R is3Including substituted or unsubstituted aryl, heteroaryl or alkyl groups, said aryl substituents including methyl, ethyl, Cl-, F-, Br-, I-, CF3-, MeO-, phenyl or CO2Et-and the like, but are not limited thereto; the heteroaryl group includes, but is not limited to, thiophene, furan, pyridine, and the like; the alkyl group includes methyl, ethyl, propyl, -CF3And the like, but not limited thereto.
In some embodiments, as shown in fig. 1, the method specifically includes: the preparation method comprises the steps of uniformly mixing 2H-aziridine, carboxylic acid compounds, a catalyst, an additive, alkali and a solvent to form a mixed reaction system, reacting at 80-110 ℃ for 12-18 hours, and carrying out nucleophilic addition reaction and ring-opening rearrangement tandem reaction to obtain a series of alpha-aminoketone derivatives.
In some embodiments, the molar ratio of 2H-aziridine to catalyst is from 10 to 100: 1.
in some embodiments, the molar ratio of the carboxylic acid compound to the catalyst is 10 to 100: 1.
in some embodiments, the molar ratio of the 2H-aziridine to the carboxylic acid compound is from 0.8 to 50: 1.
in some embodiments, the molar ratio of the additive to the carboxylic acid compound is 0.1 to 1: 1.
in some embodiments, the molar ratio of base to carboxylic acid is 0.1 to 1: 1.
in some embodiments, the concentration of the carboxylic acid compound or 2H-aziridine in the mixed reaction system is 0.1-1 mol/L.
Further, the catalyst comprises Pd (OAc) which is commercially available2But is not limited thereto.
Further, the additives include silver salt additives and additives such as DMAP (4-dimethylaminopyridine), but are not limited thereto.
Further, the silver salt additive includes chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] silver, but is not limited thereto.
Further, the base includes Li2CO3But is not limited thereto.
Further, the solvent is wide in range, and the solvent includes any one or a combination of two or more of an ether solvent, an alcohol solvent, toluene, an amide solvent, and acetonitrile, but is not limited thereto.
Further, the ether solvent includes 1, 4-dioxane, but is not limited thereto.
Still further, the amide-based solvent includes N, N-dimethylformamide, but is not limited thereto.
Further, the alcohol solvent includes ethanol, but is not limited thereto.
Preferably, the α -aminoketone derivatives include various functional group-substituted derivatives such as: me-, F-, CF3-，MeO-，Cl-，Br-，CO2Et-, etc.
For example, in some preferred embodiments, the chemical reaction of the method may be:
Figure BDA0001808210740000061
wherein R is1Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-, CF3-or-OMe etc., but not limited thereto) or heteroaryl (including thiophene, furan, pyridine etc.); the R is2Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-、I-、CF3-、CO2Et-or-OMe, etc., but are not limited thereto) or heteroaryl (including thiophene, furan, pyridine, etc.). The R is3Including aryl, heteroaryl or alkyl groups, said aryl substituents including methyl, ethyl, Cl-, F-, Br-, I-, CF3-, MeO-, phenyl or CO2Et-and the like, but are not limited thereto; the heteroaryl group includes, but is not limited to, thiophene, furan, pyridine, and the like; the alkyl group includes methyl, ethyl, propyl, -CF3And the like, but not limited thereto.
In some embodiments, the method further comprises: and after the reaction is finished, cooling the mixed reaction system to room temperature, removing the solvent, and separating to obtain the alpha-aminoketone derivative.
Further, the yield of the method is 19-92%.
Among them, in a more preferred embodiment, the method of the present invention may specifically include the steps of:
adding Pd (OAc) into the reaction vessel2Chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver, DMAP, Li2CO3Heating the 2H-aziridine 2, the carboxylic acid compound 1 and the solvent to 80-110 ℃, and reacting for 12-18H. Cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, and performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3.
The invention uses the 2H-aziridine compound as a synthon for nucleophilic addition and ring-opening rearrangement tandem reaction for the first time. The 2H-aziridine compounds are easy to generate C-C or C-N bond breakage under the conditions of metal catalysts and photocatalysis, and then generate [3+ N ] cycloaddition reaction with unsaturated bonds, and the method adopts the 2H-aziridine compounds as synthons to undergo nucleophilic addition and ring-opening rearrangement reaction, thereby providing support for expanding the reaction type of the 2H-aziridine compounds.
In addition, the method is a high-efficiency convergent synthesis method through a series connection process and nucleophilic addition reaction and ring-opening rearrangement reaction. Moreover, the substrate of the reaction of the invention has wide application range, and various functional groups are suitable for the reaction condition. The method can also achieve good reaction effect on various heterocyclic substrates.
In another aspect of embodiments of the present invention, there are also provided α -aminoketone derivatives prepared by the foregoing methods.
Furthermore, the alpha-aminoketone derivative has an alpha-aminoketone structural unit with a structural formula
Figure BDA0001808210740000071
Wherein R is1Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-, CF3-or-OMe etc., but not limited thereto) or heteroaryl (including thiophene, furan, pyridine etc.); the R is2Including aryl (the substituent group includes hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-, CF3-、CO2Et-or-OMe, etc., but are not limited thereto) or heteroaryl (including thiophene, furan, pyridine, etc.). The R is3Including aryl, heteroaryl or alkyl groups, said aryl substituents including methyl, ethyl, Cl-, F-, Br-, I-, CF3-, MeO-, phenyl or CO2Et-and the like, but are not limited thereto; the heteroaryl group includes, but is not limited to, thiophene, furan, pyridine, and the like; the alkyl group includes methyl, ethyl, propyl, -CF3And the like, but not limited thereto.
Preferably, the α -aminoketone derivatives include various functional group-substituted derivatives such as: me-, F-, CF3-，MeO-，Cl-，Br-，CO2Et-, etc., but are not limited thereto.
By the technical scheme, the invention successfully constructs the alpha-aminoketone derivative in one step by using the 2H-aziridine compound as a synthon through nucleophilic addition reaction and ring-opening rearrangement tandem reaction for the first time. The method is stable and insensitive to water and air, simple to operate, mild in reaction condition, high in reaction efficiency, wide in application range of the substrate, high in atom utilization rate, high in reaction area selectivity and chemical selectivity, and the prepared alpha-aminoketone derivative is novel in structure and has potential application value.
The technical solution of the present invention will be described in further detail with reference to several preferred embodiments and the accompanying drawings, but the present invention is not limited to the following embodiments.
Example 1
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000081
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (25.1mg,0.125mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. The reaction solution is cooled to room temperature, the solvent is removed under reduced pressure, column chromatography separation is carried out to obtain the corresponding alpha-aminoketone derivative (3aa), the structure of the alpha-aminoketone derivative is determined by a nuclear magnetic and high resolution mass spectrometry method, and the yield can reach 92% as shown in figures 2,3 and 10.
The nuclear magnetic data of the alpha-aminoketone derivative 3aa obtained in this example are as follows:
2-bromo-N- (2-oxo-1,2-diphenylethyl) benzamide (3aa) white solid (45.3mg, 92% yield) developing solvent petroleum ether/ethyl acetate 4:1.1H NMR(400MHz,CDCl3)＝8.02(dd,J＝5.2,3.4,2H),7.62(d,J＝7.0,1H),7.58(dd,J＝7.9,1.1,1H),7.56–7.51(m,2H),7.51–7.46(m,2H),7.42(dd,J＝10.6,4.8,2H),7.37–7.30(m,3H),7.30–7.24(m,2H),6.76(d,J＝7.2,1H).13C NMR(101MHz,CDCl3)＝195.2,166.5,137.0,136.8,134.2,133.9,133.5,131.5,129.9,129.2,128.8,128.5,128.4,127.5,124.4,119.6,59.2.HRMS Calculated for C21H17BrNO2 +,394.0443,found 394.0420.
Example 2
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000091
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (251.3mg, 1.25mmol), the 2H-aziridine compound 2a (241.6mg, 1.25mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. The reaction solution is cooled to room temperature, the solvent is removed under reduced pressure, column chromatography separation is carried out to obtain the corresponding alpha-aminoketone derivative (3aa), the structure of the alpha-aminoketone derivative is determined by a nuclear magnetic and high resolution mass spectrometry method, and the yield can reach 30% at most as shown in figures 2,3 and 10.
Example 3
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000092
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (20.1mg, 0.1mmol), the 2H-aziridine compound 2a (24.6mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, and performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative (3aa), wherein the developing solvent is petroleum ether/ethyl acetate 4:1, the structure of the derivative is determined by a nuclear magnetic and high-resolution mass spectrometry method, and the yield can reach 85% at most as shown in fig. 2, fig. 3 and fig. 10.
Example 4
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000101
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (1.26g,6.25mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, and performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative (3aa), wherein the developing solvent is petroleum ether/ethyl acetate 4:1, the structure of the derivative is determined by a nuclear magnetic and high-resolution mass spectrometry method, and the yield can reach 19% at most as shown in fig. 2, fig. 3 and fig. 10.
Example 5
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000102
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1a (25.1mg,0.125mmol), 2H-aziridine compound 2a (2.42g,1.25mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, and performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3aa, wherein the developing solvent is petroleum ether/ethyl acetate 4:1, and the structure of the derivative is determined by a nuclear magnetic and high-resolution mass spectrometry method, as shown in fig. 2,3 and 10, the yield is 42%.
Example 6
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000111
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (0.1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (25.1mg,0.125mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the temperature was raised to 110 ℃. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, and performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3aa, wherein the developing solvent is petroleum ether/ethyl acetate 4:1, and the structure of the derivative is determined by a nuclear magnetic and high-resolution mass spectrometry method, as shown in fig. 2, fig. 3 and fig. 10, the yield is 58%.
Example 7
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000112
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (50.2mg,0.25mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain a corresponding alpha-aminoketone derivative 3aa, wherein a developing solvent is petroleum ether/ethyl acetate 4:1, determining the structure of the derivative by a nuclear magnetic and high resolution mass spectrometry method, and the yield can reach 68% at most as shown in fig. 2, fig. 3 and fig. 10.
Example 8
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000121
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (66mg,1equiv), DMAP (1equiv), Li2CO3(0.1equiv), the carboxylic acid compound 1a (25.1mg,0.125mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, and performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3aa, wherein the developing solvent is petroleum ether/ethyl acetate 4:1, and the structure of the derivative is determined by a nuclear magnetic and high-resolution mass spectrometry method, as shown in fig. 2, fig. 3 and fig. 10, the yield is 50%.
Example 9
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000122
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (50.2mg,0.25mmol), the 2H-aziridine compound 2a (48.4mg,0.25mmol) and dioxane (2mL), and the reaction was carried out at 80 ℃ for 18 hours. The reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and column chromatography was performed to obtain the corresponding α -aminoketone derivative (3aa) in which the structure was determined by nuclear magnetic and high resolution mass spectrometry using petroleum ether/ethyl acetate 4:1 as the developing solvent, as shown in fig. 2,3 and 10, with a yield of only 73%.
Example 10
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000131
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (25.1mg,0.125mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 80 ℃ for 18 hours. The reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and column chromatography was performed to obtain the corresponding α -aminoketone derivative (3aa) in which the structure was determined by nuclear magnetic and high resolution mass spectrometry using petroleum ether/ethyl acetate 4:1 as the developing solvent, as shown in fig. 2,3 and 10, with a yield of only 38%.
Example 11
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000132
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg,0.0125mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1a (25.1mg,0.125mmol), 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 12 hours. Cooling the reaction solution to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain a corresponding alpha-aminoketone derivative 3aa, wherein a developing solvent is petroleum ether/ethyl acetate 4:1, determining the structure of the derivative by a nuclear magnetic and high resolution mass spectrometry method, and the yield can reach 80% at most as shown in fig. 2, fig. 3 and fig. 10.
Example 12
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000141
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1b (15.3mg,0.125mmol), the 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. The reaction solution is cooled to room temperature, the solvent is removed under reduced pressure, column chromatography separation is performed to obtain the corresponding alpha-aminoketone derivative 3ba, the structure of the alpha-aminoketone derivative is determined by nuclear magnetic and high-resolution mass spectrometry, and the yield can reach 70% at most as shown in fig. 4, fig. 5 and fig. 11.
The nuclear magnetic data of the α -aminoketone derivative 3ba obtained in this example are as follows:
n- (2-oxo-1,2-diphenylethyl) benzamide (3ba), white solid (27.6mg, 70% yield) developing solvent petroleum ether/ethyl acetate 10:1.1H NMR(600MHz,CDCl3)8.10–7.99(m,2H),7.91–7.81(m,2H),7.74(d,J＝6.7Hz,1H),7.57–7.47(m,4H),7.43(m,3H),7.32(t,J＝7.6Hz,2H),7.28–7.23(m,1H),6.76(d,J＝7.0Hz,1H).13C NMR(151MHz,CDCl3)＝195.8,166.3,137.3,134.2,133.9,133.9,131.8,129.3,129.2,128.8,128.6,128.4,128.3,127.2,58.9.HRMS Calculated for C21H18NO2 +,316.1338,found 316.1297.
Example 13
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000142
the specific operation steps of this embodiment are as follows:
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1c (20.9mg,0.125mmol), 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. The reaction solution is cooled to room temperature, the solvent is removed under reduced pressure, column chromatography separation is carried out to obtain the corresponding alpha-aminoketone derivative 3ca, the structure of the derivative is determined by a nuclear magnetic and high-resolution mass spectrometry method, and the yield can reach 92% at most as shown in fig. 6, 7 and 12.
The nuclear magnetic data of the α -aminoketone derivative 3ca obtained in this example are as follows:
3-Nitro-N- (2-oxo-1,2-diphenylethyl) benzamide (3ca). yellow solid (41.4mg, 92% yield).1H NMR(400MHz,CDCl3)＝8.68(t,J＝1.9,1H),8.36(m,1H),8.23–8.14(m,1H),8.06–7.99(m,2H),7.85(d,J＝6.8,1H),7.65(t,J＝8.0,1H),7.59–7.52(m,1H),7.52–7.47(m,2H),7.43(dd,J＝10.6,4.8,2H),7.39–7.32(m,2H),7.32–7.24(m,1H),6.74(d,J＝6.9,1H).13C NMR(101MHz,CDCl3)＝195.3,164.0,148.3,136.7,135.7,134.1,134.0,133.1,129.8,129.4,129.2,128.9,128.8,128.4,126.3,122.3,59.3.HRMS Calculated for C21H17N2O4 +,361.1188,found 361.1189.
Example 14
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000151
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1d (22.0mg,0.125mmol), 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressureAfter the preparation, column chromatography separation is carried out to obtain the corresponding alpha-aminoketone derivative 3da, the structure of the alpha-aminoketone derivative is determined by a nuclear magnetic resonance and high resolution mass spectrometry method, and the yield can reach 63 percent at most as shown in figures 8, 9 and 13.
The nuclear magnetic data of the α -aminoketone derivative 3da obtained in this example are as follows:
2,3, 4-trifluo-N- (2-oxo-1,2-diphenylethyl) benzamide (3da), white solid (29.1mg, 63% yield) developing solvent petroleum ether/ethyl acetate 4:1.1H NMR(400MHz,CDCl3)＝8.31–8.17(m,1H),8.10–7.98(m,2H),7.85(m,1H),7.60–7.54(m,1H),7.51(dd,J＝5.2,3.3,2H),7.45(dd,J＝10.6,4.8,2H),7.39–7.33(m,2H),7.33–7.26(m,1H),7.09(m,1H),6.74(dd,J＝6.7,1.7,1H).13C NMR(101MHz,CDCl3)＝194.9,172.7,160.6(dd,J＝4.5,1.7Hz),148.6,144.7,136.7,134.0,134.0,129.3,129.2,128.8,128.6,128.4,125.8(dd,J＝8.4,4.2Hz),124.848,112.738(dd,J＝17.4,3.5Hz),59.48.19F NMR(376MHz,CDCl3)-127.93(dd,J＝20.1,11.3Hz),-134.19(dd,J＝21.8,11.3Hz),-159.45(t,J＝21.0Hz).HRMS Calculated for C21H15F3NO2 +,370.1055,found 370.1070.
Example 15
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000161
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1e (16.0mg,0.125mmol), 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. And cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3ea, determining the structure of the alpha-aminoketone derivative by a nuclear magnetic and high-resolution mass spectrometry method, and ensuring the yield to be 67 percent at most.
The nuclear magnetic data of the α -aminoketone derivative 3ea obtained in this example are as follows:
n- (2-oxo-1, 2-diphenylethylene) thiophene-2-carboxamide (3ea) as a white solid (26.9mg, 67% yield). 1H NMR (400MHz, CDCl)3)＝8.06–7.97(m,2H),7.63–7.51(m,3H),7.51–7.38(m,5H),7.36–7.29(m,2H),7.29–7.22(m,2H),7.08(dd,J＝4.9,3.8,1H),6.71(d,J＝7.0,1H).13C NMR(101MHz,CDCl3)＝195.6,160.9,144.5,138.5,137.1,134.2,133.9,130.4,129.3,129.2,128.8,128.5,128.4,127.6,58.8.HRMS Calculated for C19H16NO2S+,322.0902,found 322.0882.
Example 16
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000162
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1f (7.5mg,0.125mmol), 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3fa, determining the structure of the derivative by a nuclear magnetic and high-resolution mass spectrometry method, and ensuring the yield to be up to 60%.
The nuclear magnetic data of the α -aminoketone derivative 3fa obtained in this example are as follows:
n- (2-oxo-1,2-diphenylethyl) acetamide (3fa), white solid (19.0mg, 60% yield).1H NMR(400MHz,CDCl3)＝8.01–7.93(m,2H),7.55–7.48(m,1H),7.44–7.36(m,4H),7.34–7.24(m,3H),6.97(d,J＝6.7,1H),6.58(d,J＝7.4,1H),2.05(s,3H).13C NMR(101MHz,CDCl3)＝195.9,169.2,137.3,134.3,133.8,129.2,129.1,128.7,128.4,128.2,58.5,23.3.HRMS Calculated for C16H16NO2+,254.1181,found 254.1180.
Example 17
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000171
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), 1g (14.3mg,0.125mmol) of the carboxylic acid compound, 2H-aziridine compound 2a (24.2mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. And cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3ga, determining the structure of the alpha-aminoketone derivative by a nuclear magnetic and high-resolution mass spectrometry method, and ensuring the yield to be up to 93 percent.
The nuclear magnetic data of the α -aminoketone derivative 3ga obtained in this example are as follows:
2,2, 2-trifloro-N- (2-oxo-1,2-diphenylethyl) acetamide (3ga). white solid (35.7mg, yield 93%). 1H NMR (400MHz, CDCl3) ═ 8.04-7.88 (m,3H),7.55(t, J ═ 7.4,1H), 7.46-7.38 (m,4H), 7.38-7.27 (m,3H),6.49(d, J ═ 7.0,1H).13C NMR (101MHz, CDCl3) ═ 193.7,156.3(q, J ═ 37.8Hz),147.1,135.3,134.4,133.4,129.5,129.3,129.2,128.9,128.3,115.7(d, J ═ 287.8Hz),58.9.19F NMR(376MHz,CDCl3)＝-75.73.HRMS Calculated for C16H13F3NO2 +,308.0898,found 308.0896.
Example 18
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000181
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), carboxylic acid compound 1a (25.1mg,0.125mmol), 2H-aziridine compound 2b (26.4mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. Cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3ab, determining the structure of the derivative by a nuclear magnetic and high-resolution mass spectrometry method, and ensuring the yield to be 92 percent at most.
The nuclear magnetic data of the α -aminoketone derivative 3ab obtained in this example are as follows:
2-Bromo-N- (1- (4-fluorophenyl) -2-oxo-2-phenylethyl) benzamide (3ab). white solid (47.4mg, 92% yield).1H NMR(400MHz,CDCl3)＝8.06–8.00(m,2H),7.70(d,J＝6.8,1H),7.64–7.54(m,3H),7.54–7.43(m,4H),7.38(td,J＝7.5,1.2,1H),7.32(dd,J＝7.7,1.8,1H),7.09–7.01(m,2H),6.79–6.73(m,1H).13C NMR(101MHz,CDCl3)＝195.1,166.5,162.62(d,J＝248.1Hz),136.9,134.1,134.0,134.0,133.6,132.75(d,J＝3.1Hz),131.5,130.24(d,J＝8.4Hz),129.8,129.03(d,J＝32.8Hz),127.5,119.6,116.21(d,J＝21.8Hz),58.4.19F NMR(376MHz,CDCl3)＝-112.85.HRMS Calculated for C21H16BrFNO2+,412.0348,found 412.0356.
Example 19
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000182
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (25.1mg,0.125mmol), the 2H-aziridine compound 2c (28.5mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. And cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3ac, and determining the structure of the alpha-aminoketone derivative by a nuclear magnetic and high-resolution mass spectrometry method, wherein the yield can reach 83 percent at most.
The nuclear magnetic data of the α -aminoketone derivative 3ac obtained in this example are as follows:
2-Bromo-N- (1- (4-chlorophenylyl) -2-oxo-2-phenylethynyl) benzamide (3ac). white solid (44.5mg, 83% yield).1H NMR(400MHz,CDCl3)＝8.02(d,J＝7.9,2H),7.73(d,J＝6.7,1H),7.64–7.52(m,3H),7.46(dd,J＝7.6,4.2,4H),7.40–7.26(m,4H),6.74(d,J＝6.9,1H).13C NMR(101MHz,CDCl3)＝194.9,166.5,136.8,135.4,134.5,134.2,133.9,133.6,131.6,129.9,129.8,129.4,129.2,128.9,127.5,119.6,58.4.HRMS Calculated for C21H16BrClNO2 +,430.0032,found 430.0034.
Example 20
The reaction synthesis procedure and product structure of this example are as follows:
Figure BDA0001808210740000191
adding Pd (OAc) into the reaction vessel2(2.8mg, mmol), chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene]Silver (6.6mg,10 mol%), DMAP (1equiv), Li2CO3(1equiv), the carboxylic acid compound 1a (25.1mg,0.125mmol), the 2H-aziridine compound 2d (25.9mg,0.125mmol) and dioxane (2mL), and the reaction was carried out at 110 ℃ for 18 hours. And cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, performing column chromatography separation to obtain the corresponding alpha-aminoketone derivative 3ad, determining the structure of the alpha-aminoketone derivative by a nuclear magnetic and high-resolution mass spectrometry method, and ensuring the yield to be up to 85 percent.
The nuclear magnetic data of the α -aminoketone derivative 3ad obtained in this example are as follows:
2-Bromo-N- (2-oxo-1-phenyl-2- (p-tolyl) ethyl) benzamide (3ad). white solid (43.4mg, 85% yield).1H NMR(400MHz,CDCl3)＝8.02(d,J＝7.5,2H),7.64–7.49(m,4H),7.37(ddd,J＝16.6,11.4,7.3,5H),7.29–7.23(1H),7.13(d,J＝7.9,2H),6.72(d,J＝7.2,1H),2.28(s,3H).13C NMR(101MHz,CDCl3)＝195.3,166.4,138.4,137.1,134.3,133.8,133.8,133.5,131.4,129.9,129.9,129.2,128.8,128.3,127.5,119.6,58.9,21.2.
Comparative example 1
This comparative example is substantially the same as example 1 except that: the reaction temperature was 40 ℃ and the corresponding product was hardly obtained.
Comparative example 2
This comparative example is substantially the same as example 1 except that: the reaction temperature was room temperature and the corresponding product was hardly obtained.
In addition, the present inventors have also made experiments with other raw materials and conditions and the like listed in the present specification by referring to the manner of example 1 to example 20, and have also succeeded in synthesizing α -aminoketone derivatives.
In conclusion, the invention uses the 2H-aziridine compound as a synthon for the first time, and successfully constructs the alpha-aminoketone derivative in one step through the nucleophilic addition reaction and the ring-opening rearrangement reaction of the carboxylic acid on the imine double bond of the 2H-aziridine compound; the method is stable and insensitive to water and air, simple to operate, mild in reaction condition, high in reaction efficiency, wide in application range of the substrate, high in atom utilization rate, high in reaction area selectivity and chemical selectivity, and the prepared alpha-aminoketone derivative is novel in structure and has potential application value.
It should be understood that the above-mentioned embodiments are merely illustrative of the technical concepts and features of the present invention, which are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and therefore, the protection scope of the present invention is not limited thereby. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (14)

1. A method for synthesizing an α -aminoketone derivative, comprising: will be provided with2HEvenly mixing aziridine, carboxylic acid compounds, a catalyst, an additive, alkali and a solvent to form a mixed reaction system, reacting at the temperature of 80-110 ℃ for 12-18 h, and carrying out nucleophilic addition reaction and ring-opening rearrangement reaction to obtain an alpha-aminoketone derivative;
wherein, the2H-aziridine of the formula
Figure DEST_PATH_IMAGE002
Wherein R is1、R2Selected from substituted or unsubstituted aryl or heteroaryl; the structural formula of the carboxylic acid compounds is
Figure DEST_PATH_IMAGE004
Wherein R is3Selected from substituted or unsubstituted aryl, heteroaryl or alkyl;
the catalyst is Pd (OAc)2The additive is selected from 4-dimethylamino pyridine and silver salt additive, the silver salt additive is chloro [1, 3-bis (2, 6-diisopropylphenyl) imidazole-2-subunit]Silver, the base being Li2CO3The solvent is selected from any one or the combination of more than two of an ether solvent, an alcohol solvent, toluene, an amide solvent and acetonitrile.
2. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the R is1The substituent is selected from hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-and CF3-or-OMe, said R2The substituent is selected from hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-and CF3-、CO2Et-or-OMe, said heteroaryl group being selected from thiophene, furan or pyridine.
3. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the R is3The substituent is selected from hydrogen atom, methyl, ethyl, Cl-, F-, Br-, I-and CF3-, MeO-, phenyl or CO2Et-, the heteroaryl is selected from thiophene, furan or pyridine, the alkyl is selected from methyl, ethyl, propyl or-CF3。
4. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the molar ratio of the carboxylic acid compound to the catalyst is 10-100: 1.
5. the method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the above-mentioned2H-the mole ratio of aziridine to catalyst is 10 to 100: 1.
6. the method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the carboxylic acid compounds and2H-the mole ratio of aziridine is 0.8 to 50: 1.
7. the method for synthesizing α -aminoketone derivatives according to claim 1, wherein: in the mixed reaction system, the carboxylic acid compound or2HThe concentration of the aziridine is 0.1 to 1 mol/L.
8. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the molar ratio of the additive to the carboxylic acid compounds is 0.1-1: 1.
9. the method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the ether solvent is 1, 4-dioxane.
10. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the amide solvent is N, N-dimethylformamide.
11. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the alcohol solvent is ethanol.
12. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the molar ratio of the alkali to the carboxylic acid compounds is 0.1-1: 1.
13. the method for synthesizing an α -aminoketone derivative according to claim 1, further comprising: and after the reaction is finished, cooling the mixed reaction system to room temperature, removing the solvent, and separating to obtain the alpha-aminoketone derivative.
14. The method for synthesizing α -aminoketone derivatives according to claim 1, wherein: the yield of the method is 19-92%.
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2018111075601;张艳青;《STN》;20200922;全文 *
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