Preparation method of N-hydroxyphthalimide ester containing quaternary carbon center

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for generating ketene in situ through Wolff rearrangement of alpha-diazonone, and reacting the ketene with a bifunctional reagent under the catalysis of transition metal to obtain N-hydroxyphthalimide ester containing a quaternary carbon center. The method comprises the following steps: in a nitrogen atmosphere, sequentially adding alpha-diazoketone, tetrakis (triphenylphosphine) palladium and a bifunctional reagent into a reaction solvent, stirring the mixture at 25 DEG C under the irradiation of a 15W blue LED lamp until the reaction is complete, filtering, separating and purifying to obtain a quaternary carbon center-containing redox active ester product. The preparation method disclosed by the invention is simple to operate (active ketene participates in the reaction through Wolff rearrangement in-situ generation), the defect that tertiary carboxylic acid with a complex structure needs to be used in a traditional method is overcome, the condition is mild, and the substrate universality is good.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing N-hydroxyphthalimide ester containing a quaternary carbon center by reacting an alpha-diazo ketone with a bifunctionalized reagent. Background Art

[0002] N-hydroxyphthalimide ester is a commonly used organic synthesis reagent and has been widely used in the field of free radical chemistry. The carboxyl radical generated by homolytic cleavage of the nitrogen-oxygen bond of N-hydroxyphthalimide ester or single-electron reduction can release an alkyl radical for subsequent functionalization reactions, so it is often used as an alkyl radical precursor. The common synthesis method of this structure is through the condensation reaction of carboxylic acid and N-hydroxyphthalimide. However, for the N-hydroxyphthalimide ester corresponding to the tertiary carboxylic acid, the source of tertiary carboxylic acid is limited and the synthesis route is relatively cumbersome, which limits the applicability of this method to a certain extent.

[0003] Document 1 (Org. Lett. 2018, 20, 4824) discloses a method for condensing α,α-dimethylphenylacetic acid with N-hydroxyphthalimide under the action of DCC to obtain an N-hydroxyphthalimide ester structure containing a quaternary carbon center.

[0004]

[0005] Document 2 (Org. Lett. 2021, 23, 7839) discloses a method for condensing α-methyl α-allylphenylacetic acid with N-hydroxyphthalimide under the action of DCC to obtain an N-hydroxyphthalimide ester structure containing a quaternary carbon center.

[0006]

[0007] Document 3 (Chem. Sci. 2021, 12, 6684) discloses a diphenylbenzyl acetic acid and N-hydroxy

[0008] The invention discloses a method for obtaining an N-hydroxyphthalimide ester structure containing a quaternary carbon center by condensing phthalimide under the action of DIC.

[0009]

[0010] Although the above methods can realize the synthesis of N-hydroxyphthalimide ester structures containing quaternary carbon centers, they all have a common problem: the tertiary carboxylic acid raw materials used often require multi-step synthesis. Therefore, it is urgent to develop a more universal and efficient method to realize the construction of this structure. The present invention mainly studies the use of α-diazo ketone compounds as precursors of enones, and produces enones in situ through Wolff rearrangement under visible light irradiation, while palladium catalysts and difunctionalizing agents release phthalimide oxygen anions and allyl palladium cations in situ, and high regio- and chemically selective difunctionalization of enones occurs, thereby realizing the efficient preparation of N-hydroxyphthalimide ester compounds containing quaternary carbon centers under mild conditions. Summary of the invention

[0011] The purpose of the present invention is to provide a general preparation method of N-hydroxyphthalimide ester compounds containing a quaternary carbon center, which is simple and efficient to operate, and aims to solve the shortcomings of the existing preparation methods, such as complex operation and limited applicable scope of raw materials.

[0012] The scheme adopted by the present invention to achieve the purpose is: under a nitrogen atmosphere, a metal catalyst, an α-diazo ketone and a difunctionalized reagent are sequentially added to a reaction solvent, stirred at a suitable temperature and irradiated with a blue LED light until the reaction is complete, and the crude reaction product is filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain an N-hydroxyphthalimide ester compound containing a quaternary carbon center.

[0013] The reaction formula of the method of the present invention can be expressed as follows:

[0014]

[0015] The compound of formula A represents a difunctionalizing agent, the compound of formula B represents an α-diazo ketone compound, and the compound of formula C represents an N-hydroxyphthalimide ester compound containing a quaternary carbon center.

[0016] Among them, R 1 is hydrogen, methyl or other alkyl, phenyl, 2-methoxyphenyl, 4-benzyloxyphenyl, 4-bromophenyl, 4-methylformylphenyl, 2-furyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, R 2 is methyl or other alkyl, phenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-naphthyl, 4-methoxyphenyl, R 3 is methyl or other alkyl, phenyl or substituted phenyl, R 2 With R 3 Can be the same or different.

[0017] The metal catalyst is one of ditriphenylphosphine palladium dichloride and tetrakistriphenylphosphine palladium, preferably tetrakistriphenylphosphine palladium.

[0018] The reaction solvent is one of dichloromethane, 1,2-dichloroethane, and trifluorotoluene, preferably dichloromethane.

[0019] The molar ratio of the α-diazo ketone to the bifunctionalized reagent is (1.5-2.0):1.0, and the concentration of the α-diazo ketone in the mixed solution is between 0.15M and 0.2M.

[0020] The reaction temperature is room temperature or 10-50°C, preferably 25°C.

[0021] The reaction time is 8-24 hours, preferably 12 hours.

[0022] The present invention has the following advantages and beneficial effects:

[0023] (1) The N-hydroxyphthalimide ester containing a quaternary carbon center prepared by the preparation method of the present invention has potential application value in the field of organic synthesis and can be used as a raw material for the synthesis of more complex structures.

[0024] (2) The bifunctionalized reagent used in the preparation method of the present invention is stable in nature and easy to prepare.

[0025] (3) Compared with the previously reported methods, the preparation method of the present invention avoids the use of polysubstituted carboxylic acids as raw materials, the raw materials are easily available, and the operation is simpler and safer. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0027] Example 1

[0028]

[0029] Under a nitrogen atmosphere, difunctionalizing agent A1 (27.9 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B1 (24 mg, 0.15 mmol, 1.5 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to a reaction solvent of dichloromethane (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius under blue LED light for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C1 (colorless liquid 39.1 mg, 95% yield). 1H NMR(400MHz,Chloroform-d)δ7.88(dd,J=5.5,3.0Hz,2H),7.78(dd,J=5.5,3.1Hz,2H),7.53-7.48(m,2H),7.46-7.42(m,2H),7.40-7.27(m,5H),7.24-7.1 8(m,1H),6.51(d,J=15.7Hz,1H),6.24(ddd,J=15.7,7.9,6.9Hz,1H),3.16(d dd,J=13.8,6.9,1.4Hz,1H),2.91(ddd,J=13.7,8.0,1.2Hz,1H),1.75(s,3H). 13 C NMR (100MHz, Chloroform-d) δ172.5,162.1,141.5,137.2,134.9,134.7,129.1,128.9,128. 7,127.8,127.5,126.4,126.3,124.5,124.1,50.3,43.2,23.1.HRMS(ESI,m / z):calculated for C 26 H 21 NO 4 [M+H] + :412.1544,found:412.1548.

[0030] Example 2

[0031]

[0032] Under a nitrogen atmosphere, difunctionalizing agent A1 (27.9 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B2 (29.1 mg, 0.15 mmol, 1.5 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to a reaction solvent of dichloromethane (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius under blue LED light for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C2 (colorless liquid 32.9 mg, 74% yield). 1H NMR(400MHz,Chloroform-d)δ8.03(d,J=8.1Hz,1H),7.87(d,J=7.9Hz,1H),7 .53-7.47(m,1H),7.42-7.35(m,1H),7.24-7.16(m,3H),7.13-7.05(m,2H),5. 86-5.71(m,1H),5.04-4.88(m,2H),3.51(d,J=13.5Hz,1H),3.23(d,J=13.5H z,1H),3.12(s,1H),2.37-2.21(m,2H),2.12-2.04(m,1H),2.03-1.89(m,1H). 13 C NMR (100MHz, Chloroform-d) δ178.7,153.3,138.1,135.5,135.3,130.6,128.5,127.2, 126.1,124.9,123.0,121.9,115.1,78.3,48.6,41.1,28.1.HRMS(ESI,m / z):calculated for C 26 H 20 ClNO 4 [M+H] + :446.1154,found:446.1158.

[0033] Example 3

[0034]

[0035] Under a nitrogen atmosphere, difunctionalizing agent A1 (27.9 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B3 (31.5 mg, 0.15 mmol, 1.5 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to a reaction solvent of dichloromethane (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius under blue LED light for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C3 (colorless liquid 35.1 mg, 76% yield). 1 H NMR (400 MHz, Chloroform-d) 1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.0Hz,1H),7.93(t,J=7.6Hz,2H),7.90-7.84(m,3H),7 .77(dd,J=5.5,3.1Hz,2H),7.61(dd,J=8.6,2.0Hz,1H),7.58-7.44(m,2H),7.41-7.35(m,2H),7 .29(dd,J=8.4,6.7Hz,2H),7.25-7.16(m,1H),6.56(d,J=15.7Hz,1H),6.26(ddd,J=15.4,7.8,7 .0Hz,1H),3.25(ddd,J=13.7,7.0,1.4Hz,1H), 3.04(ddd,J=13.7,7.9,1.3Hz,1H),1.86(s,3H). 13 C NMR(100MHz,Chloroform-d)δ172.6,162.1,138.9,137.2,134.9,134.8,133.4,132.7,129.1,128.7,128.6,128 .4,127.7,127.5,126.5,126.5,126.4,125.1,124.6,124.4,124.1,50.5,43.223.7.HRMS(ESI,m / z):calculated forC 30 H 23 NO 4 [M+H] + :462.1700,found:462.1705.

[0036] Example 4

[0037]

[0038] Under a nitrogen atmosphere, difunctionalizing reagent A1 (30.9 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B3 (24.0 mg, 0.15 mmol, 1.5 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to a reaction solvent of dichloromethane (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius under blue LED light for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C4 (colorless liquid 39.2 mg, 89% yield). 1H NMR (400MHz, Chloroform-d) δ7.87 (dd, J=5.5, 3.1Hz, 2H), 7.77 (dd, J=5.5, 3.1Hz, 2H), 7. 53-7.48(m,2H),7.47-7.41(m,3H),7.37-7.29(m,1H),7.20(ddd,J=8.9,7.3,1.7Hz,1H),6 .92(td,J=7.5,1.1Hz,1H),6.88-6.79(m,2H),6.20(ddd,J=15.9,8.0,6.8Hz,1H),3.83(s ,3H),3.17(ddd,J=13.8,6.8,1.5Hz,1H),2.93(ddd,J=13.8,8.0,1.3Hz,1H),1.76(s,3H). 13 C NMR (100MHz, Chloroform-d) δ172.6,162.1,156.5,141.6,134.9,129.2,129.1,128.8,128.5,127.7, 126.9,126.3,126.3,125.1,124.1,120.8,110.8,55.6,50.2,43.7,23.5.HRMS(ESI,m / z):calculated for C 27 H 23 NO 5 [M+Na] + :464.1469,found:464.1477.

[0039] Example 5

[0040]

[0041] Under a nitrogen atmosphere, difunctionalizing agent A1 (35.8 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B3 (24.0 mg, 0.15 mmol, 1.5 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to a reaction solvent of dichloromethane (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius under irradiation of a blue LED light for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C5 (colorless liquid 42.1 mg, 86% yield). 1H NMR(400MHz,Chloroform-d)δ7.87(dd,J=5.5,3.1Hz,2H),7.78(dd,J=5.6,3.0Hz,2H),7.51-7.47(m,2H),7.47-7.39(m,4H),7.36-7.31(m,1H),7.27-7.22(m,2H),6.45(d,J=15.7Hz,1H),6.26(ddd,J=15.6,7.9,6.8Hz,1H),3.15(ddd,J=13.7,6.8,1.4Hz,1H),2.88(ddd,J=13.7,8.0,1.1Hz,1H),1.74(s,3H). 13 C NMR(100MHz,Chloroform-d)δ172.4,162.1,141.5,136.2,134.9,133.6,131.7,129.1,128.8,128.0,127.8,126.2,125.5,124.1,121.2,50.3,43.1,23.9.HRMS(ESI,m / z):calculated for C 26 H 20 BrNO 4 [M+H] + :490.0649,found:490.0656。

Claims

1. A method for preparing an N-hydroxyphthalimide ester containing a quaternary carbon center, It is characterized in that Under the action of palladium catalyst, α-diazo ketone reacts with a difunctional reagent under light to obtain N-hydroxyphthalimide ester compounds containing a quaternary carbon center.

2. The method for preparing the N-hydroxyphthalimide ester containing a quaternary carbon center according to claim 1, It is characterized in that The method comprises the following steps: (1) Under a nitrogen atmosphere, a catalyst, an α-diazo ketone and a difunctionalizing agent are sequentially added to a reaction solvent to obtain a mixture. (2) The mixture described in step (1) is irradiated with a blue LDE lamp and stirred at a suitable temperature until the reaction is completed. The crude reaction product is filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the N-hydroxyphthalimide ester product.

3. The method for preparing the N-hydroxyphthalimide ester containing a quaternary carbon center according to claim 1, Features: The molecular structure of the obtained N-hydroxyphthalimide ester is shown in the following formula (I): In formula (I), R 1 is hydrogen, methyl or other alkyl, phenyl, 2-methoxyphenyl, 4-benzyloxyphenyl, 4-bromophenyl, 4-methylformylphenyl, 2-furyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, R 2 is methyl or other alkyl, phenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-naphthyl, 4-methoxyphenyl, R 3 is methyl or other alkyl, phenyl or substituted phenyl, R 2 With R 3 Can be the same or different.

4. The method for preparing the N-hydroxyphthalimide ester containing a quaternary carbon center according to claim 1, It is characterized in that The molecular structure of the bifunctionalized reagent is shown in the following formula (II), wherein R 1 and R in (I) 1 same.

5. The method for preparing the N-hydroxyphthalimide ester containing a quaternary carbon center according to claim 1, It is characterized in that The molar ratio of α-diazo ketone to the bifunctionalized reagent is (1.5-2.0):1.0, and the concentration of α-diazo ketone in the mixed solution is between 0.15M and 0.2M.

6. The method for preparing the N-hydroxyphthalimide ester containing a quaternary carbon center according to claim 1, It is characterized in that In step (1), the reaction solvent is dichloromethane; in step (2), the mixture is stirred at 25 degrees Celsius for 12 hours.

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