A process for the preparation of N-hydroxyphthalimide esters containing quaternary carbon centers

Abstract

This invention relates to the field of organic synthesis, specifically to a method for the in-situ generation of an enone via the Wolff rearrangement of α-diazoketone, followed by reaction with a bifunctionalizing agent under transition metal catalysis to obtain an N-hydroxyphthalimide ester containing a quaternary carbon center. In this invention, α-diazoketone, tetrakis(triphenylphosphine)palladium, and the bifunctionalizing agent are sequentially added to a reaction solvent under a nitrogen atmosphere. The mixture is stirred at 25°C under 15W blue LED irradiation until the reaction is complete. After filtration and purification, the redox-active ester product containing a quaternary carbon center is obtained. The preparation method of this invention is simple to operate (the reactive enone participates in the reaction in situ via the Wolff rearrangement), overcoming the shortcomings of traditional methods that require complex tertiary carboxylic acids. It offers mild conditions and good substrate versatility.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing N-hydroxyphthalimide esters containing quaternary carbon centers by reacting α-diazoketones with bifunctional reagents. Background Technology

[0002] N-hydroxyphthalimide esters are commonly used organic synthesis reagents and have been widely applied in the field of free radical chemistry. The carboxyl radical generated by the homolytic cleavage or single-electron reduction of the nitrogen-oxygen bond in N-hydroxyphthalimide esters can release an alkyl radical through decarboxylation, leading to subsequent functionalization reactions. Therefore, it is often used as an alkyl radical precursor. A common synthetic method for this structure is the condensation reaction of a carboxylic acid with N-hydroxyphthalimide. However, for N-hydroxyphthalimide esters corresponding to tertiary carboxylic acids, the limited availability of tertiary carboxylic acids and the relatively cumbersome synthetic routes limit the applicability of this method to some extent.

[0003] Reference 1 (Org. Lett. 2018, 20, 4824) discloses a method for obtaining an N-hydroxyphthalimide ester structure containing a quaternary carbon center by condensation of α,α-dimethylphenylacetic acid and N-hydroxyphthalimide under DCC.

[0004]

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

[0006]

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

[0008] A method for condensing phthalimides under the action of DIC to obtain N-hydroxyphthalimide ester structures containing quaternary carbon centers.

[0009]

[0010] While the methods described above can synthesize N-hydroxyphthalimide esters containing quaternary carbon centers, they all share a common problem: the tertiary carboxylic acid starting materials often require multi-step synthesis. Therefore, there is an urgent need to develop a more universal and efficient method for constructing this structure. This invention primarily investigates the use of α-diazoketone compounds as precursors for enones. Under visible light irradiation, enones are generated in situ via Wolff rearrangement. Simultaneously, a palladium catalyst and a bifunctionalizing reagent release phthalimide anions and allyl palladium ions in situ, resulting in highly regio- and chemoselective bifunctionalization of the enone. This allows for the efficient preparation of N-hydroxyphthalimide esters containing quaternary carbon centers under mild conditions. Summary of the Invention

[0011] The purpose of this invention is to provide a general method for preparing N-hydroxyphthalimide esters containing quaternary carbon centers, which is simple and efficient, and aims to solve the shortcomings of existing preparation methods such as complex operation and limited range of applicable raw materials.

[0012] The method adopted by the present invention to achieve the objective is as follows: under a nitrogen atmosphere, a metal catalyst, α-diazoketone and a bifunctional reagent are added sequentially to the reaction solvent. The mixture is stirred until the reaction is complete under a suitable temperature and under blue LED irradiation. The crude product is filtered, concentrated under reduced pressure and separated by silica gel column chromatography to obtain N-hydroxyphthalimide ester compounds containing quaternary carbon centers.

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

[0014]

[0015] Compound A represents a bifunctional reagent, compound B represents an α-diazoketone compound, and compound C represents an N-hydroxyphthalimide ester compound containing a quaternary carbon center.

[0016] Among them, R 1 It is hydrogen, methyl or other alkyl, phenyl, 2-methoxyphenyl, 4-benzyloxyphenyl, 4-bromophenyl, 4-methylcarboxylate phenyl, 2-furanyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, R 2 It is methyl or other alkyl, phenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-naphthyl, 4-methoxyphenyl, R 3 Methyl or other alkyl, phenyl and substituted phenyl, R 2 With R 3 They can be the same or different.

[0017] The metal catalyst is one of diphenylphosphine palladium dichloride and tetraphenylphosphine palladium, preferably tetraphenylphosphine palladium.

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

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

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

[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 bifunctional reagent used in the preparation method of the present invention is stable 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 readily available, and the operation is simpler and safer. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0027] Example 1

[0028]

[0029] Under a nitrogen atmosphere, bifunctional reagent A1 (27.9 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B1 (24 mg, 0.15 mmol, 1.5 equiv.), and tetra-triphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to the reaction solvent dichloromethane (1 mL). The resulting mixture was stirred at 25°C under blue LED irradiation for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and 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 NO4[M+H] + :412.1544,found:412.1548.

[0030] Example 2

[0031]

[0032] Under a nitrogen atmosphere, bifunctional reagent A1 (27.9 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B2 (29.1 mg, 0.15 mmol, 1.5 equiv.), and tetra-triphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to the reaction solvent dichloromethane (1 mL). The resulting mixture was stirred at 25°C under blue LED irradiation for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and 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 ClNO4[M+H] + :446.1154,found:446.1158.

[0033] Example 3

[0034]

[0035] Under a nitrogen atmosphere, bifunctional reagent A1 (27.9 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B3 (31.5 mg, 0.15 mmol, 1.5 equiv.), and tetra-triphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to the reaction solvent dichloromethane (1 mL). The resulting mixture was stirred at 25°C under blue LED irradiation for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and 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 (400MHz, 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 NO4[M+H] + :462.1700,found:462.1705.

[0036] Example 4

[0037]

[0038] Under a nitrogen atmosphere, bifunctional reagent A1 (30.9 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B3 (24.0 mg, 0.15 mmol, 1.5 equiv.), and tetra-triphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to the reaction solvent dichloromethane (1 mL). The resulting mixture was stirred at 25°C under blue LED irradiation for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and 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 NO5[M+Na] + :464.1469,found:464.1477.

[0039] Example 5

[0040]

[0041] Under a nitrogen atmosphere, bifunctional reagent A1 (35.8 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B3 (24.0 mg, 0.15 mmol, 1.5 equiv.), and tetra-triphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were sequentially added to the reaction solvent dichloromethane (1 mL). The resulting mixture was stirred at 25°C under blue LED irradiation for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and 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 BrNO4[M+H] + :490.0649,found:490.0656。

Claims

1. A method for preparing an N-hydroxyphthalimide ester containing a quaternary carbon center, characterized in that, Under the action of palladium catalyst, α-diazoketone reacts with a bifunctional reagent under light to give N-hydroxyphthalimide esters containing quaternary carbon centers; The α-diazoketone is selected from any one of B1-B3, as shown in the following formula: ， ， The structure of the N-hydroxyphthalimide ester is shown in formula (I): The structural formula of the bifunctionalized reagent is shown in formula (II) below. In equations (I) and (II), R 1 Selected from hydrogen, methyl, phenyl, 2-methoxyphenyl, 4-benzyloxyphenyl, 4-bromophenyl, 4-methylcarboxymethylphenyl, 2-furanyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl; R 2 Selected from methyl, phenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-naphthyl, 4-methoxyphenyl; R 3 Selected from methyl, phenyl, R 2 With R 3 They can be the same or different.

2. The method for preparing N-hydroxyphthalimide ester according to claim 1, characterized in that, The method includes the following steps: (1) Under a nitrogen atmosphere, palladium catalyst, α-diazoketone and bifunctional reagent were added sequentially to the reaction solvent to obtain a mixture; The reaction solvent is dichloromethane, the molar ratio of α-diazoketone to the bifunctional reagent is (1.5-2.0):1.0, and the concentration of α-diazoketone in the mixed solution is between 0.15 M and 0.2 M. (2) Irradiate the mixture described in step (1) with a blue LED lamp and stir it at a suitable temperature until the reaction is complete. After filtering the crude product and concentrating it under reduced pressure, separate it by silica gel column chromatography to obtain the N-hydroxyphthalimide ester product. The mixture was stirred and reacted at 25 degrees Celsius for 12 hours.

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