Synthetic method of three-stage carboxylic acid pentafluorophenol ester with participation of ketene

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for obtaining tertiary carboxylic acid pentafluorophenol ester containing a quaternary carbon center by carrying out Wolff rearrangement on alpha-diazoketone to generate ketene in situ, and reacting the ketene with three components of sodium pentafluorophenolate and allyl halide. The preparation method comprises the following steps: in a nitrogen atmosphere, sequentially adding alpha-diazoketone, tetrakis (triphenylphosphine) palladium, sodium pentafluorophenolate and allyl halide 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 the pentafluorophenol ester product containing the quaternary carbon center. The preparation method is simple to operate (active ketene participates in the reaction through Wolff rearrangement in-situ generation), the atom economy is high, the condition is mild, and the substrate universality is good.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing tertiary carboxylic acid pentafluorophenol ester by a three-component reaction of α-diazo ketone, sodium pentafluorophenol and allyl halide catalyzed by transition metal Background Art

[0002] Enone is a chemically active organic molecule. Due to the presence of accumulated double bonds, it has the characteristics of both nucleophiles and electrophiles. It is easy to undergo addition reactions with nucleophiles, becoming an effective way to construct chemical structures such as α-position multi-substituted amides and esters. At the same time, enone can also undergo cycloaddition reactions with dipolar structures or unsaturated double bonds to efficiently construct medium-ring structures. Although enone has been widely used as a raw material or reaction intermediate in organic synthesis, the three-component reaction to achieve selective difunctionalization of enone is still a very challenging direction in enone chemistry.

[0003] Document 1 (Eur. J. Org. Chem. 2010, 5863) discloses a method for synthesizing α-chlorotertiary carboxylic acid pentachlorophenol ester using chiral azacarbene as catalyst.

[0004]

[0005] Reference 2 (J. Am. Chem. Soc. 2008, 130, 17260) discloses a difunctionalization reaction of a monosubstituted enone catalyzed by a chiral quinine derivative, and successfully prepares a chiral α-fluoroester / amide structure.

[0006]

[0007] Document 3 (Org. Lett. 2023, 25, 3126) discloses a method for achieving the enantioselective synthesis of α-chlorocarboxylic acid esters by using α-diazo ketone as a starting material through a one-pot multi-step reaction.

[0008]

[0009] Although the above methods can realize the difunctionalization reaction of enone, most of them are monosubstituted enone or can only realize α-halogenation. Carboxylic acid derivatives with more complex structures containing all-carbon quaternary carbon centers are difficult to synthesize by the above methods. Therefore, it is urgent to develop a more general and efficient synthesis method. The present invention mainly studies the use of α-diazo ketone compounds as precursors of enone, in-situ generation of enone under light conditions, sodium pentafluorophenol, and allyl halide to react, so as to realize the difunctionalization of enone under mild conditions. Summary of the invention

[0010] The purpose of the present invention is to provide a general synthesis method of tertiary carboxylic acid pentafluorophenol ester with the participation of enone, which is simple and efficient to operate and aims to solve the shortcomings of the existing preparation method, such as difficulty in synthesizing raw materials and limited scope of application.

[0011] The scheme adopted by the present invention to achieve the purpose is: under a nitrogen atmosphere, a metal catalyst, α-diazo ketone, sodium pentafluorophenolate and an allyl halide are sequentially added to a reaction solvent, stirred at a suitable temperature and under blue LED irradiation until the reaction is complete, the crude reaction product is filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain a pentafluorophenol ester compound containing a quaternary carbon center.

[0012] The reaction formula of the method of the present invention can be expressed as follows:

[0013]

[0014] The compound of formula A represents an allyl halide, the compound of formula B represents an α-diazo ketone compound, and the compound of formula C represents a pentafluorophenol ester compound containing a quaternary carbon center.

[0015] Among them, R 1 is 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.

[0016] The metal catalyst is tetrakistriphenylphosphine palladium.

[0017] The reaction solvent is dichloromethane, 1,2-dichloroethane, trifluorotoluene, preferably dichloromethane.

[0018] The molar ratio of the α-diazo ketone, sodium pentafluorophenol and allyl halide is (1.5-2.0):1.0:1.0, and the concentration of the α-diazo ketone in the mixed solution is between 0.15M and 0.2M.

[0019] The reaction temperature is room temperature or 10-50°C, preferably 25°C.

[0020] The reaction time is 8-24 hours, preferably 12 hours.

[0021] The present invention has the following advantages and beneficial effects:

[0022] (1) The preparation method of the present invention has mild conditions and high atom economy.

[0023] (2) Compared with previously reported methods, the preparation method of the present invention has a simpler raw material structure and can achieve the synthesis of products with more complex structures, and has a wide range of substrate applicability. DETAILED DESCRIPTION

[0024] 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.

[0025] Example 1

[0026]

[0027] Under nitrogen atmosphere, allyl halide A1 (15.2 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B1 (24.0 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were added sequentially to the reaction solvent 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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C1 (colorless liquid 41.5 mg, 96% yield). 1 H NMR (400MHz, Chloroform-d) δ7.45-7.38(m,4H),7.37-7.32(m,1H),7.32-7.26(m,4H),7.24-7.18(m,1H),6.49(dt,J=15.7,1 .4Hz, 1H), 6.06 (dt, J=15.7, 7.4Hz, 1H), 3.12 (ddd, J=13.9, 7.5, 1.4Hz, 1H), 2.91 (ddd, J=13.9, 7.4, 1.4Hz, 1H), 1.75 (s, 3H). 19 FNMR(376MHz,Chloroform-d)δ-152.18--152.36(m,2F),-157.83(t,J=21.6Hz,1F),-162.11--162.39(m,2F). 13C NMR(100MHz,Chloroform-d)δ172.3,141.5,137.2,134.6,128.9,128.6,127.7,127.6,126.3,126.1,124.3,51.1,42.9,23.0.HRMS(ESI,m / z):calculated for C 24 H 17 F5O2[M+H] + :433.1227,found:433.1230.

[0028] Example 2

[0029]

[0030] Under nitrogen atmosphere, allyl halide A2 (22.1 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B1 (24.0 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were added sequentially to the reaction solvent 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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C2 (colorless liquid 37.1 mg, 74% yield). 1 H NMR(400MHz,Chloroform-d)δ7.51(s,1H),7.48-7.44(m,2H),7.44-7.37(m,5H),7.36-7.31(m,1H),6.51(dt,J=15.9,1.4 Hz,1H),6.14(dt,J=15.7,7.4Hz,1H),3.12(ddd,J=13.9,7.5,1.3Hz,1H),2.93(ddd,J=13.9,7.4,1.4Hz,1H),1.77(s,3H). 19 F NMR (376MHz, Chloroform-d) δ-62.70(s,3F),-152.28--152.42(m,2F),-157.68(t,J=21.7Hz,1F),-162.02--162.21(m,2F). 13C NMR(100MHz,Chloroform-d)δ 172.2,141.3,137.9,133.3,131.0(q,J=32.1),129.3,129.1,128.9,128.2,127.8,126.5,126.0,125.5,124.1( q,J=3.9Hz),123.1(q,J=3.8Hz),122.8(q,J=271),122.8,120.1,51.1,42.9,23.0.HRMS(ESI,m / z):calculated for C 25 H 16 F8O2[M+Na] + :523.0920,found:523.0928.

[0031] Example 3

[0032]

[0033] Under nitrogen atmosphere, allyl halide A3 (18.3 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B1 (24.0 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were added sequentially to the reaction solvent 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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C3 (colorless liquid 36.1 mg, 78% yield). 1 H NMR(400MHz,Chloroform-d)δ7.45-7.38(m,2H),7.35-7.30(m,2H),7.20(ddd,J=8.2,7.4,1.7Hz,1H),6.95-6.76(m,3H),6. 06(dt,J=15.8,7.4Hz,1H), 3.82(s,3H), 3.15(ddd,J=13.8,7.3,1.4Hz,1H), 2.94(ddd,J=13.8,7.5,1.4Hz,1H), 1.75(s,3H). 19 F NMR (376MHz, Chloroform-d) δ-152.00--152.28(m,2F), -157.98(t,J=21.7Hz,1F),-162.24--162.43(m,2F). 13NMR(100MHz,Chloroform-d)δ172.4,156.6,141.7,129.3,128.8,128.6,127.6,126.8, 126.3,126.1,125.0,120.7,110.9,55.5,51.2,43.2,23.1.HRMS(ESI,m / z):calculated for C 25 H 19 F5O3[M+Na] + :485.1152,found:485.1151.

[0034] Example 4

[0035]

[0036] Under nitrogen atmosphere, allyl halide A1 (15.2 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B2 (31.5 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were added sequentially to the reaction solvent 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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C4 (colorless liquid 46.3 mg, 96% yield). 1 H NMR(400MHz,Chloroform-d)δ 7.94-7.83(m,4H),7.58-7.48(m,3H),7.35-7.27(m,4H),7.25-7.19(m,1H),6.55(dd,J=15.7,1.6Hz,1H),6.0 9(dt,J=15.3,7.4Hz,1H), 3.22(ddd,J=13.9,7.6,1.3Hz,1H), 3.05(ddd,J=13.9,7.3,1.4Hz,1H), 1.86(s,3H). 19 FNMR(376MHz,Chloroform-d)δ-151.99--152.27(m,2F),-157.70(t,J=21.7Hz,1F),-161.94--162.20(m,2F). 13C NMR (100MHz, Chloroform-d) δ172.4138.9,137.1,134.7,133.3,132.6,128.7,128.7,128.3,127. 7,127.6,126.6,126.5,126.3,124.9,124.4,124.2,51.3,42.8,23.1.HRMS(ESI,m / z):calculated for C 28 H 19 F5O2[M+H] + :483.1383,found:483.1388.

[0037] Example 5

[0038]

[0039] Under nitrogen atmosphere, allyl halide A1 (15.2 mg, 0.1 mmol, 1.0 equiv.), α-diazo ketone B3 (30.8 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.) and tetrakistriphenylphosphine palladium (5.7 mg, 0.005 mmol, 0.05 equiv.) were added sequentially to the reaction solvent 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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C5 (colorless liquid 36.3 mg, 76% yield). 1 H NMR (400MHz, Chloroform-d) δ8.32-8.22(m,2H),7.64-7.54(m,2H),7.34-7.24(m,4H),7.26-7.18(m,1H),6.49(dt,J=15.6,1 .3Hz,1H),6.00(dt,J=15.7,7.5Hz,1H),3.12(ddd,J=13.9,7.5,1.3Hz,1H),2.96(ddd,J=13.9,7.4,1.4Hz,1H),1.81(s,3H). 19 FNMR(376MHz,Chloroform-d)δ-152.40--152.55(m,2F),-156.94(t,J=21.6Hz,1F),-161.49--161.70(m,2F). 13C NMR(100MHz,Chloroform-d)δ171.3,148.6,147.4,136.7,135.5,128.7,127.9,127.4,126.3,124.0,122.8,51.5,42.8,23.0.HRMS(ESI,m / z):calculated for C 24 H 16 F5NO4[M+Na] + :500.0897,found:500.0890。

Claims

1. A transition metal-catalyzed in situ ketene difunctionalization reaction, characterized in that: Under the action of palladium catalyst, α-diazo ketone, sodium pentafluorophenol and allyl halide react under light to obtain tertiary carboxylic acid pentafluorophenol ester compounds containing a quaternary carbon center, thereby achieving difunctionalization of the carbon-carbon double bond of the enone.

2. The method for difunctionalization of ketene according to claim 1, characterized in that: The method comprises the following steps: (1) Under a nitrogen atmosphere, a catalyst, α-diazo ketone, sodium pentafluorophenolate and allyl halide 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 a tertiary carboxylic acid pentafluorophenol ester product.

3. The method for difunctionalization of ketene according to claim 1, characterized in that: The molecular structure of the obtained tertiary carboxylic acid pentafluorophenol ester is shown in the following formula (I): In formula (I), R 1 is 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 difunctionalization of ketene according to claim 1, characterized in that: The molecular structure of allyl halides is shown in the following formula (II), where R 1 and R in (I) 1 same.

5. The method for difunctionalization of ketene according to claim 1, characterized in that: The molar ratio of α-diazo ketone, nucleophile and allyl halide is (1.5-2.0):1.0:1.0, and the concentration of α-diazo ketone in the mixed solution is between 0.15M and 0.2M.

6. The method for difunctionalization of ketene according to claim 1, 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.

Images