A method for synthesizing pentafluorophenol esters of tertiary carboxylic acids involving ketenes.

Abstract

This invention relates to the field of organic synthesis, specifically to a method for the in-situ reaction of an α-diazoketone with a Wolff rearrangement to generate an enone, sodium pentafluorophenolate, and an allyl halide, yielding a pentafluorophenol ester, a tertiary carboxylic acid containing a quaternary carbon center. In this invention, under a nitrogen atmosphere, α-diazoketone, tetrakis(triphenylphosphine)palladium, sodium pentafluorophenolate, and an allyl halide are sequentially added to a reaction solvent. The mixture is stirred at 25°C under 15W blue LED illumination until the reaction is complete. After filtration and purification, the pentafluorophenol 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), has high atom economy, mild conditions, and good substrate universality.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing pentafluorophenol esters of tertiary carboxylic acid by a three-component reaction of transition metal-catalyzed α-diazoketone, sodium pentafluorophenolate, and allyl halide. Background Technology

[0002] Enones are chemically reactive organic molecules. Due to the presence of accumulated double bonds, they possess both nucleophilic and electrophilic properties, readily undergoing addition reactions with nucleophiles, thus providing an effective route for constructing α-substituted polysubstituted amides, esters, and other chemical structures. Simultaneously, enones can also undergo cycloaddition reactions with dipolar structures or unsaturated double bonds, efficiently achieving the construction of medium-ring structures. Although enones are widely used as starting materials or reaction intermediates in organic synthesis, achieving selective bifunctionalization of enones through three-component reactions remains a highly challenging direction in enone chemistry.

[0003] Reference 1 ( Eur. J. Org. Chem. (2010, 5863) discloses a method for synthesizing α-chlorotercarboxylic acid pentachlorophenol ester by chiral azacarbene catalysis.

[0004]

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

[0006] Reference 3 ( Org. Lett. 2023, 25 (3126) discloses an enantioselective synthesis of α-chlorocarboxylic acid esters using α-diazoketone as a starting material through a one-pot multi-step reaction.

[0007]

[0008] While the methods described above can achieve the bifunctionalization of enones, they are mostly limited to monosubstituted enones or can only achieve α-halogenation. More complex carboxylic acid derivatives with all-carbon and quaternary carbon centers are difficult to synthesize using these methods. Therefore, there is an urgent need to develop a more general and efficient synthetic method. This invention mainly studies the use of α-diazoketone compounds as precursors for enones, where enones are generated in situ under light irradiation and react with sodium pentafluorophenolate and allyl halides to achieve bifunctionalization of enones under mild conditions. Summary of the Invention

[0009] The purpose of this invention is to provide a general synthetic method for pentafluorophenol esters of tertiary carboxylic acids involving ketenes. This method is simple and efficient, and aims to overcome the shortcomings of existing preparation methods, such as the difficulty in synthesizing raw materials and the limited scope of application.

[0010] The method adopted by the present invention to achieve the objective is as follows: under a nitrogen atmosphere, a metal catalyst, α-diazoketone, sodium pentafluorophenolate and allyl halide are added sequentially to the reaction solvent. The mixture is stirred until the reaction is complete under a suitable temperature and blue LED irradiation. The crude product is filtered, concentrated under reduced pressure and separated by silica gel column chromatography to obtain pentafluorophenol ester compounds containing quaternary carbon centers.

[0011] The reaction formula of the method of the present invention can be expressed as follows:

[0012]

[0013] Compound A represents allyl halides, compound B represents α-diazoketones, and compound C represents pentafluorophenolic esters containing quaternary carbon centers.

[0014] Among them, R 1 It is phenyl, 2-methoxyphenyl, 4-benzyloxyphenyl, 4-bromophenyl, 4-methyl carboxylate 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.

[0015] The metal catalyst is tetrakis(triphenylphosphine)palladium.

[0016] The reaction solvent is dichloromethane, 1,2-dichloroethane, or trifluorotoluene, preferably dichloromethane.

[0017] The molar ratio of α-diazoketone, sodium pentafluorophenolate, and allyl halide is (1.5~2.0):1.0:1.0, and the concentration of α-diazoketone in the mixed solution is between 0.15 M and 0.2 M.

[0018] The reaction is carried out at room temperature or 10-50 °C, preferably 25 °C.

[0019] The reaction time is 8-24 hours, preferably 12 hours.

[0020] The present invention has the following advantages and beneficial effects:

[0021] (1) The preparation method of the present invention has mild conditions and high atom economy.

[0022] (2) Compared with the 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 applications. Detailed Implementation

[0023] 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.

[0024] Example 1

[0025]

[0026] Under a nitrogen atmosphere, allyl halide A1 (15.2 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B1 (24.0 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.), and tetrakis(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 illumination 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 41.5 mg, 96% yield). 1 H NMR (400 MHz, Chloroform-d) δ 7.45 – 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, 1.4 Hz, 1H), 6.06 (dt, J = 15.7, 7.4 Hz, 1H), 3.12 (ddd, J = 13.9,7.5, 1.4 Hz, 1H), 2.91 (ddd, J = 13.9, 7.4, 1.4 Hz, 1H), 1.75 (s, 3H). 19F NMR (376 MHz, Chloroform-d) δ -152.18 – -152.36 (m, 2F), -157.83 (t, J = 21.6 Hz, 1F), -162.11 – -162.39 (m, 2F). 13 C NMR (100 MHz, Chloroform-d) δ 172.3,141.5, 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.

[0027] Example 2

[0028]

[0029] Under a nitrogen atmosphere, allyl halide A2 (22.1 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B1 (24.0 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.), and tetrakis(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 illumination 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 37.1 mg, 74% yield). 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (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, 7.4 Hz, 1H), 3.12 (ddd, J= 13.9, 7.5, 1.3 Hz, 1H), 2.93 (ddd, J = 13.9, 7.4, 1.4 Hz, 1H), 1.77 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -62.70 (s, 3F), -152.28 – -152.42 (m, 2F), -157.68 (t, J = 21.7 Hz, 1F), -162.02 – -162.21 (m, 2F). 13 C NMR (100 MHz, Chloroform-d) δ 172.2, 141.3, 137.9, 133.3, 131.0 (q, J = 32.1 Hz), 129.3, 129.1, 128.9, 128.2, 127.8, 126.5, 126.0, 125.5, 124.1 (q, J = 3.9 Hz), 123.1 (q, J = 3.8 Hz), 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.

[0030] Example 3

[0031]

[0032] Under a nitrogen atmosphere, allyl halide A3 (18.3 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B1 (24.0 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.), and tetrakis(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 illumination 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 36.1 mg, 78% yield). 1 HNMR (400 MHz, Chloroform-d) δ 7.45 – 7.38 (m,2H), 7.35 – 7.30 (m, 2H), 7.20(ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 6.95 – 6.76(m, 3H), 6.06 (dt, J = 15.8, 7.4 Hz, 1H), 3.82 (s, 3H), 3.15 (ddd, J = 13.8,7.3, 1.4 Hz, 1H), 2.94 (ddd, J = 13.8, 7.5, 1.4 Hz, 1H), 1.75 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -152.00 – -152.28 (m, 2F), -157.98 (t, J = 21.7 Hz, 1F), -162.24 – -162.43 (m, 2F). 13 NMR (100 MHz, Chloroform-d) δ 172.4, 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 forC 25 H 19 F5O3 [M+Na] +:485.1152, found: 485.1151.

[0033] Example 4

[0034]

[0035] Under a nitrogen atmosphere, allyl halide A1 (15.2 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B2 (31.5 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.), and tetrakis(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 illumination 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 46.3 mg, 96% yield). 1 HNMR (400 MHz, 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, 1.6 Hz, 1H), 6.09 (dt, J = 15.3, 7.4 Hz, 1H), 3.22 (ddd, J = 13.9,7.6, 1.3 Hz, 1H), 3.05 (ddd, J = 13.9, 7.3, 1.4 Hz, 1H), 1.86 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -151.99 – -152.27 (m, 2F), -157.70 (t, J = 21.7 Hz, 1F), -161.94 – -162.20 (m, 2F). 13C NMR (100 MHz, Chloroform-d) δ 172.4, 138.9,137.1, 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 forC 28 H 19 F5O2 [M+H] + : 483.1383, found: 483.1388.

[0036] Example 5

[0037]

[0038] Under a nitrogen atmosphere, allyl halide A1 (15.2 mg, 0.1 mmol, 1.0 equiv.), α-diazotone B3 (30.8 mg, 0.15 mmol, 1.5 equiv.), sodium pentafluorophenolate (20.6 mg, 0.1 mmol, 1.0 equiv.), and tetrakis(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 illumination 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 36.3 mg, 76% yield). 1 HNMR (400 MHz, Chloroform-d) δ 8.32 – 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, 1.3 Hz, 1H), 6.00 (dt, J = 15.7,7.5 Hz, 1H), 3.12 (ddd, J = 13.9,7.5, 1.3 Hz, 1H), 2.96 (ddd, J = 13.9, 7.4, 1.4 Hz, 1H), 1.81 (s, 3H). 19F NMR(376 MHz, Chloroform-d) δ -152.40 – -152.55 (m, 2F), -156.94 (t, J = 21.6 Hz,1F), -161.49 – -161.70 (m, 2F). 13 C NMR (100 MHz, Chloroform-d) δ 171.3,148.6, 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 bifunctionalization reaction, characterized in that, Under the action of palladium catalyst, α-diazoketone, sodium pentafluorophenolate and allyl halide react under light to give pentafluorophenol esters of tertiary carboxylic acids containing quaternary carbon centers. The molecular structural formula of the pentafluorophenol ester tertiary carboxylic acid containing a quaternary carbon center is shown in formula (I) below: The molecular structure of the allyl halide is shown in formula (II) below: The molecular structure of the α-diazoketone is shown in formula (III) below: In equations (I), (II), and (III), in equation (I), R 1 It is phenyl, 2-methoxyphenyl, 4-benzyloxyphenyl, 4-bromophenyl, 4-methyl carboxylate phenyl, 2-furanyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, R 2 It is methyl, phenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-naphthyl, 4-methoxyphenyl, R 3 Methyl, phenyl, R 2 With R 3 Same or different; X is chlorine or bromine; The palladium catalyst is one of tetra(triphenylphosphine)palladium, palladium acetate, and bis(triphenylphosphine)palladium dichloride.

2. The method for preparing pentafluorophenol ester compounds containing quaternary carbon centers according to claim 1, characterized in that, The method includes the following steps: (1) Under a nitrogen atmosphere, palladium catalyst, α-diazoketone, sodium pentafluorophenolate and allyl halide were added to the reaction solvent in sequence to obtain a mixture; The molar ratio of α-diazoketone, sodium pentafluorophenolate, and allyl halide is (1.5~2.0):1.0:1.0, and the concentration of α-diazoketone in the mixed solution is between 0.15M and 0.2M. (2) Irradiate the mixture described in step (1) with an 8 W 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 tertiary carboxylic acid pentafluorophenol ester product. The mixture was stirred and reacted at 25 degrees Celsius for 12 hours.

3. The method for preparing a pentafluorophenol ester compound containing a quaternary carbon center according to claim 2, characterized in that, In step (1), the palladium catalyst is tetra(triphenylphosphine)palladium; the reaction solvent is dichloromethane.

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