Polysubstituted internal alkenyl phosphine oxide derivative and synthesis method thereof

Abstract

The invention discloses a synthesis method of a polysubstituted internal alkenyl phosphine oxide derivative. Internal alkenyl sulfonium salt which is simple, easy to prepare and high in reaction activity is used as a raw material, diaryl phosphine oxide is used as a coupling reagent, and the Z / E isomer of the polysubstituted internal alkenyl phosphine oxide derivative is simply and efficiently synthesized through a displacement substitution reaction. Compared with the reported alkenyl phosphine oxide synthesis method, the method has the characteristics of stable raw material structure, low price, easiness in obtaining, very mild reaction conditions, simplicity in experimental operation, high reaction efficiency and good functional group compatibility, and two isomer products Z / E can be obtained through one-step separation and purification.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a polysubstituted alkenylphosphine oxide derivative and a synthesis method thereof. Background Art

[0002] Since organophosphorus compounds play important roles in many bioactive fine chemicals, functional materials, applied chemistry, etc., such as natural products, bioactive molecules, pesticides and drugs, and organic catalysts / ligands. Phosphine oxide compounds are an important structural unit, and the phosphorus-containing groups in the molecules can significantly improve the bioavailability and optoelectronic properties of the molecules. Polysubstituted alkenylphosphine oxide derivatives play important roles in many synthetic applications, are good precursors of trivalent phosphorus, and can catalyze various reactions; and are important ligands, which can coordinate with transition metals to catalyze reactions efficiently. In recent years, alkenylphosphines have received extensive attention, and scientific researchers are committed to developing various synthesis methods of polysubstituted alkenylphosphine oxide derivatives.

[0003] At present, some methods for preparing alkenylphosphine oxides have been reported. The related preparation methods mainly include: 1) nickel and ruthenium dual photocatalytic cross-coupling reaction of alkenyl tosylate and phosphite (Org. Lett. 2017, 19, 3735 - 3738); 2) photocatalyst eosin Y-catalyzed radical addition reaction of alkyne and diarylphosphine oxide (ACS Catal. 2018, 8, 10599 - 10605); 3) palladium-catalyzed hydrophosphination reaction of alkyne (J. Am. Chem. Soc. 2018, 140, 3139 - 3155); 4) synthesis of P-chiral alkenylphosphine oxide compounds by asymmetric addition reaction of alkyne and diarylphosphine oxide catalyzed by tris(dibenzylideneacetone)dipalladium (Angew. Chem. Int. Ed. 2020, 59, 20645 - 20650); 5) addition reaction of alkyne and diarylphosphine oxide catalyzed by palladium acetate (Organometallics 2023, 42, 2590 - 2597). However, the above methods generally have relatively dangerous reactions and relatively harsh reaction conditions. For example, they need to use precious metal catalysts, and the economy is poor; the reaction requires high temperature, consuming energy; the substrate scope of application is limited; and the reaction selectivity is poor. Therefore, it is of great significance to develop a new environmentally friendly, efficient and convenient synthesis method of polysubstituted alkenylphosphine oxide derivatives.

[0004] In view of the many deficiencies in the synthesis methods of polysubstituted alkenylphosphines and the need to enrich and develop new preparation methods of polysubstituted alkenylphosphine oxide derivatives, it is necessary to synthesize a series of different types of polysubstituted alkenylphosphine oxide derivatives starting from simple and easy-to-prepare and highly reactive alkenylsulfonium salts and diarylphosphine oxides through a shift substitution reaction. Summary of the Invention

[0005] The object of the present invention is to provide a method for synthesizing polysubstituted internal alkenyl phosphine oxide derivatives, which is environmentally friendly, highly efficient and convenient in reaction, mild in conditions, simple in operation and wide in substrate scope.

[0006] In order to achieve the above object, the technical solution of the present invention is as follows:

[0007] A polysubstituted internal alkenyl phosphine oxide derivative has the following molecular structural formula I or I':

[0008]

[0009] R 1 is selected from hydrogen and a benzene ring with substituents, and the substituents on the benzene ring are selected from methyl, methoxy, methylthio, fluorine, chlorine, bromine, trifluoromethyl and ester group;

[0010] R 2 is selected from hydrogen, a benzene ring with substituents and alkyl group, and the substituents on the benzene ring are selected from methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl and ester group;

[0011] Ar 1 、Ar 2 are each independently selected from phenyl, a benzene ring with substituents, naphthalene ring and heterocyclic ring (such as nitrogen-containing heterocyclic ring), and the substituents on the benzene ring are selected from methyl, methoxy, fluorine and ester group.

[0012] The above-mentioned method for synthesizing polysubstituted internal alkenyl phosphine oxide derivatives uses polysubstituted internal alkenyl sulfonium salt II with stable properties, simple preparation and high reaction activity as the starting material, and through a displacement substitution reaction with diaryl phosphine oxide III in the presence of a base and a common chemical reaction solvent, the Z / E two internal alkenyl phosphine oxide derivative isomers I and I' are efficiently synthesized in one step;

[0013] The molecular structural formulas of polysubstituted internal alkenyl sulfonium salt II and diaryl phosphine oxide III are as follows:

[0014]

[0015] R 1 、R 2 are each independently selected from hydrogen and a benzene ring with substituents, and the substituents on the benzene ring are selected from methyl, methoxy, methylthio, fluorine, chlorine, bromine, trifluoromethyl and ester group;

[0016] Ar 1 、Ar 2 are each independently selected from phenyl, a benzene ring with substituents, naphthalene ring and heterocyclic ring (such as nitrogen-containing heterocyclic ring), and the substituents on the benzene ring are selected from methyl, methoxy, fluorine and ester group.

[0017] The reaction formula of the synthesis route is:

[0018]

[0019] Further, in the above technical solution, the molar ratio of the polysubstituted alkenyl sulfonium salt II to the diarylphosphine oxide III is 1:1 - 1:2, preferably 1:1 - 1:1.5;

[0020] The base is one or a mixture of two or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide, and sodium tert-butoxide. The molar ratio of the polysubstituted alkenyl sulfonium salt II to the promoter base is 1:0 - 1:3, and the optimal molar ratio is 1:1 - 1:2.5;

[0021] The reaction solvent is one or a mixture of two or more of toluene, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, N,N-dimethylformamide, or methanol. Among them, the reaction effect is the best when using acetonitrile as the solvent. The molar concentration of the polysubstituted alkenyl sulfonium salt II in the reaction solvent is 0.1 - 2.0 M, preferably 1 - 2 M, and the optimal molar concentration is 1 - 1.5 M.

[0022] Further, in the above technical solution, the reaction time is 3 - 24 hours, preferably 6 - 18 hours, and the best reaction time is 12 hours.

[0023] Further, in the above technical solution, the reaction temperature is 10 - 80 °C, preferably 20 - 80 °C, more preferably 20 - 40 °C, and the best reaction temperature is 30 °C.

[0024] Further, in the above technical solution, the reaction may not require inert gas protection, and the reaction atmosphere is air; the reaction may also require inert gas protection, and the reaction atmosphere is nitrogen.

[0025] Further, in the above technical solution, the method for purifying the product: After the reaction is completed and cooled to room temperature, the experimental steps of separating and purifying the product by filtration and silica gel column chromatography are carried out to obtain the polysubstituted alkenylphosphine oxide derivatives I and I'.

[0026] In an air atmosphere, with the base as the promoter, using the polysubstituted alkenyl sulfonium salt II, which has stable properties, is simple to prepare, and has high reaction activity, as the starting material, and the diarylphosphine oxide as the coupling agent, through a displacement substitution reaction, the Z / E two isomeric alkenylphosphine oxide derivatives I and I' are efficiently synthesized in one step. Compared with the reported methods for synthesizing alkenylphosphine oxides, the raw materials of the present invention are rich, cheap, and easily available, the experimental operation is simple, the synthesis reaction conditions are very mild, the reaction efficiency is high, the functional group compatibility is good, the product is easy to purify, and the Z / E two isomeric products can be separated and purified in one step.

[0027] The present invention has the following advantages:

[0028] 1) The synthesis of the polysubstituted alkenyl sulfonium salt II is simple in operation, good in reaction selectivity, and wide in application scope.

[0029] 2) The polysubstituted alkenyl sulfonium salt II has the characteristics of stable structure, high reactivity, and high reactivity, and can be used to prepare different types of alkenylphosphine oxide derivatives I and I'.

[0030] 3) The coupling agent diarylphosphine oxide has low toxicity, is cheap and easily available, and has stable properties and is easy to store.

[0031] In summary, the present invention utilizes the high stereoselectivity and functional group compatibility of the polysubstituted alkenyl sulfonium salt II to prepare different types of polysubstituted alkenylphosphine oxide derivatives I and I'. The raw materials have stable properties and are easy to prepare. The experimental operation is simple, the reaction conditions are mild, the yield of the target product is high, the substrate scope is wide, and the functional group compatibility is good. Specific Embodiments

[0032] In the present invention, the experimental operation can be carried out according to the following technical scheme, but it does not limit the scope of protection of the present invention. The internal olefin compound A, cyclobutanesulfoxide, and trifluoromethanesulfonic anhydride Tf2O react under low-temperature conditions with dichloromethane DCM as a solvent in an inert atmosphere to form the polysubstituted alkenyl sulfonium salt II (Reaction Scheme 1). Then, using the sulfonium salt II as a raw material, the reaction is carried out in an organic solvent such as acetonitrile CH3CN under the promotion of a base such as cesium carbonate Cs2CO3 (Reaction Scheme 2). After the reaction is completed, the product is separated and purified by filtration and silica gel column chromatography to obtain the polysubstituted alkenylphosphine oxide derivatives I and I'.

[0033]

[0034] The specific process is as follows: Replace the nitrogen in a 100 mL three-necked round-bottom flask three times. Under a nitrogen atmosphere, successively add olefin A (10 mmol), cyclobutanesulfoxide (11 mmol), and DCM. Slowly add TfO2 (11 mmol) at -50 °C, and react for 6 hours. After the reaction is completed, add saturated sodium carbonate solution to neutralize to near neutrality, separate with a separatory funnel, extract with DCM, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Then, separate by silica gel column chromatography (the eluent is dichloromethane:methanol = 20:1, (v:v)) to obtain the target product II. The target product is further confirmed by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and single-crystal structure determination of the representative sulfonium salt structure by X-ray crystallography.

[0035] The raw materials 2a, 2b, and 2c in the following examples were prepared by the following literature methods:

[0036] J.Ma, J.Lin, Z.L.Huang, P.Wu, Y.-G.Zhou, and Z.K.Yu, Org.Chem.Front. 2023, 10, 4092-4099.

[0037]

[0038] The specific process is as follows: In a 25 mL reaction tube, vinylsulfonium salt II (0.3 mmol), cesium carbonate Cs2CO3 or sodium tert-butoxide (0.6 mmol), and diarylphosphine oxide III (0.45 mmol) were successively added, followed by 2 mL of acetonitrile or ethyl acetate, and the mixture was stirred at 30 °C for 12 h. After the reaction, insoluble substances were removed by filtration through diatomaceous earth, volatile components were removed by concentration under reduced pressure, and then the product was separated and purified by silica gel column chromatography (eluent: petroleum ether (60-90 °C) / ethyl acetate = 1.5:1, (v:v)) to obtain the polysubstituted internal alkenylphosphine oxide derivatives I and I'. The structures of the target products were confirmed by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and by referring to the literature.

[0039] The following examples are helpful for further understanding of the present invention, but the content of the present invention is not limited thereto.

[0040] Example 1

[0041]

[0042] In a 25 mL sealed tube, 1-(1,2-diphenylethenyl)tetrahydro-1H-thiophene-1-trifluoromethanesulfonate 2a (124.9 mg, 0.3 mmol), cesium carbonate Cs2CO3 (195.5 mg, 0.6 mmol), and diphenylphosphine oxide (91.0 mg, 0.45 mmol) were successively added, and then 3 mL of acetonitrile CH3CN was added. The mixture was stirred at 30 °C for 12 h. After the reaction, insoluble substances were removed by filtration through diatomaceous earth, volatile components were removed by concentration under reduced pressure, and then the product was separated and purified by silica gel column chromatography (eluent: petroleum ether (60-90 °C) / ethyl acetate = 1.5:1, (v:v)) to obtain the polysubstituted internal alkenylphosphine oxide derivative 1a (93 mg, yield 81%) and 1a' (15 mg, yield 13%). The target products were confirmed by nuclear magnetic resonance spectroscopy and by referring to the literature (Y. Unoh, K. Hirano, M. Miura, J. Am. Chem. Soc. 2017, 139, 6106-6109.).

[0043] Characterization data of typical compounds

[0044] (E)-(1,2-Diphenylethenyl)diphenylphosphine oxide (1a), white solid. 11H NMR (400 MHz, CDCl3) δ 7.74 - 7.45 (m, 5H), 7.48 - 7.25 (m, 6H), 7.22 - 6.94 (m, 8H), 6.93 (d, J = 6.6 Hz, 2H). 13 13C{ 1 1H} NMR (100 MHz, CDCl3) δ 142.8 (d, J = 9.8 Hz), 135.3 (d, J = 8.9 Hz), 135.2 (d, J = 93.5 Hz), 134.5 (d, J = 17.3 Hz), 132.0 (d, J = 9.4 Hz), 131.6 (d, J = 2.6 Hz), 130.8 (d, J = 103.3 Hz), 130.0, 129.7 (d, J = 4.1 Hz), 128.7, 128.5, 128.1, 128.0, and 127.5 (d, J = 1.9 Hz). 31 31P{ 1 1H} NMR (162 MHz, CDCl3) δ 28.2.

[0045] (Z)-(1,2-Diphenylethynyl)diphenylphosphine oxide (1a'), white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.54 (m, 7H), 7.34 (d, J = 8.0 Hz, 2H), 7.22 - 7.03 (m, 12H). 13 13C{ 1 1H} NMR (100 MHz, CDCl3) δ 148.9 (d, J = 6.8 Hz), 141.4 (d, J = 10.5 Hz), 136.7 (d, J = 91.7 Hz), 135.3 (d, J = 5.8 Hz), 133.5 (d, J = 104.1 Hz), 131.3 (d, J = 9.4 Hz), 130.8 (d, J = 2.8 Hz), 129.9 (d, J = 1.0 Hz), 128.6 (d, J = 4.4 Hz), 128.5, 128.0 (d, J = 7.5 Hz), 127.8, 127.7, and 127.0 (d, J = 0.9 Hz). 31 31P{ 1 1H} NMR (162 MHz, CDCl3) δ 23.8.

[0046] Comparative Example 1

[0047] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that cesium carbonate Cs2CO3 was not added in the reaction. After the reaction was completed, the target products 1a and 1a' were not obtained after post-treatment. It shows that cesium carbonate is the key to promoting the formation of the product.

[0048] Example 2

[0049] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that the solvent used in the reaction was 1,2-dichloroethane. After the reaction was completed, the target products 1a (71 mg, yield 62%) and 1a' (11 mg, yield 10%) were obtained through post-treatment. It was shown that 1,2-dichloroethane could also be used as the reaction solvent, but it was not the optimal one.

[0050] Example 3

[0051]

[0052] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that the vinyl sulfonium salt added to the reaction system was 2b (129 mg, 0.3 mmol). After the reaction was completed, the white solid target products 1b (105 mg, yield 88%) and 1b' (12 mg, yield 10%) were obtained through post-treatment. The target products were confirmed by nuclear magnetic resonance spectroscopy.

[0053] Characterization data of typical compounds

[0054] (E)-(Diphenyl(2-phenyl-1-(p-tolyl)vinyl)phosphine oxide (1b), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.73 - 7.62 (m, 4H), 7.54 (d, J = 20.9 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.41 - 7.25 (m, 4H), 7.18 - 7.04 (m, 5H), 6.95 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 2.24 (s, 3H). 13 C{ 1 H}NMR (100 MHz, CDCl3) δ 142.8 (d, J = 10.2 Hz), 137.4 (d, J = 2.2 Hz), 135.3 (d, J = 76.4 Hz), 134.8, 132.2 (d, J = 9.4 Hz), 131.7 (d, J = 2.4 Hz), 131.0 (d, J = 103.1 Hz), 130.1, 129.7 (d, J = 4.3 Hz), 129.4, 128.8, 128.2, 128.1, and 21.2. 31 P{ 1 H}NMR (162 MHz, CDCl3) δ 28.4.

[0055] (Z)-(Diphenyl(2-phenyl-1-(p-tolyl)vinyl)phosphine oxide (1b'), white solid. 11H NMR (400 MHz, CDCl3) δ 7.66 - 7.46 (m, 7H), 7.25 - 7.12 (m, 8H), 7.09 - 6.96 (m, 3H), 6.94 (d, J = 7.9 Hz, 2H), 2.22 (s, 3H). 13 13C{ 1 1H} NMR (100 MHz, CDCl3) δ 148.7 (d, J = 7.2 Hz), 138.4 (d, J = 10.6 Hz), 136.8, 136.6 (d, J = 91.7 Hz), 135.5 (d, J = 5.8 Hz), 133.7 (d, J = 103.9 Hz), 131.4 (d, J = 9.3 Hz), 130.8 (d, J = 2.6 Hz), 123.0, 128.7, 128.6 (d, J = 4.4 Hz), 128.4, 127.9 (d, J = 12.2 Hz), 127.7, and 21.2. 31 31P{ 1 1H} NMR (162 MHz, CDCl3) δ 23.9.

[0056] Example 4

[0057]

[0058] The reaction steps and operations were the same as those in Example 1. The difference from Example 1 was that the vinyl sulfonium salt added to the reaction system was 2c (147 mg, 0.3 mmol). After the reaction was completed, the target products 1c (78 mg, yield 58%) and 1c' (18 mg, yield 14%) were obtained as white solids after post-treatment. The target products were confirmed by nuclear magnetic resonance spectroscopy.

[0059] Characterization data of typical compounds

[0060] (E)-Methyl 4-(2-(diphenylphosphoryl)-2-(p-tolyl)vinyl)benzoate (1c), 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.5 Hz, 2H), 7.71 - 7.63 (m, 4H), 7.55 (d, J = 20.5 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.45 - 7.36 (m, 4H), 7.09 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 6.77 (dd, J = 8.1, 1.6 Hz, 2H), 3.83 (s, 3H), 2.27 (s, 3H). 13 13C{ 11H NMR (100 MHz, CDCl3) δ 166.6, 141.8 (d, J = 10.2 Hz), 139.6 (d, J = 17.4 Hz), 138.9, 138.0 (d, J = 2.7 Hz), 132.4 (d, J = 9.4 Hz), 132.0 (d, J = 2.7 Hz), 131.9, 130.9 (d, J = 103.5 Hz), 130.1, 129.9, 129.8 (d, J = 4.3 Hz), 129.6 (d, J = 1.1 Hz), 129.4, 128.4 (d, J = 12.0 Hz), 52.2, and 21.3. 31 P{ 1 1H NMR (162 MHz, CDCl3) δ 28.4.

[0061] (Z)-4-(2-(Diphenylphosphoryl)-2-(p-tolyl)vinyl)benzoic acid methyl ester (1c'), 1 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 2H), 7.64 - 7.37 (m, 7H), 7.38 - 7.00 (m, 8H), 6.97 (d, J = 7.5 Hz, 2H), 3.83 (s, 3H), 2.22 (s, 3H). 13 C{ 1 1H NMR (100 MHz, CDCl3) δ 166.7, 147.0 (d, J = 7.0 Hz), 140.0 (d, J = 5.9 Hz), 139.2 (d, J = 90.3 Hz), 138.0 (d, J = 10.2 Hz), 137.2, 133.3 (d, J = 103.9 Hz), 131.3 (d, J = 9.4 Hz), 131.0 (d, J = 2.5 Hz), 129.8, 129.4, 128.9 (d, J = 8.8 Hz), 128.4 (d, J = 4.4 Hz), 128.0 (d, J = 12.1 Hz), 52.1, and 21.1. 31 P{ 1 1H NMR (162 MHz, CDCl3) δ 23.6.

Claims

1. A multi-substituted alkenylphosphine oxide derivative, whose molecular structural formula I or I' is as follows: R 1 and R 2 are each independently selected from hydrogen and a benzene ring with substituents, where the substituents on the benzene ring are selected from methyl, methoxy, methylthio, fluorine, chlorine, bromine, trifluoromethyl, and ester group; Ar 1 、Ar 2 are each independently selected from phenyl, a substituted benzene ring, a naphthalene ring, and a heterocyclic ring, wherein the substituent on the benzene ring is selected from methyl, methoxy, fluorine, and an ester group.

2. The synthesis method of the multi-substituted alkenyl phosphine oxide derivative according to claim 1, wherein: Under the promotion of a base, using alkenylsulfonium salt II as a reaction raw material and diarylphosphine oxide III as a coupling reagent, the alkenylphosphine oxide derivatives I and I' are synthesized in one step by reaction; The reaction formula of the synthesis route is: R 1 ,R 2 ,R 3 ,Ar 1 、Ar 2 are defined as in claim 1.

3. The synthesis method according to claim 2, characterized in that: The molar ratio of the multi-substituted alkenylsulfonium salt II to the diarylphosphine oxide III is 1:1 - 1:2; The base is selected from one or a mixture of two or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide, sodium tert-butoxide, and the molar ratio of the multi-substituted alkenylsulfonium salt II to the base is 1:1 - 1:3; The reaction solvent is selected from one or a mixture of two or more of toluene, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, N,N-dimethylformamide, or methanol, and the molar concentration of the multi-substituted alkenylsulfonium salt II in the reaction solvent is 0.1 - 2.0 M.

4. The synthesis method according to claim 3, characterized in that: The reaction time is 3 - 24 hours; the reaction temperature is 10 - 80 °C; the reaction atmosphere is air or nitrogen.

5. The synthesis method according to claim 3, characterized in that: After the reaction is completed, the steps of filtering and silica gel column chromatography are carried out for the separation and purification of the product to obtain the multi-substituted alkenylphosphine oxide derivatives I and I'.

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