A method for synthesizing fluoroalkenyl phosphates

Abstract

The application belongs to the field of organic synthesis and relates to a synthesis method of fluoroalkenyl phosphorus. Fluoroalkenyl phosphorus compounds in E configuration are obtained by reacting fluoroacrylic acid and phosphine compound as raw materials, using trispyridine ruthenium chloride hexahydrate as a catalyst, triethylenediamine as a base, t-butyl peroxybenzoate as an initiator and acetonitrile as a solvent. The fluoroalkenyl phosphorus compounds are prepared efficiently and conveniently for the first time by using fluoroacrylic acid and phosphine compound as raw materials. The reaction raw materials are cheap and easy to obtain, the product yield and selectivity are high, the functional group compatibility is good, the substrate application range is wide, and the synthesis economic value is high.

Description

Technical Field

[0001] This invention relates to the preparation of compounds, belonging to the field of organic synthesis. Specifically, it relates to a method for synthesizing fluoroolefinic phosphorus. Background Technology

[0002] Organophosphorus compounds, due to their unique chemical and biological properties, have wide applications in advanced materials, coordination chemistry, pesticides and pharmaceuticals, and life sciences. Furthermore, they serve as synthetic intermediates, organic catalysts, and ligands in organic synthetic chemistry. Among them, alkenyl phosphorus compounds have outstanding application value. Firstly, they are synthetic modules for obtaining functional phosphorus compounds. Moreover, they exhibit remarkable pharmaceutical properties. Given their importance, the preparation of alkenyl phosphorus compounds has received considerable attention.

[0003] It is well known that the introduction of fluorine atoms can effectively regulate the metabolic stability, lipophilicity, and bioavailability of parent molecules. Among these, monofluoroalkenyl fragments are an important class of fluorine-containing skeletons, serving as key skeletons for the synthesis of fluorine-containing molecules. Furthermore, in drug research, monofluoroalkenyl groups can also serve as ideal bioisosteres for peptide bonds, improving conformational and peptidase stability. Therefore, exploring more practical and efficient synthetic methods for monofluoroalkenyl phosphorus compounds is imperative. The synthesis of monofluoroalkenyl phosphorus compounds was first achieved through alkenylation reactions (Equation 1, J. Chem. Soc., Chem. Commun. 1982, 1270-1271). However, this reaction requires harsh conditions at -78 degrees Celsius, necessitates the preparation of fluorine and phosphorus-containing reagents, and yields an E / Z mixture, making product separation difficult.

[0004]

[0005] Beier et al. synthesized fluoroenylphosphine compounds by eliminating α,α-difluorophosphine esters. This reaction requires multiple steps, harsh reaction conditions, and poor functional group compatibility (Equation 2, Synlett 2011, 331-334).

[0006]

[0007] The Poisson group has developed a copper-promoted method for the synthesis of monofluorobenzylphosphine from unstable diazocarbonyl derivatives. This method requires the preparation of unstable diazocarbonyl derivatives, the use of toxic reagents and excess cesium fluoride, and has a limited range of substrates (Equation 3, Angew. Chem. Int. Ed. 2016, 55, 14141-14145).

[0008]

[0009] Recently, a scheme for synthesizing fluoroalkenylphosphine from geminal fluorohaloalkenes has been reported. However, such reactions require the synthesis of geminal fluorohaloalkenes with a defined configuration, and the reactions all yield mixed E / Z products. The product selectivity is very low, product separation is difficult, and an excess of phosphorus-containing reagents is required (Equation 4, Org. Lett. 2022, 24, 8343-8347; Eur. J. Org. Chem. 2019, 2019, 1170-1177; J. Fluorine Chem. 2001, 112, 47-54).

[0010]

[0011] Existing methods for synthesizing fluoroenyl phosphorus compounds still suffer from numerous problems: demanding reaction conditions, lack of stereoselectivity (E / Z mixtures), limited substrate range, and the need for multi-step synthesis. Therefore, there is an urgent need to develop more convenient, practical, and efficient methods for synthesizing monofluoroenyl phosphorus compounds with high stereoselectivity and good functional group compatibility. Summary of the Invention

[0012] To address the shortcomings of current methods for synthesizing fluoroolefin phosphorus compounds, such as demanding reaction conditions, poor stereoselectivity, narrow substrate compatibility, and the need for multi-step synthesis, this invention provides a highly efficient, selective method for synthesizing fluoroolefin phosphorus compounds using readily available fluoroacrylic acid and phosphate compounds as raw materials, exhibiting excellent functional group compatibility.

[0013] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for synthesizing fluoroolefinic phosphorus, characterized in that: using fluoroacrylic acid and phosphorus hydrides as raw materials, using terpyridine ruthenium chloride hexahydrate as a catalyst, triethylenediamine as a base, tert-butyl peroxide as an initiator, and acetonitrile as a solvent, the reaction is carried out according to the following reaction formula to obtain a class of E-configuration fluoroolefinic phosphorus compounds having general formula (I):

[0014]

[0015] Where R represents hydrogen, halogen, ester group, cyano group, trifluoromethyl, trifluoromethoxy, tetrafluorophenyl, pentafluorophenyl, etc.; R1 represents aryl, methoxy, ethoxy, etc.

[0016] Preferably, the amount of terpyridine ruthenium chloride hexahydrate is 3% of the amount of fluoroacrylic acid.

[0017] Preferably, the amount of triethylenediamine is twice the amount of fluoroacrylic acid.

[0018] Preferably, the amount of the phosphohydrogen compound is twice the amount of the fluoroacrylic acid.

[0019] Preferably, the amount of tert-butyl peroxide is three times the amount of fluoroacrylic acid.

[0020] Preferably, the light wavelength is 465 nanometers, the reaction time is 10 hours, and the reaction temperature is room temperature.

[0021] This method represents the first efficient and convenient preparation of fluoroolefinic phosphorus compounds using fluoroacrylic acid and phosphate compounds as raw materials. The reaction mixture features inexpensive and readily available raw materials, high product yield and selectivity, a simple feeding method, good functional group compatibility, a wide range of applicable substrates, and high economic value. It provides an efficient and highly selective method for the preparation of E-configuration fluoroolefinic phosphorus compounds. Detailed Implementation

[0022] The technical solution of the present invention will be further described below through specific embodiments:

[0023] Example 1, the reaction formula of this example is as follows:

[0024]

[0025] (1) Under air, 1 mol% ruthenium tripyridine chloride hexahydrate, 2 equiv triethylenediamine, 0.2 mmol (1 equiv) 2-fluoro-3-phenylpropionic acid, and 2 equiv diphenylphosphine oxide were added to a sealed reaction tube with a side arm and a magnetic inlet. The reaction tube was purged with argon three times. Under argon protection, 1.5 mL of acetonitrile was added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 10 hours.

[0026] (2) The solvent in the organic phase obtained in step (2) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 72%, E / Z > 30:1, and the product purity was 1000%.

[0027] Example 2

[0028] The reaction formula for this embodiment is as follows:

[0029]

[0030] (1) Tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), 2-fluoro-3-p-fluorophenylacrylic acid (0.2 mmol), and diphenylphosphine oxide (2 equiv) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was purged with argon three times. Under argon protection, 1.5 mL of acetonitrile was added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 10 hours.

[0031] (2) The solvent in the organic phase obtained in step (2) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 75%, E / Z > 30:1, and the product purity was 100%.

[0032] Example 3

[0033] The reaction formula for this embodiment is as follows:

[0034]

[0035] (1) Tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), 2-fluoro-3-pentafluorophenylpropionic acid (0.2 mmol), and diphenylphosphine oxide (2 equiv) were added to a sealed reaction tube with a side arm and a magnetic dome under air. The reaction tube was purged with argon three times. Under argon protection, 1.5 mL of acetonitrile was added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 10 hours.

[0036] (2) The solvent in the organic phase obtained in step (2) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 46%, E / Z > 30:1, and the product purity was 100%.

[0037] Example 4

[0038] The reaction formula for this embodiment is as follows:

[0039]

[0040] (1) Tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), 2-fluoro-3-phenylpropionic acid (0.2 mmol), and di-p-bromophenylphosphine (2 equiv) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was purged with argon three times. Under argon protection, 1.5 mL of acetonitrile was added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 10 hours.

[0041] (2) The solvent in the organic phase obtained in step (2) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 70%, E / Z > 30:1, and the product purity was 100%.

[0042] Example 5

[0043] The reaction formula for this embodiment is as follows:

[0044]

[0045] (1) Tris(2-phenylpyridine)iridium (1 mol%), triethylenediamine (1 equiv), estrone derivative fluoroacrylic acid (0.2 mmol), and diphenylphosphine oxide (2 equiv) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was purged with argon three times. Under argon protection, 1.5 mL of acetonitrile was added to the reaction tube, and the reaction was carried out at room temperature under 465 nm light for 10 hours.

[0046] (2) The solvent in the organic phase obtained in step (2) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 58%, E / Z > 30:1, and the product purity was 100%.

[0047] The amounts of each substance used and the reaction conditions were experimentally extended to the examples to demonstrate that the technical solution of the present invention has good functional group compatibility.

[0048] The present invention has been described in detail above. The above description is only an embodiment of the present invention and should not be construed as limiting the scope of this application. All equivalent changes and modifications made within the scope of this application should still fall within the scope of the present invention.

[0049]

[0050] Attached Figure Description

[0051] Figure 1 The proton nuclear magnetic resonance spectrum of product 3a prepared in this invention;

[0052] Figure 2 The nuclear magnetic resonance fluorine spectrum of product 3a prepared in this invention;

[0053] Figure 3 The phosphorus nuclear magnetic resonance spectrum of product 3a prepared in this invention;

[0054] Figure 4 The carbon NMR spectrum of product 3a prepared in this invention.

[0055] Figure 5 The proton NMR spectrum of product 4f prepared in this invention;

[0056] Figure 6 The nuclear magnetic resonance fluorine spectrum of product 4f prepared in this invention;

[0057] Figure 7 The phosphorus NMR spectrum of product 4f prepared in this invention;

[0058] Figure 8 The carbon NMR spectrum of product 4f prepared in this invention;

[0059] Figure 9 The proton nuclear magnetic resonance spectrum of product 6a prepared in this invention;

[0060] Figure 10 The nuclear magnetic resonance fluorine spectrum of product 6a prepared in this invention;

[0061] Figure 11 The phosphorus nuclear magnetic resonance spectrum of product 6a prepared in this invention;

[0062] Figure 12 The carbon NMR spectrum of product 6a prepared in this invention.

Claims

1. A method for synthesizing fluoroolefinic phosphorus, characterized in that: Using fluoroacrylic acid and phosphorus compounds as raw materials, ruthenium chloride hexahydrate of terpyridine as a catalyst, triethylenediamine as a base, tert-butyl peroxide as an initiator, and acetonitrile as a solvent, the reaction is carried out according to the following reaction formula to obtain a class of E-configuration fluoroolefinic phosphorus compounds with general formula (I): Where R represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, tetrafluorophenyl, or pentafluorophenyl; and R1 represents aryl, methoxy, or ethoxy.

2. The method for synthesizing fluoroolefinic phosphorus according to claim 1, characterized in that: The amount of terpyridine ruthenium chloride hexahydrate is 3% of the amount of fluoroacrylic acid.

3. The method for synthesizing fluoroolefinic phosphorus according to claim 1, characterized in that: The amount of triethylenediamine is twice the amount of fluoroacrylic acid.

4. The method for synthesizing fluoroolefinic phosphorus according to claim 1, characterized in that: The amount of the phosphohydrogen compound is twice the amount of the fluoroacrylic acid.

5. The method for synthesizing fluoroolefinic phosphorus according to claim 1, characterized in that: The amount of tert-butyl peroxide is three times the amount of fluoroacrylic acid.

6. The method for synthesizing fluoroolefinic phosphorus according to claim 1, characterized in that: The light wavelength was 465 nanometers, the reaction time was 10 hours, and the reaction temperature was room temperature.

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