Process for the preparation of difluoroalkenones and their conversion to difluoroacetates and amides

Abstract

This invention relates to the field of organic synthesis, specifically to a method for the preparation of difluoroenones and their in-situ reaction with amines, alcohols, etc., to convert them into the corresponding difluoroacetamides and difluoroacetic acid esters. The invention involves sequentially adding potassium fluoride, an amine or alcohol, and a difluorobromoacrylsilyl compound to a reaction solvent under a nitrogen atmosphere to obtain a mixture. This mixture is stirred at 25°C until the reaction is complete, filtered, and purified to obtain the difluoroacetamide or difluoroacetic acid ester compound. The preparation method of this invention is simple to operate (highly reactive difluoroenones are generated in situ and participate in the reaction), achieving efficient synthesis of difluoroacetamide / difluoroacetic acid esters and avoiding the use of highly volatile difluoroacetyl chloride. The difluorobromoacrylsilyl used in this invention can be conveniently prepared on a large scale and can be purified by distillation. The reaction conditions involved in the preparation method of this invention have good substrate tolerance and can be applied to aliphatic amines, aromatic amines, and various primary and secondary alcohols.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to the study of in-situ generation of difluoroenone from difluorobromoacetylsilylsilane and subsequent conversion into difluoroacetate / difluoroacetamide compounds. Background Technology

[0002] Difluoroenones are highly reactive fluorinated compounds, exhibiting greater reactivity than other haloenones (dichloroenones, dibromoenones). Due to their inherent instability (lifetimes on the order of microseconds), difluoroenones can only be detected under extreme conditions. The existence of this structure was not confirmed until 2005, when the first transition metal-chelated difluoroenone complex was isolated and identified (Angew. Chem. Int. Ed. 2004, 43, 6366). Due to their extremely high reactivity and instability, difluoroenones have seen almost no application in synthetic chemistry since their first report in 1968, except for one other report (J. Fluorine Chem. 1987, 37, 177).

[0003] Currently, the main methods for producing difluoroenones involve the reaction of zinc powder with difluorohaloacyl chlorides, specifically the reaction of zinc with bromodifluoroacetyl chloride (J. Org. Chem. 1968, 33, 816) and the reaction of zinc with chlorodifluoroacetyl chloride (J. Fluorine Chem. 1987, 37, 177). Both methods share the drawback of requiring pre-activation of the zinc powder and slow dropwise addition of the acyl chloride. Furthermore, the bromodifluoroacetyl chloride preparation route in the former method is complex, dangerous, and difficult to obtain. The chlorodifluoroacetyl chloride in the latter method has a low boiling point (20°C), making operation inconvenient. Against this backdrop, developing a new, simple, and practical strategy for the preparation of difluoroenones is of great significance.

[0004] This invention investigates a method for the in-situ generation of difluoroenones under mild conditions using difluorobromoacetylsilyl as a novel precursor. Due to the high reactivity of difluoroenones, they rapidly undergo addition reactions in the presence of amines / alcohols, transforming into the corresponding difluoroacetate / difluoroacetamide compounds. This type of structure is an important subclass of fluorinated compounds and a crucial synthetic intermediate; its efficient preparation is of significant value (WO2011102439A1, CN103113220A, CN102875379A, CN101270050A, etc.). Summary of the Invention

[0005] The purpose of this invention is to provide a method for producing difluoroenone and its application in the preparation of difluoroacetate and difluoroacetamide.

[0006] This invention is achieved as follows: under the action of an activating reagent, difluorobromoacetylsilyl compounds can generate difluoroenone intermediates in situ, which then undergo addition reactions with amines and alcohols in the system to yield difluoroacetamide / difluoroacetate compounds. The reaction formula of the method of this invention is shown in the following formula (III):

[0007]

[0008] In equation (III), R 1 It is 1-adamantyl, 4-methylsulfonylphenyl or other alkyl, cycloalkyl, aryl; R 2 It is a benzyl, pregnenolone fragment or other alkyl group; R 3 R 4 R 5 It can be an alkyl group or a phenyl group, and they can be the same or different.

[0009] The method involved in this invention includes the following steps:

[0010] (1) Under a nitrogen atmosphere, difluorobromoacetylsilane, amine / alcohol and activator are added sequentially to the reaction solvent in a molar ratio of (1.0-5.0):1.0:(1.0-5.0) to obtain a mixture; wherein the activator is potassium fluoride, cesium carbonate, sodium acetate or other activating reagents.

[0011] (2) Stir the mixture described in step (1) at a suitable temperature until the reaction is complete, and separate the crude product by short silica gel column chromatography to obtain the expected difluoroacetamide / difluoroacetate compound.

[0012] Preferably, in step (1), the amine is R. 1 Amine compounds with substituent groups; wherein, R 1 It is 1-adamantyl, 4-methylsulfonylphenyl or other alkyl, cycloalkyl, aryl; the alcohol is R 2 Alcohols with substituent groups; wherein, R 2 It can be benzyl, pregnenolone fragment, or other alkyl groups.

[0013] Preferably, in step (1), the reaction solvent is acetonitrile; in step (2), the mixture is stirred at 25 degrees Celsius for 10 hours.

[0014] Compared with the shortcomings of existing technologies, the present invention has the following advantages:

[0015] (1) Compared with the previous use of difluorobromoacetyl chloride and difluorochloroacetyl chloride, which are difficult to prepare or have low boiling points, as difluoroenone precursors, this method uses difluorobromoacetylsilyl compounds as alternatives, which are more stable and easier to operate. Difluorobromoacetylsilyl compounds can be prepared on a ten-gram scale according to the method in the literature (J.Org.Chem.2004, 69, 6323) and can be purified by distillation.

[0016] (2) Compared with the previous method which required the slow addition of difluorobromoacetyl chloride and difluorochloroacetyl chloride, the method used in this invention can add them in one pot, which is more convenient to operate and the equipment can also be simplified.

[0017] (3) The method used in this invention uses inexpensive potassium fluoride, sodium acetate and other low-cost activating agents, avoiding the use of active activating zinc powder in previous methods. Attached Figure Description

[0018] Figure 1 This is the proton spectrum of compound 1 in the embodiments of the present invention;

[0019] Figure 2 This is the fluorine spectrum of compound 1 in the embodiments of the present invention;

[0020] Figure 3 This is the carbon spectrum of compound 1 in the embodiments of the present invention;

[0021] Figure 4 This is the proton spectrum of compound 2 in the embodiments of the present invention;

[0022] Figure 5 This is the fluorine spectrum of compound 2 in the embodiments of the present invention;

[0023] Figure 6 This is the carbon spectrum of compound 2 in the embodiments of the present invention;

[0024] Figure 7 This is the proton spectrum of compound 3 in the embodiments of the present invention;

[0025] Figure 8 This is the fluorine spectrum of compound 3 in the embodiments of the present invention;

[0026] Figure 9 This is the carbon spectrum of compound 3 in the embodiments of the present invention; Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] Example 1

[0029]

[0030] Under a nitrogen atmosphere, difluorobromoacetyltriethylsilane (0.3 mmol, 1.5 equiv.), 1-adamantaneamine (0.2 mmol, 1.0 equiv.), and potassium fluoride (0.3 mmol, 1.5 equiv.) were sequentially added to the reaction solvent acetonitrile (3 mL). The resulting mixture was stirred at 25 °C for 10 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 target compound 1 (30.3 mg, 66% yield). 1 HNMR (400MHz, Chloroform-d) δ5.90 (br, 1H), 5.74 (t, J=54.7Hz, 1H), 2.13-2.06 (m, 3H), 2.03-1.98 (m, 6H), 1.71-1.65 (m, 6H). 19 F NMR (377MHz, Chloroform-d) δ-125.06 (d, J=54.2Hz, 2F). 13 C10 NMR (101 MHz, Chloroform-d) δ 161.5 (t, J = 23.4 Hz), 108.6 (t, J = 253.9 Hz), 52.7, 41.2, 36.2, 29.4. HRMS (ESI, m / z): calculated for [M+H]+: 230.1351, found: 230.1354. The 1H, fluorine, and carbon NMR spectra of this compound are as follows: Figure 1 , Figure 2 and Figure 3 As shown.

[0031] Example 2

[0032]

[0033] Under a nitrogen atmosphere, difluorobromoacetyltriethylsilane (0.3 mmol, 1.5 equiv.), 4-methylsulfonylaniline (0.2 mmol, 1.0 equiv.), and potassium fluoride (0.3 mmol, 1.5 equiv.) were sequentially added to the reaction solvent acetonitrile (3 mL). The resulting mixture was stirred at 25 °C for 10 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 target compound 2 (31.9 mg, 64% yield). 1HNMR (400MHz, Dimethyl sulfoxide-d6) δ11.14 (br, 1H), 7.93-7.84 (m, 4H), 6.39 (t, J=53.5Hz, 1H), 3.16 (s, 3H). 19 F NMR (377MHz, Dimethyl sulfoxide-d6) δ-125.49 (d, J=53.3Hz, 2F). 13 C NMR (101MHz, Dimethyl sulfoxide-d6) δ 161.8 (d, J = 26.1Hz), 142.3, 136.8, 128.9, 120.7, 108.7 (t, J = 246.7Hz), 44.2. HRMS (ESI, m / z): calculated for [M+H] + Found: 250.0344, found: 250.0340. The 1H NMR, fluorine NMR, and 1C NMR spectra of this compound are as follows: Figure 4 , Figure 5 and Figure 6 As shown.

[0034] Example 3

[0035]

[0036] Under a nitrogen atmosphere, difluorobromoacetyltriethylsilane (0.3 mmol, 1.5 equiv.), pregnenolone (0.2 mmol, 1.0 equiv.), and potassium fluoride (0.3 mmol, 1.5 equiv.) were sequentially added to the reaction solvent acetonitrile (3 mL). The resulting mixture was stirred at 25 °C for 10 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 target compound 3 (16.6 mg, 21% yield). 1 HNMR (400MHz, Chloroform-d) δ5.87 (t, J=53.5Hz, 1H), 5.44-5.38 (m, 1H), 4.84-4.73 (m, 1H), 2.59-2.50 (m, 1H), 2.49-2.35 (m, 1H) ), 2.27-2.09(m, 4H), 2.08-1.88(m, 4H), 1.78-1.57(m, 4H), 1.56-1.40(m, 3H), 1.23-1.12(m, 3H), 1.08-0.97(m, 4H), 0.63(s, 3H). 19 F NMR (377MHz, Chloroform-d) δ-126.48 (d, J=53.1Hz, 2F).13 C NMR (101MHz, Chloroform-d) δ209.8, 162.1 (t, J=28.5Hz), 138.8, 123.3, 106.8 (t, J=249.4Hz), 63.7, 56.9, 49 .9, 44.1, 38.8, 37.7, 36.9, 36.6, 31.8, 31.7, 27.4, 24.6, 22.9, 21.1, 19.3, 13.3.HRMS (ESI, m / z): calculated for[M+H] + Found: 395.2392, found: 395.2393. The 1H NMR, fluorine NMR, and 1C NMR spectra of this compound are as follows: Figure 7 , Figure 8 and Figure 9 As shown.

[0037] The above description is only a partial embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing difluoroacetamide or difluoroacetate compounds by reacting an in-situ generated difluoroenone with an amine or alcohol, characterized in that: The molecular structure of this type of compound is shown in formula (I) below: ； In formula (I), R 1 is 4-methylsulfonylphenyl, cycloalkyl or aryl; R 2 It is benzyl; The method includes the following steps: (1) Under a nitrogen atmosphere, the activator, amine or alcohol and difluoroenone precursor are added sequentially to the reaction solvent to obtain a mixture; The activator is potassium fluoride. The difluoroenone precursor is difluorobromoacetyltriethylsilane; (2) Stir the mixture described in step (1) at a suitable temperature until the reaction is complete. Filter the crude product, concentrate it under reduced pressure, and then separate it by silica gel column chromatography to obtain the expected difluoroacetamide or difluoroacetate compound.

2. The method for preparing difluoroacetamide or difluoroacetate compounds by reacting in-situ generated difluoroenone with amines or alcohols according to claim 1, characterized in that, The R 1 It is 1-adamantyl.

3. The method for preparing difluoroacetamide or difluoroacetate compounds by reacting in-situ generated difluoroenone with amines or alcohols according to claim 1, characterized in that, In step (1), The amine is 1-adamantaneamine or 4-methylsulfonylaniline.

4. The method for preparing difluoroacetamide or difluoroacetate compounds by reacting in-situ generated difluoroenone with amines or alcohols according to claim 1, characterized in that, The molar ratio of the activator, amine / alcohol, and difluoroenone precursor is (1.0–5.0):1.0:(1.0–5.0), and the concentration of amine / alcohol in the mixed solution is between 0.1 M and 1 M.

5. The method for preparing difluoroacetamide or difluoroacetate compounds by reacting an in-situ generated difluoroenone with an amine or alcohol according to claim 1, characterized in that, In step (1), the reaction solvent is acetonitrile or tetrahydrofuran; in step (2), the mixture is stirred at 25 degrees Celsius for 10 hours.

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