A method for preparing γ,γ-geminal difluoroallyl ketone compound

Abstract

The present invention relates to a method for preparing γ,γ-gem-difluoroallyl ketone compounds. Specifically, α-trifluoromethylstyrene and iodinated alkanes are prepared in a one-pot process in a carbon monoxide atmosphere under photocatalytic conditions. The present invention starts from iodinated alkanes, which are widely available substrates and commercially available, and classic organic building blocks α-trifluoromethylstyrene, and obtains a series of γ,γ-gem-difluoroallyl ketone compounds through defluorination carbonylation reaction under photocatalytic conditions.

Description

Technical Field

[0001] The invention relates to a method for synthesizing gamma, gamma-geminal difluoroallyl ketone derivative compounds. Background Art

[0002] γ,γ-Geminal difluoroallyl ketone is a very important chemical structure fragment because it is widely present in many natural products and modern drugs and has good biological activity. In addition, γ,γ-Geminal difluoroallyl ketone is a very important intermediate for the synthesis of many fluorine-containing compounds. In the past, the synthesis of γ,γ-Geminal difluoroallyl ketone was generally achieved by the addition of metal reagents and subsequent β-fluorine elimination. In recent years, the preparation of γ,γ-Geminal difluoroallyl ketone by visible light catalytic addition reaction has become a promising method. However, these reported reactions also have some disadvantages, such as the need to use carbonyl-containing substrates, such as carboxylic acids, aldehydes, and α-ketocarboxylic acids, which greatly limits the scope of substrates.

[0003] Compared with the previous methods for synthesizing γ,γ-gem-difluoroallyl ketone, we have developed a defluorination carbonylation reaction to synthesize γ,γ-gem-difluoroallyl ketone. Using simple and easy-to-prepare iodoalkanes and simple and easy-to-prepare α-trifluoromethylstyrene, we can synthesize γ,γ-gem-difluoroallyl ketone with high yield, good selectivity and a wide range of substrates under mild conditions.

[0004] In summary, this paper describes a photocatalytic defluorination carbonylation method to prepare γ,γ-gem-difluoroallyl ketone derivatives. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing γ,γ-geminal difluoroallyl ketone derivatives.

[0006]

[0007] Reaction equation 1: Synthesis of γ,γ-gem-difluoroallyl ketone derivatives

[0008] The specific operation steps are as follows (reaction equation 1):

[0009] The reaction is carried out in a high-pressure reactor, wherein the photocatalyst iridium metal complex, triethylamine, α-trifluoromethylstyrene 1, and iodinated alkane 2 are weighed, and the reaction is placed in a carbon monoxide atmosphere under 60 atmospheric pressure and irradiated with blue light, and the reaction is carried out at 20-40° C., preferably 25° C. The reaction time is 10.0-24.0 hours, preferably 20.0 hours; after the reaction is completed, the γ,γ-gem-difluoroallyl ketone derivative 3 is separated.

[0010] The molar ratio of α-trifluoromethylstyrene 1 to iodinated alkane 2 is 1:2, preferably 1:1.0-1.5, more preferably 1:1.0.

[0011] The gas pressure of carbon monoxide is 20-80 atmospheres, preferably 60 atmospheres.

[0012] The solvent is one or more of 1,2-dichloroethane, n-hexane, tetrahydrofuran, ether, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, and acetonitrile-water mixture, preferably acetonitrile-water mixture (the volume ratio of acetonitrile to water is 10:1); the amount of the solvent is 1.0-5.0 ml of the solvent per 0.1 mmol of iodinated alkane 2, preferably 3.0 ml.

[0013] The photocatalyst is fac-Ir(ppy)3, Ru(bpy)2(PF6)2, [Ir(dtbbpy)(ppy)2]PF6, (Ir[dF(CF3)ppy]2(dtbpy))PF6, preferably (Ir[dF(CF3)ppy]2(dtbpy))PF6; the amount of the photocatalyst used is 0.1-3.0% of the molar number of the iodinated alkane 2, preferably 1.0%.

[0014] The amount of triethylamine used is 0.1-0.5 mmol, preferably 0.3 mmol, per 0.1 mmol of iodinated alkane 2.

[0015] The present invention has the following advantages:

[0016] First, it does not require carbonyl-containing substrates or metal reagents to synthesize γ,γ-difluoroallyl ketone, which greatly expands the substrate range. Second, the reaction can apply biologically active molecules to the reaction, broadening the applicability of the reaction. Third, using a very small amount of iridium complex as a photoreaction catalyst greatly reduces the cost. DETAILED DESCRIPTION

[0017] In order to better understand the present invention, the following examples are provided for illustration. The reaction materials and results of Examples 1-15 are shown in Table 1.

[0018] Table 1 Reaction results of different substituted α-trifluoromethylstyrene 1 and iodinated alkane 2

[0019]

[0020]

[0021]

[0022]

[0023]

[0024] Example 1

[0025] The reaction was carried out in a high-pressure reactor. First, α-trifluoromethylstyrene 1a (0.2 mmol), iodoalkane 2a (0.2 mmol), triethylamine (0.6 mmol), and photocatalyst (Ir[dF(CF3)ppy]2(dtbpy))PF6 (0.002 mmol) were added to a 10 ml glass vial. 6.0 ml of acetonitrile / water with a volume ratio of 10:1 was added. The mouth of the glass vial was tightly covered with a rubber bottle cap. The tip of a syringe needle was inserted into the vial through the bottle cap, so that the vial was connected to the outside through the needle. , and then put the reaction vial into a high-pressure reactor, the interior of the vial is connected to the interior of the reactor outside through a needle, the high-pressure reactor is replaced with carbon monoxide, and 60 atmospheres of carbon monoxide are filled to raise the pressure inside the high-pressure reactor to 60 atmospheres. At this time, the carbon monoxide in the reactor is connected to the interior of the vial through the needle, and the reaction is carried out under blue light (465 nanometers) at 25°C for 20.0 hours. After the reaction is completed, γ,γ-gem-difluoroallyl ketone compound 3a is obtained by column chromatography separation with a yield of 82%, and the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0026] The test data are as follows:

[0027] 3a: colorless oil (39 mg, 82%). 1 H NMR(700MHz,Chloroform-d)δ7.25(t,J=7.7Hz,2H),7.22–7.19(m,2H),7.19–7.16(m,1H),3.36 (s,2H),2.35(t,J=7.5Hz,2H),1.48–1.42(m,2H),1.19(q,J=7.5Hz,2H),0.79(t,J=7.4Hz,3H). 13 C NMR(176MHz, CDCl3) δ206.7(dd,J=2.8,2.9Hz),154.8(dd,J=293.5,293.5Hz),133.3(t,J=4.1Hz),12 8.6, 127.9 (t, J = 3.7Hz), 127.5, 87.3 (dd, J = 22.2, 22.7Hz), 42.2 (d, J = 2.0Hz), 41.8, 25.7, 22.2, 13.8. 19 FNMR(56MHz,Chloroform-d)δ-87.7(d,J=36.5Hz),-89.2(d,J=36.5Hz).HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 14 H 16 F2O 239.1242; Found:239.1239.

[0028] Embodiment 2:

[0029] The operation process and conditions were the same as those in Example 1, except that the yield of raw materials 1 and / or 2 in Table 1 and 3b was 74%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0030] Embodiment 3:

[0031] The operation process and conditions were the same as those in Example 1, except that the raw materials 1 and / or 2 in Table 1 and the yield of 3c were 75%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0032] Embodiment 4:

[0033] The operation process and conditions are the same as those in Example 1, except that the raw materials 1 and / or 2 are shown in Table 1, and the yield of 3d is 69%. The structure of the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0034] Embodiment 5:

[0035] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2 and 3e in Table 1 is 82%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0036] Embodiment 6:

[0037] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2 and 3f in Table 1 is 72%, and the structure of the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0038] Embodiment 7:

[0039] The operation process and conditions are the same as those in Example 1, except that the raw materials 1 and / or 2 in Table 1 have a 3 g yield of 74%. The compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0040] Embodiment 8:

[0041] The operation process and conditions are the same as those in Example 1, except that the raw materials 1 and / or 2 are shown in Table 1. The 3h yield is 72%, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0042] Embodiment 9:

[0043] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2 in Table 1 is 69%, and the structure of the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0044] Embodiment 10:

[0045] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2, 3j in Table 1 is 68%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0046] Embodiment 11:

[0047] The operation process and conditions are the same as those in Example 1, except that the raw materials 1 and / or 2 in Table 1, 3k have a yield of 68%, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0048] Embodiment 12:

[0049] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2, 31 in Table 1 is 55%, and the structure of the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0050] Embodiment 13:

[0051] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2, 3m in Table 1 is 59%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0052] Embodiment 14:

[0053] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2, 3n in Table 1 is 54%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0054] Embodiment 15:

[0055] The operation process and conditions are the same as those in Example 1, except that the yield of raw materials 1 and / or 2 in Table 1 is 48%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0056] Application Example 1:

[0057]

[0058] Reaction equation 2: Synthesis of γ,γ-geminal difluoropropyl alcohol

[0059] The product 3e can be obtained in high yield by a one-step reduction method to obtain the important organic building block intermediate γ,γ-geminal difluoropropyl alcohol 4a (known compound, refer to the literature: C. Zhang, Z. Lin, Y. Zhu, C. Wang, J. Am. Chem. Soc., 2021, 143, 11602-11610. The 3ab compound in the literature). The specific operation is as follows (Formula 2):

[0060] Under nitrogen protection, 3e (0.2 mmol) was dissolved in methanol (5.0 mL), sodium borohydride (0.4 mmol) was added and stirred at 40 °C for 2 h. After that, the solvent was dried and the target product 4a was obtained by column chromatography. The compound was confirmed by NMR (hydrogen spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0061] 4a: colorless oil (54 mg, 99%).

[0062] 1 H NMR (400MHz, Chloroform-d) δ = 7.35-7.12 (m, 2H), 6.88 (d, J = 8.8Hz, 2H), 3.83 (s, 3H) ,3.66-3.47(m,1H),2.53-2.40(m,2H),1.48-1.21(m,6H),0.86(t,J=7.0Hz,3H)ppm. 13 C NMR (101MHz, Chloroform-d) δ = 158.4, 154.6 (dd, J = 289.7, 287.9Hz), 129.6 (t, J = 3.2Hz, 2C), 125.5 (dd, J = 4.3, 3.1 Hz), 114.1 (2C), 89.4 (dd, J = 21.3, 14.6Hz), 69.8 (t, J = 2.7Hz), 55.4, 36.7, 36.1 (d, J = 1.5Hz), 27.8, 22.8, 14.1ppm. 19 F NMR(376MHz,Chloroform-d)δ=–90.98(d,J=43.1Hz,1F),–91.37(d,J=43.5Hz,1F)ppm.HRMS(ESI)m / zcalculated for C 15 H 20 F2O2Na[M+Na]+:293.1324,found:293.1323.

[0063] Example 16

[0064] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the photocatalytic aid of the reaction is changed to Ru(bpy)2(PF6)2, and the yield of the target product γ,γ-gemini-difluoroallyl ketone compound will be 10%.

[0065] Embodiment 17

[0066] The other reaction conditions described in Example 1 remain unchanged (ie, the operation process and conditions are the same as in Example 1), except that the reaction temperature is raised to 35 degrees Celsius, and the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced to 61%.

[0067] Embodiment 18

[0068] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the pressure of the reaction carbon monoxide is reduced to 40 atmospheres, and the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced to 14%.

[0069] Embodiment 19

[0070] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the wavelength of the reaction light is adjusted to 365 nanometers and 500 nanometers, and the yields of the target product γ,γ-gemini-difluoroallyl ketone complex are reduced to 55% and 30%, respectively.

[0071] Embodiment 20

[0072] The other reaction conditions described in Example 1 remain unchanged (ie, the operation process and conditions are the same as in Example 1), except that 2 equivalents of triethylamine are added, and the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 52%.

[0073] Embodiment 21

[0074] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as Example 1), the difference is that 2 equivalents (0.4 mmol) of triethylamine are added, and the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 51%.

[0075] Embodiment 22

[0076] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as in Example 1), except that no water is added to the solvent, the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 62%.

[0077] Embodiment 23

[0078] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the ratio of 1a to 2a is 1:1.5, and the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 50%.

[0079] Embodiment 24

[0080] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as in Example 1), except that the solvent used is 4.0 ml, the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 32%.

[0081] Comparative Example 1

[0082] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction temperature is raised to 50 degrees Celsius, the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced to 5%, and a large amount of raw materials remain.

[0083] Comparative Example 2

[0084] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction time is reduced to 5 hours, the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced to 15%, and the raw material is not fully converted.

[0085] Comparative Example 3

[0086] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the photocatalyst of the reaction is removed, and the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced to 0%.

[0087] The other reaction conditions described in Example 1 remain unchanged (ie, the operation process and conditions are the same as in Example 1), except that the light is removed from the reaction, and the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 0%.

[0088] Comparative Example 5

[0089] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that triethylamine is replaced by potassium carbonate or no triethylamine is added, and the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 0%.

[0090] Comparative Example 6

[0091] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction is carried out at 5 atmospheres of carbon monoxide pressure, the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced by 1%, and a large amount of raw materials remain.

[0092] Comparative Example 7

[0093] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as Example 1), the difference is that the solvent is changed to pure water, the yield of the target product γ,γ-gem-difluoroallyl ketone compound is reduced to 0%, and a large amount of raw materials remain.

[0094] Comparative Example 8

[0095] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the photocatalyst is replaced by an organic dye such as methylene blue, rhodamine B, phenol red, etc., and the yield of the target product γ,γ-geminal difluoroallyl ketone compound is reduced by 0%.

Claims

1. A method for preparing a γ,γ-geminal difluoroallyl ketone compound, characterized in that: α-Trifluoromethylstyrene 1 and iodoalkane 2 shown in the following formula are used as raw materials to generate γ,γ-gem-difluoroallyl ketone derivative 3, and the reaction formula is as follows: ； R 1 It is one or more of hydrogen, methyl, tert-butyl, fluorine, chlorine, trifluoromethoxy, methoxy, methylthio, hydroxyl, phenyl, benzyloxy, and N,N-dimethyl, and the number thereof is 1 to 5; R 2 is one of ethyl, n-butyl, n-hexyl, isopropyl, isobutyl, cyclopentyl, cyclohexyl, 3-oxetanyl, 4-oxetanyl, 3-chloro-n-propyl, 3-fluoro-n-propyl, 3,3,3-trifluoro-n-propyl, 6-alkynyl-n-hexyl, 3-hydroxy-n-propyl, 2-phenylethyl, and 2-methoxyethyl; The photocatalyst is (Ir[dF(CF3)ppy]2(dtbpy))PF6; The amount of photocatalyst used is 0.1-3.0% of the mole number of iodinated alkane 2; The solvent is acetonitrile or an acetonitrile-water mixture; the volume ratio of acetonitrile to water in the acetonitrile-water mixture is 8-10:1; the amount of the solvent is 3 ml of the solvent for every 0.1 mmol of iodinated alkane 2; The reaction is carried out at 20-40°C for 10.0-24.0 hours; The atmospheric pressure of carbon monoxide is 55-60 atmospheres.

2. The method according to claim 1, characterized in that: The amount of the photocatalyst used is 0.8-1.0% of the mole number of the iodinated alkane 2.

3. The method according to claim 1, characterized in that: The volume ratio of acetonitrile to water is 9.5-10:

1.

4. The method according to claim 1, characterized in that: The specific steps are as follows: The reaction is carried out in a high-pressure reactor. The photocatalyst, triethylamine, α-trifluoromethylstyrene 1, and iodinated alkane 2 are weighed and placed in a carbon monoxide atmosphere under 55-60 atmospheres of pressure and irradiated with 450-470 nanometer blue light. After the reaction is completed, γ,γ-gem-difluoroallyl ketone derivative 3 is separated and obtained.

5. The method according to claim 4, characterized in that: The molar ratio of α-trifluoromethylstyrene 1 to iodinated alkane 2 is 1:1.0-2.

6. The method according to claim 5, characterized in that: The molar ratio of α-trifluoromethylstyrene 1 to iodinated alkane 2 is 1:1.0-1.

5.

7. The method according to claim 4, characterized in that: The amount of triethylamine used is 0.1-0.5 mmol per 0.1 mmol of iodinated alkane 2.

8. The method according to claim 7, characterized in that: The amount of triethylamine used is 0.25-0.3 mmol per 0.1 mmol of iodinated alkane 2.

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