Method for synthesizing difluoroolefin compound through tungsten / chromium concerted catalysis of non-activated alkane

Abstract

The invention discloses a method for synthesizing a difluoroolefin compound through tungsten / chromium concerted catalysis of non-activated alkane. Compared with the prior art, the invention provides the method for realizing direct difluoroallylation by synergistically catalyzing the non-activated alkyl C (sp3)-H bond by tungsten / chromium instead of noble metal. The preparation method provided by the invention is simple in operation steps and good in substrate universality, multiple primary, secondary and tertiary C-H bonds in covering polycyclic and heterocyclic ring substituted alpha-trifluoromethyl styrene, such as naphthalene, dibenzothiophene and dibenzofuran, as well as cyclic alkane and straight-chain alkane, are very easily modified, and the method has wide functionality tolerance, and is suitable for industrial production. The method has the advantages of mild reaction conditions and high yield, and is a green chemical synthesis method with good application prospects.

Description

Technical Field

[0001] The invention relates to a mild and efficient method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium coordinated catalysis. Background Art

[0002] Non-activated alkyl C(sp 3 )-H bonds are widely present in various compounds in nature. If they can play more roles by introducing activating groups, their potential will be infinitely magnified. For a long time, transition metal catalysis has been chosen when constructing CC bonds in organic chemistry. Chromium is one of the most abundant transition metals on earth. If Cr can be used as a low-cost substitute for precious metals, adding fluorine will reduce the production cost. HAT (Hydrogen Atom Transfer) is an important method for selective functionalization of non-activated aliphatic CH bonds. However, traditional HAT requires harsh conditions and relies on the use of harmful reagents such as Cl2 and peroxides.

[0003] α-Trifluoromethyl olefin is one of the important fluorinated scaffolds for the synthesis of partially fluorinated or non-fluorinated compounds with diverse structures. α-Trifluoromethyl olefin reacts with alkyl radicals to generate α-trifluoromethyl olefin, which is then eliminated by β-fluorine to generate geminal difluoroolefin. Geinal difluoroolefin is an important core skeleton of many pharmacologically and agromedically active molecules and has received extensive attention in the field of drug design and development. Photoinduced intermolecular HAT can functionalize non-activated CH bonds under mild conditions, converting abundant and inexpensive chemical raw materials into high value-added compounds, and its application prospects will be very broad. Summary of the invention

[0004] Purpose of the invention: In order to overcome the limitations of the prior art methods, as a supplement to the existing research on the functionalization of non-activated CH compounds by visible light synergistic metal catalysis, the present invention provides a mild and efficient method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis.

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0006] One of the technical solutions of the present invention is a method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis, the structural formula of which is:

[0007]

[0008] Wherein, R is any one of phenyl, methyl, methoxy, methylthio, benzyloxy, cyano, halogen atom, polycyclic aromatic group, and heterocyclic group, and R 1 For various alkyl groups.

[0009] The second technical solution of the present invention provides a reaction method for synthesizing a difluoroolefin compound from the above-mentioned α-trifluoromethyl olefin and a non-activated alkane, comprising the following steps:

[0010]

[0011] Among them, R 1 It is an alkyl group.

[0012] The α-trifluoromethyl olefin shown in Formula 1, the non-activated alkane shown in Formula 2, a base and a photocatalyst are dissolved in an organic solvent, and stirred for reaction at room temperature for 12 hours under visible light irradiation. After the reaction is completed, the reaction system is separated and purified to obtain the target product of Formula 3.

[0013] The molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 may be 1:20 to 1:300.

[0014] The photocatalyst is tetrabutylammonium decatungstate (TBADT).

[0015] The method for synthesizing geminal difluoroallylglycine or polypeptide derivatives is characterized in that the molar ratio of the glycine derivative represented by formula (1) to the α-trifluoromethyl olefin represented by formula (2) is 1:3 to 2:1.

[0016] The inorganic base includes potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like.

[0017] The molar ratio of the compound shown in Formula 1 to the photocatalyst is 1:0.1.

[0018] The reaction is carried out under blue light irradiation with a wavelength of 390nm.

[0019] The reaction organic solvent is acetonitrile, acetone, dichloromethane and the like.

[0020] The reaction is carried out under an inert gas environment, and the inert gas atmosphere may be nitrogen.

[0021] The transition metal inorganic salts include CrCl3, CrCl2, CeCl3, and FeCl3.

[0022] In the eluent, the volume ratio of petroleum ether to ethyl acetate is 1000:1 to 1:1.

[0023] The progress of the reaction can be monitored by conventional monitoring methods in the art (eg, TLC).

[0024] The steps of separating and purifying the reaction system of the reaction are as follows: the reaction system is directly concentrated under reduced pressure, the obtained concentrate is separated and purified by column chromatography on silica gel, the eluent is petroleum ether or a mixture of petroleum ether and ethyl acetate, the eluent is collected and the solvent is evaporated to obtain the target product.

[0025] In a certain embodiment of the present invention, the difluoroolefin product as shown in Formula 3 includes but is not limited to any of the following structures:

[0026]

[0027] The beneficial effects of the present invention are as follows: the present invention provides a method for synthesizing difluoroolefin compounds from non-activated alkanes using tungsten / chromium synergistic catalysis, wherein the raw materials are stable and easy to prepare, the reaction conditions are mild, the experimental operation is simple, the production capacity is efficient, the functional group tolerance is wide, and the chemical selectivity is good, and the method is a green chemical synthesis method with good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0029] Figure 1 is the reaction formula of α-trifluoromethyl olefin and non-activated alkane;

[0030] Figure 2 The H NMR spectrum of compound 3a prepared in Example;

[0031] Figure 3 The H NMR spectrum of compound 3b prepared in Example;

[0032] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of compound 3c prepared in Example;

[0033] Figure 5-1 The H NMR spectrum of compound 3d prepared in Example;

[0034] Figure 5-2 The carbon NMR spectrum of compound 3d prepared in Example;

[0035] Figure 6-1 This is the hydrogen nuclear magnetic resonance spectrum of compound 3e prepared in Example;

[0036] Figure 6-2 The carbon NMR spectrum of compound 3e prepared in Example;

[0037] Figure 7-1 This is the hydrogen NMR spectrum of compound 3f prepared in Example;

[0038] Figure 7-2 The carbon NMR spectrum of compound 3f prepared in Example;

[0039] Figure 8-1 The hydrogen nuclear magnetic resonance spectrum of compound 3g prepared in Example;

[0040] Figure 8-2 The carbon NMR spectrum of compound 3g prepared in Example;

[0041] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of compound 3h prepared in Example;

[0042] Fig.10 This is the hydrogen nuclear magnetic resonance spectrum of compound 3i prepared in Example;

[0043] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of compound 3j prepared in Example; DETAILED DESCRIPTION

[0044] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0045] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0046] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0047] Example 1: Preparation of 4-(3-cyclohexyl-1,1-difluoropropyl-1-en-2-yl)-1,1'-biphenyl 3a, the formula is as follows:

[0048]

[0049] 4-phenyl-α-trifluoromethylene (0.2mmol), TBADT (10mol%), CrCl3 (5mol%) and potassium phosphate (1.2equiv) were added to a Shrek tube equipped with a stirrer, and the atmosphere was replaced with nitrogen three times. Cyclohexane (20.0equiv) and MeCN (4.0mL) were added under a nitrogen atmosphere. The reaction mixture was sealed, irradiated with a 40W blue LED lamp with a wavelength of 390nm, and stirred at room temperature for 12 hours. After the reaction was completed, the system was concentrated under reduced pressure to remove the solvent to obtain a crude product, which was then purified by column chromatography using petroleum ether as the eluent to obtain 45.6mg of the product with a yield of 73%.

[0050] NMR analysis: 1 H NMR (400MHz, CDCl3) δ7.66-7.59(m, 4H), 7.49-7.44(m, 2H), 7.44-7.34(m, 3H), 2.36-2. 31(m, 2H), 1.76-1.65(m, 5H), 1.36-1.28(m, 1H), 1.20-1.12(m, 3H), 1.02-0.92(m, 2H).

[0051] Example 2: Preparation of 4-(3-cyclopentyl-1,1-difluoroprop-1-en-2-yl)-1,1′-biphenyl 3b, the formula is as follows:

[0052]

[0053] 4-phenyl-α-trifluoromethylene (0.2mmol), TBADT (10mol%), CrCl3 (5mol%) and potassium phosphate (1.2equiv) were added to a Shrek tube equipped with a stirrer, and the atmosphere was replaced with nitrogen three times. Cyclohexane (20.0equiv) and MeCN (4.0mL) were added under a nitrogen atmosphere. The reaction mixture was sealed, irradiated with a 40W blue LED lamp with a wavelength of 390nm, and stirred at room temperature for 12 hours. After the reaction was completed, the system was concentrated under reduced pressure to remove the solvent to obtain a crude product, which was then purified by column chromatography using petroleum ether as the eluent to obtain 33.1mg of the product with a yield of 55%.

[0054] NMR analysis: 1 H NMR (600MHz, CDCl3) δ7.64-7.58(m, 4H), 7.47-7.43(m, 2H), 7.43-7.33(m, 3H), 2.47-2.41(m, 2H) , 1.91-1.83(m, 1H), 1.73-1.67(m, 2H), 1.66-1.60(m, 2H), 1.53-1.46(m, 2H), 1.22-1.15(m, 2H).

[0055] Example 3: Preparation of 4-(3-cycloheptyl-1,1-difluoroprop-1-en-2-yl)-1,1′-biphenyl 3c, except that the cyclohexane in Example 1 was replaced with an equal molar amount of cycloheptane, the target compound 30.0 mg was obtained in a yield of 46%.

[0056] NMR analysis: 1 H NMR (400MHz, CDCl3) δ7.65-7.58 (m, 4H), 7.46 (t, J=7.5Hz, 2H), 7.42-7.33 (m, 3H), 2.38-2.31 (m, 2 H), 1.74-1.69(m, 2H), 1.67-1.61(m, 2H), 1.54-1.48(m, 4H), 1.41-1.30(m, 3H), 1.26-1.18(m, 2H).

[0057] Example 4: Preparation of 4-(3-cyclooctyl-1,1-difluoroprop-1-en-2-yl)-1,1′-biphenyl 3d. The same method as Example 1 was used, except that the cyclohexane in Example 1 was replaced with an equal molar amount of cyclooctane, to obtain 41.2 mg of the target compound with a yield of 61%.

[0058] NMR analysis: 1 H NMR (400MHz, CDCl3) δ7.65-7.58(m,4H), 7.48-7.44(m,2H), 7.41-7.33(m,3H) , 2.37-2.31(m, 2H), 1.71-1.59(m, 5H), 1.52-1.46(m, 4H), 1.44-1.30(m, 6H). 13 CNMR(101 MHz, CDCl3) δ154.2 (dd, J=290.0, 286.4Hz), 140.7, 140.0, 133.1-133.0 (m), 128.9, 128.9-12 8.8 (m), 127.5, 127.2, 127.1, 91.5 (dd, J=21.6, 12.8Hz), 35.4, 35.4, 31.5, 27.5, 26.2, 25.2.

[0059] Example 5: Preparation of 4-(3-cyclododecyl-1,1-difluoroprop-1-en-2-yl)-1,1′-biphenyl 3e. The same method as Example 1 was used, except that the cyclohexane in Example 1 was replaced with an equal molar amount of cyclododecane, to obtain 34.3 mg of the target compound with a yield of 43%.

[0060] NMR analysis: 1H NMR (400MHz, CDCl3) δ7.64-7.57 (m, 4H), 7.48-7.43 (m, 2H), 7.41-7.32 (m, 3H), 2.38-2.32 (m, 2H), 1.38-1.16 (m, 23H). 13 C NMR (101MHz, CDCl3) δ154.1 (t, J=288.1Hz), 140.8, 140.0, 133.0 (d, J=0.9Hz), 128.9, 128.8 (t, J=3 .1Hz), 127.5, 127.2, 91.6 (dd, J=17.7, 16.7Hz), 32.8, 32.1, 28.9, 24.8, 24.0, 23.5, 23.3, 21.6, one C(Ar)missing.

[0061] Example 6: Preparation of 7-(2-([1,1′-biphenyl]-4-yl)-3,3-difluoroallyl)bicyclo[2.2.1]heptane 3f was carried out in the same manner as in Example 1, except that the bridge ring in Example 1 was replaced with an equal molar amount, to obtain 35.7 mg of the target compound with a yield of 55%.

[0062] NMR analysis: 1 H NMR (600MHz, CDCl3) δ7.64-7.58(m, 4H), 7.46(t, J=7.6Hz, 2H), 7.39-7.36(m, 3H), 2.42-2.36(m ,1H), 2.27-2.18(m, 2H), 2.00(s, 1H), 1.50-1.39(m, 4H), 1.36-1.30(m, 1H), 1.14-1.02(m, 4H). 13 C NMR (101MHz, CDCl3) δ154.3 (dd, J=289.9, 286.8Hz), 140.7, 140.0, 133.1-133.0 (m), 128.9, 128.9, 128.8, 127.5 , 127.2 (d, J=10.1Hz), 91.6 (dd, J=20.2, 10.1Hz), 40.6, 40.0 (t, J=10.1Hz), 37.4, 36.9, 35.4, 34.3, 29.9, 28.8.

[0063] Example 7: Preparation of 3 g of 4-(3-cyclohexyl-1,1-difluoroprop-1-en-2-yl)-N-methylbenzamide. The same method as in Example 1 was used, except that the 4-phenyl-α-trifluoromethylene in Example 1 was replaced with an equal molar amount of N-methyl-4-(3,3,3-trifluoroprop-1-en-2-yl)benzamide and column chromatography purification was performed using petroleum ether:ethyl acetate = 5:1 as the eluent to obtain 43.3 mg of the target compound with a yield of 74%.

[0064] NMR analysis: 1 H NMR (400MHz, CDCl3) δ7.74 (d, J = 8.3Hz, 2H), 7.36 (d, J = 7.5Hz, 2H), 6.31 (s, 1H), 3.00 (d, J = 4.8Hz, 3H), 2 .28(dt,J=7.1, 2.2Hz, 2H), 1.69-1.57(m, 5H), 1.24-1.17(m, 1H), 1.14-1.02(m, 3H), 0.96-0.84(m, 2H). 13 C NMR (101MHz, CDCl3) δ168.03, 154.22 (dd, J=291.8, 287.2Hz), 137.59-137.45 (m), 133.35, 128. 51 (t, J=3.3Hz), 127.07, 90.86 (dd, J=22.7, 12.0Hz), 35.87, 35.00, 32.92, 26.98, 26.44, 26.13.

[0065] Example 8: Preparation of 2-(3-cyclohexyl-1,1-difluoroprop-1-en-2-yl)naphthalene 3h. The same method as Example 1 was used, except that the 4-phenyl-α-trifluoromethyl olefin in Example 1 was replaced with an equal molar amount of 2-(3,3,3-trifluoroprop-1-en-2-yl)naphthalene to obtain 30.7 mg of the target compound with a yield of 54%.

[0066] NMR analysis: 1 H NMR (400MHz, CDCl3) δ7.93-7.78 (m, 4H), 7.59-7.45 (m, 3H), 2.47-2.39 (m, 2H) ,1.79-1.61 (m, 5H), 1.35-1.28 (m, 1H), 1.20-1.07 (m, 3H), 1.05-0.93 (m, 2H).

[0067] Example 9: Preparation of 4-(3-cyclohexyl-1,1-difluoroprop-1-en-2-yl)dibenzo[b,d]thiophene 3i. The same method as Example 1 was used, except that the 4-phenyl-α-trifluoromethyl olefin in Example 1 was replaced with an equal molar amount of 4-(3,3,3-trifluoroprop-1-en-2-yl)dibenzo[b,d]thiophene, to obtain 51.7 mg of the target compound with a yield of 75%.

[0068] NMR analysis: 1 H NMR (400MHz, CDCl3) δ8.19-8.10(m, 2H), 7.91-7.85(m, 1H), 7.52-7.45(m, 3H), 7.37-7.30(m, 1H), 2.42(s , 2H), 1.79 (d, J=12.1Hz, 2H), 1.71-1.59 (m, 3H), 1.27-1.19 (m, 1H), 1.17-1.06 (m, 3H), 1.04-0.94 (m, 2H).

[0069] Example 10: Preparation of 4-(3-cyclohexyl-1,1-difluoroprop-1-en-2-yl)dibenzo[b,d]furan 3j. The same method as Example 1 was used, except that the 4-phenyl-α-trifluoromethyl olefin in Example 1 was replaced with an equal molar amount of 4-(3,3,3-trifluoroprop-1-en-2-yl)dibenzo[b,d]furan, to obtain 77.4 mg of the target compound with a yield of 89%.

[0070] NMR analysis: 1 H NMR (400MHz, CDCl3) δ7.98 (d, J=7.7Hz, 1H), 7.95-7.89 (m, 1H), 7.64-7.59 (m, 1H), 7.52-7.46 (m, 1H), 7.37 (dd, J=9.7, 6.2Hz , 3H), 2.54-2.45 (m, 2H), 1.76 (d, J=12.8Hz, 2H), 1.68-1.57 (m, 3H), 1.25-1.17 (m, 1H), 1.14-1.03 (m, 3H), 1.02-0.91 (m, 2H).

[0071] Embodiment 11:

[0072] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that any modification, equivalent substitution and improvement made by a person skilled in the art without departing from the principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis, characterized in that The α-trifluoromethyl olefin represented by formula (1), the non-activated alkyl compound represented by formula (2), a base and a photocatalyst are dissolved in an organic solvent, and reacted at room temperature for 12 to 36 hours under visible light irradiation. After the reaction is completed, the reaction system is separated and purified to obtain the target product, that is, the geminal difluoroolefin represented by formula (3) and its derivatives are synthesized. The reaction formula is as follows:

2. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that The molar ratio of the α-trifluoromethyl olefin represented by formula (1) to the non-activated alkyl compound represented by formula (2) is 1:20 to 1:

300.

3. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that The photocatalyst was tetrabutylammonium decatungstate (TBADT).

4. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that: The inorganic base includes potassium phosphate, sodium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like.

5. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that The molar ratio of the trifluoromethyl olefin represented by formula (1) to the photocatalyst is 1:0.

1.

6. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that Visible light is blue light.

7. The method for synthesizing difluoroolefin compounds by catalytic synthesis of non-activated alkanes using tungsten and chromium according to claim 1, characterized in that Organic solvents include acetonitrile, acetone, etc.

8. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that The reaction is preferably carried out under an inert atmosphere, which may be nitrogen.

9. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that The transition metal inorganic salts such as CrCl3, CrCl2, CeCl3, FeCl 3。 10. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that The steps of separating and purifying the reaction system are as follows: the reaction system is directly concentrated under reduced pressure, the obtained concentrate is separated and purified by column chromatography on silica gel, the eluent is petroleum ether or a mixture of petroleum ether and ethyl acetate, the eluate is collected and the solvent is evaporated to obtain the target product.

11. The method for synthesizing difluoroolefin compounds from non-activated alkanes by tungsten / chromium synergistic catalysis according to claim 1, characterized in that In the eluent, the volume ratio of petroleum ether to ethyl acetate is 1000:1 to 1:1.

Images