Method for promoting synthesis of trifluoromethyl alkane from alcohol derivative through electron donor-acceptor complex

Abstract

The invention discloses a method for promoting synthesis of trifluoromethyl alkane from an alcohol derivative through an electron donor-acceptor complex. Compared with the prior art, the invention provides a method for directly realizing trifluoroalkylation without a photocatalyst. The preparation method provided by the invention is simple in operation steps and good in substrate universality, covers polycyclic and heterocyclic substituted alpha-trifluoromethyl olefins such as naphthalene, dibenzothiophene, modified alcohols and bioactive molecules and natural products, has wide functionality tolerance, is mild in reaction conditions and high in yield, and is suitable for industrial production. The method is a green chemical synthesis method with a good application prospect.

Description

Technical Field

[0001] The invention relates to a mild and efficient method for synthesizing trifluoromethyl alkane from alcohol derivatives by promoting an electron donor-acceptor complex. Background Art

[0002] The introduction of fluorine into target molecules can significantly change their physicochemical and biochemical properties, including dipole moment, hydrogen bonding, lipophilicity, and metabolic stability. Currently, about 20% of pharmaceuticals and 30-40% of pesticides on the market contain fluorine. Among various organofluorine entities, trifluoromethylalkanes are particularly important and commonly found in biologically active molecules.

[0003] Alcohols are among the most abundant raw material chemicals, with low cost, stability, non-toxicity, structural diversity, and a wide range of renewable sources, including biomass and other natural resources. These properties make alcohols excellent precursors for alkyl radicals. α-Trifluoromethyl olefin is one of the important fluorinated scaffolds for the synthesis of structurally diverse partially fluorinated or non-fluorinated compounds. α-Trifluoromethyl olefin reacts with alkyl radicals to generate α-trifluoromethyl olefins, which are then converted into trifluoromethyl alkanes through hydrogen atom transfer. Trifluoromethyl alkanes are important core skeletons of many pharmacologically and agromedically active molecules and have received extensive attention in the field of drug design and development. In this context, one-step modification of alcohols can yield N-alkoxyphthalimides, which can be used as versatile alkyl radical precursors. The use of cheap and readily available photocatalysts under light induction to convert abundant and inexpensive chemical raw materials into high value-added compounds will have broad application prospects. Summary of the invention

[0004] Purpose of the invention: In order to break the limitations of the prior art methods, as a supplement to the existing research methods for dehydrogenation and alkylation of α-trifluoromethyl olefins, the present invention provides a mild and efficient method for synthesizing trifluoromethyl alkanes from alcohol derivatives through electron donor-acceptor complexes.

[0005] 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 trifluoromethylalkanes from alcohol derivatives by promoting an electron donor-acceptor complex, the structural formula of which is:

[0007]

[0008] Wherein, R is any one of phenyl, cyano, ester, halogen, amide, polycyclic aromatic, and heterocyclic groups. 1 For various alkyl groups.

[0009] The second technical solution of the present invention provides a reaction method of the above-mentioned α-trifluoromethyl olefin and N-alkoxyphthalimide, comprising the following steps:

[0010]

[0011] Among them, R 1 , R 2 It is hydrogen, methyl, and phenyl.

[0012] The α-trifluoromethyl olefin shown in Formula 1, the N-alkoxyphthalimide shown in Formula 2, and the reducing agent are dissolved in an organic solvent, and reacted at room temperature for 12 hours under 456nm blue light irradiation. After the reaction, the reaction system is separated and purified to obtain the target product, that is, the target product of Formula 3 is synthesized.

[0013] The reducing agent is Hantzsch ester.

[0014] The organic solvent is acetonitrile, toluene, and tetrahydrofuran.

[0015] The visible light is blue light with a wavelength of 456nm.

[0016] The molar ratio of the compound represented by Formula 1 to the compound represented by Formula 2 may be 1:1.2 or 1:2.

[0017] The molar ratio of the compound represented by Formula 1 to the compound represented by the Hantzsch ester may be 1:1.5.

[0018] The reaction is carried out under an inert gas environment, and the inert gas atmosphere may be nitrogen.

[0019] In the eluent, the volume ratio of petroleum ether to ethyl acetate is 1000:1 to 5:1.

[0020] The progress of the reaction can be monitored by conventional monitoring methods in the art (eg, TLC).

[0021] 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.

[0022] In a certain embodiment of the present invention, the trifluoromethylalkane product as shown in Formula 3 includes but is not limited to any of the following structures:

[0023]

[0024] The beneficial effects of the present invention are as follows: the present invention provides a mild and efficient method for synthesizing trifluoromethylalkanes from alcohol derivatives by promoting an electron donor-acceptor complex without the need for a catalyst, the raw materials are stable and easy to prepare, the reaction conditions are mild, the experimental operation is simple, the production capacity is high, the functional group tolerance is wide, and the chemical selectivity is good. It is a green chemical synthesis method with good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative labor. Among them:

[0026] Figure 1 is the reaction formula of α-trifluoromethyl olefin and N-alkoxyphthalimide;

[0027] Figure 2-1 The H NMR spectrum of compound 3a prepared in Example;

[0028] Figure 2-2 The carbon NMR spectrum of compound 3a prepared in Example;

[0029] Figure 3-1 The H NMR spectrum of compound 3b prepared in Example;

[0030] Figure 3-2 The carbon NMR spectrum of compound 3b prepared in Example;

[0031] Figure 4-1 This is the hydrogen nuclear magnetic resonance spectrum of compound 3e prepared in Example;

[0032] Figure 4-2 The carbon NMR spectrum of compound 3e prepared in Example;

[0033] Figure 5-1 This is the hydrogen NMR spectrum of compound 3f prepared in Example;

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

[0035] Figure 6-1 The hydrogen nuclear magnetic resonance spectrum of compound 3g prepared in Example;

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

[0037] Figure 7-1This is the hydrogen nuclear magnetic resonance spectrum of compound 3h prepared in Example;

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

[0039] Figure 7-2 The carbon NMR spectrum of compound 3h prepared in Example;

[0040] Figure 8-1 The H NMR spectrum of compound 3k prepared in Example;

[0041] Figure 8-2 The carbon NMR spectrum of compound 3k prepared in Example;

[0042] Figure 9-1 The H NMR spectrum of compound 3n prepared in Example;

[0043] Figure 9-2 The carbon NMR spectrum of compound 3n prepared in Example;

[0044] Figure 10-1 The H NMR spectrum of compound 3s prepared in Example;

[0045] Figure 10-2 The carbon NMR spectrum of compound 3s prepared in Example; DETAILED DESCRIPTION

[0046] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation of the present invention is described in detail below in conjunction with the embodiment of the specification.

[0047] 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.

[0048] 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 is it a separate or selective embodiment that is mutually exclusive with other embodiments.

[0049] Example 1: Preparation of tert-butyl 2-(2-([1,1′-biphenyl]-4-yl)-3,3,3-trifluoropropyl)pyrrolidineamine-1-carboxylate 3a, the formula is as follows:

[0050]

[0051] 4-phenyl-α-trifluoromethylene (0.2 mmol), tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate (1.2 equiv), and Hantzsch ester (1.5 equiv) were added to a Shrek tube equipped with a stirrer, and the atmosphere was replaced with nitrogen three times. Acetonitrile (2.0 mL) was added under a nitrogen atmosphere. The reaction mixture was sealed, irradiated with a 40W blue LED lamp with a wavelength of 456 nm, 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: ethyl acetate (10:1-5:1) as the eluent to obtain 61.2 mg of the product with a yield of 73%.

[0052] NMR analysis: 1 H NMR (400 MHz, CDCl 3 )δ7.70-7.59(m, 4H), 7.57-7.33(m, 5H), 4.02-3.22(m, 4H), 2.72-2.34(m, 1H), 2.07-1.68(m, 5H), 1.59-1.43(m, 9H). At RT, this compound appears as an mixture of rotamers. 13 C NMR (101 MHz, CDCl 3 )δ154.5, 141.2, 140.5, 134.6, 129.7, 129.4, 128.9, 127.5, 127.2, 127.1 (q, J=282.2Hz), 79.8, 57.5-53.7(m), 47.6, 46.3, 35.1, 31.2, 28.6, 23.1.Peaks corresponding to the minor rotamerare present at δ141.4, 140.7, 132.7, 129.8, 127.2, 79.3, 47.9, 47.2, 46.7, 46.0, 32.6, 29.9, 28.7, 23.9.

[0053] Example 2: Preparation of tert-butyl ((3S)-5-((1,1′-biphenyl)-4-yl)-6,6,6-trifluoro-2-methylhexan-3-yl)carbamate 3b, the formula is as follows:

[0054]

[0055] The same method as Example 1 was followed, except that the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate in Example 1 was replaced with 2.0 equiv of tert-butyl ((R)-(1-((1,3-dioxolan-2-yl)oxy)-3-methylbutan-2-yl)carbamate to obtain 61.0 mg of the target compound in a yield of 72%.

[0056] NMR analysis: 1 H NMR (400 MHz, CDCl 3 )δ7.64-7.55(m, 4H), 7.50-7.44(m, 2H), 7.42-7.33(m, 3H), 4.09(d,1H), 3.74-3.38(m, 2H), 2. 34-2.17(m, 1H), 2.04-1.89(m, 1H), 1.83-1.72(m, 1H), 1.49-1.34(m, 9H), 0.97-0.86(m, 6H).At PT,this compound appears as anmixture of rotamers. 13 C NMR (101 MHz, CDCl 3 )δ155.8, 141.2, 140.6, 133.3, 129.4, 128.9, 127.6, 127.2, 127.1 (q, J=282.8Hz) 79.3, 52.5, 48.7-46.0 (m), 33.0, 31.8, 28.5, 20.1, 17.9.Peaks corresponding to the minor rotamer are present at δ155.7, 141.1, 140.7, 134.6, 129.8, 128.8, 127.5, 127.5, 127.3, 79.1, 54.5, 53.7, 33.7, 32.6, 32.4, 29.0, 28.5, 28.2, 19.2, 18.8, 17.5, 17.0.

[0057] Example 3: Preparation of 2-(2-((1,1′-biphenyl)-4-yl)-3,3,3-trifluoropropyl)tetrahydrofuran 3e, except that the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate in Example 1 was replaced with an equal molar amount of 2-((tetrahydrofuran-2-yl)methoxy)isoindole-1,3-dione. The preparation was carried out in the same manner as in Example 1 to obtain 31.6 mg of the target compound with a yield of 50%.

[0058] NMR analysis: 1H NMR (400 MHz, CDCl 3 )67.68-7.56(m, 4H), 7.49-7.39(m, 4H), 7.39-7.34(m, 1H), 3.93-3.78(m, 1H), 3.75-3. 61(m, 2H), 3.62-3.49(m, 1H), 2.19-2.00(m, 2H), 1.99-1.71(m, 3H), 1.56-1.42(m, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ141.1, 140.7, 133.6, 129.8, 128.9, 127.6, 127.5, 127.3 (q, J=279.3Hz), 127.2, 75.0, 67.7, 47.2 (q, J=26.8Hz), 35.3, 31.7, 25.8.

[0059] Example 4: Preparation of methyl 5-((1,1′-biphenyl)-4-yl)-6,6,6-trifluorohexylcarboxylate 3f. The same method as in Example 1 was used, except that the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate in Example 1 was replaced with an equal molar amount of 2-((tetrahydrofuran-2-yl)oxy)isoindolin-1,3-dione to obtain 27.6 mg of the target compound with a yield of 43%.

[0060] NMR analysis: 1 H NMR (400 MHz, CDCl 3 )δ8.04 (s, 1H), 7.68-7.59 (m, 4H), 7.52-7.45 (m, 2H), 7.44-7.33 (m, 3H), 4.15 (t, J = 6.6Hz, 2H), 3.41-3.20(m, 1H), 2.15-2.05(m, 1H), 2.04-1.92(m, 1H), 1.77-1.63(m, 2H), 1.39-1.29(m, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ161.1, 141.2, 140.4, 133.5, 129.4, 128.9, 127.5, 127.5, 127.1, 126.9 (q, J=282.8Hz), 63.5, 49.7 (q, J=26.5Hz), 28.4, 28.2, 23.3.

[0061] Example 5: Preparation of 3 g of methyl 6-((1,1′-biphenyl)-4-yl)-7,7,7-trifluoroheptanoate. The same method as Example 1 was used, except that the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate in Example 1 was replaced with an equal molar amount of 2-((tetrahydro-2H-pyran-2-yl)oxy)isoindole-1,3-dione to obtain 45.3 mg of the target compound with a yield of 65%.

[0062] NMR analysis: 1 H NMR (400 MHz, CDCl 3 )δ8.08-7.99(m, 1H), 7.68-7.55(m, 4H), 7.53-7.31(m, 5H), 4.13(t, J=6.6Hz, 2H), 3.45-3.09(m, 1 H), 2.14-1.99(m, 1H), 1.99-1.86(m, 1H), 1.68-1.57(m, 2H), 1.48-1.33(m, 2H), 1.31-1.24(m, 2H). 13 C NMR (151 MHz, CDCl 3 )δ161.2, 141.2, 140.6, 133.8, 129.5, 128.9, 127.6, 127.5, 127.2, 63.9, 49.8 (q, J=26.5Hz) 28.7, 28.3, 26.5, 25.7.

[0063] Example 6: Preparation of methyl ((4S,5S)-5-(2-((1,1′-biphenyl)-4-yl)-3,3,3-trifluoropropyl)-2,2-dimethyl-1,3-dioxolan-4-yl)((S)-2,2-dimethyl-1,3-dioxolan-4-yl)carboxylate 3h, except that the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy The same method as in Example 1 was followed except that 2-(((3aS,6aS)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuran(3,4-d)(1,3)dioxolan-4-yl)oxy)isoindole-1,3-dione was used to obtain 55.8 mg of the target compound with a yield of 55%.

[0064] NMR analysis: 1 H NMR (600 MHz, CDCl 3)δ7.89 (s, 1H), 7.65-7.55 (m, 4H), 7.45 (t, J = 7.6Hz, 2H), 7.40-7.31 (m, 3H), 5.08 ( dd, J=6.3, 2.9Hz, 1H), 4.22 (q, J=6.2Hz, 1H), 4.00 (dd, J=8.8, 6.4Hz, 1H), 3.89 (dd, J=8.0, 2.9Hz, 1H), 3.79 (dd, J=8.8, 6.1Hz, 1H), 3.67 (dd, J=18.5, 9.2Hz, 1H), 3.47 -3.34 (m, 1H), 2.27-2.10 (m, 2H), 1.42 (s, 3H), 1.33 (d, J = 11.2Hz, 6H), 1.23 (s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ159.8, 141.3, 140.6, 132.3, 129.8, 129.0, 127.7, 127.4, 127.2, 127.0 (q, J=282.8Hz), 10 9.7, 109.4, 79.7, 74.9, 72.9, 69.8, 66.2, 46.8 (q, J=27.3Hz), 31.7, 27.5, 26.6, 26.5, 25.5. 19 F NMR (565MHz, CDCl 3 )δ-69.94(s).

[0065] Example 7: Preparation of 3-(1,1,1-trifluoro-3-(tetrahydrofuran-2-yl)propan-2-yl)benzonitrile 3k, except that the 4-phenyl-α-trifluoromethyl olefin in Example 1 was replaced by an equal molar amount of 3-(3,3,3-trifluoroprop-1-en-2-yl)benzonitrile and the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate was replaced by an equal molar amount of 2-((tetrahydrofuran-2-yl)methoxy)isoindole-1,3-dione. The same method as Example 1 was used to obtain 24.2 mg of the target compound with a yield of 45%.

[0066] NMR analysis: 1 H NMR (600 MHz, CDCl 3 )δ7.66-7.52(m, 3H), 7.52-7.43(m, 1H), 3.87-3.80(m, 1H), 3.74-3.59(m, 2H), 3.45-3. 32(m, 1H), 2.11-1.95(m, 2H), 1.95-1.85(m, 2H), 1.86-1.75(m, 1H), 1.55-1.41(m, 1H). 13C NMR (151 MHz, CDCl 3 ) δ136.2, 134.0, 132.9, 132.0, 129.7, 128.7, 118.5, 113.1, 74.5, 67.8, 47.1 (q, J=27.3Hz), 35.0, 31.7, 25.7.

[0067] Example 8: Preparation of methyl 4-(1,1,1-trifluoro-3-(tetrahydrofuran-2-yl)propan-2-yl)benzoate 3n. The same method as in Example 1 was used, except that the 4-phenyl-α-trifluoromethyl olefin in Example 1 was replaced with an equal molar amount of methyl 4-(3,3,3-trifluoroprop-1-en-2-yl)benzoate and the tert-butyl (R)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate was replaced with an equal molar amount of 2-((tetrahydrofuran-2-yl)methoxy)isoindole-1,3-dione. The target compound (49.6 mg) was obtained in a yield of 82%.

[0068] NMR analysis: 1 H NMR (600 MHz, CDCl 3 )δ8.18-7.89(m, 1H), 7.58-7.34(m, 1H), 3.92(s, 1H), 3.91-3.77(m, 1H), 3.76-3.68(m, 1H), 3 .67-3.62(m, 1H), 2.14-1.96(m, 1H), 1.96-1.84(m, 1H), 1.83-1.73(m, 1H), 1.52-1.40(m, 1H). 13 C NMR (151MHz, CDCl3) 6166.8, 139.7, 130.2, 130.0, 129.5, 126.9 (q, J=279.6Hz), 74.8, 67.7, 52.3, 47.4 (q, J=26.9Hz), 35.2, 31.7, 25.7.

[0069] Example 9: Preparation of tert-butyl 2-(2-(4-((4-(ethoxycarbonyl)phenyl)carbamoyl)phenyl)-3,3,3-trifluoropropyl)pyrrolidine-1-carboxylate 3s, except that the 4-phenyl-α-trifluoromethyl olefin in Example 1 was replaced with an equal molar amount of ethyl 4-(4-(3,3,3-trifluoroprop-1-en-2-yl)benzoyl)benzoate, the result was carried out in the same manner as Example 1 to obtain 99.4 mg of the target compound with a yield of 93%.

[0070] NMR analysis: 1 H NMR (400 MHz, CDCl 3)δ8.91-8.30(m, 1H), 8.13-7.97(m, 2H), 7.92-7.80(m, 2H), 7.80-7.66(m, 2H), 7.57-7.29(m, 2H), 4.36(q, J=7.1Hz, 2 H), 3.86-3.66 (m, 1H), 3.52-3.09 (m, 3H), 2.74-2.23 (m, 1H), 2.14-1.53 ​​(m, 5H), 1.46 (s, 9H), 1.39 (t, J=7.1Hz, 3H).At RT,this compound appears as an mixture of rotamers. 13 C MR (101MHz,CDCl 3 )δ171.3, 1663, 157.2, 154.4, 142.6, 139.5, 130.7, 129.3, 127.8, 126.0, 119.5, 80.3, 67.5, 60.9, 54.2, 47.6, 31.2, 28.5, 24.0, 21.1, 14.4, one C(CF 3 )missing.Peakscorresponding to the minor rotamer are present at δ155.1, 154.7, 129.6, 129.5, 129.2, 127.6, 79.9, 79.7, 79.4, 60.5, 60.1, 56.3, 55.0, 46.3, 34.9, 28.7, 28.6, 28.4, 23.0, 21.9, 14.2.

[0071] Embodiment 10:

[0072] The description of the above embodiments is only used to help understand the method of the present invention and its core concept. It should be pointed out that for ordinary technicians in this technical field, any modifications, equivalent substitutions and improvements made without departing from the principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing trifluoromethylalkanes from alcohol derivatives by promoting an electron donor-acceptor complex, characterized in that The α-trifluoromethyl olefin shown in Formula 1, the N-alkoxyphthalimide shown in Formula 2, and the reducing agent are dissolved in an organic solvent, and reacted 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, that is, the trifluoromethyl alkane and its derivatives shown in Formula 3 are synthesized, and the reaction formula is as follows:

2. A method for synthesizing trifluoromethylalkanes from alcohol derivatives by promoting an electron donor-acceptor complex according to claim 1, characterized in that The reducing agent is Hantzsch ester.

3. The method of claim 1, wherein the method comprises: The solvent is acetonitrile, toluene and tetrahydrofuran.

4. The method of claim 1, wherein the method comprises: The visible light is blue light.

5. The method of claim 1, wherein the method comprises: The molar ratio of the α-trifluoromethyl olefin shown in Formula 1 to the N-alkoxyphthalimide shown in Formula 2 is 1:1.2 or 1:

2.

6. The method of claim 1, wherein the method comprises: The reaction is preferably carried out under an inert atmosphere, which may be nitrogen.

7. The method of claim 1, wherein the method comprises: 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.

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