Method for synthesizing polysubstituted trifluoromethyl olefin from gem-difluoroallyl alcohol

Abstract

The invention discloses a method for synthesizing a polysubstituted trifluoromethyl olefin compound from gem-difluoroallyl alcohol. The preparation method comprises the following steps: in a nitrogen (N2) atmosphere, sequentially adding a gem-difluoroallyl alcohol (R1R2OHCR3C = CF2) compound, acetic anhydride (Ac2O), a solvent dichloromethane (DCM) and a fluorine source pyridine hydrofluoride (Py.9HF) reagent into a 10mL Schlenk tube to obtain a mixture, stirring the mixture at room temperature (rt) until the reaction is finished, filtering, washing and drying to obtain the compound. A crude product obtained by the reaction is subjected to silica gel column chromatography separation to obtain the high-selectivity polysubstituted trifluoromethyl olefin compound. The preparation method disclosed by the invention can be carried out under mild conditions and is simple and convenient to operate, most of the adopted raw materials are simple and easily available or commercialized reagents, the reaction raw materials are easily available, the yield of the target product is high, the functional group compatibility of the product is good, and the application range of a substrate is relatively wide; the obtained polysubstituted trifluoromethyl olefin compound contains a plurality of functional groups such as trifluoromethyl, olefin and the like. The method provides a more efficient and safer new strategy for synthesizing the polysubstituted trifluoromethyl olefin under mild conditions, particularly, metal participation is avoided, a new opportunity is provided for green medicine synthesis, and the method is predicted to have wide application prospects in the fields of medicine research and development, natural product derivative synthesis, life science and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and in particular relates to a green, metal-free method for synthesizing trifluoromethyl olefin compounds. Background Technology

[0002] In 2024, 31 of the top 200 drugs by retail sales contained fluorine, accounting for 15.5%, of which 6 contained "trifluoromethyl olefins." Trifluoromethyl olefin derivatives, as an important class of fluorine-containing compounds, are not only widely found in bioactive molecules, drugs, and functional materials, but also have been widely used in the preparation of more refined fluorine-containing compounds, as shown in the figure below. Therefore, how to prepare structurally complex and functionally diverse trifluoromethyl olefins in a green and efficient manner (especially those synthetic methods that require expensive metals and poorly biocompatible metals, and how to develop new green synthetic methods to replace those impractical methods) has attracted great interest from researchers in related fields. To date, the developed synthetic methodologies are quite mature. In the reference section, we reviewed the methods for synthesizing trifluoromethyl olefins, which can be categorized as: 1. Alkenylation reaction for the synthesis of trifluoromethyl substituted alkenes; 2. Transition metal-catalyzed trifluoromethylation of olefin derivatives; 3. Direct trifluoromethylation of olefin C-H bonds; and 4. Addition functionalization reaction of alkynes for the synthesis of trifluoromethyl olefins.

[0003]

[0004] The trifluoromethyl functional group, due to its unique properties, makes trifluoromethyl-modified pharmaceutical and pesticide molecules widely used in our lives. Regarding the preparation of polysubstituted trifluoromethyl alkenes, chemists have developed numerous strategies to date, which will be illustrated below.

[0005] 1. The synthesis of trifluoromethyl substituted alkenes by alkenylation reaction is most traditionally the Wittig reaction of fluorinated quaternary phosphonium salts with aldehydes and ketones. In the ylide reaction, the reaction center is the ylide carbon atom. However, in fluorinated ylides, the electron-withdrawing effect of the fluorinated group greatly reduces the reactivity of the ylide. In reference 1, in 1993, the Shen research group (YCShen; WMQiu, Acta. Chim. Sin. 1993, 53, 1209-1213.) made a new discovery in the alkenylation reaction of fluorinated ylides in the method (2-b). The authors used ordinary ylides to react with trifluoroacetic anhydride to obtain trifluoroacetylmethylene quaternary phosphonium salt. This quaternary phosphonium salt can react with lithium reagents to attack the carbonyl carbon and then remove triphenylphosphine oxide to obtain trifluoromethyl polysubstituted alkene products. Reference 2, 2002, Ishibashi research group (T. Kobayashi; T. Eda; O. Tamura; H. Ishibashi, J. Org. Chem. 2002, 67, 3156-315910) . In the disclosed method (2-a), trifluoroethyl diphenylphosphine is used as a phosphine ylide, and under the condition of using tetrabutylammonium fluoride as a base, the alkenylation reaction of aldehydes can be realized to synthesize trifluoromethyl substituted alkenes, as shown in the figure below.

[0006]

[0007] 2. Transition Metal Catalyzed Trifluoromethylation of Alkene Derivatives: With the widespread discovery of trifluoromethylating agents, the synthesis of trifluoromethyl-containing organic molecules has rapidly developed in the field of synthetic methodology. The advantage of trifluoromethylating agents is that they can introduce the CF3 group into the organic molecule at any stage of the synthetic reaction. To meet the demand for trifluoromethyl-containing compounds in production and daily life, an increasing number of trifluoromethyl-containing reagents have been developed. The following is a brief introduction to the trifluoromethylation reactions involving Chern's reagent, Ruppert-Prakash reagent (TMSCF3), Umemoto reagent, Togni reagent, and Langois reagent (CF3SO2Na). Chern's reagent is a difluorocarbene + fluoride anion; Ruppert-Prakash reagent is a nucleophilic trifluoromethylating agent; Umemoto and Togni reagents are electrophilic trifluoromethylating agents; and CF3SO2Na is a radical trifluoromethylating agent, as shown in the figure below.

[0008]

[0009] With the rapid development of trifluoromethyl reagents in recent years, the synthesis of trifluoromethyl-substituted alkenes has also been extensively studied. This paper summarizes and discusses reports on the synthesis of trifluoromethyl alkenes using trifluoromethylating reagents. Firstly, it discusses the synthesis of polysubstituted alkenes using alkene derivatives via trifluoromethylation reactions. For alkenyl halides, the corresponding alkenes can be constructed directly using substitution reactions with nucleophilic trifluoromethyl reagents. Reference 3 (F.-L Qing, X. Zhang, Y. Peng, J Fluor. Chem., 2001, 111, 185-187.) describes a method published by Qing's group in 2001 that utilizes vinyl halides, with "Chen reagent" as the trifluoromethyl source, and is catalyzed by transition metal copper (Cu) to construct trifluoromethyl alkene compounds, as shown in the figure below.

[0010]

[0011] Of course, alkenes with leaving groups can also undergo trifluoromethylation under palladium catalysis. Reference 4 (EJCho, S.L. Buchwald, Org. Lett., 2011, 13, 6552-6555), published by Buchwald's group in 2011, describes the synthesis of cyclic trifluoromethyl olefin compounds from easily leaving-group-substituted cyclic alkenes using TMSCF3 or TESCF3 as the trifluoromethyl source, as shown in the figure below.

[0012]

[0013] Reference 5 (Z. He, T. Luo, M. Hu, Y. Cao, J. Hu, Angew. Chem. Int. Ed. 2012, 51, 3944-3947.) states that in 2012, Hu's research group published a method that more conveniently utilizes alkenyl carboxylic acids to achieve decarboxylation trifluoromethylation with trifluoromethylating reagents under copper catalysis, thereby obtaining trifluoromethyl olefins, as shown in the figure below.

[0014]

[0015] Reference 6 (SRDubbaka, M.Salla, R.Bolisettia, S.Nizalapur, RSCAdv., 2014, 4, 6496-6499.) describes a method published by Dubbaka's group in 2014 in which alkenylboronic acid or alkenyl fluoroborates were used to construct trifluoromethyl olefin compounds in the presence of cuprous chloride, an oxidant, and sodium trifluoromethyl sulfinate, as shown in the figure below.

[0016]

[0017] 3. Direct trifluoromethylation of olefin CH bonds: With the development of trifluoromethylation reactions of olefin derivatives, it was realized that the stereoselectivity of the reaction products was still not well controlled. At the same time, the preparation of alkenyl derivatives was relatively cumbersome. In view of the problems with the above strategies, researchers began to explore the direct trifluoromethylation reaction of olefin substrates to synthesize trifluoromethyl olefins. After long-term exploration, it was found that the target transformation could be well completed using trifluoromethylating reagents under copper catalysis, as shown in the figure below. In order to better control the stereoselectivity of the reaction, generally speaking, only styrene substrates and alkenes modified with directing groups (carbonyl, imine, etc.) can yield stereospecific trifluoromethyl olefins under copper catalysis.

[0018]

[0019] Reference 7 (M. Beller, Chem. Commun., 2020, 56, 15157.) states that in 2020, Beller's research group disclosed a direct perfluoroalkylation reaction of carbon-hydrogen bonds in alkenes and cyclic alkenes, constructing perfluoroalkyl-substituted alkenes. The reaction was carried out under nickel(I) catalysis and sodium tert-butoxide as a base, with high reaction efficiency and a product yield of 90%, as shown in the figure below.

[0020]

[0021] Reference 8 (EJCho, J.Org.Chem.2012, 77, 11383-11387.) states that in 2017, Cho's research group disclosed a method for the high-efficiency synthesis of terminal trifluoromethyl olefins from terminal olefins, with a yield of 95% and a selectivity for the single E configuration. The reaction was achieved under ruthenium catalysis and DBU as a base, as shown in the figure below.

[0022]

[0023] 4. Synthesis of trifluoromethyl alkenes via addition functionalization of alkynes. Although the direct trifluoromethylation of alkenes has made significant progress, the exploration of trifluoromethyl alkene synthesis has not stopped. Trifluoromethyl alkenes can also be obtained by the addition functionalization of alkynes. The more mature research is on the use of trifluoromethylating reagents to achieve the hydrogen trifluoromethylation of terminal alkynes or the addition functionalization of trifluoromethyl-substituted non-terminal alkynes, as shown in the figure below. Such reactions can be achieved under metal catalysis. However, the stereoselectivity of the reaction has not been well solved.

[0024]

[0025] Reference 9 (N. Iqbal, J. Jung, S. Park, EJ. Cho, Angew. Chem. Int. Ed. 2014, 53, 539-542.) states that in 2014, Cho's group disclosed a trifluoromethyl functionalization reaction of terminal alkynes, yielding trifluoromethyl olefin products in high yield and with high selectivity. Under ruthenium catalysis, this reaction yields a bifunctionalized product, simultaneously introducing trifluoromethyl and iodine into the alkyne feedstock. However, under iridium catalysis, the target product is obtained with only one trifluoromethyl group. The reaction can yield the target product in up to 95% yield, but the selectivity is not good, as shown in the figure below.

[0026]

[0027] Reference 10 (S.-L. Zhang, J.-J. Dong, Org. Lett. 2019, 21, 6893-6896.) states that Zhang's research group disclosed the trifluoromethylation reaction of aryl-terminated alkynes in 2019. The target reaction was achieved under the action of equivalent trifluoromethyl copper, and the target product was obtained in 77% yield. However, when using a substrate with an ortho-carbon substituent as an aldehyde, the reaction generates a benzofuran analog, and the trifluoromethyl alkene structure still exists, as shown in the figure below.

[0028]

[0029] Reference 11 (A. Jacksonb, J. Fluor. Chem., 2022, 253, 109922.) states that in 2022, Jackson's research group disclosed a method for constructing trifluoromethyl olefins by hydrosilylation of bis(trifluoromethylacetylene). This reaction is highly efficient, essentially an equivalence reaction, and has good functional group compatibility and a wide substrate range, as shown in the figure below.

[0030]

[0031] However, these strategies all have some drawbacks, such as high requirements for reaction temperature, long reaction time, complex solvent systems, and expensive fluorine sources. Therefore, developing simple, convenient, and practical new strategies for the preparation of trifluoromethyl olefins remains of great significance. This type of research is expected to play a significant role in organic synthesis and drug development. Summary of the Invention

[0032] The primary objective of this invention is to provide a green method for synthesizing polysubstituted trifluoromethyl olefins from gem-difluoroallyl alcohol, aiming to solve the problems of high requirements for precious metals and poorly biocompatible metals, high temperature requirements, long reaction times, complex solvent systems, and expensive fluorine sources in existing methods for synthesizing trifluoromethyl olefins.

[0033] Another object of the present invention is to provide the above-mentioned trifluoromethyl olefin compounds and to synthesize bioactive molecules, drugs and functional materials containing trifluoromethyl olefin groups by green methods.

[0034] This invention is achieved by providing a trifluoromethyl olefin compound with the following chemical structural formula (I):

[0035]

[0036] In equation (I), R 1 It can be phenyl, benzyl, phenethyl, naphthylethyl, alkyl, heterocyclic group, cyclic group or other alkyl or functionalized alkyl, wherein benzyl includes 4-bromobenzyl, 4-chlorobenzyl, 3-trifluoromethylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, phenyl includes 4-cyanophenyl, phenethyl includes 4-methoxyphenethyl, 4-tert-butylphenethyl, 4-isobutylphenethyl, 4-trifluoromethoxyphenethyl, heterocyclic group includes 3-thiophene group, cyclic group includes cyclohexyl, cyclobutyl, 3-phenylcyclobutyl, thiophene group, benzocyclopentyl group, etc.

[0037] R 2 It can be a hydrogen, methyl, ethyl, propyl, cyclic hydrocarbon drug molecule fragment, or other alkyl or functionalized alkyl groups.

[0038] R 3 It can be hydrogen, iodine, aryl or other groups, among which aryl includes phenyl, 4-methoxyphenyl, 4-methyl carboxylate phenyl and other phenyl substituents.

[0039] This invention further discloses a method for preparing the above-mentioned trifluoromethyl olefin compounds, the method comprising the following steps:

[0040] (1) Under a nitrogen (N2) atmosphere, gem-difluoroallyl alcohol (R) 1 R 2 OHCR 3C=CF2) compounds, acetic anhydride (Ac2O), dichloromethane (DCM) solvent, and pyridine hydrofluoric acid (Py·9HF) reagent were sequentially added to a 10 mL Schlenk tube to obtain a mixture. The mixture was stirred at room temperature (rt) until the reaction was complete. The crude product obtained from the reaction was separated by silica gel column chromatography to obtain highly selective polysubstituted trifluoromethyl olefin compounds.

[0041] Preferably, in step (1), the R of the gem-difluoroallyl alcohol... 1 It can be phenyl, benzyl, phenethyl, naphthylethyl, alkyl, heterocyclic group, cyclic group or other alkyl or functionalized alkyl, wherein benzyl includes 4-bromobenzyl, 4-chlorobenzyl, 3-trifluoromethylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, phenyl includes 4-cyanophenyl, phenethyl includes 4-methoxyphenethyl, 4-tert-butylphenethyl, 4-isobutylphenethyl, 4-trifluoromethoxyphenethyl, heterocyclic group includes 3-thiophene group, cyclic group includes cyclohexyl, cyclobutyl, 3-phenylcyclobutyl, thiophene group, benzocyclopentyl group, etc.;

[0042] R 2 It can be a hydrogen, methyl, ethyl, propyl, cyclic hydrocarbon drug molecule fragment, or other alkyl or functionalized alkyl groups;

[0043] R 3 It can be hydrogen, iodine, aryl or other groups, among which aryl includes phenyl, 4-methoxyphenyl, 4-methyl carboxylate phenyl and other phenyl substituents.

[0044] Preferably, in step (1), the reaction solvent is dichloromethane, and the mixture is stirred and reacted at room temperature for 12 hours.

[0045] This invention further discloses a method for synthesizing trifluoromethyl olefin compounds using nucleophilic fluorine reagents and gem-difluoroallyl alcohol.

[0046] This invention overcomes the shortcomings of existing technologies and provides a strategy for synthesizing trifluoromethyl olefin compounds under mild conditions. Under a nitrogen (N2) atmosphere, gem-difluoroallyl alcohol (R... 1 R 2 OHCR 3 C=CF2) compounds, acetic anhydride (Ac2O), dichloromethane (DCM) solvent, and pyridine hydrofluoric acid (Py·9HF) reagent were sequentially added to a 10 mL Schkenk tube to obtain a mixture. The mixture was stirred at room temperature (rt) until the reaction was complete. The crude product obtained from the reaction was separated by silica gel column chromatography to obtain highly selective polysubstituted trifluoromethyl olefin compounds.

[0047] In the preparation method of this invention, when the auxiliary dehydroxylation reagent is acetic anhydride (Ac2O) and the fluorine source is pyridine hydrofluoric acid (Py·9HF), the reaction equation for the preparation of trifluoromethyl olefin compounds is as follows:

[0048]

[0049] Therefore, in this invention, commercially available pyridine hydrofluoric acid salt (Py·9HF) generates fluoride anions in a solvent. These fluoride anions selectively attack geminal difluorocarbons, while leaving groups (such as acetic acid or water molecules) leave, thus enabling the one-pot preparation of important trifluoromethyl olefin compounds.

[0050] Fluorine atoms or fluorine-containing groups are functional structural segments in many bioactive molecules. The trifluoromethyl olefin compounds prepared in this invention are expected to have great potential in drug development. Furthermore, these compounds can be transformed into more fluorine-containing or fluorine-free compounds using well-developed organic synthesis chemistry, and these compounds can also play very important roles in synthetic chemistry or medicinal chemistry.

[0051] Compared with the shortcomings and deficiencies of existing technologies, the present invention has the following advantages:

[0052] (1) It is metal-free and environmentally friendly, reacts under mild conditions at room temperature, has a wide range of substrates, produces highly selective and high-yield products, and uses inexpensive and readily available raw materials, making it economically viable.

[0053] (2) The method of the present invention for preparing trifluoromethyl olefin compounds is highly efficient and has good functional group compatibility;

[0054] (3) The preparation method of trifluoromethyl olefin compounds provided by the present invention can be used for the functionalization research of drug molecules in the later stage, and has broad application prospects in drug development and organic synthesis. Attached Figure Description

[0055] Figure 1 This is the "Abstract Drawings" section of the present invention patent;

[0056] Figure 2 This is the 1H NMR spectrum of the target product 1-(1-(4,4-dimethylcyclohexyl)-2,2,2-trifluorovinyl)-4-methoxybenzene (2a) in Example 1 of this invention;

[0057] Figure 3 This is the fluorine spectrum of the target product 1-(1-(4,4-dimethylcyclohexyl)-2,2,2-trifluorovinyl)-4-methoxybenzene (2a) in Example 1 of the present invention;

[0058] Figure 4This is the carbon spectrum of the target product 1-(1-(4,4-dimethylcyclohexyl)-2,2,2-trifluorovinyl)-4-methoxybenzene (2a) in Example 1 of the present invention;

[0059] Figure 5 This is the 1H NMR spectrum of the target product (cis / trans)-3-bromo-2-(4,4,4-trifluoro-3-iodo-but-2-en-2-yl)thiophene (2b) in Example 2 of this invention;

[0060] Figure 6 This is the fluorine spectrum of the target product (cis / trans)-3-bromo-2-(4,4,4-trifluoro-3-iodo-but-2-en-2-yl)thiophene (2b) in Example 2 of the present invention;

[0061] Figure 7 This is the carbon spectrum of the target product (cis / trans)-3-bromo-2-(4,4,4-trifluoro-3-iodo-but-2-en-2-yl)thiophene (2b) in Example 2 of this invention. Detailed Implementation

[0062] 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 examples described herein are merely illustrative and not intended to limit the invention.

[0063] Example 1

[0064] Reaction: (1) Under a nitrogen (N2) atmosphere, 1-(2,2-difluoro-1-(4-methoxyphenyl)vinyl)-4,4-dimethylcyclohexane-1-ol (1a) (0.15 mmol, 1.0 equiv.), dichloromethane (DCM) (1 mL, 0.15 M), acetic anhydride (Ac2O) (0.075 mmol, 0.5 equiv.), and pyridine hydrofluoric acid salt (Py·9HF) (3.0 mmol HF, 20.0 equiv. of HF) were added sequentially to 10 mL of Schlenk to obtain a mixture. The mixture was stirred at room temperature (rt) until the reaction was completed.

[0065] (2) The mixture from reaction (1) was treated with {eluent: ethyl acetate (EA) and stationary phase: diatomaceous earth}, filtered to obtain the crude target product, concentrated and evaporated of the solvent, and then loaded onto the dry silica gel after the concentrated and evaporated eluent by a dry loading method (the product was mixed with silica gel and eluent, and the dry silica gel was loaded onto the silica gel after the eluent was evaporated). The expected trifluoromethyl olefin compound was obtained by silica gel column chromatography. Column chromatography separation conditions: stationary phase: 300-400 mesh silica gel powder, mobile phase: ethyl acetate (EA) and petroleum ether (PE), mobile phase change program (EA / PE) of 0:100-5:100, finally yielding 37.3 mg of the target product 1-(1-(4,4-dimethylcyclohexyl)-2,2,2-trifluorovinyl)-4-methoxybenzene (2a), the reaction equation of which is shown below:

[0066]

[0067] The obtained (1-(1-(4,4-didimethylcyclohexyl)-2,2,2-trifluorovinyl)-4-methoxybenzene (2a) was characterized, and the NMR spectrum is shown below. Figure 2 , 3 As shown in Figure 4, its morphological and characterization data are as follows:

[0068] Appearance: Colorless oily substance (37.3 mg, 0.125 mmol, yield: 83%). 1 H NMR (400MHz, CDCl3): δ7.10-7.03 (m, 2H), 6.92-6.86 (m, 2H), 3.82 (s, 3H), 2.57-2 .50(m, 2H), 2.05-1.98(m, 2H), 1.54-1.48(m, 2H), 1.34-1.29(m, 2H), 0.98(s, 6H). 19 F NMR (376MHz, CDCl3): δ-54.37 (s, 3F). 13 C NMR (101MHz, CDCl3): δ159.05, 151.72, 151.69, 151.66, 151.63 (q, J=2.93Hz), 131.20, 128.42, 127.77, 125.68, 124.44, 124.14, 123.85, 123 .55 (q, J=29.69Hz), 122.94, 120.20 (q, J=274.64Hz), 113.69, 55.28, 40.69, 40.64, 30.17, 28.98, 28.13, 27.36. HRMS (ESI, m / z): calculated for C 17 H 22F3O[M+H] + :299.1623, found:299.1623.Rf=0.8 (PE / EA=20:1).

[0069] Example 2

[0070] Reaction: (1) Under a nitrogen (N2) atmosphere, 2-(3-bromothiophene-2-yl)-4,4-difluoro-3-iodo-but-3-en-2-ol (1b) (0.15 mmol, 1.0 equiv.), dichloromethane (DCM) (1 mL, 0.15 M), acetic anhydride (Ac2O) (0.075 mmol, 0.5 equiv.), and pyridine hydrofluoric acid salt (Py·9HF) (3.0 mmol HF, 20.0 equiv. of HF) were added sequentially to 10 mL of Schlenk to obtain a mixture. The mixture was stirred at room temperature (rt) until the reaction was completed.

[0071] (2) The mixture from reaction (1) was treated with {eluent: dichloromethane (DCM) and stationary phase: diatomaceous earth}, filtered to obtain the crude target product, concentrated and evaporated the solvent, and then loaded onto the silica gel after the eluent was concentrated and evaporated by dry loading. The expected trifluoromethyl olefin compound was obtained by silica gel column chromatography. Column chromatography separation conditions: stationary phase: 300-400 mesh silica gel powder, mobile phase: ethyl acetate (EA) and petroleum ether (PE), mobile phase change program (EA / PE) of 0:1-5:100, finally yielding 30.9 mg of the target product (cis / trans)-3-bromo-2-(4,4,4-trifluoro-3-iodo-but-2-en-2-yl)thiophene (2b), the reaction equation of which is shown below:

[0072]

[0073] The above (cis / trans)-3-bromo-2-(4,4,4-trifluoro-3-iodo-but-2-en-2-yl)thiophene (2b) was characterized, and the NMR spectrum is shown below. Figure 5 , 6 As shown in Figures 7 and 8, its morphological and characterization data are as follows:

[0074] Appearance: Colorless oily substance (30.9 mg, 0.078 mmol, yield: 52%, E / Z = 4:1). 1 H NMR (400MHz, CDCl3): δ7.30 (d, J=5.2Hz, 1H), 6.95 (d, J=5.3Hz, 1H), 2.39 (q, J=2.0Hz, 3H). 19F NMR (376MHz, CDCl3): δ-56.49 (s, 3F). 13 C NMR (101MHz, CDCl3): δ145.42, 145.38, 145.35, 145.31 (q, J=3.54Hz), 134.20, 130.04, 126.23, 124.76, 122.04, 119.32, 116.59 (q, J=273.47Hz), 108.77, 93.20, 92.86, 92.51, 92.16 (q, J=35.28HZ), 33.01, 22.79. HRMS (ESI, m / z): calculated for C8H5BrF3ISNa[M+Na] + : 418.8190, found: 418.8189.Rf=0.6 (PE / EA=50:1).

[0075] Examples 3-9 are basically the same as Example 1, except that the gem-difluoroallyl alcohol is different. The specific structure of gem-difluoroallyl alcohol is shown in the table below:

[0076] Table 1 Examples 3-9

[0077]

[0078] The above description is only a preferred 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 synthesizing gem-difluoroallyl alcohol using purchased aldehydes, ketones, and other raw materials, followed by the synthesis of trifluoromethyl olefin compounds from gem-difluoroallyl alcohol, characterized in that... The chemical structural formula of this type of compound is shown in formula (I) below: In equation (I), R 1 It can be phenyl, benzyl, phenethyl, naphthylethyl, alkyl, heterocyclic group, cyclic group, or other alkyl or functionalized alkyl groups. Among them, benzyl includes 4-bromobenzyl, 4-chlorobenzyl, 3-trifluoromethylbenzyl, 4-methoxybenzyl, and 3,4-dimethoxybenzyl; phenyl includes 4-cyanophenyl; phenethyl includes 4-methoxyphenethyl, 4-tert-butylphenethyl, 4-isobutylphenethyl, and 4-trifluoromethoxyphenethyl; heterocyclic group includes 3-thiophene group; and cyclic group includes cyclohexyl, cyclobutyl, 3-phenylcyclobutyl, thiophene group, benzocyclopentyl group, etc. R 2 It can be a hydrogen, methyl, ethyl, propyl, cyclic hydrocarbon drug molecule fragment, or other alkyl or functionalized alkyl groups. R 3 It can be hydrogen, iodine, aryl or other groups, among which aryl includes phenyl, 4-methoxyphenyl, 4-methyl carboxylate phenyl and other phenyl substituents.

2. The method for preparing the trifluoromethyl olefin compound according to claim 1, characterized in that, The method includes the following steps: (1) Under a nitrogen (N2) atmosphere, gem-difluoroallyl alcohol (R) 1 R 2 OHCR 3 C=CF2) compounds, acetic anhydride (Ac2O), dichloromethane (DCM) solvent, and pyridine hydrofluoric acid (Py·9HF) reagent were sequentially added to a 10 mL Schlenk tube to obtain a mixture. The mixture was stirred at room temperature (rt) until the reaction was complete. The crude product obtained from the reaction was separated by silica gel column chromatography to obtain highly selective polysubstituted trifluoromethyl olefin compounds.

3. The method for preparing trifluoromethyl olefin compounds as described in claim 2, characterized in that, In step (1), in the general structural formula of the gem-difluoroallyl alcohol, R 1 It can be phenyl, benzyl, phenethyl, naphthylethyl, alkyl, heterocyclic group, cyclic group or other alkyl or functionalized alkyl, wherein benzyl includes 4-bromobenzyl, 4-chlorobenzyl, 3-trifluoromethylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, phenyl includes 4-cyanophenyl, phenethyl includes 4-methoxyphenethyl, 4-tert-butylphenethyl, 4-isobutylphenethyl, 4-trifluoromethoxyphenethyl, heterocyclic group includes 3-thiophene group, cyclic group includes cyclohexyl, cyclobutyl, 3-phenylcyclobutyl, thiophene group, benzocyclopentyl group, etc. R 2 It can be a hydrogen, methyl, ethyl, propyl, cyclic hydrocarbon drug molecule fragment, or other alkyl or functionalized alkyl groups. R 3 It can be hydrogen, iodine, aryl or other groups, among which aryl includes phenyl, 4-methoxyphenyl, 4-methyl carboxylate phenyl and other phenyl substituents.

4. The method for preparing trifluoromethyl olefin compounds as described in claim 2, characterized in that, In step (1), the fluorine source for the reaction is pyridine hydrofluoric acid (Py·9HF), the solvent is dichloromethane, and the mixture is stirred and reacted at room temperature (rt) for 12 h.

Images