A method for preparing β-trifluoromethylamine compounds

Abstract

This invention discloses a method for preparing β-trifluoromethylamine compounds, comprising the following steps: reacting compounds A, B, and C in the presence of an organic base with an addition reaction, followed by acid hydrolysis after the reaction to obtain β-trifluoromethylamine compounds; wherein, the structural formula of compound A is shown in Formula 1, the structural formula of compound B is shown in Formula 2, the structural formula of compound C is shown in Formula 3, and the β-trifluoromethylamine compounds contain the ionic structure shown in Formula 4. This invention achieves for the first time the efficient synthesis of β-trifluoromethylamine compounds from trifluoromethylsulfinyl chloride, hydroxyoxime, and olefins via free radical addition reaction under the catalysis of an organic base, thus filling a technological gap in this field. This process does not rely on transition metal catalysts or photoinduction, significantly improving the compatibility of functional groups.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing β-trifluoromethylamine compounds. Background Technology

[0002] β-trifluoromethylamine compounds, with their unique biological properties and powerful functionality, have become a highly anticipated class of skeletal compounds. These compounds are ubiquitous in natural products and drug molecules, and their applications cover a wide range of important fields, including medicine and materials. Therefore, in-depth research and effective modification of the structure of β-trifluoromethylamine compounds are of paramount importance for drug discovery and the optimization of drug structures.

[0003] In recent years, researchers have conducted in-depth studies on the trifluoromethyl amination of alkenes and have made some progress. However, only a few studies have reported on the synthesis of β-trifluoromethylimine compounds via photocatalytic addition reactions. The challenge of this method lies in how to construct the target compound simply and efficiently through radical reactions. For example, some research teams have successfully synthesized a novel bifunctionalizing agent—trifluoromethylsulfonylimide. Under photocatalytic conditions, this agent achieves the trifluoromethyl amination of alkenes through a continuous NSC bond cleavage process, yielding a series of trifluoromethylimine products. However, it is worth noting that this photocatalytic reaction depends on specific photoinduction conditions and the participation of a photocatalyst, which to some extent limits its convenience and wide applicability in practical applications.

[0004] In addition, studies have explored the synthesis of β-trifluoromethylamine products via transition metal catalysis. While this method is feasible in certain situations, it also requires the participation of a transition metal catalyst, which not only increases the complexity and cost of the reaction but also may have potential environmental impacts.

[0005] Therefore, it is necessary to develop a new method for preparing β-trifluoromethylamine compounds, which allows for milder reaction conditions and can be completed without the need for metal catalysts and photoinduced conditions. Summary of the Invention

[0006] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention proposes a method for preparing β-trifluoromethylammonium chloride compounds, which can prepare β-trifluoromethylamine compounds without the need for metal catalysts or photoinduction.

[0007] According to one aspect of the present invention, a method for preparing β-trifluoromethylamine compounds is provided, comprising the following steps:

[0008] Compounds A, B and C were subjected to an addition reaction in the presence of an organic base. After the reaction was completed, acid was added for hydrolysis to obtain β-trifluoromethylamine compounds.

[0009] Wherein, the structural formula of compound A is shown in Formula 1, the structural formula of compound B is shown in Formula 2, the structural formula of compound C is shown in Formula 3, and the β-trifluoromethylamine compound contains an ionic structure as shown in Formula 4:

[0010]

[0011] In the formula, R1 is selected from alkyl, primary amine, secondary amine, tertiary amine, and sulfur; R2 and R3 are independently selected from H or alkyl; R4 is selected from cyano, carboxyl, nitro, ester, or aryl; the alkyl or aryl group may or may not have substituents, and if so, the substituents on the alkyl group are independently selected from at least one of C1 to C6 alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, aldehyde, or trifluoromethyl.

[0012] The substituents on the phenyl group are independently selected from at least one of C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, nitro, halogen, cyano, ester, aldehyde or trifluoromethyl groups.

[0013] According to a preferred embodiment of the present invention, at least the following beneficial effects are achieved: The present invention, for the first time, realizes the efficient synthesis of β-trifluoromethylamine compounds from trifluoromethylsulfinyl chloride, hydroxyoxime, and olefins via free radical addition reactions catalyzed by organic bases, thus filling a technological gap in this field. This process does not rely on transition metal catalysts or photoinduction, significantly improving the compatibility of functional groups. Compared with traditional photoinducible transition metal-catalyzed addition reactions, the present invention not only simplifies the reaction process and reduces operational difficulty, but also has a wide substrate applicability, inexpensive and readily available raw materials, and high reaction efficiency, meeting the requirements of high efficiency and practicality in industrial production. The generated β-trifluoromethylammonium chloride compounds have wide applications in pharmaceuticals and organic synthesis, possessing significant industrial application value. Furthermore, when synthesizing β-trifluoromethylammonium chloride compounds using the method of the present invention, the product yield is high, reaching up to 75%, and the generated β-trifluoromethylammonium chloride compounds have wide applications in pharmaceuticals, possessing significant application value.

[0014] In some embodiments of the present invention, R1, R2 or R3 are C1 to C6 alkyl groups.

[0015] In some embodiments of the present invention, the aryl group is selected from C6 to C6. 30 Aryl groups.

[0016] In some embodiments of the present invention, the aryl group is selected from phenyl or naphthyl.

[0017] In some embodiments of the present invention, the molar ratio of compounds A, B and C is 0.5–2:0.5–2:1.

[0018] In some embodiments of the present invention, the addition reaction is carried out in solution, and the molar concentration of compound C in the solution is 0.5-2 mol / L.

[0019] In some embodiments of the present invention, the amount of the organic base used is 0.5-3% of the molar amount of compound C.

[0020] In some embodiments of the present invention, the organic base includes at least one of triethylamine, diisopropylamine, or pyridine.

[0021] In some embodiments of the present invention, the organic base is triethylamine.

[0022] In some embodiments of the present invention, the solvent of the solution is at least one selected from ethyl acetate, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran. The solvent has low toxicity, is environmentally friendly, and is beneficial for large-scale industrial production.

[0023] In some embodiments of the present invention, the solvent of the solution is ethyl acetate.

[0024] In some embodiments of the present invention, the dosage equivalent of compound A is 1.5 eq.

[0025] In some embodiments of the present invention, the dosage equivalent of compound B is 2.0 eq.

[0026] In some embodiments of the present invention, the temperature of the addition reaction is -40 to 90°C, such as 0°C or 60°C. The method of the present invention has mild process conditions, does not require high temperatures, and has good prospects for industrial application.

[0027] In some embodiments of the present invention, the method includes first mixing compounds A and B with an organic base for pre-reaction, and then adding compound C for an addition reaction.

[0028] In some embodiments of the present invention, the total time for the pre-reaction and addition reaction is 12 to 24 hours, such as 12 hours.

[0029] In some embodiments of the present invention, the acid is hydrochloric acid.

[0030] In some embodiments of the present invention, compound B is selected from any of the following structural formulas:

[0031]

[0032] In some embodiments of the present invention, compound C is selected from any of the following structural formulas:

[0033]

[0034] In some embodiments of the present invention, the β-trifluoromethylamine compound is selected from any one of the following structural formulas:

[0035]

[0036] In some embodiments of the present invention, the structural formulas of compounds A and B are shown in the following formulas:

[0037]

[0038] Compound C is selected from any of the following structural formulas:

[0039]

[0040] The β-trifluoromethylamine compound is selected from any one of the following structural formulas:

[0041]

[0042] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0043] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0044] Figure 1 The 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride prepared in Example 1 of this invention 1 HNMR spectrum;

[0045] Figure 2 The 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride prepared in Example 1 of this invention 13 CNMR spectrum;

[0046] Figure 3 The 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride prepared in Example 1 of this invention 19 FNMR spectrum;

[0047] Figure 4 The 3,3,3-trifluoromethyl-1-(p-tolyl)prop-1-ammonium chloride prepared in Example 2 of this invention 1HNMR spectrum;

[0048] Figure 5 The 3,3,3-trifluoromethyl-1-(p-tolyl)prop-1-ammonium chloride prepared in Example 2 of this invention 13 CNMR spectrum;

[0049] Figure 6 The 3,3,3-trifluoromethyl-1-(p-tolyl)prop-1-ammonium chloride prepared in Example 2 of this invention 19 FNMR spectrum;

[0050] Figure 7 The 3,3,3-trifluoromethyl-1-(4-fluorophenyl)prop-1-ammonium chloride prepared in Example 3 of this invention 1 HNMR spectrum;

[0051] Figure 8 The 3,3,3-trifluoromethyl-1-(4-fluorophenyl)prop-1-ammonium chloride prepared in Example 3 of this invention 13 CNMR spectrum;

[0052] Figure 9 The 3,3,3-trifluoromethyl-1-(4-fluorophenyl)prop-1-ammonium chloride prepared in Example 3 of this invention 19 FNMR spectrum;

[0053] Figure 10 The 1-(4-chlorophenyl)-3,3,3-trifluoromethylpropane-1-ammonium chloride prepared in Example 4 of this invention 1 HNMR spectrum;

[0054] Figure 11 The 1-(4-chlorophenyl)-3,3,3-trifluoromethylpropane-1-ammonium chloride prepared in Example 4 of this invention 13 CNMR spectrum;

[0055] Figure 12 The 1-(4-chlorophenyl)-3,3,3-trifluoromethylpropane-1-ammonium chloride prepared in Example 4 of this invention 19 FNMR spectrum;

[0056] Figure 13 The 3,3,3-trifluoromethyl-1-(4-nitrophenyl)prop-1-ammonium chloride prepared in Example 5 of this invention 1 HNMR spectrum;

[0057] Figure 14 The 3,3,3-trifluoromethyl-1-(4-nitrophenyl)prop-1-ammonium chloride prepared in Example 5 of this invention 13 CNMR spectrum;

[0058] Figure 15 The 3,3,3-trifluoromethyl-1-(4-nitrophenyl)prop-1-ammonium chloride prepared in Example 5 of this invention 19 FNMR spectrum;

[0059] Figure 16 The 3,3,3-trifluoromethyl-1-(4-(trifluoromethyl)phenyl)prop-1-ammonium chloride prepared in Example 6 of this invention 1 HNMR spectrum;

[0060] Figure 17 The 3,3,3-trifluoromethyl-1-(4-(trifluoromethyl)phenyl)prop-1-ammonium chloride prepared in Example 6 of this invention 13 CNMR spectrum;

[0061] Figure 18 The 3,3,3-trifluoromethyl-1-(4-(trifluoromethyl)phenyl)prop-1-ammonium chloride prepared in Example 6 of this invention 19 FNMR spectrum;

[0062] Figure 19 The 1-carboxy-3,3,3-trifluoropropane-1-ammonium chloride prepared in Example 7 of this invention 1 HNMR spectrum;

[0063] Figure 20 The 1-carboxy-3,3,3-trifluoropropane-1-ammonium chloride prepared in Example 7 of this invention 13 CNMR spectrum;

[0064] Figure 21 The 1-carboxy-3,3,3-trifluoropropane-1-ammonium chloride prepared in Example 7 of this invention 19 FNMR spectrum. Detailed Implementation

[0065] The following will clearly and completely describe the concept and technical effects of the present invention in conjunction with embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available. Unless otherwise specified, the same parameter value is the same in all embodiments. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0066] In the description of this invention, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0067] Example 1

[0068] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride. The specific preparation process is as follows:

[0069] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, styrene (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride, was given in 75% yield.

[0070] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 1 , Figure 2 , Figure 3 As shown):

[0071] 1 H NMR (400MHz, MeOD) δ7.58–7.40 (m, 5H), 4.69 (t, J = 7.2Hz, 1H), 3.03 (qd, J = 10.3, 7.2Hz, 2H).

[0072] 13C NMR (101MHz, MeOD) δ135.27, 129.60, 129.18, 127.12, 123.72 (q, J = 276.3Hz), 49.95 (d, J = 3.3Hz), 37.55 (q, J = 29.0Hz).

[0073] 19 F NMR (376MHz, MeOD) δ-65.09 (t, J = 10.2Hz).

[0074] Example 2

[0075] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(p-tolyl)prop-1-ammonium chloride. The specific preparation process is as follows:

[0076] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, 1-methyl-4-styrene (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 3,3,3-trifluoromethyl-1-(p-tolyl)prop-1-ammonium chloride, was given in 51% yield.

[0077] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 4 , Figure 5 , Figure 6 As shown):

[0078] 1 H NMR (400MHz, MeOD) δ7.42(d,J=8.2Hz,1H),7.30(d,J=7.9Hz,1H),4.64(t,J=7.2Hz,1H),3.02(qdd,J=10.2,7.2,2.3Hz,1H),2.37(s,1H).

[0079] 13 C NMR (101MHz, MeOD) δ139.84, 132.23, 129.70, 127.08, 125.11 (q, J = 276.3Hz), 49.74 (q, J = 3.4Hz), 37.53 (q, J = 28.8Hz), 19.84.

[0080] 19 F NMR (376MHz, MeOD) δ-65.04 (t, J = 10.2Hz).

[0081] Example 3

[0082] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(4-fluorophenyl)prop-1-ammonium chloride. The specific preparation process is as follows:

[0083] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, 1-fluoro-4-styrene (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 3,3,3-trifluoromethyl-1-(4-fluorophenyl)prop-1-ammonium chloride, was obtained in 63% yield.

[0084] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 7 , Figure 8 , Figure 9 As shown):

[0085] 1 H NMR (400MHz, MeOD) δ7.66–7.58(m,2H),7.25(t,J=8.7Hz,2H),4.75(t,J=7.3Hz,1H),3.07(qd,J=10.2,7.2Hz,2H).

[0086] 13 C NMR (101MHz, MeOD) δ163.46 (d, J = 248.0Hz), 131.26 (d, J = 3.5Hz), 129.62 (d, J = 8.7Hz), 125.03(q,J=276.3Hz), 115.94(d,J=22.3Hz), 49.27(d,J=3.5Hz), 37.45(q,J=29.0Hz).

[0087] 19 F NMR (376MHz, MeOD) δ -65.02 (t, J = 10.2Hz), -113.37 (ddd, J = 13.6, 8.5, 5.0Hz). Example 4

[0088] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 1-(4-chlorophenyl)-3,3,3-trifluoromethylpropane-1-ammonium chloride. The specific preparation process is as follows:

[0089] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, 1-chloro-4-styrene (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 1-(4-chlorophenyl)-3,3,3-trifluoromethylpropane-1-ammonium chloride, was given in 63% yield.

[0090] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 10 , Figure 11 , Figure 12 (as shown);

[0091] 1H NMR (400MHz, MeOD) δ7.58(d,J=8.6Hz,1H),7.50(d,J=8.6Hz,1H),4.74(t,J=7.3Hz,1H),3.07(qd,J=10.2,7.2Hz,1H).

[0092] 13 C NMR (101MHz, MeOD) δ135.51, 133.92, 129.23, 129.12, 126.66–120.41 (m), 49.30 (d, J = 3.8Hz), 37.33 (q, J = 29.1Hz).

[0093] 19 F NMR (376MHz, MeOD) δ-64.91 (t, J = 10.2Hz).

[0094] Example 5

[0095] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(4-nitrophenyl)prop-1-ammonium chloride. The specific preparation process is as follows:

[0096] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, 1-nitro-4-styrene (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 3,3,3-trifluoromethyl-1-(4-nitrophenyl)prop-1-ammonium chloride, was obtained in 60% yield.

[0097] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 13 , Figure 14 , Figure 15 As shown):

[0098] 1H NMR (400MHz, MeOD) δ8.36(d,J=8.7Hz,1H),7.88(d,J=8.7Hz,1H),4.93(t,J=7.3Hz,1H),3.16(qd,J=10.2,7.1Hz,1H).

[0099] 13 C NMR (101MHz, MeOD) δ148.77, 141.87, 128.97, 124.94 (q, J = 276.5Hz), 124.03, 49.22 (d, J = 3.3Hz), 37.27 (q, J = 29.3Hz).

[0100] 19 F NMR (376MHz, MeOD) δ-64.80 (t, J = 10.3Hz).

[0101] Example 6

[0102] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(4-(trifluoromethyl)phenyl)prop-1-ammonium chloride. The specific preparation process is as follows:

[0103] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, 1-trifluoromethyl-4-styrene (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 3,3,3-trifluoromethyl-1-(4-(trifluoromethyl)phenyl)prop-1-ammonium chloride, was given in 73% yield.

[0104] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 16 , Figure 17 , Figure 18 As shown):

[0105] 1 H NMR (400MHz, MeOD) δ7.82(d,J=8.2Hz,1H),7.74(d,J=8.2Hz,1H),4.84(t,J=7.2Hz,1H),3.20–2.90(m,1H).

[0106] 13 C NMR(101MHz,MeOD)δ139.40,131.43(q,J=32.6Hz),128.50,125.94(q,J=3.8Hz ), 124.98 (q, J = 276.3Hz), 123.89 (q, J = 271.4Hz), 49.55, 37.35 (q, J = 29.1Hz).

[0107] 19 F NMR (376MHz, MeOD) δ-64.43,-65.04 (t, J=10.3Hz).

[0108] Example 7

[0109] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 1-carboxy-3,3,3-trifluoropropane-1-ammonium chloride. The specific preparation process is as follows:

[0110] After purging the 20 mL Schlenk tube with a PTFE-coated stir bar four times with argon, trifluoromethylsulfinyl chloride (0.75 mmol, 1.5 eq.) and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime (1 mmol, 2 eq.) dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq.). After 3 hours, acrylonitrile (0.5 mmol, 1 eq.) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The final product, 1-carboxy-3,3,3-trifluoropropane-1-ammonium chloride, was given in 40% yield.

[0111] The chemical shift information of the product in the 1H NMR, 1C NMR, and fluorine NMR spectra is as follows (e.g.) Figure 16 , Figure 17 , Figure 18 As shown):

[0112] 1 H NMR (600MHz, D2O) δ4.35 (dd, J=8.0, 5.0Hz, 1H), 3.06–2.72 (m, 2H).

[0113] 13 C NMR (151MHz, D2O) δ169.74, 124.89 (q, J = 276.4Hz), 47.61, 34.62 (q, J = 30.2Hz).

[0114] 19 F NMR(565MHz,D2O)δ-63.87(t,J=10.5Hz).

[0115] To facilitate a more intuitive verification of the applicability of different reactants to the preparation method of this invention, the above results are summarized in Table 1 below:

[0116] Table 1

[0117]

[0118]

[0119] As can be seen from the table above, the reaction raw materials of the present invention are applicable to substrates with a variety of functional groups.

[0120] Example 8

[0121] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride. The main difference from Example 1 lies in the dosage equivalents (molar ratio of trifluoromethylsulfinyl chloride to activated olefin) of Formula 1 and Formula 2, specifically, the dosage equivalents of trifluoromethylsulfinyl chloride and acetone oxime are 1.0 eq, 1.5 eq, and 2.0 eq, respectively.

[0122] The specific steps are as follows:

[0123] In a 20 mL Schlenk tube equipped with a PTFE-coated stir bar, after purging with argon four times, 1.0 eq, 1.5 eq, and 2.0 eq of trifluoromethylsulfinyl chloride and 2 mL of dry ethyl acetate were added, respectively. The container was sealed with a rubber stopper and cooled to 0 °C. Then, benzophenone oxime dissolved in 3 mL of dry ethyl acetate (1.5 eq, 2.0 eq, 2.5 eq) was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq). After 3 hours, styrene (structural formula shown in Table 1; 0.5 mmol, 1.0 eq) was added, and the container was heated to 60 °C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to obtain the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The yields were 70%, 75%, and 69%, respectively. The results indicate that the optimal yields were obtained by adding 1.5 eq of Formula 1 and 2.0 eq of Formula 2.

[0124] Example 9

[0125] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride. The main difference from Example 1 is the change in reaction temperature, specifically reacting overnight at 0°C, 20°C, and 60°C.

[0126] The specific steps are as follows:

[0127] In a 20 mL Schlenk tube fitted with a PTFE-coated stir bar, after purging four times with argon, 1.5 eq of trifluoromethylsulfinyl chloride and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, 2.0 eq of benzophenone oxime dissolved in 3 mL of dry ethyl acetate was added, followed by the slow dropwise addition of triethylamine (1.5 mmol, 3.0 eq). After 3 hours, styrene (0.5 mmol, 1.0 eq) was added, and the mixture was reacted overnight (8–12 h) at 0 °C, 20 °C, and 60 °C, respectively. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to give the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The yields were 62%, 69%, and 75%, respectively. The experimental results show that the target product can also be obtained under other temperature conditions, but the optimal yield was achieved by reacting overnight at 60 °C.

[0128] Example 10

[0129] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride. The main difference from Example 1 is the change in the type of organic base used, specifically reacting with triethylamine, diisopropylamine, and pyridine, respectively.

[0130] The specific steps are as follows:

[0131] In a 20 mL Schlenk tube fitted with a PTFE-coated stir bar, after purging four times with argon, 1.5 eq of trifluoromethylsulfinyl chloride and 2 mL of dry ethyl acetate were added. The container was sealed with a rubber stopper and cooled to 0 °C. Then, 2.0 eq of benzophenone oxime dissolved in 3 mL of dry ethyl acetate was added, followed by the slow addition of triethylamine, diisopropylamine, and pyridine (1.5 mmol, 3.0 eq.). After 3 hours, styrene (0.5 mmol, 1.0 eq.) was added, and the reaction was carried out overnight (8–12 h) at 60 °C. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to obtain the corresponding imine. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by the dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The yields were 75%, 68%, and 66%, respectively. The experimental results indicate that other organic bases are suitable for the reaction, with triethylamine yielding the best results.

[0132] Example 11

[0133] This example provides a method for preparing a β-trifluoromethylamine compound, specifically 3,3,3-trifluoromethyl-1-(phenyl)prop-1-ammonium chloride. The main difference from Example 1 is the change in the reaction solvent; specifically, 5 mL of dry ethyl acetate, trifluorotoluene, N,N-dimethylformamide, 1,2-dichloroethane, and dimethyl sulfoxide are added respectively.

[0134] The specific steps are as follows:

[0135] In a 20 mL Schlenk tube equipped with a PTFE-coated stir bar, after purging four times with argon gas, 1.5 eq of trifluoromethylsulfinyl chloride was added, followed by 2 mL of dry ethyl acetate, trifluorotoluene, N,N-dimethylformamide, 1,2-dichloroethane, and dimethyl sulfoxide, respectively. The container was sealed with a rubber stopper and cooled to 0 °C. Then, 2.0 eq of benzophenone oxime dissolved in 3 mL of dry ethyl acetate, trifluorotoluene, N,N-dimethylformamide, 1,2-dichloroethane, and dimethyl sulfoxide, respectively, was added, followed by the slow addition of triethylamine (1.5 mmol, 3.0 eq). After 3 hours, styrene (structural formula shown in Table 1; 0.5 mmol, 1.0 eq) was added, and the reaction was carried out overnight (8–12 h) at 60 °C. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100:1) to obtain the corresponding imines. Subsequently, the obtained imine and diethyl ether (10.0 mL) were added to a 50 mL round-bottom flask, followed by dropwise addition of hydrochloric acid (10 mL, 3 M). The mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC). The resulting mixture was then extracted with water (3 × 20 mL) and washed with Et₂O (3 × 20 mL). The yields were 75%, 68%, 59%, 63%, and 65%, respectively. The experimental results indicate that ethyl acetate, trifluorotoluene, N,N-dimethylformamide, 1,2-dichloroethane, and dimethyl sulfoxide are all suitable for the reaction, with ethyl acetate being the optimal choice.

[0136] In summary, this invention utilizes a method for synthesizing β-trifluoromethylammonium chloride compounds via the radical addition reaction of trifluoromethylsulfinyl chloride, hydroxime, and olefins. The method involves a bifunctionalization reaction between activated olefins, trifluoromethylsulfinyl chloride, and hydroxime to yield β-trifluoromethylimine compounds, which are then hydrolyzed with hydrochloric acid to obtain the β-trifluoromethylammonium chloride compounds. This invention is the first to achieve the generation of trifluoromethyl and imine radicals from trifluoromethylsulfinyl chloride and hydroxime without a catalyst or photoinduction, followed by the rapid construction of β-trifluoromethylimine compounds through the reaction of these radicals with olefins. This fills a gap in existing technologies (currently, there is no method for obtaining β-trifluoromethylammonium chloride compounds via the radical addition reaction of trifluoromethylsulfinyl chloride and hydroxime with olefins without a catalyst or photoinduction). Furthermore, the method for synthesizing β-trifluoromethylammonium chloride compounds is safe and simple to operate, uses readily available and inexpensive raw materials, has high reaction efficiency, broad substrate adaptability, is environmentally friendly, and is beneficial for industrial production. Furthermore, the method of this invention yields high β-trifluoromethylammonium chloride compounds, up to 75%; the generated β-trifluoromethylammonium chloride compounds have wide applications in pharmaceuticals and organic synthesis. Those skilled in the art will anticipate that replacing the hydrochloric acid in the embodiments of this invention with other acids will also yield similarly good results in preparing other amine compounds; therefore, this invention has significant application value.

[0137] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing β-trifluoromethylamine compounds, characterized in that: Includes the following steps: Compounds A, B and C were subjected to an addition reaction in the presence of an organic base. After the reaction was completed, acid was added for hydrolysis to obtain β-trifluoromethylamine compounds. Wherein, the structural formula of compound A is shown in Formula 1, the structural formula of compound B is shown in Formula 2, the structural formula of compound C is shown in Formula 3, and the β-trifluoromethylamine compound contains an ionic structure as shown in Formula 4: In the formula, R1 is selected from alkyl groups with substituents, and the substituent is phenyl; R2 and R3 are independently selected from H or C1~C6 alkyl groups; R4 is selected from naphthyl, phenyl with or without substituents; the substituent on the substituted phenyl is selected from at least one of C1-C6 alkyl, C1-C6 alkoxy, nitro, aldehyde, halogen, cyano or trifluoromethyl. The organic base is selected from at least one of triethylamine, diisopropylamine, or pyridine.

2. The method for preparing β-trifluoromethylamine compounds according to claim 1, characterized in that: The molar ratio of compounds A, B and C is 0.5~2:0.5~2:

1.

3. The method for preparing β-trifluoromethylamine compounds according to claim 1, characterized in that: The addition reaction is carried out in solution, and the molar concentration of compound C in the solution is 0.5-2 mol / L.

4. The method for preparing β-trifluoromethylamine compounds according to claim 1, characterized in that: The addition reaction is carried out in solution, wherein the solvent of the solution is at least one selected from ethyl acetate, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran.

5. The method for preparing β-trifluoromethylamine compounds according to any one of claims 1 to 4, characterized in that: The amount of the organic base used is 0.5-3% of the molar amount of compound C.

6. The method for preparing β-trifluoromethylamine compounds according to any one of claims 1 to 4, characterized in that: The addition reaction is performed at temperatures ranging from -40 to 90°C.

7. The method for preparing β-trifluoromethylamine compounds according to any one of claims 1 to 4, characterized in that: The addition reaction is performed at a temperature of 0~60℃.

8. The method for preparing β-trifluoromethylamine compounds according to any one of claims 1 to 4, characterized in that: The method includes first mixing compounds A and B with an organic base for pre-reaction, and then adding compound C for an addition reaction.

9. The method for preparing β-trifluoromethylamine compounds according to claim 8, characterized in that: The total time for the pre-reaction and addition reaction is 12-24 hours.

10. A method for preparing β-trifluoromethylamine compounds, characterized in that: The process includes the following steps: compounds A, B and C undergo an addition reaction in the presence of an organic base, followed by acid hydrolysis after the reaction is complete to obtain β-trifluoromethylamine compounds; The raw materials used in the method satisfy at least one of the following characteristics: 1) The structural formula of compound A is shown in Formula 1: 2) Compound B is selected from any of the following structural formulas: ； 3) Compound C is shown in Formula 3. Selected from the following structural formulas: ； 4) The organic base is selected from at least one of triethylamine, diisopropylamine, or pyridine; The β-trifluoromethylamine compounds contain the ionic structure shown in Formula 4: .

11. The method for preparing β-trifluoromethylamine compounds according to any one of claims 1 to 4, characterized in that: The acid is hydrochloric acid, and the β-trifluoromethylamine compound is selected from any one of the following structural formulas: 。 12. The method for preparing β-trifluoromethylamine compounds according to claim 11, characterized in that: The structural formulas of compounds A and B are shown below: ； ； Compound C is selected from any of the following structural formulas: 。

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