Preparation method and application of N-trifluoromethyl secondary amine compound

Abstract

The application discloses a preparation method and application of N-trifluoromethyl secondary amine compounds, and belongs to the technical field of fine chemical industry. The preparation method of the N-trifluoromethyl secondary amine compounds provided by the application comprises the following steps: isonitrile is used as a reaction substrate, and the reaction is carried out under the action of iodine, silver fluoride and tert-butyl dimethyl silane to obtain the N-trifluoromethyl secondary amine compounds. Compared with the prior art, the preparation method of the N-trifluoromethyl secondary amine compounds avoids the use of irritating toxic gases such as fluorine gas, hydrogen fluoride gas and sulfur light gas, effectively improves the experimental safety, and the reaction raw materials are easy to obtain, the product is easy to separate, and the reaction condition is mild, so that the application is a safer, more efficient and milder new method for preparing N-trifluoromethyl secondary amine compounds.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of fine chemical industry, and particularly relates to a preparation method of N-trifluoromethyl secondary amine compounds and application thereof. BACKGROUND

[0002] The connection of trifluoromethyl and heteroatoms can endow the compounds with special properties. In recent years, researchers have shown great interest in O-CF3, S-CF3 and other functional groups formed by the connection of trifluoromethyl and heteroatoms. However, compared with them, the research on N-CF3 groups is still very few. The main reason is the lack of reagents that can directly introduce trifluoromethyl into the amino nitrogen atom, and the poor stability of trifluoromethyl amine, which is easy to cause fluorine elimination. Compared with methyl-substituted amine compounds, trifluoromethyl-substituted amine compounds can have higher lipophilicity and metabolic stability.

[0003] Until now, there are few methods for synthesizing N-trifluoromethyl secondary amine compounds, and only a few examples, such as: a) In 1980, a study used isonitrile to synthesize N-trifluoromethyl secondary amine compounds under the conditions of fluorine gas and hydrogen fluoride; b) In 2022, a study prepared N-trifluoromethyl secondary amine by generating isothiocyanate in situ to form a difluoroimine intermediate, and reacted with silane and silver fluoride, and the N-trifluoromethyl secondary amine could be converted into sulfonamide derivatives. The reaction schemes of the above methods are as follows:

[0004] a) Access to N-CF3 through isocyanide

[0005]

[0006] b) Access to N-CF3 through isothiocyanate

[0007]

[0008] Although the above methods can obtain N-trifluoromethyl secondary amine compounds, there are still many limitations. For example, method a) needs to use fluorine gas and hydrogen fluoride gas, both of which are toxic gases, which greatly reduces the safety of synthesis; method b) needs to synthesize isothiocyanate, which usually needs to use sulfuric acid gas, which is highly toxic and irritating. The disadvantage of the above two methods is that the reaction involves the use of gases harmful to human body and environment, therefore, in order to solve the use of the above toxic gases, a new method for preparing N-trifluoromethyl secondary amine compounds which is safer, more practical and mild and efficient is needed. SUMMARY

[0009] To overcome at least one problem existing in the prior art, one of the purposes of the present application is to provide a preparation method of N-trifluoromethyl secondary amine compounds, which does not use toxic and harmful gases such as fluorine gas, hydrogen fluoride or sulfuric thiogas, and can prepare N-trifluoromethyl secondary amine compounds mildly and efficiently.

[0010] The second purpose of the present application is to provide an application of the above preparation method.

[0011] To achieve the above purposes, the technical solution adopted by the present application is as follows:

[0012] The first aspect of the present application provides a preparation method of N-trifluoromethyl secondary amine compounds, comprising the following steps: using isonitrile as a reaction substrate, and reacting under the action of iodine, silver fluoride and tert-butyl dimethyl silane to obtain the N-trifluoromethyl secondary amine compounds.

[0013] Preferably, the reaction specifically comprises: isonitrile generates an intermediate difluoro imine under the action of iodine and silver fluoride; tert-butyl dimethyl silane generates a hydronium ion under the action of silver fluoride; the intermediate difluoro imine generates the N-trifluoromethyl secondary amine compounds under the action of the hydronium ion and silver fluoride. The reaction formula is as follows:

[0014]

[0015] Preferably, the reaction of isonitrile under the action of iodine and silver fluoride comprises at least one of the following reactions: (1) isonitrile and iodine undergo an oxidation reaction to generate diiodo imine, and the diiodo imine and silver fluoride undergo a displacement reaction to generate the intermediate difluoro imine; (2) isonitrile and iodine undergo an oxidation reaction to generate diiodo imine, and the diiodo imine and silver fluoride undergo a displacement reaction to generate fluoroiodo imine, and the fluoroiodo imine and silver fluoride undergo a displacement reaction to generate the intermediate difluoro imine. The reaction formula is as follows:

[0016] (1)

[0017] (2)

[0018] Preferably, in the preparation method of the N-trifluoromethyl secondary amine compounds, the molar ratio of the isonitrile to the iodine is 1:(0.5-2); further preferably 1:(1-1.5); and more preferably 1:(1.05-1.2).

[0019] Preferably, in the preparation method of the N-trifluoromethyl secondary amine compounds, the molar ratio of the isonitrile to the silver fluoride is 1:(5-10); further preferably 1:(5.5-9); and more preferably 1:(6-8).

[0020] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the molar ratio of the isonitrile to the tert-butyldimethylsilane is 1:(1-2); further preferably 1:(1.2-1.8); more preferably 1:(1.3-1.5).

[0021] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the temperature of the reaction is 30-50℃; further preferably 32-48℃; more preferably 35-45℃.

[0022] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the time of the reaction is 2-6h; further preferably 2.5-5.5h; more preferably 3-5h.

[0023] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the reaction is carried out in a solvent.

[0024] Preferably, the solvent is selected from 1,4-dioxane.

[0025] Preferably, in the method for preparing the N-trifluoromethyl secondary amine compound, the reaction is followed by a post-treatment step.

[0026] Preferably, the post-treatment step comprises washing the product with diethyl ether, solid-liquid separation, and drying.

[0027] Preferably, the solid-liquid separation is selected from filtration; further preferably, the filtration uses a filter medium selected from diatomite.

[0028] Preferably, the drying is selected from vacuum rotary evaporation.

[0029] In some embodiments of the present application, the N-trifluoromethyl secondary amine compound has a structural formula as shown in formula (I):

[0030]

[0031] wherein R is a substituted or unsubstituted C1-C30 alkyl, a substituted or unsubstituted C6-C30 aromatic ring, or a substituted or unsubstituted C6-C30 aromatic heterocycle; each of the substituents of the substitution is independently selected from at least one of halogen, nitro, amino, cyano, hydroxyl, ester, sulfonyl, thiol, C1-C10 alkyl, C1-C10 alkoxy, C6-C60 aromatic ring, and C3-C60 aromatic heterocycle; wherein the number of substitution is single substitution to maximum number of substitution, and if the number of substitution is equal to or greater than 2, the two adjacent substituents can be connected to form a fused ring; the substituents are further substituted or unsubstituted; the heteroatoms in the heterocycle include S, O, and N.

[0032] In some embodiments of the present application, R is a monosubstituted phenyl, a polysubstituted phenyl, a biaryl, a benzo-heterocyclic aromatic, a nitrogen beta position ester group disubstituted alkyl, a nitrogen alpha position disubstituted alkyl, each of the substituents of the substituent is independently selected from at least one of halogen, nitro, amino, cyano, hydroxyl, ester group, sulfonyl, sulfhydryl, C1-C10 alkyl, C1-C10 alkoxy, C6-C60 aromatic ring, C3-C60 aromatic heterocycle; the substituent is further substituted or not further substituted; the heteroatom in the heterocycle includes S, O, N.

[0033] In some embodiments of the present application, the N-trifluoromethyl secondary amine compound is selected from any one of the following:

[0034]

[0035] The second aspect of the present application provides the use of the preparation method of the first aspect of the present application in the preparation of an N-trifluoromethyl secondary amine compound, an N-trifluoromethyl sulfonamide compound or an N-trifluoromethyl fluorocarbamide compound.

[0036] The present application has the following advantages compared with the prior art:

[0037] Specifically, compared with the prior art, the present application has the following advantages:

[0038] 1. When R is an aryl group, the structure of the compound is relatively stable, and when R is an alkyl group, the stability of the compound is poor, so hydrogen can be replaced by further reaction to prepare sulfonamide, fluorocarbonyl substituted derivatives, and obtain compounds with better stability, thereby more simply, conveniently and quickly preparing compounds with high value in medicine.

[0039] 2. The preparation method of the compound is simple, and the aryl isocyanide or alkyl isocyanide is used as a starting material, and the target product can be obtained by reaction in the presence of silver fluoride, iodine and tert-butyl dimethyl silane. The reaction substrate has wide applicability and can be used to prepare a variety of 2-aryl substituted N-trifluoromethyl secondary amine compounds. At the same time, the reaction conditions of the method are mild and safe, without high temperature or high pressure, and the operation is simple and the post-treatment is simple, which is a high-efficiency method for synthesizing N-trifluoromethyl secondary amine compounds. DETAILED DESCRIPTION

[0040] The following specific embodiments further illustrate the content of the present invention in detail. It should also be understood that the following embodiments are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art based on the principles described herein are all within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make selections within a suitable range based on the description herein, and are not intended to be limited to the specific data in the examples below. Unless otherwise specified, the raw materials, reagents, or apparatus used in the following embodiments and comparative examples can be obtained from conventional commercial sources or by existing known methods.

[0041] In embodiments of the present invention, a method for preparing N-trifluoromethyl secondary amine compounds is provided, comprising the following steps: using isonitriles as reaction substrates, reacting them in the presence of elemental iodine, silver fluoride, and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compounds.

[0042] In some embodiments, the reaction specifically includes: isonitrile reacting with iodine and silver fluoride to generate the intermediate difluoroimine; tert-butyldimethylsilane reacting with silver fluoride to generate a hydride ion; and the intermediate difluoroimine reacting with the hydride ion and silver fluoride to generate an N-trifluoromethyl secondary amine compound.

[0043] In some embodiments, the reaction of isonitrile under the action of iodine and silver fluoride includes at least one of the following reactions: (1) isonitrile reacts with iodine to generate diiodoimine, and diiodoimine reacts with silver fluoride to generate intermediate difluoroimine; (2) isonitrile reacts with iodine to generate diiodoimine, and diiodoimine reacts with silver fluoride to generate fluoroiodoimine, and fluoroiodoimine reacts with silver fluoride to generate intermediate difluoroimine.

[0044] In some embodiments, the reaction formula is as follows:

[0045]

[0046] The following detailed description is based on specific embodiments.

[0047] Example 1

[0048] Synthesis of compound 2a:

[0049] To a Schlenk tube, 0.5 mmol (1.0 equiv) of 1-isocyano-4-(methylsulfonyl)benzene, 3.5 mmol (7.0 equiv) of silver fluoride, 0.55 mmol (1.1 equiv) of I₂, and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, 0.7 mmol (1.4 equiv) of tert-butyldimethylsilane was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a white solid with a yield of 82%.

[0050] Compound 2a is 4-(methylsulfonyl)-N-(trifluoromethyl)aniline, and its structure is shown below:

[0051]

[0052] The NMR and high-resolution characterization of compound 2a were performed, and the results are as follows:

[0053] 1 H NMR (400MHz, Chloroform-d) δ7.86 (d, J = 8.7Hz, 2H), 7.07 (d, J = 8.4Hz, 2H), 5.90 (s, 1H), 3.04 (s, 3H).

[0054] 13 C NMR (126MHz, Chloroform-d) δ142.7, 133.9, 129.3, 120.7 (q, J = 257.3Hz), 116.4 (q, J = 2.3Hz), 44.8.

[0055] 19 F NMR (376MHz, Chloroform-d) δ-56.23 (d, J=4.6Hz).

[0056] HRMS(ESI):m / z calculated for C8H7F3NO2S - [MH] - ,238.0155;Found 238.0156.

[0057] Example 2

[0058] Synthesis of compound 2b:

[0059] To a Schlenk tube, 0.5 mmol of 1-isocyano-4-nitrobenzene (1.0 equiv), 3.5 mmol of silver fluoride (7.0 equiv), 0.55 mmol of I₂ (1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, 0.7 mmol of tert-butyldimethylsilane (1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid with a yield of 95%.

[0060] Compound 2b is 4-nitro-N-(trifluoromethyl)aniline, and its structure is shown below:

[0061]

[0062] The NMR and high-resolution characterization of compound 2b are shown in the following results:

[0063] 1 H NMR (400MHz, Acetonitrile-d3) δ8.08(d,J=9.2Hz,2H),7.46(s,1H),6.99(d,J=8.8Hz,2H).

[0064] 13 C NMR (101MHz, Acetonitrile-d3) δ145.3, 143.3, 126.5, 122.0 (q, J = 254.9Hz), 116.7 (q, J = 2.3Hz).

[0065] 19 F NMR (376MHz, Acetonitrile-d3) δ-57.13 (d, J=5.3Hz).

[0066] HRMS(FTMS-cAPCI):m / z calculated for C7H4N2O2F3 - [MH] - ,205.0230;Found205.0232.

[0067] Example 3

[0068] Synthesis of compound 2c:

[0069] To a Schlenk tube, 1-iodo-4-isocyanobenzene (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and evaporated under vacuum again to obtain the product, a brown liquid with a yield of 93%.

[0070] Compound 2c is 4-iodo-N-(trifluoromethyl)aniline, and its structure is shown below:

[0071]

[0072] The NMR and high-resolution characterization of compound 2c were performed, and the results are as follows:

[0073] 1 H NMR (500MHz, Chloroform-d) δ7.59 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.24 (s, 1H).

[0074] 13 C NMR (126MHz, Chloroform-d) δ138.3, 137.4, 121.3 (q, J = 256.4Hz), 119.7 (q, J = 1.9Hz), 86.0.

[0075] 19 F NMR (376MHz, Chloroform-d) δ-56.00 (d, J=5.4Hz).

[0076] HRMS(FTMS-cAPCI):m / z calculated for C7H4NF3I - [MH] - ,285.9342; Found285.9346. Example 4

[0077] Synthesis of compound 2d:

[0078] Add (4-isocyanophenyl)(methyl)sulfane (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent sequentially to a Schlenk tube. After stirring for five minutes, dilute tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40°C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a brown liquid with a yield of 90%.

[0079] Compound 2d is 4-(methylthio)-N-(trifluoromethyl)aniline, and its structure is shown below:

[0080]

[0081] The NMR and high-resolution characterization of compound 2d were performed, and the results are as follows:

[0082] 1 H NMR (400MHz, Chloroform-d) δ7.27–7.21(m,2H),6.96–6.89(m,2H),5.11(s,1H),2.46(s,3H).

[0083] 13 C NMR (126MHz, Chloroform-d) δ135.2, 132.7, 128.8, 121.6 (q, J = 256.0Hz), 119.1 (q, J = 2.0Hz), 16.9.

[0084] 19 F NMR (376MHz, Chloroform-d) δ-55.85 (d, J=5.4Hz).

[0085] HRMS(FTMS-cAPCI):m / z calculated for C8H7F3NS - [MH] - ,266.0260; Found266.0257. Example 5

[0086] Synthesis of compound 2e:

[0087] To a Schlenk tube, 1-(4-isocyanophenyl)cyclopentane-1-carbonitrile (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a yellow solid, with a yield of 96%.

[0088] Compound 2e is 1-(4-((trifluoromethyl)amino)phenyl)cyclopentane-1-carbonitrile, and its structure is shown below:

[0089]

[0090] The NMR and high-resolution characterization of compound 2e are shown in the following results:

[0091] 1 H NMR (400MHz, Chloroform-d) δ7.39–7.35(m,2H),6.97(d,J=7.8Hz,2H),5.36(s,1H),2.49–2.42(m,2H),2.08–1.99(m,4H),1.97–1.89(m,2H).

[0092] 13 C NMR (101MHz, Chloroform-d) δ137.2, 134.4, 127.2, 124.4, 121.4 (q, J = 256.4Hz), 117.9 (q, J = 2.2Hz), 47.1, 40.3, 24.1.

[0093] 19 F NMR(376MHz,Chloroform-d)δ-55.91.

[0094] HRMS(FTMS-cAPCI):m / z calculated for C 13 H 12 F3N2 - [MH] -,253.0958;Found253.0960.

[0095] Example 6

[0096] Synthesis of compound 2f:

[0097] To a Schlenk tube, 1-(benzyloxy)-4-isocyanobenzene (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid, with a yield of 78%.

[0098] Compound 2f is 4-(benzyloxy)-N-(trifluoromethyl)aniline, and its structure is shown below:

[0099]

[0100] The NMR and high-resolution characterization of compound 2f were performed, and the results are as follows:

[0101] 1 H NMR (400MHz, Chloroform-d) δ7.47–7.38 (m, 4H), 7.36 (d, J = 6.9Hz, 1H), 7.03–6.92 (m, 4H), 5.05 (s, 2H), 4.87 (s, 1H).

[0102] 13 C NMR (126MHz, Chloroform-d) δ 155.8, 136.9, 130.5, 128.7, 128.1, 127.5, 122.0 (q, J = 255.6Hz), 122.0, 115.7, 70.4.

[0103] 19 F NMR (376MHz, Chloroform-d) δ-56.05 (d, J=6.0Hz).

[0104] HRMS(FTMS-cAPCI):m / z calculated for C 14 H11 F3NO - [MH] - ,266.0798;Found266.0798.

[0105] Example 7

[0106] Synthesis of compound 2g:

[0107] (4-isocyanophenyl)(phenyl)methanone (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially to a Schlenk tube. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours, then diluted with 10 mL of diethyl ether. The solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid with a yield of 98%.

[0108] Compound 2g is phenyl(4-((trifluoromethyl)amino)phenyl)methanone, and its structure is shown below:

[0109]

[0110] The NMR and high-resolution characterization of compound 2g were performed, and the results are as follows:

[0111] 1 H NMR (500MHz, Chloroform-d) δ7.78(dd,J=19.4,7.9Hz,4H),7.58(t,J=7.6Hz,1H),7.48(t,J=7.5Hz,2H),7.02(d,J=8.3Hz,2H),6.24(s,1H).

[0112] 13 C NMR (126MHz, Chloroform-d) δ196.0, 142.1, 137.8, 132.3, 132.2, 131.3, 129.8, 128.3, 121.0 (q, J = 256.7Hz), 115.7 (q, J = 2.2Hz).

[0113] 19F NMR (376MHz, Chloroform-d) δ-55.90 (d, J=4.8Hz).

[0114] ESI-MS: calculated for C 14 H 11 NOF3 + [M+H] + ,266.0787;Found 266.0782.

[0115] Example 8

[0116] Synthesis of compound 2h:

[0117] Add 0.5 mmol of 4-isocyano-3-methylbenzonitrile (1.0 equiv), 3.5 mmol of silver fluoride (7.0 equiv), 0.55 mmol of I₂ (1.1 equiv), and 2.0 mL of 1,4-dioxane solvent to a Schlenk tube sequentially. After stirring for five minutes, dilute 0.7 mmol of tert-butyldimethylsilane (1.4 equiv) in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40 °C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a brown solid, with a yield of 95%.

[0118] Compound 2h is 3-methyl-4-((trifluoromethyl)amino)benzonitrile, and its structure is shown below:

[0119]

[0120] The NMR and high-resolution characterization of compound 2h were performed, and the results are as follows:

[0121] 1 H NMR (500MHz, Chloroform-d) δ7.48(d,J=8.5Hz,1H),7.44(s,1H),7.14(d,J=8.6Hz,1H),5.44(s,1H),2.26(s,3H).

[0122] 13 C NMR (126MHz, Chloroform-d) δ140.1, 134.3, 131.6, 125.4, 120.9 (q, J = 257.1Hz), 118.9, 115.6, 105.6, 17.3.

[0123] 19 F NMR (376MHz, Chloroform-d) δ-55.72 (d, J=4.4Hz).

[0124] HRMS(FTMS-cAPCI):m / z calculated for C9H6N2F3 - [MH] - ,199.0487; Found 199.0489. Example 9

[0125] Synthesis of compound 2i:

[0126] To a Schlenk tube, 2-chloro-4-isocyanobenzonitrile (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid with a yield of 95%.

[0127] Compound 2i is 2-chloro-4-((trifluoromethyl)amino)benzonitrile, and its structure is shown below:

[0128]

[0129] The NMR and high-resolution characterization of compound 2i are shown in the following results:

[0130] 1 H NMR (400MHz, Chloroform-d) δ7.58(d,J=8.5Hz,1H),7.07(d,J=2.2Hz,1H),6.90(dd,J=8.6,2.3Hz,1H),6.02(s,1H).

[0131] 13 C NMR (126MHz, Chloroform-d) δ142.7, 138.4, 135.1, 120.3 (q, J = 257.9Hz), 117.0, 116.0, 114.6 (q, J = 2.1Hz), 106.4.

[0132] 19 F NMR (376MHz, Chloroform-d) δ-56.33 (d, J=4.5Hz).

[0133] HRMS(ESI):m / z calculated for C8H3N2F3Cl - [MH] - ,218.9942;Found 218.9949.

[0134] Example 10

[0135] Synthesis of compound 2j:

[0136] To a Schlenk tube, 2-fluoro-5-isocyanobenzonitrile (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid, with a yield of 80%.

[0137] Compound 2j is 2-fluoro-5-((trifluoromethyl)amino)benzonitrile, and its structure is shown below:

[0138]

[0139] The NMR and high-resolution characterization of compound 2j were performed, and the results are as follows:

[0140] 1 H NMR (400MHz, Chloroform-d) δ7.23 (dd, J=7.2, 4.1Hz, 2H), 7.18 (dd, J=10.0, 7.9Hz, 1H), 5.60 (s, 1H).

[0141] 13C NMR(126MHz,Chloroform-d)δ158.3(d,J=255.7Hz).,133.5,123.9(d,J=8.1Hz),121.1 (d, J = 2.4Hz), 120.1 (q, J = 257.1Hz), 116.6 (d, J = 21.0Hz), 112.5, 100.9 (d, J = 16.9Hz).

[0142] 19 F NMR (376MHz, Chloroform-d) δ -56.48 (d, J = 2.8Hz), -113.74 (dt, J = 8.9, 4.8Hz).

[0143] HRMS(ESI):m / z calculated for C8H3F4N2 - [MH] - ,203.0238;Found 203.0244.

[0144] Example 11

[0145] Synthesis of compound 2k:

[0146] Dimethyl 5-isocyanoisophthalate (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially to a Schlenk tube. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid, with a yield of 98%.

[0147] Compound 2k is dimethyl 5-((trifluoromethyl)amino)isophthalate, and its structure is shown below:

[0148]

[0149] The NMR and high-resolution characterization of compound 2k were performed, and the results are as follows:

[0150] 1H NMR (400MHz, Chloroform-d) δ8.34 (s, 1H), 7.90 (s, 2H), 6.21 (d, J = 5.7Hz, 1H), 3.95 (s, 6H).

[0151] 13 C NMR (126MHz, Chloroform-d) δ 166.1, 138.8, 131.7, 124.7, 122.2, 121.2 (q, J = 257.4Hz), 52.6.

[0152] 19 F NMR (376MHz, Chloroform-d) δ-56.07 (d, J=5.0Hz).

[0153] HRMS(ESI):m / z calculated for C 11 H 10 F3NO4Na + [M+Na] + ,300.0454; Found 300.0464. Example 12

[0154] Synthesis of compound 2l:

[0155] To a Schlenk tube, 1,3-dibromo-5-isocyano-2-methylbenzene (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid, with a yield of 94%.

[0156] Compound 2l is 3,5-dibromo-4-methyl-N-(trifluoromethyl)aniline, and its structure is shown below:

[0157]

[0158] The NMR and high-resolution characterization of compound 2l were performed, and the results are as follows:

[0159] 1H NMR (400MHz, Chloroform-d) δ7.06 (s, 2H), 5.07 (s, 1H), 2.40 (s, 3H).

[0160] 13 C NMR (126MHz, Chloroform-d) δ 135.7, 131.2, 124.4, 120.1, 120.0 (q, J = 256.8Hz), 21.8.

[0161] 19 F NMR (376MHz, Chloroform-d) δ-55.98 (d, J=5.1Hz).

[0162] HRMS(ESI):m / z calculated for C8H6Br2NF3[MH] - ,331.8665;Found 331.8664.

[0163] Example 13

[0164] Synthesis of compound 2m:

[0165] To a Schlenk tube, 2-bromo-6-isocyanonaphthalene (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid, with a yield of 78%.

[0166] Compound 2m is 6-bromo-N-(trifluoromethyl)naphthalen-2-amine, and its structure is shown below:

[0167]

[0168] The NMR and high-resolution characterization of compound 2m were performed, and the results are as follows:

[0169] 1H NMR(400MHz,Chloroform-d)δ7.93(d,J=1.9Hz,1H),7.68(d,J=8.8Hz,1H),7.59(d,J=8.7Hz,1H ),7.53(dd,J=8.8,2.0Hz,1H),7.32(d,J=2.1Hz,1H),7.11(dd,J=8.8,2.3Hz,1H),5.33(s,1H).

[0170] 13 C NMR (126MHz, Chloroform-d) δ 134.4, 131.3, 129.8, 129.1, 128.6, 127.6, 127.5, 120.4 (q, J = 256.6Hz), 118.3, 117.3, 112.1.

[0171] 19 F NMR (376MHz, Chloroform-d) δ-55.85 (d, J=5.4Hz).

[0172] HRMS(ESI):m / z calculated for C 11 H6BrNF3 - [MH] - ,287.9641;Found 287.9638.

[0173] Example 14

[0174] Synthesis of compound 2n:

[0175] To a Schlenk tube, 0.5 mmol (1.0 equiv) of 6-isocyano-3,4-dihydronaphthalen-1(2H)-one, 3.5 mmol (7.0 equiv) of silver fluoride, 0.55 mmol (1.1 equiv) of I₂, and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, 0.7 mmol (1.4 equiv) of tert-butyldimethylsilane was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a yellow solid with a yield of 94%.

[0176] Compound 2n is 6-((trifluoromethyl)amino)-3,4-dihydronaphthalen-1(2H)-one, and its structure is shown below:

[0177]

[0178] The NMR and high-resolution characterization of compound 2n were performed, and the results are as follows:

[0179] 1 H NMR(500MHz,Chloroform-d)δ7.98(d,J=8.5Hz,1H),6.84(dd,J=8.6,2.3Hz,1H),6.79 (s,1H),6.09(s,1H),2.92(t,J=6.1Hz,2H),2.73–2.53(m,2H),2.11(p,J=6.4Hz,2H).

[0180] 13 C NMR (126MHz, Chloroform-d) δ197.6, 146.8, 142.5, 129.3, 127.3, 120.9 (q, J = 256.3Hz), 114.8 (dd, J = 6.1, 2.0Hz), 38.8, 30.0, 23.2.

[0181] 19 F NMR (376MHz, Chloroform-d) δ-55.76 (d, J=4.6Hz).

[0182] HRMS(ESI):m / z calculated for C 11 H 10 F3NONa + [M+Na] + ,252.0607; Found252.060. Example 15

[0183] Synthesis of compound 2o:

[0184] To a Schlenk tube, 0.5 mmol of 2-isocyano-9H-fluorene (1.0 equiv), 3.5 mmol of silver fluoride (7.0 equiv), 0.55 mmol of I₂ (1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, 0.7 mmol of tert-butyldimethylsilane (1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a pale pink solid, with a yield of 77%.

[0185] Compound 2o is N-(trifluoromethyl)-9H-fluoren-2-amine, and its structure is shown below:

[0186]

[0187] The NMR and high-resolution characterization of compound 2o were performed, and the results are as follows:

[0188] 1 H NMR(400MHz,Chloroform-d)δ7.71(dd,J=11.3,7.8Hz,2H),7.37(t,J=7.5Hz,1H) ,7.32–7.24(m,1H),7.19(s,1H),6.98(d,J=8.1Hz,1H),5.15(s,1H),3.88(s,2H).

[0189] 13 C NMR(126MHz,Chloroform-d)δ144.9,142.8,141.2,137.5,136.3,126.9,126.4 ,125.0,121.8(q,J=255.9Hz),120.6,119.5,117.4,115.2(q,J=1.9Hz),37.0.

[0190] 19 F NMR (376MHz, Chloroform-d) δ-55.56 (d, J=5.5Hz).

[0191] HRMS(FTMS-cAPCI):m / z calculated for C 14 H9F3N - [MH] - ,248.0692; Found 248.0692. Example 16

[0192] Synthesis of compound 2p:

[0193] Add 0.5 mmol of 3-isocyanodibenzo[b,d]furan, 3.5 mmol of silver fluoride, 7.0 equiv of silver fluoride, 0.55 mmol of I₂, and 2.0 mL of 1,4-dioxane solvent to a Schlenk tube. After stirring for five minutes, dilute 0.7 mmol of tert-butyldimethylsilane in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40 °C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a brown solid, with a yield of 79%.

[0194] Compound 2p is N-(trifluoromethyl)dibenzo[b,d]furan-3-amine, and its structure is shown below:

[0195]

[0196] The NMR and high-resolution characterization of compound 2p were performed, and the results are as follows:

[0197] 1 H NMR (400MHz, Chloroform-d) δ7.88(dd,J=7.7,1.3Hz,1H),7.83(d,J=8.3Hz,1H),7.54(d,J=8.2Hz,1H),7.42(ddd,J =8.3,7.2,1.4Hz,1H),7.33(td,J=7.5,1.0Hz,1H),7.23(d,J=1.9Hz,1H),6.94(dd,J=8.4,2.0Hz,1H),5.34(s,1H).

[0198] 13 C NMR(126MHz,Chloroform-d)δ155.9,155.4,135.9,125.5,122.9,121.9,120.5(q, J=256.3Hz),120.2,119.1,118.8,112.6(q,J=1.8Hz),110.5,100.4(q,J=2.2Hz).

[0199] 19 F NMR (376MHz, Chloroform-d) δ-55.87 (d, J=5.3Hz).

[0200] HRMS(FTMS-cAPCI):m / z calculated for C7H3NF3I - [MH] - ,250.0485; Found 250.0488. Example 17

[0201] Synthesis of compound 2q:

[0202] Add 0.5 mmol of 2-isocyanodibenzo[b,d]thiophene (1.0 equiv), 3.5 mmol of silver fluoride (7.0 equiv), 0.55 mmol of I₂ (1.1 equiv), and 2.0 mL of 1,4-dioxane solvent to a Schlenk tube in sequence. After stirring for five minutes, dilute 0.7 mmol of tert-butyldimethylsilane (1.4 equiv) in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40 °C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a brown solid, with a yield of 84%.

[0203] Compound 2q is N-(trifluoromethyl)dibenzo[b,d]thiophen-2-amine, and its structure is shown below:

[0204]

[0205] The NMR and high-resolution characterization of compound 2q were performed, and the results are as follows:

[0206] 1 H NMR (400MHz, Chloroform-d) δ8.13–8.07(m,1H),7.87–7.82(m,1H),7.80–7.73(m,2H),7.51–7.42(m,2H),7.11(dd,J=8.5,2.2Hz,1H),5.24(s,1H).

[0207] 13 C NMR(126MHz,Chloroform-d)δ140.4,136.5,135.0,134.6,134.5,127.1,124.4,12 3.6, 122.9, 121.8 (q, J = 256.0Hz), 121.7, 118.9 (q, J = 1.7Hz), 111.6 (q, J = 2.0Hz).

[0208] 19F NMR (376MHz, Chloroform-d) δ-55.72 (d, J=5.0Hz).

[0209] HRMS(FTMS-cAPCI):m / z calculated for C 13 H7F3NO - [MH] - ,266.0260;Found266.0257.

[0210] Example 18

[0211] Synthesis of compound 2r:

[0212] Add 0.5 mmol of 5-isocyano-1-tosyl-1H-indole (1.0 equiv), 3.5 mmol of silver fluoride (7.0 equiv), 0.55 mmol of I₂ (1.1 equiv), and 2.0 mL of 1,4-dioxane solvent sequentially to a Schlenk tube. After stirring for five minutes, dilute 0.7 mmol of tert-butyldimethylsilane (1.4 equiv) in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40 °C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a brown solid, with a yield of 73%.

[0213] Compound 2r is 1-tosyl-N-(trifluoromethyl)-1H-indol-5-amine, and its structure is shown below:

[0214]

[0215] The NMR and high-resolution characterization of compound 2r were performed, and the results are as follows:

[0216] 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.8Hz,1H),7.77–7.70(m,2H),7.55(d,J=3.6Hz,1H),7.20(d,J =8.1Hz,2H),7.17(s,1H),6.96(dd,J=8.9,2.2Hz,1H),6.57(d,J=3.6Hz,1H),5.25(s,1H),2.32(s,3H).

[0217] 13C NMR(101MHz,Chloroform-d)δ144.1,134.0,132.3,130.6,130.4,128.9,126.4 ,125.7,120.8(q,J=255.6Hz),116.1,113.2,110.2(q,J=2.2Hz),107.9,20.5.

[0218] 19 F NMR (376MHz, Chloroform-d) δ-55.81 (d, J=5.3Hz).

[0219] HRMS(FTMS-cAPCI):m / z calculated for C 16 H 12 F3N2O2S - [MH] - ,353.0575;Found353.0577.

[0220] Example 19

[0221] Synthesis of compound 2s:

[0222] To a Schlenk tube, ethyl 5-isocyanobenzofuran-2-carboxylate (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (0.7 mmol, 1.4 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a brown solid with a yield of 90%.

[0223] Compound 2S is ethyl 5-((trifluoromethyl)amino)benzofuran-2-carboxylate, and its structure is shown below:

[0224]

[0225] The NMR and high-resolution characterization of compound 2s were performed, and the results are as follows:

[0226] 1H NMR(400MHz,Chloroform-d)δ7.50(d,J=9.1Hz,1H),7.46(d,J=0.8Hz,1H),7.33(d,J=2.2Hz ,1H),7.10(dd,J=8.9,2.3Hz,1H),5.28(s,1H),4.44(q,J=7.1Hz,2H),1.42(t,J=7.2Hz,3H).

[0227] 13 C NMR (126MHz, Chloroform-d) δ 159.5, 152.5, 146.6, 133.8, 127.7, 121.8 (q, J = 255.7Hz), 120.6, 113.6, 113.0, 112.3 (q, J = 1.7Hz), 61.7, 14.3.

[0228] 19 F NMR (376MHz, Chloroform-d) δ-56.11 (d, J = 5.9Hz).

[0229] HRMS(FTMS-cAPCI):m / z calculated for C 12 H9F3NO3 - [MH] - ,272.0540;Found272.0540.

[0230] Example 20

[0231] Synthesis of compound 2t:

[0232] Add 4-((4-isocyanophenyl)sulfonyl)-N-(trifluoromethyl)aniline (0.5 mmol, 1.0 equiv), silver fluoride (7.0 mmol, 14.0 equiv), I2 (1.1 mmol, 2.2 equiv), and 4.0 mL of 1,4-dioxane solvent sequentially to a Schlenk tube. After stirring for five minutes, dilute tert-butyldimethylsilane (1.4 mmol, 2.8 equiv) in 2.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40°C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a yellow solid, with a yield of 80%.

[0233] Compound 2t is 4,4'-sulfonylbis(N-(trifluoromethyl)aniline), and its structure is shown below:

[0234]

[0235] The NMR and high-resolution characterization of compound 2t were performed, and the results are as follows:

[0236] 1 H NMR (400MHz, Acetonitrile-d3) δ7.76 (d, J = 8.9 Hz, 4H), 7.28 (s, 2H), 7.01 (d, J = 7.9 Hz, 4H).

[0237] 13 C NMR (126MHz, Acetonitrile-d3) δ143.5, 135.6, 129.7, 121.8 (q, J = 254.8Hz), 116.9 (q, J = 2.1Hz).

[0238] 19 F NMR (376MHz, Acetonitrile-d3) δ-57.00 (d, J=5.0Hz).

[0239] HRMS(Q-TOF EI):m / z calculated for C 14 H 11 F6N2O2S + [M+H] + ,385.0445;Found385.0444.

[0240] Example 21

[0241] Synthesis of compound 2u:

[0242] To a Schlenk tube, methyl(S)-2-isocyano-3-(1-tosyl-1H-indol-3-yl)propanoate (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (1.0 mmol, 2.0 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a yellow liquid with a yield of 94%.

[0243] Compound 2u is methyl 1-tosyl-Na-(trifluoromethyl)-L-tryptophanate, and its structure is shown below:

[0244]

[0245] The NMR and high-resolution characterization of compound 2u were performed, and the results are as follows:

[0246] 1 H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.2Hz,1H),7.59(d,J=8.1Hz,2H),7.35(d,J=7.8Hz,1H),7.30(s,1H),7.19(t,J=7.1Hz,1H),7.13( d,J=7.7Hz,1H),7.08(d,J=8.1Hz,2H),3.93(dt,J=8.7,5.9Hz,1H),3.65(t,J=7.8Hz,1H),3.52(s,3H),2.99(d,J=5.8Hz,2H),2.20(s,3H).

[0247] 13 C NMR(101MHz,Chloroform-d)δ171.3,143.9,134.0,129.5,128.8,125.7,123.9,123.8, 122.3(q,J=255.6Hz),122.2,118.2,115.7,112.8,52.6(q,J=2.3Hz),51.7,28.1,20.5.

[0248] 19F NMR (376MHz, Chloroform-d) δ-57.69 (d, J=7.2Hz).

[0249] HRMS(FTMS-cAPCI):m / z calculated for C 20 H 21 O4N2SF3 + [M+H] + ,441.1090;Found441.1092.

[0250] Example 22

[0251] Synthesis of compound 2v:

[0252] To a Schlenk tube, methyl(S)-2-isocyano-3-(4-nitrophenyl)propanoate (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (1.0 mmol, 2.0 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a yellow solid, with a yield of 95%.

[0253] Compound 2v is methyl(S)-3-(4-nitrophenyl)-2-((trifluoromethyl)amino)-propanoate, and its structure is shown below:

[0254]

[0255] The NMR and high-resolution characterization of compound 2v were performed, and the results are as follows:

[0256] 1 H NMR (400MHz, Chloroform-d) δ8.17(d,J=8.7Hz,2H),7.35(d,J=8.7Hz,2H),4.11–4.02(m,1H),3.77(s,3H),3.12(qd,J=13.7,6.0Hz,2H).

[0257] 13C NMR (101MHz, Chloroform-d) δ170.9, 146.2, 142.3, 129.4, 122.6, 122.2 (q, J = 255.8Hz), 53.3 (q, J = 2.3Hz), 51.9, 38.2.

[0258] 19 F NMR (376MHz, Chloroform-d) δ-57.92 (d, J=7.3Hz).

[0259] HRMS(FTMS-cAPCI):m / z calculated for C 11 H5O4N2F3 - [M-3H] - ,289.0442;Found289.0442.

[0260] Example 23

[0261] Synthesis of compound 2w:

[0262] To a Schlenk tube, methyl(R)-3-(4-bromophenyl)-2-isocyanopropanoate (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I₂ (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent were added sequentially. After stirring for five minutes, tert-butyldimethylsilane (1.0 mmol, 2.0 equiv) was diluted in 1.0 mL of 1,4-dioxane solvent and injected into the tube using a syringe. The mixture was stirred at 40 °C for 4 hours. Then, 10 mL of diethyl ether was added for dilution, and the solution was filtered through diatomaceous earth and the solvent was evaporated under vacuum. Another 10 mL of diethyl ether was added to dissolve the product, which was then filtered through diatomaceous earth and the solvent was evaporated under vacuum again to obtain the product, a yellow liquid with a yield of 95%.

[0263] Compound 2w is methyl(R)-3-(4-bromophenyl)-2-((trifluoromethyl)amino)propanoate, and its structure is shown below:

[0264]

[0265] The NMR and high-resolution characterization of compound 2w were performed, and the results are as follows:

[0266] 1H NMR (400MHz, Chloroform-d) δ7.42(d,J=8.4Hz,2H),7.04(d,J=8.4Hz,2H),4.00(dt,J=8.6,6.0Hz,1H),3.74(s,3H),2.98(d,J=5.9Hz,2H).

[0267] 13 C NMR (101MHz, Chloroform-d) δ171.3, 133.5, 130.6, 130.1, 122.3 (q, J = 255.7Hz), 120.2, 53.5 (q, J = 2.3Hz), 51.6, 37.9.

[0268] 19 F NMR (376MHz, Chloroform-d) δ-57.75 (d, J=7.4Hz).

[0269] HRMS(FTMS-cAPCI):m / z calculated for C 11 H5O2NBrF3 - [M-3H] - ,321.9696;Found 321.9695.

[0270] Example 24

[0271] Synthesis of compound 2x:

[0272] Add bis(4-cyanobenzyl)(R)-2-isocyanosuccinate (0.5 mmol, 1.0 equiv), silver fluoride (3.5 mmol, 7.0 equiv), I2 (0.55 mmol, 1.1 equiv), and 2.0 mL of 1,4-dioxane solvent sequentially to a Schlenk tube. After stirring for five minutes, dilute tert-butyldimethylsilane (1.0 mmol, 2.0 equiv) in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40°C for 4 hours, then add 10 mL of diethyl ether for dilution. Filter through diatomaceous earth and evaporate the solvent under vacuum. Add another 10 mL of diethyl ether to dissolve the product, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a yellow liquid with a yield of 94%.

[0273] Compound 2x is bis(4-cyanobenzyl)(trifluoromethyl)-D-aspartate, and its structure is shown below:

[0274]

[0275] The NMR and high-resolution characterization of compound 2x were performed, and the results are as follows:

[0276] 1 H NMR(500MHz,Chloroform-d)δ7.64(d,J=8.0Hz,4H),7.42(t,J=7.3Hz,4H),5.2 4(s,2H),5.15(d,J=3.9Hz,2H),4.14(dt,J=6.2,3.3Hz,2H),3.07–2.87(m,2H).

[0277] 13 C NMR(126MHz,Chloroform-d)δ170.6,169.7,140.4,140.0,132.5,132.4,128.5,1 28.4,123.2(q,J=255.6Hz),118.4,118.4,112.5,112.3,67.1,65.8,50.4,37.9.

[0278] 19 F NMR (376MHz, Chloroform-d) δ-57.82 (d, J=6.7Hz).

[0279] HRMS(FTMS-cAPCI):m / z calculated for C 21 H 17 O4N3F3 + [M+H] + ,432.1166,Found432.1160.

[0280] Example 25

[0281] Synthesis of compound 2y:

[0282] Add 0.5 mmol of 4-isocyano-1-tosylpiperidine (1.0 equiv), 3.5 mmol of silver fluoride (7.0 equiv), 0.55 mmol of I₂ (1.1 equiv), and 2.0 mL of 1,4-dioxane solvent to a Schlenk tube sequentially. After stirring for five minutes, dilute 1.0 mmol of tert-butyldimethylsilane (2.0 equiv) in 1.0 mL of 1,4-dioxane solvent and inject the solution into the tube using a syringe. Stir at 40 °C for 4 hours, then dilute with 10 mL of diethyl ether. Filter through diatomaceous earth and evaporate the solvent under vacuum. Dissolve the product in another 10 mL of diethyl ether, filter through diatomaceous earth, and evaporate the solvent under vacuum again to obtain the product, a white solid with a yield of 97%.

[0283] Compound 2y is 1-tosyl-N-(trifluoromethyl)piperidin-4-amine, and its structure is shown below:

[0284]

[0285] The NMR and high-resolution characterization of compound 2y were performed, and the results are as follows:

[0286] 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.3Hz,2H),7.32(d,J=8.3Hz,2H),3.76–3.59(m,2H),3.01–2.88(m,1H ),2.75(t,J=7.3Hz,1H),2.50–2.39(m,5H),1.97(dd,J=13.3,3.7Hz,2H),1.57(dtd,J=14.4,10.8,4.0Hz,2H).

[0287] 13 C NMR(101MHz,Chloroform-d)δ142.8,131.7,128.7,126.7,122.7(q,J=255.0Hz),46.6,43.8,31.4,20.5

[0288] 19 F NMR (376MHz, Chloroform-d) δ-55.67 (d, J=7.4Hz).

[0289] HRMS(FTMS-cAPCI):m / z calculated for C 13 H 17 O2N2F3 - [MH] - ,323.1036;Found323.1032.

[0290] In the above embodiments, among the N-trifluoromethyl secondary amine compounds, the structure of the compound is relatively stable when R is aryl, and the structural stability of the compound is poor when R is alkyl. Therefore, by further reacting to replace hydrogen, N-trifluoromethylsulfonamide compounds and N-trifluoromethylfluoroformamide compounds can be prepared to obtain compounds with better stability, thereby enabling simpler, more convenient and faster preparation of compounds with high pharmaceutical value.

[0291] The compound preparation method in this invention is simple, using readily available aryl isonitriles or alkyl isonitriles as starting materials. The target product can be obtained by reacting in the presence of silver fluoride, elemental iodine, and tert-butyldimethylsilane. The reaction substrate has wide applicability and can prepare a variety of 2-aryl-substituted N-trifluoromethyl secondary amine compounds. At the same time, the reaction conditions are mild and safe, without the need for high temperature or high pressure, and the operation is simple and the post-processing is straightforward. It is an efficient method for synthesizing N-trifluoromethyl secondary amine compounds.

[0292] In summary, the method for preparing N-trifluoromethyl secondary amine compounds provided by this invention avoids the use of irritating and toxic gases such as fluorine, hydrogen fluoride, and phosgene, effectively improving experimental safety. Furthermore, the reaction raw materials of this invention are readily available, the products are easy to separate, and the reaction conditions are mild. Therefore, this invention is a safer, more efficient, and milder new method for preparing N-trifluoromethyl secondary amine compounds.

Claims

1. A method for preparing an N-trifluoromethyl secondary amine compound, characterized in that, Includes the following steps: Using isonitriles as reaction substrates, the reaction was carried out in the presence of elemental iodine, silver fluoride and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compounds; The structural formula of the N-trifluoromethyl secondary amine compound is shown in formula (I): （I）； Wherein, R is a substituted or unsubstituted C1-C30 alkyl group, a substituted or unsubstituted C6-C30 aromatic ring, or a substituted or unsubstituted C6-C30 aromatic heterocycle; each of the substituted substituents is independently selected from at least one of halogen, nitro, amino, cyano, hydroxyl, mercapto, C1-C10 alkyl, C1-C10 alkoxy, C6-C60 aromatic ring, or C3-C60 aromatic heterocycle; wherein the number of substitutions ranges from monosubstituted to the maximum number of substitutions, and if the number of substitutions is greater than or equal to 2, two adjacent substituents may be connected to form a fused ring; the heteroatom in the aromatic heterocycle is selected from S, O, or N.

2. The preparation method according to claim 1, characterized in that, The reaction specifically includes: isonitrile reacting with iodine and silver fluoride to generate the intermediate difluoroimine; tert-butyldimethylsilane reacting with silver fluoride to generate a hydride ion; and the intermediate difluoroimine reacting with the hydride ion and silver fluoride to generate an N-trifluoromethyl secondary amine compound.

3. The preparation method according to claim 2, characterized in that, The reactions of isonitriles under the action of iodine and silver fluoride include at least one of the following reactions: (1) isonitriles react with iodine to form diiodoimine, and diiodoimine reacts with silver fluoride to form the intermediate difluoroimine; (2) isonitriles react with iodine to form diiodoimine, and diiodoimine reacts with silver fluoride to form fluoroiodoimine, and fluoroiodoimine reacts with silver fluoride to form the intermediate difluoroimine.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The molar ratio of the isonitrile to the iodine is 1:(0.5~2). And / or, the molar ratio of the isonitrile to the silver fluoride is 1:(5~10). And / or, the molar ratio of the isonitrile to the tert-butyldimethylsilane is 1:(1~2).

5. The preparation method according to claim 1, characterized in that, The reaction temperature is 30~50℃; And / or, the reaction time is 2 to 6 hours.

6. The preparation method according to claim 1, characterized in that, The reaction is carried out in a solvent.

7. The preparation method according to claim 6, characterized in that, The solvent is selected from 1,4-dioxane.

8. The preparation method according to claim 1, characterized in that, The reaction also includes a post-processing step.

9. The preparation method according to claim 8, characterized in that, The post-processing steps include: washing the product with diethyl ether, solid-liquid separation, and drying.

10. A method for preparing an N-trifluoromethyl secondary amine compound, characterized in that, Includes the following steps: Using isonitriles as the reaction substrate, the reaction is carried out in the presence of elemental iodine, silver fluoride, and tert-butyldimethylsilane to obtain the N-trifluoromethyl secondary amine compound; the N-trifluoromethyl secondary amine compound is selected from any one of the following: 。 11. The application of the preparation method according to any one of claims 1 to 10 in the preparation of N-trifluoromethyl secondary amine compounds.

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