Synthesis method of allyl azoaryl methylamine compounds

Abstract

The present invention provides a method for synthesizing allyl azaaryl methylamine compounds. By reacting azaaryl derivatives with allyl carbonates under the catalysis of palladium acetate, a series of allyl azaaryl methylamine compounds are prepared. Azaaryl methylamine derivatives are commonly found in biological medicines and natural products, and their allylated products with deprotonated benzyl positions can serve as a kind of active intermediate with medicinal value and have certain antifungal activity against dermatophytes. Compared with traditional methods, the palladium-catalyzed allylic alkylation reaction of the present invention has the characteristics of economical and efficient synthesis. The reaction is carried out by a simple one-pot method without relatively harsh reaction conditions such as high temperature and high pressure, greatly improving the synthesis process.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing allyl azaaryl methylamines. Background Art

[0002] Azaaryl methylamine derivatives are commonly found in biological medicines and natural products. The allylated product with deprotonation at the benzylic position can be used as a pharmaceutically valuable active intermediate, which has certain antifungal activity against dermatophytes.

[0003] The traditional method for synthesizing such substances is usually through the reaction of imines with pre-prepared allyl metal reagents. In 2016, the Walsh research group reported a palladium-catalyzed reaction of Cr(CO)3-activated benzyl nucleophiles with cyclic or chain allyl carbonates to synthesize a series of allyl-substituted products. This reaction has high yields and good chemoselectivity. However, this reaction system requires the addition of activating groups, making the reaction steps more cumbersome and reducing the atom economy of the reaction. Therefore, the allyl alkylation reaction with in-situ deprotonation of the substrate without using activating groups is particularly important. In the process of synthesizing an allyl azaaryl methylamine compound of the present invention, the substrate can be deprotonated in-situ without an activating group to undergo an allyl alkylation reaction, and this type of compound can be efficiently prepared. Summary of the Invention

[0004] The present invention discloses a method for synthesizing allyl azaaryl methylamines, belonging to the field of organic synthesis. In the present invention, the azaaryl methylamine shown in Formula 1 and the allyl carbonate shown in Formula 2 are mixed with an organic solvent in the presence of a transition metal catalyst, a Brønsted base, and undergo an allylation reaction of the azaaryl methylamine to synthesize the allyl azaaryl methylamine and its derivatives shown in Formula 3. The preparation method of the present invention is simple, convenient, and mild in conditions, suitable for large-scale production, and has an important impact on the synthesis of such compounds. The specific scheme is as follows:

[0005]

[0006] A method for synthesizing allyl azaaryl methylamines, in which the azaaryl methylamine compound shown in Formula 1 and the allyl carbonate compound shown in Formula 2 are mixed with an organic solvent in the presence of a transition metal catalyst, a phosphine ligand, and a Brønsted base, and undergo an allylation reaction to synthesize the allyl azaaryl methylamine compound shown in Formula 3.

[0007] Wherein R 1 is selected from any one of 1-morpholinyl, dimethylamino, diethylamino, N-methyl-N-phenylamino, N-methyl-N-benzylamino, 1-thiomorpholinyl, 4-methylpiperazin-1-yl; R 2Any one selected from hydrogen and phenyl.

[0008] Preferably, the reaction is carried out under the protection of an inert gas. Preferably, the inert gas is nitrogen.

[0009] Preferably, the synthesis occurs in the presence of a transition metal catalyst, a Bronsted base, a phosphine ligand, and an organic solvent.

[0010] Preferably, the transition metal catalyst is a palladium catalyst; the Bronsted base is sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or lithium bis(trimethylsilyl)amide; the phosphine ligand is 4,6-bis(diphenylphosphino)phenoxazine.

[0011] Preferably, the palladium catalyst is palladium acetate.

[0012] More preferably, the Bronsted base is lithium bis(trimethylsilyl)amide.

[0013] Preferably, the organic solvent is 2-methyltetrahydrofuran.

[0014] The reaction temperature is 0 - 45 °C, the preferred temperature is 0 - 25 °C, and the more preferred temperature is 0 °C.

[0015] Preferably, by using the method of the present invention, an allylmethylated azoarylmethylamine compound with the following structure can be synthesized:

[0016]

[0017] Adopting the technical solution of the present invention can achieve at least one of the following beneficial effects:

[0018] The raw materials used in the synthesis method of the present invention are all cheap and easily available;

[0019] The operation steps required by the present invention are relatively simple, without extreme heating or cooling, and only need to react under normal pressure;

[0020] R in the present invention 1 and R 2 can have multiple choices. Therefore, the method of the present invention has a wider applicability and can synthesize various compounds with an allylalkylated structure of azoarylmethylamine. Description of the Drawings

[0021] The drawings are the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectra of the products of each example. The serial numbers of the drawings correspond to the serial numbers of the examples. In the drawings, A is the hydrogen spectrum nuclear magnetic resonance spectrum, and B is the carbon spectrum nuclear magnetic resonance spectrum. For example, Figure 1A is the hydrogen spectrum nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B is the carbon spectrum nuclear magnetic resonance spectrum of the product obtained in Example 1;Figure 2A 1H NMR spectrum of the product obtained in Example 2 Figure 2B 13C NMR spectrum of the product obtained in Example 2 Figure 3A 1H NMR spectrum of the product obtained in Example 3 Figure 3B 13C NMR spectrum of the product obtained in Example 3 Figure 4A 1H NMR spectrum of the product obtained in Example 4 Figure 4B 13C NMR spectrum of the product obtained in Example 4 Figure 5A 1H NMR spectrum of the product obtained in Example 5 Figure 5B 13C NMR spectrum of the product obtained in Example 5 Figure 6A 1H NMR spectrum of the product obtained in Example 6 Figure 6B 13C NMR spectrum of the product obtained in Example 6 Figure 7A 1H NMR spectrum of the product obtained in Example 7 Figure 7B 13C NMR spectrum of the product obtained in Example 7 Figure 8A 1H NMR spectrum of the product obtained in Example 8 Figure 8B 13C NMR spectrum of the product obtained in Example 8 Specific Examples

[0022] For the convenience of those skilled in the art to understand, the concept of the present invention will be further described below in conjunction with examples. The following specific descriptions of the examples are not limitations on the present invention, but only for the convenience of those skilled in the art to understand the technical solution. The sodium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide of Lewis base involved in the specification were purchased from Aldrich, the palladium catalyst was purchased from alfa and Anyky, and the organic solvents used in the reaction were all ultra-dry solvents, purchased from J&K Scientific. All kinds of raw materials were purchased from the market or synthesized simply, and other drugs were purchased from Sigma-Aldrich, Alfa Aesar, TCI China. The model of the nuclear magnetic resonance spectrometer was Bruker-400M or JEOL of Japan Electron.

[0023] Example 1

[0024] In a nitrogen-filled glove box, palladium acetate of transition metal (2.5 mo1%, 0.025 equiv), ligand Nixantphos (3.75 mol%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stirrer. After stirring for coordination for about 10 min, substrate 4-(pyridin-2-ylmethyl)morpholine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was completed, the reaction was continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatographic column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (28.5 mg, 98% yield). The 1H NMR and 13C NMR spectra of the product are respectively Figure 1A and Figure 1B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.59 (dd, J = 2.8, 2.0 Hz, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.18 - 7.13 (m, 1H), 5.69 - 5.55 (m, 1H), 4.96 - 4.89 (m, 2H), 3.70 - 3.68 (m, 4H), 3.54 (t, J = 6.9 Hz, 1H), 2.70 - 2.68 (m, 2H), 2.61 - 2.51 (m, 2H), 2.48 - 2.38 (m, 2H) ppm. 13 13C{ 1 1H} NMR (125 MHz, CDCl3) δ: 160.1, 149.3, 136.1, 135.2, 123.6, 122.3, 116.9, 71.3, 67.3, 51.1, 36.0 ppm.

[0025] By changing the raw materials in Example 1, the following 10 groups of experimental examples were designed. The first group of experiments was Example 1, and the NMR spectra of the corresponding product were Figure 1A and Figure 1B . The serial numbers of the NMR spectra of the products in the remaining Groups 2 - 10 correspond to the serial numbers of the corresponding examples.

[0026] The structural formulas of the products in Examples 1-10 are listed in the table. In the first 10 examples, only the types of the two substrates, azaarylmethylamine and allyl carbonate, are different, while other raw materials, dosages, conditions, etc. are kept consistent. The last column lists the yields of the products in each example.

[0027]

[0028]

[0029] Example 2

[0030] In a nitrogen-filled glove box, palladium acetate (2.5 mol%, 0.025 equiv) as a transition metal, ligand Nixantphos (3.75 mol%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stirrer. After stirring for coordination for about 10 min, substrate N,N-dimethyl-1-(pyridin-2-yl)methylamine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was complete, the reaction was continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatography column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (17.25 mg, 98% yield). The 1H NMR and 13C NMR spectra of the product are Figure 2A and Figure 2B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.59 (d, J = 5.0 Hz, 1H), 7.64 (td, J = 7.7, 1.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 - 7.15 (m, 1H), 5.68 - 5.60 (m, 1H), 5.00 - 4.90 (m, 2H), 3.51 - 3.48 (m, 2H), 2.73 - 2.62 (m, 2H), 2.26 (s, 6H) ppm. 13 13C{ 1 1H} NMR (125 MHz, CDCl3) δ: 160.5, 149.2, 136.1, 135.5, 123.6, 122.2, 116.9, 71.6, 42.9, 36.7 ppm.

[0031] Example 3

[0032] In a nitrogen-filled glove box, palladium acetate (2.5 mol%, 0.025 equiv) of transition metal, ligand Nixantphos (3.75 mo1%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. Stir for coordination for about 10 min, and then substrate N-ethyl-N-(pyridin-2-ylmethyl)ethylamine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was completed, the reaction was continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatography column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (17.8 mg, 87% yield). The 1H NMR and 13C NMR spectra of the product are respectively Figure 3A and Figure 3B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.56 (d, J = 4.8 Hz, 1H), 7.61 (td, J = 7.6, 1.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.14 - 7.12 (m, 1H), 5.75 - 5.66 (m, 1H), 5.01 - 4.85 (m, 2H), 3.90 - 3.88 (m, 1H), 2.74 - 2.63 (m, 4H), 2.51 - 2.45 (m, 2H), 1.01 (t, J = 7.1 Hz, 6H) ppm. 13 13C{ 1 1H} NMR (125 MHz, CDCl3) δ: 149.0, 136.5, 135.9, 123.7, 122.0, 116.3, 66.0, 43.7, 35.9, 13.1 ppm.

[0033] Example 4

[0034] In a nitrogen-filled glove box, palladium acetate (2.5 mol%, 0.025 equiv) of transition metal, ligand Nixantphos (3.75 mol%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. Stir for coordination for about 10 min, and then substrate N-methyl-N-(pyridin-2-ylmethyl)aniline (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was complete, the reaction was continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatographic column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain the crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (21.5 mg, 90% yield). The 1H NMR and 13C NMR spectra of the product are respectively Figure 4A and Figure 4B , and the spectral data are as follows: 1 1H NMR (300 MHz, CDCl3) δ: 8.62 - 8.60 (m, 1H), 7.59 (td, J = 7.7, 1.8 Hz, 1H), 7.27 - 7.14 (m, 4H), 6.84 (d, J = 8.1 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 5.94 - 5.81 (m, 1H), 5.20 - 5.00 (m, 3H), 3.18 - 3.09 (m, 1H), 2.85 (s, 3H), 2.85 - 2.71 (m, 1H) ppm. 13 13C{ 1 1H} NMR (75 MHz, CDCl3) δ: 160.7, 150.2, 148.9, 136.3, 135.8, 129.0, 121.9, 121.8, 116.6, 116.5, 112.8, 63.3, 35.4, 32.0 ppm.

[0035] Example 5

[0036] In a nitrogen-filled glove box, palladium acetate (2.5 mo1%, 0.025 equiv) of transition metal, ligand Nixantphos (3.75 mo1%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. After stirring for coordination for about 10 min, substrate N-benzyl-N-methyl-1-(pyridin-2-yl)methanamine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was completed, the reaction was continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatographic column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (11.7 mg, 57% yield). The 1H NMR and 13C NMR spectra of the product are respectively Figure 5A and Figure 5B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.56 (d, J = 4.8 Hz, 1H), 7.61 (td, J = 7.6, 1.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.14 - 7.12 (m, 1H), 5.75 - 5.66 (m, 1H), 5.01 - 4.85 (m, 2H), 3.90 - 3.88 (m, 1H), 2.74 - 2.63 (m, 4H), 2.51 - 2.45 (m, 2H), 1.01 (t, J = 7.1 Hz, 6H) ppm. 13 13C{ 1 1H} NMR (125 MHz, CDCl3) δ: 149.0, 136.5, 135.9, 123.7, 122.0, 116.3, 66.0, 43.7, 35.9, 13.1 ppm.

[0037] Example 6

[0038] In a nitrogen-filled glove box, palladium acetate (2.5 mol%, 0.025 equiv) of transition metal, ligand Nixantphos (3.75 mol%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stirrer. Stir for coordination for about 10 min, and then substrate 4-(pyridin-2-ylmethyl)thiomorpholine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was completed, the reaction continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatography column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (21.6 mg, 92% yield). The 1H NMR and 13C NMR spectra of the product are respectively Figure 6A and Figure 6B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.59 - 8.58 (m, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.21 - 7.19 (m, 1H), 7.17 - 7.14 (m, 1H), 5.75 - 5.67 (m, 1H), 5.01 - 4.91 (m, 2H), 3.68 (dd, J = 8.5, 6.0 Hz, 1H), 2.88 - 2.72 (m, 5H), 2.68 - 2.58 (m, 5H) ppm. 13 13C{ 1 1H}NMR (125 MHz, CDCl3) δ: 159.5, 149.1, 136.0, 135.9, 123.6, 122.2, 116.6, 71.3, 52.3, 35.2, 28.5 ppm.

[0039] Example 7

[0040] In a nitrogen-filled glove box, palladium acetate of transition metal (2.5 mol%, 0.025 equiv), ligand Nixantphos (3.75 mol%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stir bar. Stir for coordination for about 10 min, and then substrate 1-methyl-4-(pyridin-2-ylmethyl)piperazine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and allyl tert-butyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was completed, the reaction was continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatographic column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (18.8 mg, 81% yield). The 1H NMR and 13C NMR spectra of the product are Figure 7A and Figure 7B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.58 - 8.57 (m, 1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.16 - 7.13 (m, 1H), 5.68 - 5.59 (m, 1H), 4.96 - 4.88 (m, 2H), 3.59 (dd, J = 8.6, 5.4 Hz, 1H), 2.78 - 2.31 (m, 10H), 2.26 (s, 3H) ppm. 13 13C{ 1 1H} NMR (125 MHz, CDCl3) δ: 160.1, 149.2, 136.1, 135.5, 123.7, 122.2, 116.8, 70.9, 55.4, 50.1, 46.0, 36.2 ppm.

[0041] Example 8

[0042] In a nitrogen-filled glove box, palladium acetate (2.5 mol%, 0.025 equiv) of transition metal, ligand Nixantphos (3.75 mol%, 0.0375 equiv), and organic solvent 2-methyltetrahydrofuran (0.5 mL) were successively added to a dry microwave tube equipped with a magnetic stirrer. After stirring for coordination for about 10 min, substrate 4-(pyridin-2-ylmethyl)morpholine (0.1 mmol) and base lithium bis(trimethylsilyl)amide (0.4 mmol, 4 equiv) were successively added to the reaction solution. The microwave tube was sealed and taken out of the glove box. Subsequently, the microwave tube was placed in a cold trap at 0 °C, and tert-butyl cinnamyl carbonate (0.3 mmol, 3 equiv) was slowly added dropwise. After the addition was complete, the reaction continued at this temperature for 12 h. After the reaction was completed, the microwave tube was opened in air, 3 drops of water were added to quench the reaction, and the obtained crude product was transferred to a short chromatographic column filled with silica gel and filtered with ethyl acetate (5 mL). The filtrate was distilled under reduced pressure to obtain a crude product, and the crude product was finally separated by column chromatography to obtain a brown oily product (22.7 mg, 77% yield). The 1H NMR and 13C NMR spectra of the product are Figure 8A and Figure 8B , and the spectral data are as follows: 1 1H NMR (500 MHz, CDCl3) δ: 8.61 - 8.59 (m, 1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 7.27 - 7.20 (m, 5H), 7.17 - 7.14 (m, 2H), 6.29 (d, J = 15.8 Hz, 1H), 6.05 - 6.00 (m, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.62 (dd, J = 8.1, 5.7 Hz, 1H), 2.84 (dd, J = 13.8, 7.0 Hz, 2H), 2.87 - 2.82 (m, 2H), 2.61 - 2.58 (m, 2H), 2.50 - 2.46 (m, 2H) ppm. 13 13C{ 1 1H}NMR (125 MHz, CDCl3) δ: 160.1, 149.4, 137.8, 136.2, 132.0, 128.6, 127.3, 127.1, 126.1, 123.7, 122.4, 71.6, 67.4, 51.2, 35.1 ppm.

[0043] Example 9

[0044] The temperature in Example 1 was changed to 25 °C, and other conditions remained unchanged. Finally, a product (20.9 mg, 96% yield) was obtained.

[0045] Example 10

[0046] The temperature in Example 1 was changed to 45 °C, and other conditions remained unchanged. Finally, the product was obtained (9.8 mg, 45% yield).

[0047] Example 11

[0048] The amount of allyl tert-butyl carbonate in Example 1 was reduced from 3 equivalents to 2 equivalents, and other conditions remained unchanged. Finally, the product was obtained (19.8 mg, 91% yield).

[0049] Example 12

[0050] The amount of allyl tert-butyl carbonate in Example 1 was increased from 3 equivalents to 5 equivalents, and other conditions remained unchanged. Finally, the product was obtained (18.9 mg, 87% yield).

[0051] Example 13

[0052] The Bronsted base lithium bis(trimethylsilyl)amide in Example 1 was changed to sodium bis(trimethylsilyl)amide, and the amount of the base was reduced from 4-fold to 2-fold. Other conditions remained unchanged. Finally, the product was obtained (11% yield). The 11% yield here refers to the NMR yield measured using dibromomethane as an internal standard after the reaction was completed.

Claims

1. A method for synthesizing allyl azoaryl methylamine compounds, characterized in that: In an inert gas environment, the azaarylmethylamine shown in Formula 1 and the allyl carbonate shown in Formula 2 are mixed and reacted with an organic solvent 2-methyltetrahydrofuran in the presence of palladium acetate, 4,6-bis(diphenylphosphino)phenoxazine, a Brønsted base sodium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide to synthesize an allyl alkylation product of the azaarylmethylamine shown in Formula 3 and its derivatives; wherein R 1 is selected from any one of 1-morpholinyl, dimethylamino, diethylamino, N-methyl-N-phenylamino, N-methyl-N-benzylamino, 1-thiomorpholinyl, 4-methylpiperazin-1-yl; R 2 is selected from any one of hydrogen and phenyl.

2. The synthesis method according to claim 1, characterized in that, The inert gas is nitrogen.

3. The synthesis method according to claim 1, characterized in that, The reaction temperature is 0 - 45 °C.

4. The synthesis method according to claim 1, wherein The azoaryl methylamine compounds, allyl carbonate compounds and products are one of the following tables: 。

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