Synthesis method of an α-allyl-substituted azaaryl methylamine derivative

Abstract

The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing α-allyl-substituted azaaryl methylamine derivatives. Using azaaryl methylamine derivatives and allyl carbonates as raw materials, CoCl2 / Nixantphos as a catalyst, and LiN(SiMe3)2 as the base in the reaction system, a series of α-allyl-substituted azaaryl methylamine derivatives are prepared. The present invention uses inexpensive cobalt metal as a catalyst to construct a cross-coupling reaction of C-C bonds, which has the advantages of mild reaction conditions and high economy. Moreover, this synthesis method obtains the target product with excellent reactivity and diastereoselectivity.

Description

Technical Field

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

[0002] Transition metal-catalyzed allylic substitution reactions have become one of the effective strategies for constructing C-C, C-O, and C-N bonds. Compared with the cross-coupling reactions catalyzed by transition metals palladium or nickel for constructing C-C bonds, the cross-coupling reactions catalyzed by cobalt for constructing C-C bonds have the advantages of mild reaction conditions and high economy. Previously, we achieved the allylation alkylation reaction of azaaryl methylamine derivatives using transition metal palladium. However, when using substrates of cyclic secondary allylic electrophiles, the diastereoselectivity of the reaction was not ideal. Therefore, there is an urgent need for a simple and efficient synthesis method to prepare α-allyl-substituted azaaryl methylamine derivatives with excellent reactivity and diastereoselectivity. Summary of the Invention

[0003] The present invention provides a cross-coupling reaction of allyl carbonates and azaaryl methylamine derivatives catalyzed by a transition metal, which can obtain various α-allyl-substituted azaaryl methylamine derivatives with biological activities and medicinal values, and chemically selectively construct carbon-carbon bonds in a direct and easy-to-operate method, and the synthesis method is simple and efficient. The specific scheme is as follows:

[0004]

[0005] A method for synthesizing an α-allyl-substituted azaaryl methylamine derivative, wherein the allyl carbonate shown in Formula 1 and the azaaryl methylamine derivatives shown in Formulas 2, 4, and 6 are mixed with an organic solvent in the presence of a transition metal catalyst, a phosphine ligand, and a base for a cross-coupling reaction to synthesize the α-allyl-substituted azaaryl methylamine derivatives shown in Formulas 3, 5, and 7.

[0006] Wherein R 1 is selected from any one of 1-morpholinyl, 1-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidinyl, dimethylamino, diethylamino, N-methyl-N-benzylamino; R 2 is selected from 1-morpholinyl. The method of the present invention can achieve the one-pot generation of α-allyl-substituted azaaryl methylamine derivatives, reduce the reaction steps, thereby improving the product yield; the raw materials used in the synthesis method are simple and economical; R 1 , R 2 in the present invention can have multiple selections, and the applicability is wider.

[0007] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen.

[0008] Preferably, the synthesis occurs in the presence of a transition metal catalyst, a phosphine ligand, and an organic solvent.

[0009] Preferably, the transition metal catalyst is a cobalt catalyst; the phosphine ligand is 4,6-bis(diphenylphosphino)phenazine; and the base is lithium bis(trimethylsilyl)amide.

[0010] Preferably, the cobalt catalyst is cobalt iodide.

[0011] Preferably, the organic solvent is tetrahydrofuran.

[0012] Preferably, the molar ratio of the allyl carbonate shown in Formula 1, the azaarylmethylamine derivative shown in Formula 2, and the catalyst in the reaction is: 1-2:1-2:0.05-0.2;

[0013] Preferably, the reaction temperature is 25 °C.

[0014] Preferably, by using the method of the present invention, an α-allyl-substituted azaarylmethylamine derivative having the following structure can be synthesized:

[0015]

[0016]

[0017] Under the action of the base LiN(SiMe3)2, the transition metal CoI2 and the ligand Nixantphos, the azaarylmethylamine derivative undergoes an allylic alkylation reaction with various cyclic allyl carbonate electrophiles to finally prepare an α-allyl-substituted azaarylmethylamine derivative.

[0018] By adopting the technical solution of the present invention, at least one of the following beneficial effects can be achieved:

[0019] The raw materials used in the synthesis method of the present invention are all cheap and easily available;

[0020] The present invention adopts a one-pot synthesis method. Since the number of reaction steps is small, the loss of raw materials is reduced, and the yield of the product is improved;

[0021] The operation steps required by the present invention are relatively simple. There is no need for extreme heating or cooling, and the reaction can be carried out only under normal pressure, which is safe and convenient;

[0022] R in the present invention 1 、R 2 can have various selections. Therefore, the method of the present invention has a wider applicability and can synthesize various α-allyl-substituted azaarylmethylamine derivatives. Description of the Drawings

[0023] The accompanying drawings are the hydrogen nuclear magnetic resonance spectra and carbon nuclear magnetic resonance spectra of the products of each embodiment. The serial numbers of the accompanying drawings correspond to the serial numbers of the embodiments. In the figures, A is the hydrogen nuclear magnetic resonance spectrum, and B in the figures is the carbon nuclear magnetic resonance spectrum. As Figure 1A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 1; Figure 2A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2, Figure 2B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 2; Figure 3A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3, Figure 3B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 3; Figure 4A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4, Figure 4B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 4; Figure 5A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5, Figure 5B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 5; Figure 6A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6, Figure 6B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 6; Figure 7A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7, Figure 7B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 7; Figure 8A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8, Figure 8B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 8; Figure 9A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 9, Figure 9B is the carbon nuclear magnetic resonance spectrum of the product obtained in Example 9. Specific embodiments

[0024] For the convenience of those skilled in the art to understand, the following further illustrates the concept of the present invention in combination with embodiments. The specific descriptions of the following embodiments are not limitations on the present invention, but only for the convenience of those skilled in the art to understand the technical solution. All kinds of raw materials involved in the specification are purchased from the market or are obtained through simple synthesis. Other drugs, etc. are purchased from Energy Chemical, Bidepharm, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K. The model of the nuclear magnetic resonance spectrometer is Bruker 400M.

[0025] Example 1

[0026] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 4-(2-methylpyridinyl)morpholine (0.2 mmol, 1.0 equiv), tert-butylcyclohexyl-2-en-1-carbonate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and three drops of water were added to quench the reaction. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 4-(cyclohex-2-en-1-(pyridin-2-yl)methyl)morpholine (39.1 mg, 76% yield). The 1H NMR and 13C NMR spectra of the product are Figure 1A and Figure 1B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.63 (d, J = 4.7 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.19 - 7.15 (m, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.17 (d, J = 10.3 Hz, 1H), 5.84 - 5.73 (m, 1H), 3.73 - 3.62 (m, 4H), 3.34 (d, J = 10.6 Hz, 1H), 2.98 (s, 1H), 2.56 - 2.39 (m, 4H), 1.98 (s, 2H), 1.69 - 1.63 (m, 1H), 1.53 - 1.44 (m, 1H), 1.43 - 1.37 (m, 1H), 1.04 - 0.94 (m, 1H) ppm. 13 13C{ 1 1H} NMR (101 MHz, CDCl3) δ: 157.4, 149.1, 135.5, 129.5, 127.8, 124.1, 122.0, 75.3, 67.5, 49.8, 34.2, 26.6, 25.5, 21.7 ppm.

[0027] Changing the raw materials in Example 1, 9 groups of experimental examples were designed as follows. The first group of experiments is Example 1, and the NMR spectra of the corresponding product are Figure 1A and Figure 1B . The serial numbers of the NMR spectra of the products in the remaining groups 2 - 9 correspond to the serial numbers of the corresponding examples.

[0028] The structural formulas of the products in Examples 1 - 9 are listed in the table. In the 9 examples, only the types of azaarylmethylamine derivatives used are different, and other raw materials, dosages, conditions, etc. are kept the same. The yields of the products in each example are listed in the last column.

[0029]

[0030] Example 2

[0031] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv) and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 4-(2-methylpyridinyl)thiomorpholine (0.2 mmol, 1.0 equiv), tert-butylcyclohexyl-2-ene-1-carboxylate (0.4 mmol, 2.0 equiv) and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 hours. It was cooled to room temperature, the lid was opened and 3 drops of water were added to quench the reaction. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 4-(cyclohex-2-en-1-(pyridin-2-yl)methyl)thiomorpholine (39.5 mg, 72% yield). The 1H NMR and 13C{1H} NMR spectra of the product are respectively Figure 2A and Figure 2B , and the spectral data are as follows: 1 H NMR (400 MHz, CHCl3) δ: 8.62 (d, J = 3.9 Hz, 1H), 7.63 (t, J = 8.5 Hz, 1H), 7.18 - 7.15 (m, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.17 (d, J = 11.3 Hz, 1H), 5.91 - 5.74 (m, 1H), 3.29 (d, J = 11.2 Hz, 1H), 2.98 (d, J = 2.7 Hz, 1H), 2.88 (s, 2H), 2.69 - 2.59 (m, 6H), 2.01 - 1.97 (m, 2H), 1.67 - 1.61 (m, 1H), 1.53 - 1.46 (m, 1H), 1.34 (d, J = 4.9 Hz, 1H), 0.96 - 0.88 (m, 1H) ppm. 13 C{ 1 H}NMR (101 MHz, CDCl3) δ: 157.4, 149.1, 135.5, 129.5, 127.8, 123.9, 121.9, 76.5, 52.0, 34.1, 28.5, 27.0, 25.6, 21.7 ppm.

[0032] Example 3

[0033] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 2-(1-methylpyrrol)pyridine (0.2 mmol, 1.0 equiv), tert-butylcyclohexyl-2-en-1-carbonate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and the reaction was quenched by adding three drops of water. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 2-(cyclohex-2-en-1-(pyrrolidin-1-yl)methyl)pyridine (26.1 mg, 54% yield). The 1H NMR and 13C{1H} NMR spectra of the product are respectively Figure 3A and Figure 3B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.63 - 8.47 (m, 1H), 7.65 - 7.51 (m, 1H), 7.28 (dd, J = 53.1, 7.9 Hz, 1H), 7.17 - 7.07 (m, 1H), 5.90 (d, J = 10.3 Hz, 1H), 5.72 - 5.61 (m, 1H), 3.44 (dd, J = 40.0, 6.6 Hz, 1H), 2.94 - 2.80 (m, 1H), 2.63 - 2.37 (m, 4H), 1.94 - 1.60 (m, 8H), 1.51 - 1.45 (m, 1H), 1.28 - 1.08 (m, 1H) ppm. 13 13C{ 1 1H} NMR (101 MHz, CDCl3) δ: 159.6, 148.6, 135.3, 129.7, 127.4, 124.0, 121.7, 73.6, 51.8, 50.6, 38.1, 25.3, 25.0, 23.1, 21.8 ppm.

[0034] Example 4

[0035] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 2-(N,N-dimethyl)methylpyridine (0.2 mmol, 1.0 equiv), tert-butylcyclohexyl-2-ene-1-carbonate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and the reaction was quenched by adding three drops of water. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain N-(cyclohex-2-en-1-(pyridin-2-yl)methyl)-N-methylmethanamine (32.0 mg, 74% yield). The 1H NMR and 13C{1H} NMR spectra of the product are respectively Figure 4A and Figure 4B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.63 (dd, J = 4.7, 1.8 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.17 (dd, J = 6.9, 4.3 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.06 (d, J = 10.1 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H), 3.36 (d, J = 10.4 Hz, 1H), 2.98 - 2.90 (m, 1H), 2.22 (s, 6H), 1.99 - 1.92 (m, 2H), 1.64 (dd, J = 6.1, 3.2 Hz, 1H), 1.52 - 1.40 (m, 2H), 1.06 - 0.97 (m, 1H) ppm. 13 13C{ 1 1H}NMR (101 MHz, CDCl3) δ: 148.9, 135.3, 129.3, 127.8, 124.2, 121.8, 74.7, 41.5, 35.1, 26.3, 25.5, 21.4 ppm.

[0036] Example 5

[0037] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 2-(N,N-diethyl)methylpyridine (0.2 mmol, 1.0 equiv), tert-butylcyclohexyl-2-en-1-carbonate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and the reaction was quenched by adding three drops of water. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain N-(cyclohex-2-en-1-(pyridin-2-yl)methyl)-N-ethylethylamine (33.7 mg, 69% yield). The 1H NMR and 13C{1H} NMR spectra of the product are Figure 5A and Figure 5B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.64 (d, J = 5.7 Hz, 1H), 7.72 - 7.58 (m, 1H), 7.22 - 7.16 (m, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.06 (d, J = 11.5 Hz, 1H), 5.80 (dd, J = 8.2, 4.9 Hz, 1H), 3.38 (d, J = 10.8 Hz, 1H), 3.10 - 2.78 (m, 4H), 2.64 - 2.42 (m, 5H), 2.03 - 1.91 (m, 2H), 1.68 - 1.48 (m, 6H) ppm. 13 13C{ 1 1H} NMR (101 MHz, CDCl3) δ: 159.0, 148.9, 135.2, 130.5, 127.0, 123.9, 121.5, 69.9, 43.6, 35.4, 27.2, 25.6, 21.9, 14.1 ppm.

[0038] Example 6

[0039] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were successively added and stirred for 1 h. Then, 2-(N-methyl-N-benzyl)methylpyridine (0.2 mmol, 1.0 equiv), tert-butyl cyclohex-2-en-1-yl carbonate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and three drops of water were added to quench the reaction. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain N-benzyl-1-(cyclohex-2-en-1-yl)-N-methyl-1-(pyridin-2-yl)methanamine (17.5 mg, 30% yield). The 1H NMR and 13C{1H} NMR spectra of the product are Figure 6A and Figure 6B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.70 - 8.63 (m, 1H), 7.71 - 7.61 (m, 1H), 7.36 - 7.27 (m, 4H), 7.24 - 7.07 (m, 3H), 6.35 (d, J = 8.8 Hz, 1H), 5.90 - 5.76 (m, 1H), 3.67 (dd, J = 29.1, 13.7 Hz, 1H), 3.50 (d, J = 10.9 Hz, 1H), 3.33 (d, J = 13.7 Hz, 1H), 3.13 - 3.01 (m, 1H), 2.14 (d, J = 4.3 Hz, 3H), 2.04 - 1.94 (m, 2H), 1.63 (d, J = 8.4 Hz, 2H), 1.49 - 1.34 (m, 1H), 1.00 - 0.81 (m, 1H) ppm. 13 13C{ 1 1H} NMR (101 MHz, CDCl3) δ: 157.7, 149.1, 140.2, 135.4, 129.9, 128.6, 128.1, 127.5, 126.6, 124.3, 121.8, 73.7, 58.1, 37.6, 35.0, 27.0, 25.6, 21.7 ppm.

[0040] Example 7

[0041] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 4-(4-methylpyridinyl)morpholine (0.2 mmol, 1.0 equiv), tert-butyl cyclohexyl-2-ene-1-carboxylate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and the reaction was quenched by adding three drops of water. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 4-(cyclohex-2-ene-1-(pyridin-4-yl)methyl)morpholine (43.9 mg, 85% yield). The 1H NMR and 13C{1H} NMR spectra of the product are Figure 7A and Figure 7B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.52 - 8.42 (m, 2H), 7.07 - 7.02 (m, 1H), 7.00 (s, 1H), 5.99 - 5.89 (m, 1H), 5.76 - 5.65 (m, 1H), 3.67 - 3.57 (m, 4H), 3.09 (dd, J = 19.9, 8.9 Hz, 1H), 2.71 (dd, J = 7.2, 4.4 Hz, 1H), 2.39 - 2.22 (m, 4H), 1.94 - 1.76 (m, 2H), 1.63 - 1.53 (m, 1H), 1.52 - 1.24 (m, 2H), 1.06 - 0.70 (m, 1H) ppm. 13 13C{ 1 1H}NMR (101 MHz, CDCl3) δ: 149.2, 145.5, 128.5, 124.5, 124.2, 73.7, 67.1, 49.8, 34.1, 26.0, 25.3, 21.5 ppm.

[0042] Example 8

[0043] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 2-(1-methylpiperidin-1-yl)pyridine (0.2 mmol, 1.0 equiv), tert-butyl cyclohex-2-en-1-yl carbonate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and the reaction was quenched by adding three drops of water. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 2-(cyclohex-2-en-1-yl(piperidin-1-yl)methyl)pyridine (43.5 mg, 85% yield). The 1H NMR and 13C{1H} NMR spectra of the product are Figure 8A and Figure 8B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.66 - 8.56 (m, 1H), 7.67 - 7.57 (m, 1H), 7.17 - 7.13 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.18 (d, J = 10.3 Hz, 1H), 5.78 (dd, J = 10.2, 2.5 Hz, 1H), 3.33 (d, J = 10.9 Hz, 1H), 3.09 - 2.93 (m, 1H), 2.48 (s, 2H), 2.29 (s, 2H), 1.97 (dd, J = 6.9, 3.7 Hz, 2H), 1.68 - 1.61 (m, 1H), 1.59 - 1.45 (m, 5H), 1.41 - 1.33 (m, 1H), 1.33 - 1.26 (m, 2H), 1.03 - 0.83 (m, 1H) ppm.1 3 13C{ 1 1H} NMR (101 MHz, CDCl3) δ: 158.1, 148.8, 135.2, 130.0, 127.3, 123.9, 121.6, 75.7, 50.6, 34.4, 27.8, 26.9, 26.6, 25.6, 24.9, 21.8 ppm.

[0044] Example 9

[0045] In the glove box, CoI2 (10 mol%, 0.10 equiv), ligand Nixantphos (11 mol%, 0.11 equiv), and tetrahydrofuran (1 mL) were added successively and stirred for 1 h. Then 4-(2-methylquinoline)morpholine (0.2 mmol, 1.0 equiv), tert-butyl cyclohex-2-ene-1-carboxylate (0.4 mmol, 2.0 equiv), and base LiN(SiMe3)2 (0.6 mmol, 3.0 equiv) were added. After that, the microwave tube was sealed and taken out of the glove box. The microwave tube was placed at 25 °C for reaction for 12 h. It was cooled to room temperature, the lid was opened, and the reaction was quenched by adding three drops of water. The solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 4-(cyclohex-2-ene-1-(quinolin-2-yl)methyl)morpholine (55.4 mg, 90% yield). The 1H NMR and 13C NMR spectra of the product are respectively Figure 9A and Figure 9B , and the spectral data are as follows: 1 1H NMR (400 MHz, CHCl3) δ: 8.01 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.21 - 5.93 (m, 1H), 5.69 (d, J = 9.2 Hz, 1H), 3.60 (d, J = 12.2 Hz, 4H), 3.51 (d, J = 10.2 Hz, 1H), 2.98 (s, 1H), 2.48 (s, 4H), 1.88 (s, 2H), 1.56 (s, 1H), 1.49 - 1.31 (m, 2H), 1.10 - 0.89 (m, 1H) ppm. 13 13C{ 1 1H}NMR (101 MHz, CDCl3) δ: 158.7, 147.7, 135.2, 129.5, 129.3, 129.2, 127.8, 127.5, 127.2, 126.0, 121.6, 75.9, 67.5, 34.6, 26.5, 25.5, 21.8, 1.0 ppm.

[0046] Example 10

[0047] The reaction temperature in Example 1 was changed to 40 °C, and other conditions remained unchanged to obtain the product 4-(cyclohex-2-ene-1-(pyridin-2-yl)methyl)morpholine with a yield of 30%.

[0048] Example 11

[0049] Replace LiN(SiMe3)2 in Example 1 with NaN(SiMe3)2, and keep other conditions unchanged to obtain the product 4-(cyclohex-2-en-1-(pyridin-2-yl)methyl)morpholine with a yield of 13%.

[0050] Example 12

[0051] Replace the solvent in Example 1 with 2-methyltetrahydrofuran, and keep other conditions unchanged to obtain the product 4-(cyclohex-2-en-1-(pyridin-2-yl)methyl)morpholine with a yield of 48%.

Claims

1. A method for synthesizing an α-allyl-substituted azaaryl methylamine derivative, characterized in that: In an inert gas environment, allyl carbonate shown in Formula 1 and azaaryl methylamine derivatives shown in Formulas 2, 4, and 6 are mixed and reacted with an organic solvent, tetrahydrofuran, in the presence of cobalt iodide, 4,6-bis(diphenylphosphino)phenazine, and a base, lithium bis(trimethylsilyl)amide, to synthesize α-allyl-substituted azaaryl methylamine derivatives shown in Formulas 3, 5, and 7; wherein R 1 is selected from any one of 1-morpholinyl, 1-thiomorpholinyl, 1-piperidinyl, 1-pyrrolidinyl, dimethylamino, diethylamino, and N-methyl-N-benzylamino; R 2 is selected from 1-morpholinyl.

2. The synthesis method according to claim 1, wherein The inert gas is nitrogen.

3. The synthesis method according to claim 1, characterized in that The reaction temperature is 25 °C.

4. The synthesis method according to claim 1, characterized in that, The allyl carbonate, the azaaryl methylamine derivative, and the product α-allyl-substituted azaaryl methylamine derivative are one of the following tables:

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