A method for preparing an allylamine compound

Abstract

The application discloses an allyl amine compound and a preparation method thereof. Under the condition of no water and no oxygen, MBH alcohol compound and tetra(dimethylamino)diboron are added into 1,4-dioxane, and after stirring reaction at 100 DEG C for 12 hours, a reaction solution is obtained, and the reaction solution is separated and purified to obtain the allyl amine compound. Compared with the prior art, the preparation method does not need the participation of a catalyst, the Lewis acidity of the reactant itself is used to realize dehydration coupling to construct a C-N bond, the reaction condition is relatively mild, the substrate universality is high, various kinds of MBH alcohol compounds modified by different functional groups can be subjected to allylation with high yield, and the application has potential application value in fine chemistry and industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to an allyl amine compound and a preparation method and application thereof. BACKGROUND

[0002] Allylamine skeleton widely exists in natural products, drug molecules and fine chemicals, for example: the classic antifungal drugs nafitifine and terbinafine, the drug for treating nervous system diseases flunarizine and guanabenz. In addition, as an intermediate in organic synthesis, allylamine compounds are also widely used in the preparation of nitrogen heterocyclic compounds and allyl primary amines. Therefore, the research on the synthesis method of allylamine has attracted widespread attention.

[0003] The traditional construction method of allylamine is generally to use functionalized allyl compounds and amine compounds to prepare under the catalysis of transition metals, but these reactions will produce different stoichiometric amounts of harmful by-products, and the atom economy is low. With the development of research, it is found that alcohol is a relatively abundant resource, which exists widely in nature, and is cheap, easy to obtain and environmentally friendly. The most ideal way to construct the allyl skeleton is to directly use allyl alcohol and amine compounds for dehydration coupling reaction. However, it is well known that the C-OH bond energy is too large and difficult to break, so it is difficult for the hydroxyl group to leave in many organic reactions. Therefore, finding a suitable method to cut off the carbon-oxygen bond of the hydroxyl group is a problem that people always hope to solve.

[0004] The application develops a method, which directly uses Morita-Baylis-Hillman alcohol and tetra(dimethylamino)diboron as starting raw materials, does not need a catalyst, and realizes the breaking of the C-OH bond by using the Lewis acidity of the reactants themselves to couple with dimethylamine to form a C-N bond. The method does not need the participation of a catalyst, the raw materials are cheap and easy to obtain, the operation is simple, the yield is high, the by-product of the reaction is water, it is green and environmentally friendly, and has good application prospect in medicinal chemistry. SUMMARY

[0005] The application aims at solving the problems of the prior art, and provides an allyl amine compound and a preparation method thereof.

[0006] The application is implemented in the following manner: a preparation method of an allyl amine compound, which comprises the following steps:

[0007] (1) under an inert gas atmosphere, MBH alcohol compounds and tetra(dimethylamino)diboron are added to 1,4-dioxane, and stirring reaction is carried out at 100 DEG C for 12 hours;

[0008] (2) after TLC monitoring of the complete reaction, the reaction liquid obtained in step (1) is subjected to solvent removal and purification to obtain an allyl amine compound.

[0009] Preferably, in step (1), the molar ratio of the MBH alcohol compound and tetra (dimethylamino) diboron is 1:0.7.

[0010] Preferably, in step (1), the MBH alcohol compound is selected from any one of methyl 2-(hydroxy(phenyl)methyl)acrylate, methyl 2-(hydroxy(m-methylphenyl)methyl)acrylate, methyl 2-((2,4-dichlorophenyl)(hydroxy)methyl)acrylate, methyl 2-(bicyclo[2.2.1]hept-5-en-2-yl(hydroxy)methyl)acrylate, methyl 2-(hydroxy(naphthalen-2-yl)methyl)acrylate, methyl 2-(hydroxy(4-nitrophenyl)methyl)acrylate, methyl 2-((4-bromophenyl)(hydroxy)methyl)acrylate, methyl 2-((4-chlorophenyl)(hydroxy)methyl)acrylate, methyl 2-((4-fluorophenyl)(hydroxy)methyl)acrylate, methyl 2-(hydroxy(thiophen-3-yl)methyl)acrylate, methyl 3-hydroxy-2-methylene-5-phenyl-4-pentenoate, methyl 2-(hydroxy(4-methoxyphenyl)methyl)acrylate, methyl 2-(furan-3-yl(hydroxy)methyl)acrylate, methyl 3-hydroxy-2-methylenepentadecanoate, methyl 3-hydroxy-5,9-dimethyl-2-methylenedoced-8-enoate, methyl 2-(cyclohexyl(hydroxy)methyl)acrylate, (2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(hydroxymethyl)acrylate.

[0011] Preferably, in step (1), the reaction is stirred at 100℃ for 12h.

[0012] Preferably, in step (2), the removing solvent is by vacuum rotary evaporator, and the purifying is by thin layer chromatography / column chromatography, and the developing system is petroleum ether / ethyl acetate=1 / 1.

[0013] The present application overcomes the deficiencies of the prior art, and provides a preparation method of allyl amine compound, comprising the following steps:

[0014] (1) under inert gas atmosphere, the MBH alcohol compound and tetra (dimethylamino) diboron are added into 1,4-dioxane, and the reaction is stirred at 100℃ for 12h. The chemical equation of the reaction is as follows:

[0015]

[0016] In the reaction formula, compound 1 is the MBH alcohol compound, wherein, R 1a normal aryl group selected from a C1-C15 alkyl group, a fused ring aryl group, a heteroaryl group, or a benzene ring having a methyl group, a methoxy group, a cyano group, a nitro group, a t-butyl group, a fluoro group, a trifluoromethyl group, a chloro group, a bromo group, a ferrocenyl group, an ethynyl group, or a trimethylsilyl ethynyl group; R 2 is any one selected from a methyl group, an ethyl group, a phenyl group, and a t-butyl group; and compound 2 is tetra(dimethylamino)diboron.

[0017] (2) removing the reaction solvent of the reaction solution obtained in step (1), and then purifying by a thin layer chromatography / column chromatography to obtain an allyl amine compound.

[0018] In the preparation method of the present application, the C-OH bond is broken and coupled with dimethylamine to form a C-N bond under the condition of no catalyst, by using the Lewis acidity of the reactant itself, so that the reaction occurs under mild conditions in an environmentally friendly manner.

[0019] Compared with the disadvantages and deficiencies of the prior art, the present application has the following beneficial effects: alcohol is a kind of cheap and low-toxicity compound, which is widely present in natural products, and direct use of alcohol compounds as reaction raw materials is in line with the development trend of green chemistry; the MBH alcohol used in the preparation method of the present application is an alcohol compound which is simple to synthesize and has a high conversion rate, has a wide range of applicable substrates, and has the characteristics of low preparation cost; in addition, the preparation method of the present application has the characteristics of simple steps, easy operation, high product yield, and only water as by-product, and has the characteristics of high atom economy and green environmental protection; and the preparation method of the present application does not need to use any catalyst and ligand, and has potential application value for fine chemicals and industrial production; the obtained allyl amine compound can be used as an organic synthesis building block for various derivatization by using the allyl and ester groups, and is also an important skeleton widely existing in natural products, organisms and drug molecules, and has potential biological activity and drug activity. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of compound 3 in Example 1 of the present application;

[0021] Figure 2 is the nuclear magnetic resonance carbon spectrum of compound 3 in Example 1 of the present application;

[0022] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of compound 5 in Example 2 of the present application;

[0023] Figure 4 is the nuclear magnetic resonance carbon spectrum of compound 5 in Example 2 of the present application;

[0024] Figure 5 is the nuclear magnetic resonance hydrogen spectrum of compound 7 in Example 3 of the present application;

[0025] Figure 6 is the nuclear magnetic resonance hydrogen spectrum of compound 9 in the embodiment 4 of the present application;

[0026] Figure 7 is the nuclear magnetic resonance hydrogen spectrum of compound 9 in the embodiment 4 of the present application;

[0027] Figure 8 is the nuclear magnetic resonance carbon spectrum of compound 9 in the embodiment 4 of the present application.

[0028] Figure 9 is the nuclear magnetic resonance hydrogen spectrum of compound 11 in the embodiment 5 of the present application;

[0029] Figure 10 is the nuclear magnetic resonance carbon spectrum of compound 11 in the embodiment 5 of the present application. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the present application more clear, the present application is further described in detail below in combination with the drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application.

[0031] Example 1

[0032] (1) In a 10 mL Schlenk tube, 0.2 mmol of methyl 2-(hydroxy(phenyl)methyl)acrylate, 0.14 mmol of tetrakis(dimethylamino)diboron were added to 1 mL of 1,4-dioxane under nitrogen atmosphere, and stirred at 100°C for 12 h, and the reaction equation was as follows:

[0033]

[0034] (2) After the reaction was completed by TLC monitoring, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography, and the developing agent was a petroleum ether / ethyl acetate system (1 / 1), and the product was a light yellow liquid compound 3, and the yield was 80%.

[0035] Compound 3 was characterized, and the nuclear magnetic spectrum was as shown in Figures 1-2 , and specifically:

[0036] 1 H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.61-7.57 (m, 2H), 7.42-7.32 (m, 3H), 3.83 (s, 3H), 3.30 (s, 2H), 2.23 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 169.1, 142.9, 135.5, 130.5, 130.4, 128.9, 128.5, 54.5, 52.2, 45.2.

[0037] The characterization results show that compound 3 is (E)-methyl 2-((dimethylamino)methyl)-3-phenylacrylate.

[0038] Example 2

[0039] (1) In a 10 mL Schlenk tube, 0.2 mmol of methyl 2-((4-chlorophenyl)(hydroxy)methyl)acrylate, 0.14 mmol of tetrakis(dimethylamino)diboron were added to 1 mL of 1,4-dioxane under a nitrogen atmosphere, and stirred at 100°C for 12 h, and the reaction equation is as follows:

[0040]

[0041] (2) After the reaction was completed by TLC monitoring, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography, and the developing agent was a petroleum ether / ethyl acetate system (1 / 1), and the product was a light yellow liquid compound 5, with a yield of 73%.

[0042] Compound 5 was characterized, and the nuclear magnetic spectrum is as shown in Figures 3-4 , and specifically:

[0043] 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.64-7.51 (m, 2H), 7.42-7.34 (m, 2H), 3.83 (s, 3H), 3.25 (s, 2H), 2.23 (s, 6H). 13 C (101 MHz, Chloroform-d) δ 168.0, 141.0, 134.2, 133.0, 131.0, 130.0, 127.9, 53.6, 51.4, 44.3.

[0044] The characterization results show that compound 5 is (E)-methyl 3-(4-chlorophenyl)-2-((dimethylamino)methyl)acrylate.

[0045] Example 3

[0046] (1) In a 10 mL Schlenk tube, 0.2 mmol of methyl 3-hydroxy-5,9-dimethyl-2-methyleneundec-8-enoate, 0.14 mmol of tetrakis(dimethylamino)diboron were added to 1 mL of 1,4-dioxane under a nitrogen atmosphere, and stirred at 100°C for 12 h, and the reaction equation is as follows:

[0047]

[0048] (2) After the reaction was completed, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography with a developing agent of petroleum ether / ethyl acetate system (1 / 1), and the product was a light yellow liquid compound 7 with a yield of 47%.

[0049] Compound 7 was characterized, and the nuclear magnetic spectrum was as shown in Figures 5-6 Specifically, the compound 7 was characterized, and the nuclear magnetic spectrum was as shown in

[0050] 1 H NMR (400 MHz, Chloroform-d) δ 6.94 (t, J = 7.6 Hz, 1H), 5.13-5.04 (m, 1H), 3.76 (s, 3H), 3.15 (d, J = 1.5 Hz, 2H), 2.33-2.25 (m, 1H), 2.22 (d, J = 5.6 Hz, 6H), 2.18-2.08 (m, 1H), 2.09-1.90 (m, 2H), 1.71-1.66 (m, 3H), 1.60 (d, J = 1.4 Hz, 3H), 1.41-1.14 (m, 3H), 0.94-0.89 (m, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.4, 145.5, 131.6, 130.0, 124.5, 54.4, 52.0, 45.4, 36.9, 36.0, 32.8, 25.8, 25.7, 25.6, 19.7, 17.8.

[0051] The characterization results show that the compound 7 is methyl 2-((dimethylamino)methyl)-5,9-dimethyldec-2,8-dienoate.

[0052] Example 4

[0053] (1) In a 10 mL Schlenk tube, 0.2 mmol of methyl 2-(cyclohexyl(hydroxy)methyl)acrylate, 0.14 mmol of tetrakis(dimethylamino)diboron were added to 1 mL of 1,4-dioxane under a nitrogen environment, and stirred at 100°C for 12 h, and the reaction equation was as follows:

[0054]

[0055] (2) After the reaction was completed, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography with a developing agent of petroleum ether / ethyl acetate system (1 / 1), and the product was a light yellow liquid compound 9 with a yield of 61%.

[0056] Compound 9 was characterized, and the magnetic spectrum was as shown in Figures 7-8As shown, in particular:

[0057] 1 H NMR (400 MHz, Chloroform-d) δ 6.61 (d, J = 10.4 Hz, 1H), 3.68 (s, 3H), 3.08 (s, 2H), 2.43-2.32 (m, 1H), 2.16 (s, 6H), 1.72-1.64 (m, 2H), 1.59-1.51 (m, 2H), 1.29-1.02 (m, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 168.7, 150.9, 127.4, 54.4, 51.9, 45.3, 37.8, 32.1, 25.8, 25.5.

[0058] The characterization results show that compound 9 is (E)-3-cyclohexyl-2-((dimethylamino)methyl) methyl acrylate.

[0059] Example 5

[0060] (1) In a 10 mL Schlenk tube, 0.2 mmol (2S, 5R)-2-isopropyl-5-methylcyclohexyl 2- (hydroxymethyl) acrylate, 0.14 mmol tetrakis(dimethylamino) diboron were added to 1 mL of 1,4-dioxane under nitrogen atmosphere, and stirred at 100 °C for 12 h, and the reaction equation is as follows:

[0061]

[0062] (2) After TLC monitoring the reaction was complete, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography, and the developing agent was petroleum ether / ethyl acetate system (1 / 1), and the product was a light yellow liquid compound 11, with a yield of 78%.

[0063] Compound 11 was characterized, and the nuclear magnetic spectrum is as shown in Figures 9-10 , in particular:

[0064] 1H NMR (400 MHz, Chloroform-d) δ 6.28 - 6.23 (m, 2H), 5.72 (q, J = 1.5 Hz, 2H), 4.80 - 4.69 (m, 2H), 3.18 (d, J = 14.4 Hz, 2H), 3.10 (d, J = 14.4 Hz, 2H), 2.24 (s, 11H), 2.10 - 2.00 (m, 2H), 1.97 - 1.85 (m, 2H), 1.75 - 1.64 (m, 4H), 1.57 - 1.38 (m, 3H), 1.16 - 0.97 (m, 4H), 0.90 (dd, J = 6.8, 3.3 Hz, 13H), 0.76 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, Chloroform-d) δ 166.6, 138.2, 126.4, 74.6, 59.8, 47.3, 45.4, 40.9, 34.4, 31.5, 26.4, 23.6, 22.1, 20.9, 16.5.

[0065] The characterization results show that compound 11 is (2S, 5R)-2-isopropyl-5- methylcyclohexyl 2-((dimethylamino)methyl)acrylate.

[0066] Examples 6-10

[0067] Examples 6-10 are basically the same as Example 1, and the differences are shown in Table 1 below:

[0068] Table 1 Comparison of differences

[0069] Number Reaction solvent Temperature Yield Example 6 Toluene 120℃ 73％ Example 7 Isopropanol 100℃ 11％ Example 8 Dimethylformamide 100℃ 58％ Example 9 Acetonitrile 100℃ 62％ Example 10 Tetrahydrofuran 60℃ 36％

[0070] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement and improvement within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing an allylamine compound, characterized in that, The structural formula of the allylamine compounds is shown in formula (I): Among them, R 1 Selected from C1-C15 alkyl, C1-C15 fused-ring aryl, and C1-C15 heteroaryl groups, R 2 Selected from any one of methyl, ethyl, phenyl, and tert-butyl; The method for preparing the allylamine compound is characterized by comprising the following steps: (1) Under an inert gas atmosphere, MBH alcohols and tetra(dimethylamino)diboron were added to 1,4-dioxane and stirred at 100°C for 12 h. (2) After the reaction was completed by TLC monitoring, the solvent was removed and the reaction solution obtained in step (1) was purified to obtain allylamine compounds; In step (1), the structural formula of the MBH alcohol is shown in formula (II): In equation (II), R 1 R 2 In the same formula (I), R 1 R 2 The correspondence is consistent.

2. The method for preparing allylamine compounds as described in claim 1, characterized in that, In step (1), the molar ratio of the MBH alcohol compound and tetra(dimethylamino)diboron is 1:0.

7.

3. The method for preparing allylphthalide compounds as described in claim 1, characterized in that, In step (1), the MBH alcohol compound is selected from methyl 2-(hydroxy(phenyl)methyl)acrylate.

4. The method for preparing the allylamine compound according to any one of claims 2 to 3, characterized in that, In step (2), the separation and purification method is as follows: the solvent removal is carried out by removing the reaction solvent by vacuum rotary evaporator, and the purification is carried out by thin layer chromatography / column chromatography, with the developing solvent system being petroleum ether / ethyl acetate = 1 / 1.

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