Preparation method of 1, 4-diamine compound

Abstract

The invention discloses a preparation method of a 1, 4-diamine compound, which comprises the following steps: in an organic solvent, by taking a difunctional N-free radical precursor (1), non-activated olefin (2) and a Michael receptor (3) as initial raw materials, adding a photosensitizer, and reacting at room temperature under the illumination of visible light for 6-12 hours to prepare a 1, 4-diamine product (A); according to the method, a strategy of inducing olefin 1, 4-diamination reaction by visible light is adopted, so that efficient conversion of olefin with different electronic characteristics and diversified structures is realized. The method has the characteristics of mild reaction conditions, no need of transition metal catalysis, no need of additional oxidants, non-toxic reaction system, environmental friendliness and the like. Meanwhile, the method shows wide applicability and excellent regioselectivity, and has important research value and wide application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a 1,4-diamine compound. BACKGROUND

[0002] As an important organic synthesis intermediate, the 1,4-diamine skeleton has wide application value in drug development, catalyst design and natural product synthesis.

[0003] However, the current synthesis method of the 1,4-diamine compound mainly has the following technical problems:

[0004] (1) Low efficiency of the synthesis route: the traditional method relies on multi-step reactions, and the reaction conditions are harsh, and the atom economy is poor;

[0005] (2) Insufficient environmental friendliness: the existing process often uses toxic reagents or produces harmful by-products, which does not meet the development trend of green chemistry. SUMMARY

[0006] In view of the defects of the prior art, the application provides a visible light catalytic olefin 1,4-diamination reaction method, which solves the problems of transition metal dependence, complicated steps and environmental unfriendliness in the traditional process, and realizes efficient and green synthesis of 1,4-diamine products. With the help of the energy transfer process induced by visible light, two N-center free radicals are generated from the bifunctional N-radical precursor, and then the non-activated olefin and Michael acceptor are subjected to a cascade reaction mechanism to precisely construct 1,4-diamination products.

[0007] To achieve the above purpose, the application adopts the following technical solutions:

[0008] In an organic solvent, a bifunctional N-radical precursor (1), a non-activated olefin (2) and a Michael acceptor (3) are used as raw materials, a photosensitizer is added, and the reaction is carried out at room temperature under specific wavelength light for 6-12 hours, and then 1,4-diamine product (A) is obtained after separation and purification:

[0009]

[0010] wherein R1 and R2 are independently selected from at least one of hydrogen, aryl, C1-C8 alkyl; and EWG is selected from one of ester, cyano, nitro, amide and phosphite.

[0011] Preferably, the photocatalyst is thioxanthone (TXT), [Ir(ppy)2(dtbbpy)](PF6), [Ir(dtbbpy)[dF(CF3)ppy]2]PF6, Ir[dF(Me)PPy]2(dtbbpy)PF6, 4CzIPN, fac-Ir(ppy)3, and the amount of use is 2-10 mol%.

[0012] Preferably, the solvent is ethyl acetate, acetonitrile, isopropyl acetate, dichloromethane, and the amount of use is 0.1 M.

[0013] Preferably, the molar ratio of the bifunctional N-radical precursor 1, the non-activated olefin 2 and the Michael acceptor 3 is 1:2:2, 1:4:2, 1:8:2, 1:0.5:0.5.

[0014] Preferably, the light irradiation condition is 390-485 nm.

[0015] Preferably, the reaction system is subjected to separation and purification post-processing, the reaction system is concentrated under vacuum, and then subjected to rapid column chromatography separation and purification through "pre-alkalization" silica gel, the eluent is a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 60:1-5:1, the eluent is collected and the solvent is removed under vacuum, and the pure 1,4-diamine product A is obtained.

[0016] Compared with the prior art, the present application has the following beneficial effects:

[0017] (1) The present application realizes the visible light catalytic synthesis of olefin 1,4-diamine reaction for the first time, uses a novel bifunctional N-radical precursor 1 as a nitrogen source, the precursor is simple to synthesize, and can produce two different reactive N-center radicals under visible light photochemical conditions, which can regionally and selectively construct 1,4-diamine products.

[0018] (2) The synthesis strategy developed in the present application uses a photocatalytic system with an easily available photosensitizer as a photocatalyst, which has the advantages of mild reaction conditions, simple experimental operation, no chemical toxicity and environmental friendliness;

[0019] (3) The synthesis strategy developed in the present application has a wide range of substrates and is compatible with various different electronic properties and structural diversity of olefins, which has high practicability and broad research prospects. BRIEF DESCRIPTION OF DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed to be used in the embodiments description will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without any creative effort on the basis of these drawings. Among them:

[0021] Figure 1 Chemical reaction formula for preparing 1,4-diamine compound; Figure 2 NMR hydrogen spectrum of compound A1 prepared in Example 1;

[0022] Figure 3 NMR carbon spectrum of compound A1 prepared in Example 1;

[0023] Figure 4 NMR hydrogen spectrum of compound A2 prepared in Example 2;

[0024] Figure 5 NMR carbon spectrum of compound A2 prepared in Example 2;

[0025] Figure 6 NMR hydrogen spectrum of compound A3 prepared in Example 3;

[0026] Figure 7 NMR carbon spectrum of compound A3 prepared in Example 3;

[0027] Figure 8 NMR hydrogen spectrum of compound A4 prepared in Example 4;

[0028] Figure 9 NMR carbon spectrum of compound A4 prepared in Example 4;

[0029] Figure 10 NMR hydrogen spectrum of compound A5 prepared in Example 5;

[0030] Figure 11 NMR carbon spectrum of compound A5 prepared in Example 5; DETAILED DESCRIPTION

[0031] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below with reference to the embodiments of the present application.

[0032] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, it will be appreciated that the present application can be practiced in a variety of ways beyond the specifics set forth herein, which can be practiced in any number of manners. These and other variations are possible and are contemplated by the disclosure, the essential characteristics of which are set forth in the claims.

[0033] It is also noted that, as used herein, "one embodiment" or "an embodiment" means a particular implementation of the application, and that a specific feature, structure, or characteristic described in one or more embodiments can be combined in any and all combinations with one or more other features, structures, or characteristics described in one or more other embodiments.

[0034] 1,4-Diamination of olefins to prepare 1,4-diamine products

[0035] General experimental procedure: In a magnetic stirring flask, difunctional N-radical precursor 1 (0.6 mmol, 1.0 equiv.) and photosensitizer (2-10 mol%) were added. After purging the reaction flask with N2for 3 times, the solvent (0.1 M) and unactivated olefin 2 (0.5-8 equiv.) and Michael acceptor 3 (0.5-2 equiv.) were added successively under N2atmosphere in a glovebox. The reaction mixture was stirred under irradiation of 390-485 nm LED light source for 6-12 h until the reaction was completed. After the reaction was completed, the volatile materials were removed by rotary evaporation, and the corresponding 1,4-diamine product A was obtained by flash column chromatography on pre-alkalized silica gel. The general reaction scheme is as follows:

[0036]

[0037] Example 1

[0038] General experimental procedure: In a magnetic stirring flask, difunctional N-radical precursor 1 (0.6 mmol, 1.0 equiv.) and photosensitizer (2-10 mol%) were added. After purging the reaction flask with N2for 3 times, the solvent (0.1 M) and unactivated olefin 2 (0.5-8 equiv.) and Michael acceptor 3 (0.5-2 equiv.) were added successively under N2atmosphere in a glovebox. The reaction mixture was stirred under irradiation of 390-485 nm LED light source for 6-12 h until the reaction was completed. After the reaction was completed, the volatile materials were removed by rotary evaporation, and the corresponding 1,4-diamine product A was obtained by flash column chromatography on pre-alkalized silica gel. The general reaction scheme is as follows:

[0039]

[0040] Characterization data: 1H NMR (400 MHz, Chloroform-d) δ 7.92 (t, J = 5.8 Hz, 1H), 7.87 (t, J = 5.5 Hz, 1.5H), 7.48 - 7.37 (m, 15H), 7.33 - 7.29 (m, 5H), 7.25 - 7.22 (m, 3H), 7.20 - 7.17 (m, 2H), 3.64 (s, 4.5H), 3.63 (s, 3H), 3.60 - 3.45 (m, 5H), 3.40 (s, 4.5H), 3.25 (s, 3H), 3.01 - 2.79 (m, 5H), 2.49 (dd, J = 14.7, 7.2 Hz, 1.5H), 2.34 (dd, J = 14.8, 4.2 Hz, 1H), 2.20 (dd, J = 14.8, 8.0 Hz, 1H), 2.04 - 2.01 (m, 2H), 1.95 (d, J = 4.4 Hz, 1H), 1.91 (d, J = 4.5 Hz, 1.5H), 1.41 - 1.37 (m, 7.5H), 1.30 - 1.26 (m, 7.5H), 0.89 (t, J = 6.6 Hz, 7.5H). 13 C NMR (101 MHz, Chloroform-d) δ 173.4 (2C), 170.7, 170.6, 170.0, 168.7, 162.3, 162.2, 140.8, 140.6, 137.0, 136.2, 130.6, 130.4, 129.0, 128.9, 128.5 (2C), 128.3 (2C), 128.2 (2C), 128.0, 92.9, 92.8, 67.7, 67.1, 52.0, 51.8 (3C), 45.4, 44.9, 42.6, 42.5, 42.2, 41.0, 35.0, 34.7, 34.3, 34.2, 29.1, 28.9, 22.9, 14.0 (2C). HRMS (ESI) (m / z): [M+H] + calculated for C 28 H 33 Cl3N2O5: 583.1528, found: 583.1533 Rf: (petroleum ether / EtOAc 6:1) = 0.28.

[0041] Example 2

[0042] Using difunctional N-radical precursor 1 (204.96 mg, 0.6 mmol), dimethyl methylene succinate (189.78 mg, 1.2 mmol) and 1-octene (67.32 mg, 1.2 mmol) as starting materials, 2 mol% [lr(ppy)2(dtbbpy)](PF6) as catalyst, acetonitrile as solvent, 410 nm as reaction wavelength, reaction time of 12 h, after the reaction was completed using the general experimental procedure, flash column chromatography separation was performed using pre-alkalized silica gel and PE:EtOAc (30:1 ~ 5:1, v:v) as eluent, the product A2 (64.1 mg, yield 35%) was obtained as a light yellow viscous oil. The structural formula of product A2 is as follows:

[0043]

[0044] Characterization data: 1 H NMR (400 MHz, Chloroform-d) δ 7.86 (t, J = 5.7 Hz, 1 H), 7.82 (t, J = 5.3 Hz, 1.5 H), 7.49 - 7.45 (m, 5 H), 7.44 - 7.40 (m, 7.5 H), 7.40 - 7.38 (m, 1.5 H), 7.37 - 7.36 (m, 1 H), 7.32 - 7.29 (m, 5 H), 7.24 - 7.22 (m, 2.5 H), 7.20 - 7.07 (m, 2.5 H), 3.63 (s, 4.5 H), 3.62 (s, 3 H), 3.59 - 3.40 (m, 5 H), 3.39 (s, 4.5 H), 3.26 (s, 3 H), 3.01 - 2.80 (m, 5 H), 2.47 (dd, J = 14.7, 7.2 Hz, 1.5 H), 2.32 (dd, J = 14.8, 4.3 Hz, 1 H), 2.20 (dd, J = 14.8, 7.8 Hz, 1 H), 2.06 - 2.00 (m, 1.5 H), 1.96 (d, J = 4.5 Hz, 1 H), 1.92 (d, J = 4.5 Hz, 1.5 H), 1.41 - 1.35 (m, 10 H), 1.30 - 1.26 (m, 15 H), 0.89 - 0.86 (m, 7.5 H). 13C NMR (101 MHz, Chloroform-d) δ 173.5, 173.3, 170.7, 170.6, 169.9, 168.6, 162.3, 162.1, 140.8, 140.6, 136.9, 136.2, 130.6, 130.4, 129.0, 128.9, 128.5 (2C), 128.3 (2C), 128.2 (2C), 128.0, 92.9 (2C), 67.1 (2C), 51.9, 51.8 (2C), 51.7, 45.5, 44.9, 42.5 (2C), 42.1 (2C), 35.1, 34.7, 34.6, 34.5, 31.7 (2C), 29.5, 26.9, 26.7, 22.6, 14.1. HRMS (ESI) (m / z): [M+H] + C 30 H 38 Cl3N2O5: 611.1841, found: 611.1831. Rf: (petroleum ether / EtOAc 6:1) = 0.31.

[0045] Example 3

[0046] General experimental procedure was used with difunctional N-radical precursor 1 (204.96 mg, 0.6 mmol), dimethyl methylene succinate (189.78 mg, 1.2 mmol) and 4-methyl-1-pentene (202.20 mg, 2.4 mmol) as starting materials, 2 mol% [lr(dtbbpy)[dF(CF3)ppy]2]PF6as photosensitizer, dichloromethane as solvent, 450 nm as reaction wavelength, reaction time 12 h. After reaction, the product A3 (52.4 mg, 30% yield) was obtained as a yellowish viscous oil using pre-alkalized SiO2for flash column chromatography separation and PE:EtOAc (30:1~5:1, v:v) as eluent. The structure of product A3 is as follows:

[0047]

[0048] Characterization data: 1H NMR (400 MHz, Chloroform-d) δ 7.87 (t, J = 5.8 Hz, 1H), 7.83 (t, J = 5.8 Hz, 1.5H), 7.49 - 7.46 (m, 5H), 7.45 - 7.40 (m, 7.5H), 7.38 (dq, J = 6.8, 1.7 Hz, 2.5H), 7.33 - 7.30 (m, 5H), 7.25 - 7.23 (m, 2.5H), 7.20 - 7.18 (m, 2.5H), 3.64 (s, 4.5H), 3.63 (s, 3H), 3.60 - 3.47 (m, 5H), 3.41 (s, 4.5H), 3.25 (s, 3H), 3.04 - 2.79 (m, 5H), 2.50 (dd, J = 14.8, 8.2 Hz, 1.5H), 2.30 (dd, J = 14.8, 4.0 Hz, 1H), 2.21 (dd, J = 14.8, 8.5 Hz, 1H), 2.12 - 2.10 (m, 1.5H), 1.97 - 1.96 (m, 1H), 1.89 (dd, J = 14.8, 4.0 Hz, 1.5H), 1.79 - 1.73 (m, 2.5H), 1.32 - 1.25 (m, 2.5H), 1.22 - 1.18 (m, 1.5H), 1.16 - 1.12 (m, 1H), 0.91 - 0.87 (m, 15H). 13 C NMR (101 MHz, Chloroform-d) δ 173.4, 173.3, 170.8, 170.6, 170.1, 168.7, 162.3, 162.2, 140.8, 140.6, 137.0, 136.1, 130.6, 130.5, 129.0, 128.9, 128.5 (2C), 128.3 (2C), 128.2, 128.0, 93.0, 92.9, 67.7, 67.1, 52.0, 51.8 (3C), 45.3, 44.6, 44.1, 44.0, 43.0, 42.5, 41.0, 32.9, 32.6, 25.1 (2C), 23.2, 23.1, 22.4, 22.3. HRMS (ESI) (m / z): [M+H] + calculated for C 30 H 38 Cl3N2O5: 611.1841, found: 611.1831. Rf: (petroleum ether / EtOAc 6:1) = 0.28.

[0049] Example 4

[0050] General experimental procedure was used with difunctional N-radical precursor 1 (204.96 mg, 0.6 mmol), dimethyl methylene succinate (189.78 mg, 1.2 mmol) and allyltrimethylsilane (548.48 mg, 4.8 mmol) as starting materials, 5 mol% fac-Ir(ppy)3as photosensitizer, isopentyl acetate as solvent, 485 nm as reaction wavelength, reaction time 6 h. After the reaction, the product A4 (106.5 mg, 58% yield) was obtained as a yellowish viscous oil using pre-alkalized SiO2for flash column chromatography separation with PE:EtOAc (30:1-5:1, v:v) as eluent. The structural formula of product A4 is as follows:

[0051]

[0052] Characterization data: 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (t, J = 6.0 Hz, 1H), 7.80 (t, J = 5.8 Hz, 1.5H), 7.48 - 7.37 (m, 15H), 7.39 - 7.37 (m, 5H), 7.24 - 7.22 (m, 3H), 7.19 - 7.17 (m, 2H), 3.63 (s, 7.5H), 3.61 - 3.59 (m, 1H), 3.54 - 3.50 (m, 1.5H), 3.45 (t, J = 6.6 Hz, 1H), 3.41 (s, 4.5H), 3.36 - 3.32 (m, 1.5H), 3.23 (s, 3H), 3.02 - 2.77 (m, 5H), 2.56 (dd, J = 14.7, 8.2 Hz, 1.5H), 2.38 - 2.35 (m, 1H), 2.25 (dd, J = 14.7, 8.3 Hz, 1H), 2.18 - 2.17 (m, 1.5H), 2.14 - 2.12 (m, 1H), 1.91 (dd, J = 14.7, 4.6 Hz, 1.5H), 0.76 - 0.63 (m, 5H), 0.06 (s, 9H), 0.05 (s, 13.5H). 13C NMR (101 MHz, Chloroform-d) δ 173.3, 173.2, 170.6, 170.5, 169.9, 168.7, 162.3, 162.2, 140.8, 140.6, 137.0, 136.1, 130.6, 130.5, 129.0, 128.9, 128.5, 128.4 (2C), 128.3, 128.2 (2C), 128.0, 93.0, 67.7, 67.3, 51.9, 51.8 (2C), 47.4, 46.9, 45.6, 42.6, 41.0, 32.0, 31.9, 23.1, 22.8, -0.7. HRMS (ESI) (m / z): [M+H] + C 28 H 35 Cl3N2O s Si: 613.1454, found: 613.1452. Rf: (petroleum ether / EtOAc 6:1) = 0.35.

[0053] Example 5

[0054] Using difunctional N-radical precursor 1 (204.96 mg, 0.6 mmol), dimethyl methylene succinate (47.45 mg, 0.3 mmol) and 6-bromo-1-hexene (48.92 mg, 0.3 mmol) as starting materials, 10 mol% 4CzIPN as photosensitizer, acetonitrile as solvent, 450 nm as reaction wavelength, reaction time was 8 h, after the reaction was completed by using the general experimental operation, pre-alkalized silica gel was used for flash column chromatography separation and PE:EtOAc (30:1 ~ 5:1, v:v) as eluent, the product A5 (99.0 mg, yield 58%) was obtained as a light yellow viscous oil. The structural formula of product A5 is as follows:

[0055]

[0056] Characterization data: 1H NMR (400 MHz, Chloroform-d) δ 7.87 (t, J = 5.7 Hz, 1H), 7.83-7.81 (m, 1.5H), 7.62-7.37 (m, 15H), 7.33-7.29 (m, 5H), 7.24-7.20 (m, 3H), 7.19-7.17 (m, 2H), 4.22-3.76 (m, 2.5H), 3.71-3.62 (m, 7.5H), 3.59-3.41 (m, 5H), 3.39-3.32 (m, 7.5H), 3.26 (s, 2.5H), 3.01-2.79 (m, 5H), 2.50 (dd, J = 14.7, 7.6 Hz, 1.5H), 2.32 (dd, J = 14.8, 4.1 Hz, 1H), 2.20 (dd, J = 14.6, 8.1 Hz, 1H), 2.08-2.02 (m, 1.5H), 1.95 (d, J = 4.4 Hz, 1H), 1.91 (d, J = 5.4 Hz, 1.5H), 1.85-1.79 (m, 5H), 1.64-1.46 (m, 5H), 1.44-1.38 (m, 3H), 1.30-1.26 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 173.4, 173.3, 170.7, 170.6, 170.0, 168.8, 162.4, 162.3, 140.7, 140.5, 136.8, 136.1, 130.5, 130.1, 128.9, 128.7, 128.5, 128.4, 128.3 (2C), 128.2 (2C), 128.1, 128.0, 92.9, 92.8, 67.7, 67.1, 52.0, 51.9, 51.8 (2C), 45.2, 44.4, 42.5, 42.2, 41.9, 41.1, 41.0, 35.1, 34.8, 33.7, 33.6, 33.5, 32.9, 25.6, 25.5. HRMS (ESI) (m / z): [M+H] + calculated for C 28 H 32 BrCl3N2O5: 661.0633, found: 661.0628. Rf: (petroleum ether / EtOAc 5:1) = 0.28.

[0057] The reaction general formula is shown in the general experimental procedures; the reaction products and results of different substrate selection are shown in Table 1.

[0058] Table 1 Reaction products and results of different substrate selection

[0059]

[0060] Table 2 (continued)

[0061]

[0062] The above description is merely that of the preferred embodiments of the application and is not intended to limit its scope, for the application is susceptible to modifications in certain parts, as those skilled in the pertinent art will readily understand from this description. Accordingly, the disclosures and descriptions of the preferred embodiments are intended for purposes of illustration and are subject to change without departing from the spirit and scope of the present application.

Claims

1. A method for producing a 1,4-diamine compound, characterized by, The method comprises the following steps: A 1,4-diamine compound (A) is prepared by using a bifunctional N-radical precursor (1), a non-activated olefin (2) and a Michael acceptor (3) as starting materials, adding a photosensitizer, and reacting under visible light at room temperature for 6-12 hours; wherein the bifunctional N-radical precursor (1), the non-activated olefin (2), the Michael acceptor (3) and the 1,4-diamine compound (A) have the following structural formulas: wherein R1 and R2 are independently selected from at least one of hydrogen, an aromatic group and C1-C8 alkyl; and EWG is selected from one of an ester group, a cyano group, a nitro group, an amide group and a phosphite group.

2. The method for preparing a 1,4-diamine compound according to claim 1, characterized in that, The photosensitizer is selected from one of thioxanthone (TXT), 4CzIPN, fac-Ir(ppy)3, [Ir(ppy)2(dtbbpy)](PF6), Ir[dF(Me)ppy]2(dtbbpy)PF6, [Ir(dtbbpy)[dF(CF3)ppy]2]PF6.

3. The method for preparing a 1,4-diamine compound according to claim 2, characterized in that, The amount of the photosensitizer is 2-10 mol% of the bifunctional N-radical precursor.

4. The method for preparing a 1,4-diamine compound according to claim 1, characterized in that, The organic solvent is one of ethyl acetate, acetonitrile, isopropyl acetate or dichloromethane.

5. The method for preparing a 1,4-diamine compound according to claim 4, characterized in that, The concentration of the organic solvent is 0.1 M.

6. The method for preparing a 1,4-diamine compound according to claim 1, characterized in that, The molar ratio of the bifunctional N-radical precursor (1) to the non-activated olefin (2) to the Michael acceptor (3) is 1:(0.5-8):(0.5-2).

7. The method for preparing a 1,4-diamine compound according to claim 1, characterized in that, The wavelength of the visible light is 390-485 nm.

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