Preparation method of (E)-2-(3-seleno-1-propylene-1-yl) aniline and method for preparing (E)-2-(3-seleno-1-propylene-1-yl) aniline

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of (E)-2-(3-seleno-1-propylene-1-yl) aniline. According to the technical scheme, the preparation method is characterized by comprising the following steps: dissolving a catalyst system [Rh (COD) 2BF4 / dppm], aryl selenol (or dialkyl diselenide and diphenyl phosphine oxide) and a vinyl benzoxazinone compound in an anhydrous solvent N, N-dimethylformamide, and reacting to prepare the target product (E)-2-(3-seleno-1-propylene-1-yl) aniline. According to the method disclosed by the invention, (E)-2-(3-seleno-1-propylene-1-yl) aniline is directly prepared through'one time 'type decarboxylation hydroselenylation reaction, selenium can be introduced to the terminal of olefin in a site-selective manner, a regioisomer mixture is avoided, the reaction efficiency is improved, and an important synthesis method is provided for introducing selenium into small organic molecules; the synthesis method has the advantages of simple and available raw materials, mild reaction conditions and simple reaction operation, has the advantages of excellent regioselectivity, high atom economy and wide substrate application range, and has a wide application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of (E)-2-(3-seleno-1-propylene-1-yl)aniline. Background Art

[0002] Selenium is an essential trace element for the human body, and selenium deficiency can easily cause serious loss of body function. Embedding selenium in active small molecules can significantly improve the physicochemical properties or biological activity of the compounds. Studies have shown that selenium-containing compounds have a variety of pharmacological activities, such as antioxidant, antiviral, antifibrotic, anti-inflammatory, antifungal and anticancer, and are widely used in the field of pharmaceuticals and chemicals. Hydroselenation is one of the effective ways to introduce selenium into unsaturated substrates, and has attracted much research interest from organic syntheses. In recent years, several cases of Pd(II) or Rh(I)-catalyzed asymmetric hydroselenation of non-activated olefins have been reported, all of which use selenol (phenol) or selenol (phenol) generated in situ by diselenide and diphenylphosphine oxide to directly add to the unsaturated double bond to generate selenium-containing compounds. However, the above methods are not suitable for the construction of allylic selenium compounds. Vinylbenzoxazinones are a class of easily available organic synthesis intermediates that easily generate zwitterionic π-allyl metal species under transition metal catalysis, providing opportunities for the regioselective control of subsequent reactions. Therefore, the study used vinylbenzoxazinone and selenol (phenol) [or selenol (phenol) generated in situ using diselenide and diphenylphosphine] as reaction raw materials to directly construct (E)-2-(3-seleno-1-propen-1-yl)aniline through decarboxylation hydroselenation reaction under the catalysis of transition metal Rh(I). This not only has simple reaction operation and good regioselectivity, but also provides an important synthetic method for introducing selenium into small organic molecules. Summary of the invention

[0003] The present invention aims to provide a method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline. The method uses easily available vinylbenzoxazinone and selenol (phenol) [or selenol (phenol) generated in situ by using diselenide and diphenylphosphine] as starting materials, and synthesizes the target product (E)-2-(3-seleno-1-propene-1-yl)aniline with high regioselectivity through decarboxylation hydrogen selenization reaction under the action of Rh(COD)2BF4 / dppm catalytic system. The reaction operation is simple in the synthesis process, the reaction conditions are relatively mild, and the method has the advantages of excellent regioselectivity and high atom economy.

[0004] The purpose of the present invention can be achieved through the following technical solutions: A method for preparing (E)-2-(3-seleno-1-propylene-1-yl)aniline, comprising the following specific steps: dissolving a catalyst system [Rh(COD)2BF4 / dppm], compound 1 (or compound 4 and compound 5, which can generate alkyl selenol in situ) and compound 2 in an anhydrous solvent N,N-dimethylformamide (DMF), stirring at room temperature for 15 minutes, and then reacting at 80°C to obtain a target product, namely compound 3. The reaction equation of the synthesis method is:

[0005] or

[0006] Compound 1 is phenylselenol; Compound 2 is a vinylbenzoxazinone compound; Compound 3 is (E)-2-(3-seleno-1-propene-1-yl)aniline; Compound 4 is a dialkyl diselenide; and Compound 5 is diphenylphosphine oxide.

[0007] Wherein R1 is one of hydrogen, methyl, methoxy, fluorine or trifluoromethyl, R2 is one of p-toluenesulfonyl, acetyl or tert-butoxycarbonyl, and R is benzyl or ethyl.

[0008] Further preferably, in reaction equation (1), the molar ratio of benzoselenol, vinylbenzoxazinone compound, Rh(COD)2BF4, and dppm is 1:1.5:0.05:0.1, and the feeding ratio of benzoselenol to N,N-dimethylformamide is 1mmol:10mL; in reaction equation (2), the molar ratio of dialkyl diselenide, diphenylphosphine, vinylbenzoxazinone compound, Rh(COD)2BF4, and dppm is 1:1.5:1.5:0.05:0.1, and the feeding ratio of dialkyl diselenide to N,N-dimethylformamide is 1mmol:10mL.

[0009] Wherein, (E)-2-(3-seleno-1-propylene-1-yl)aniline is one of the following compounds:

[0010] Compared with the existing hydrogen selenization reaction technology, the beneficial effects of the present invention are: First, the raw materials are readily available and stable, the reaction operation is simple, and the reaction conditions are mild; second, the excellent regional (site) selectivity, high atom economy and wide substrate applicability give this reaction broad application prospects.

[0011] Research and calculation show that the comprehensive yield of the target product of the preparation method disclosed in the present invention under the catalytic condition of Rh(COD)2BF4 / dppm is 46%-76%; in addition, the method directly prepares (E)-2-(3-seleno-1-propylene-1-yl)aniline through a "one-pot" decarboxylation hydrogen selenization reaction, which can site-selectively introduce selenium at the end of the olefin, avoid the occurrence of regional isomer mixtures, improve the reaction efficiency, and provide an important synthesis method for introducing selenium into organic small molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to facilitate understanding by those skilled in the art, the present invention is further described below with reference to the accompanying drawings.

[0013] Figure 1 For the compound 3g of the present invention 1 H NMR spectrum; Figure 2 For the compound 3g of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0014] The technical scheme of the present invention will be described clearly and completely below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments (e.g., diselenide is also applicable to diaryl diselenide, but the present invention only provides two embodiments of dibenzyl diselenide and diethyl diselenide). Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0015] Embodiment 1: As shown in the following reaction equation:

[0016] A method for preparing (E)-2-(3-seleno-1-propylene-1-yl)aniline, In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 1 (31.4 mg, 0.2 mmol), 2a (98.8 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 50:1) to obtain a white solid product 3a (67.3 mg, yield 76%).

[0017] The characterization data of compound 3a are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.42-7.46 (m, 4H),7.21-7.27 (m, 4H), 7.07-7.13 (m, 4H), 7.00-7.03 (m, 1H), 5.89-5.96 (m, 2H),5.63 (d, J = 15.6 Hz, 1H), 3.41 (d, J = 7.6 Hz, 2H), 2.30 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 143.9, 136.7, 134.7, 133.1, 131.7, 130.3, 129.7, 129.29,129.25, 128.4, 128.1, 127.19, 127.16, 126.4, 125.9, 125.2, 30.7, 21.6.

[0018] Embodiment 2: As shown in the following reaction equation:

[0019] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 1 (31.4 mg, 0.2 mmol), 2b (103.0 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 50:1) to obtain a white solid product 3b (61.2 mg, yield 67%).

[0020] The characterization data of compound 3b are as follows: 1H NMR (400 MHz, CDCl3) δ 7.42-7.44 (m, 4H), 7.24-7.30 (m, 3H), 7.12 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.86-6.94 (m, 2H), 5.87-5.95 (m, 1H), 5.67 (br s, 1H), 5.56 (d, J = 15.6 Hz, 1H), 3.39 (d, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H); 13 C NMR (100 MHz, CDCl3)δ 143.8, 136.8, 136.5, 134.7, 132.0, 130.4, 129.7, 129.6, 129.3, 129.2,128.1, 127.5, 127.2, 126.1, 126.0, 30.8, 21.7, 21.1.

[0021] Embodiment three: As shown in the following reaction equation:

[0022] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 1 (31.4 mg, 0.2 mmol), 2c (107.8 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 40:1) to obtain a light yellow solid product 3c (43.5 mg, yield 46%).

[0023] The characterization data of compound 3c are as follows: 1H NMR (400 MHz, CDCl3) δ 7.40-7.44 (m, 4H), 7.23-7.31 (m, 3H), 7.12 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.62-6.67 (m, 2H), 5.88-5.96 (m, 1H), 5.57 (br s, 1H), 5.54 (d, J = 15.6 Hz, 1H), 3.69 (s, 3H), 3.36 (d, J = 7.6 Hz, 2H), 2.32 (s, 3H); 13 C NMR (100 MHz, CDCl3)δ 158.5, 143.7, 136.7, 134.8, 134.6, 129.7, 129.6, 129.4, 129.2, 128.9,128.1, 127.3, 126.3, 125.7, 113.9, 111.5, 55.5, 30.7, 21.7.

[0024] Embodiment 4: As shown in the following reaction equation:

[0025] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 1 (31.4 mg, 0.2 mmol), 2d (104.2 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 ° C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 50:1) to obtain a white solid product 3d (46.0 mg, yield 50%).

[0026] The characterization data of compound 3d are as follows: 1H NMR (400 MHz, CDCl3) δ 7.40-7.44 (m, 4H),7.25-7.33 (m, 3H), 7.13-7.19 (m, 3H), 6.76-6.85 (m, 2H), 5.89-5.97 (m, 1H),5.64 (br s, 1H), 5.49 (d, J = 15.6 Hz, 1H), 3.36 (d, J = 7.6 Hz, 2H), 2.32(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 161.2 (d, J = 244.8 Hz), 144.0, 136.4,134.8, 134.7, 131.0, 129.7, 129.2, 129.1, 128.7 (d, J = 2.8 Hz), 128.6 (d, J = 8.8 Hz), 128.2, 127.1, 125.0 (d, J = 1.6 Hz), 115.2 (d, J = 22.6 Hz), 113.2 (d, J = 23.2 Hz), 30.5, 21.6.

[0027] Embodiment five: As shown in the following reaction equation:

[0028] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 1 (31.4 mg, 0.2 mmol), 2e (119.2 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 50:1) to obtain a light yellow oily product 3e (63.3 mg, yield 62%).

[0029] The characterization data of compound 3e are as follows: 1H NMR (400 MHz, CDCl3) δ 7.49-7.51 (m, 2H), 7.44-7.46 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.25-7.33 (m, 5H), 7.16 (d, J =8.0 Hz, 2H), 6.10 (br s, 1H), 5.94-6.02 (m, 1H), 5.60 (d, J = 15.6 Hz, 1H), 3.44 (d, J = 8.0 Hz, 1.2 Hz, 2H), 2.32 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ144.4, 136.4, 135.0, 132.7, 131.6, 130.6, 129.9, 129.4, 128.9, 128.4, 127.6(q, J = 32.4 Hz), 127.1, 125.1 (q, J = 3.7 Hz), 124.7 (q, J = 3.7 Hz), 124.3, 123.9 (q, J = 270.5 Hz), 123.1, 30.4, 21.7.

[0030] Embodiment six: As shown in the following reaction equation:

[0031] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 1 (31.4 mg, 0.2 mmol), 2f (65.2 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 20:1) to obtain a light yellow oily product 3f (38.3 mg, yield 58%).

[0032] The characterization data of compound 3f are as follows: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0Hz, 1H), 7.46-7.48 (m, 2H), 7.14-7.23 (m, 5H), 7.01-7.04 (m, 1H), 6.59 (br s,1H), 6.11-6.19 (m, 1H), 6.06 (d, J = 15.6 Hz, 1H), 3.60 (d, J = 6.8 Hz, 2H), 2.01 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.3, 134.8, 134.2, 130.2, 129.4,129.3, 129.1, 128.2, 127.8, 127.1, 126.5, 125.4, 123.9, 30.9, 24.4.

[0033] Embodiment seven: As shown in the following reaction equation:

[0034] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1mg, 0.01mmol), dppm (7.7mg, 0.02mmol), 1 (31.4mg, 0.2mmol), 2g (82.6mg, 0.3mmol) were added to a 10mL sealed tube in sequence, and 2mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15min, and then heated to 80°C for 16h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 80:1) to obtain 3g (56.7mg, yield 73%) of colorless oily product.

[0035] The characterization data of compound 3g are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6Hz, 1H), 7.46-7.48 (m, 2H), 7.10-7.23 (m, 5H), 6.91-6.95 (m, 1H), 6.04-6.14(m, 2H), 5.89 (br s, 1H), 3.59 (d, J = 6.4 Hz, 2H), 1.46 (s, 9H); 13C NMR (100MHz, CDCl3) δ 153.1, 134.9, 134.8, 129.8, 129.3, 129.1, 128.2, 127.9, 127.1,126.6, 124.0, 121.9, 80.6, 31.0, 28.5.

[0036] Embodiment eight: As shown in the following reaction equation:

[0037] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 4a (68.0 mg, 0.2 mmol), 5 (60.7 mg, 0.3 mmol), 2a (98.8 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 ° C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 50:1) to obtain a light yellow oily product 3h (59.3 mg, yield 65%).

[0038] The characterization data of compound 3g are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4Hz, 2H), 7.07-7.27 (m, 11H), 6.43 (s, 1H), 6.14 (d, J = 15.6 Hz, 1H), 5.91-5.99 (m, 1H), 3.64 (s, 2H), 3.10 (d, J = 7.2 Hz, 2H), 2.26 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 143.9, 139.2, 136.5, 132.9, 132.3, 130.7, 129.7, 129.1,128.7, 128.3, 127.3, 127.0, 126.9, 126.8, 125.6, 27.2, 25.9, 21.6.

[0039] Embodiment nine: As shown in the following reaction equation:

[0040] In a glove box (N2 atmosphere), Rh(COD)2BF4 (4.1 mg, 0.01 mmol), dppm (7.7 mg, 0.02 mmol), 4b (43.2 mg, 0.2 mmol), 5 (60.7 mg, 0.3 mmol), 2a (98.8 mg, 0.3 mmol) were added to a 10 mL sealed tube in sequence, and 2 mL of anhydrous DMF was added as solvent. The sealed tube was placed on a parallel reactor with magnetic stirring, stirred at room temperature for 15 min, and then heated to 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column (n-hexane / ethyl acetate = 50:1) to obtain a white solid product 3i (51.3 mg, yield 65%).

[0041] The characterization data of compound 3g are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0Hz, 2H), 7.27-7.29 (m, 1H), 7.14-7.17 (m, 3H), 7.05-7.12 (m, 2H), 6.34 (br s,1H), 6.11 (d, J = 15.6 Hz, 1H), 5.94-6.02 (m, 1H), 3.17 (d, J = 7.6 Hz, 2H), 2.43 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H), 1.31 (t, J = 7.6 Hz, 3H); 13 C NMR (100MHz, CDCl3) δ 144.0, 136.6, 133.0, 132.3, 131.1, 129.7, 128.3, 127.3, 127.1,126.8, 125.4, 125.2, 25.0, 21.7, 17.1, 15.7.

[0042] The preferred embodiments of the present invention disclosed above are only used to help explain the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to only specific implementation methods. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing (E)-2-(3-seleno-1-propylene-1-yl)aniline, characterized in that: The catalyst system, phenylselenol (1), and vinylbenzoxazinone compound (2) are dissolved in anhydrous N,N-dimethylformamide, stirred at room temperature for 15 minutes, and then reacted at 80°C to obtain the target product (E)-2-(3-seleno-1-propene-1-yl)aniline (3); the catalyst system comprises Rh(COD)2BF4 and dppm.

2. The method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline according to claim 1, characterized in that: The reaction equation for synthesizing (E)-2-(3-seleno-1-propylene-1-yl)aniline is: 。 3. The method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline according to claim 2, characterized in that: Wherein R1 is one of hydrogen, methyl, methoxy, fluorine or trifluoromethyl, and R2 is one of p-toluenesulfonyl, acetyl or tert-butyloxycarbonyl.

4. The method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline according to claim 2, characterized in that: The molar ratio of phenylselenol (1), vinylbenzoxazinone compound (2), Rh(COD)2BF4 and dppm is 1:1.5:0.05:0.1, and the molar ratio of phenylselenol (1) to N,N-dimethylformamide is 1 mmol:10 mL.

5. A method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline, characterized in that: The catalyst system, dialkyl diselenide (4), diphenylphosphine (5), and vinylbenzoxazinone compound (2) are dissolved in anhydrous N,N-dimethylformamide, stirred at room temperature for 15 minutes, and then reacted at 80°C to obtain the target product (E)-2-(3-seleno-1-propene-1-yl)aniline (3); the catalyst system comprises Rh(COD)2BF4 and dppm.

6. The method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline according to claim 5, characterized in that: The reaction equation for synthesizing (E)-2-(3-seleno-1-propylene-1-yl)aniline is: 。 7. The method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline according to claim 6, characterized in that: Wherein R1 is one of hydrogen, methyl, methoxy, fluorine or trifluoromethyl, R2 is one of p-toluenesulfonyl, acetyl or tert-butoxycarbonyl, and R is benzyl or ethyl.

8. The method for preparing (E)-2-(3-seleno-1-propene-1-yl)aniline according to claim 6, characterized in that: The feeding molar ratio of dialkyl diselenide (4), diphenylphosphine (5), vinylbenzoxazinone compound (2), Rh(COD)2BF4, and dppm is 1:1.5:1.5:0.05:0.1, and the feeding ratio of the dialkyl diselenide (4) and N,N-dimethylformamide is 1 mmol:10 mL.

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