CN113861069B - Preparation method of nitrile compound - Google Patents

Abstract

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing nitrile compounds. Aldoxime derivatives are used as raw materials, DPPA and DBU are added, reacted in an organic solvent, and nitrile compounds are prepared in one step. The synthetic route is as follows:

Wherein, R is aryl, alkyl, alkenyl. The nitrile compound prepared by the invention has the advantages of cheap and easy-to-obtain raw materials, short synthetic route, simple reaction operation, short reaction time, high yield, easy post-treatment, little environmental pollution, objective economic and practical value, and simultaneously has great potential in the field of drug synthesis. Wide application prospects.

Description

A kind of preparation method of nitrile compound

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of nitrile compounds.

Background technique

Nitrile is a very important intermediate in organic synthesis. As important raw materials and intermediates commonly used in the production of fine chemicals, nitrile compounds are widely used in the fields of medicine, materials, agriculture and chemical industry. In recent years, with the rapid development of science and technology, nitrile compounds are more widely used in various fields. Therefore, studying the synthesis methods of nitrile compounds and expanding the variety of nitrile compounds has become one of the hot topics in the field of organic chemistry.

At present, there are many reports on the synthesis methods of nitrile compounds. According to the different synthetic materials, they are mainly divided into: preparation by cyanation of halogenated hydrocarbons, preparation by oxidative dehydrogenation of amines, preparation by cleavage of C-H or C-C bonds of aromatic alkanes, preparation of aromatic olefins C =C bond cleavage preparation, aromatic alkyne C≡C bond cleavage preparation, aromatic alcohol C-O bond cleavage preparation, aromatic aldehydes, ketones and amides C=O bond cleavage preparation, aldoxime C=N bond cleavage preparation, etc. Wherein, it is an important direction to prepare nitrile compounds by cleavage of aldoxime C=N bond, mainly adopt the method of dehydration in the process of preparing nitrile C≡N by aldoxime C=N conversion, traditional dehydrating agent has strong acidity (acetic anhydride , trifluoromethanesulfonic anhydride, phthalic anhydride, thionyl chloride, sulfonic acid, etc.), strong alkalinity (sodium hydroxide, potassium hydroxide, etc.) and metal compounds (pyridinium chlorochromate, scandium trifluoroacetate, etc. ), however, there are still some limitations in the above method, such as the use of metal (heavy metal or transition metal) dehydrating agent, harsh reaction conditions (high temperature, anhydrous environment, long reaction time), limited substrate applicability, etc. Therefore, it is of great significance to explore new methods for the synthesis of nitrile compounds.

Contents of the invention

In order to solve the above problems, the present invention provides a preparation method of nitrile compounds, the raw materials are cheap and easy to obtain, the synthesis route is short, the reaction operation is simple, the reaction speed is fast, the post-treatment is easy, the yield is high, and the environmental pollution is small, which is suitable for industrial production , the preparation method of the nitrile compound with objective economic and practical value.

The purpose of this invention is to provide a kind of preparation method of nitrile compound, take aldoxime derivative as raw material, add DPPA and DBU, react in organic solvent, one-step preparation obtains nitrile compound, 1, its synthetic route is as follows:

Wherein, R is an aryl group, an alkyl group, or an alkenyl group.

Preferably, the aryl group is a benzene aromatic ring, a pyridine, an imidazole, a thiophene, a thiazole, a pyrimidine or an indole.

Preferably, the molar ratio of diphenylphosphoryl azide DPPA, 1,8-diazabicycloundec-7-ene DBU and aldoxime derivative is 1.2:1.1:1.

Preferably, the organic solvent is one of acetonitrile, dichloromethane and chloroform.

Preferably, the reaction time is 0.5-2h.

Preferably, the reaction temperature is 25-80°C.

Preferably, the nitrile compound comprises the following steps of preparation: adding an organic solvent to the reaction flask, then adding aldoxime derivatives and 1,8-diazabicycloundec-7-ene DBU in sequence, and stirring evenly Slowly add diphenylphosphoryl azide DPPA, react at room temperature, and concentrate under reduced pressure to obtain crude nitrile compounds, which are then separated by chromatography.

Preferably, thin layer chromatography is used to detect whether the reaction is complete, and the reaction is stopped after the reaction is complete.

Preferably, the eluent of the chromatographic separation is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate is 2-10:1.

Compared with the prior art, the present invention has the following beneficial effects:

The process has the advantages of cheap and easy-to-obtain raw materials, short synthesis route, simple reaction operation, short reaction time, high yield, easy post-treatment, less environmental pollution, objective economic and practical value, and has broad application prospects in the field of drug synthesis.

Description of drawings

Fig. 1 is the synthetic route figure that the present invention prepares nitrile compound;

Fig. 2 is the ¹ H-NMR figure of the 2-nitrobenzonitrile compound prepared in Example 2 of the present invention;

Fig. 3 is the ¹ H-NMR chart of the 4-bromoxynil compound prepared in Example 3 of the present invention;

Fig. 4 is the ¹ H-NMR figure of the methyl 4-cyanobenzoate compound prepared in Example 4 of the present invention;

Fig. 5 is the ¹ H-NMR chart of the 4-propoxybenzonitrile compound prepared in Example 5 of the present invention;

Fig. 6 is the ¹ H-NMR chart of the 4-butoxybenzonitrile compound prepared in Example 6 of the present invention;

Figure 7 is the ¹ H-NMR chart of the 4-benzyloxybenzonitrile compound prepared in Example 7 of the present invention;

Fig. 8 is the ¹ H-NMR chart of the 2,2-dimethoxybenzonitrile compound prepared in Example 8 of the present invention;

Fig. 9 is the ¹ H-NMR chart of the 2-cyanopyridine compound prepared in Example 9 of the present invention;

Figure 10 is the ¹ H-NMR chart of (E)-cinnamonitrile compound prepared in Example 10 of the present invention;

Figure 11 is the ¹ H-NMR chart of (E)-4-chlorocinnamonitrile compound prepared in Example 11 of the present invention;

Figure 12 is the ¹ H-NMR figure of (E)-2-benzylidene heptanonitrile compound prepared in Example 12 of the present invention;

Figure 13 is the ¹ H-NMR chart of (E)-3-(furan-2-yl)acrylonitrile compound prepared in Example 13 of the present invention;

Fig. 14 is a single crystal structure diagram of (E)-3-(furan-2-yl)acrylonitrile compound prepared in Example 13 of the present invention.

Detailed ways

The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

It should be noted that the technical terms used in the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the protection scope of the present invention. Unless otherwise specified, each of the terms used in the following embodiments of the present invention All raw materials, reagents, instruments and equipment can be purchased from the market or prepared by existing methods, wherein DPPA is diphenylphosphoryl azide, and DBU is 1,8-diazabicycloundec-7-ene .

Example 1

A kind of preparation method of nitrile compound, take aldoxime derivative as raw material, add DPPA and DBU, react in organic solvent, one-step preparation obtains nitrile compound, and its synthetic route is as follows:

Wherein, R is aryl, alkyl, alkenyl, pyridine. The synthetic route diagram of its nitrile compound is shown in Figure 1, and possible reaction mechanism is as follows:

The synthesis of embodiment 2 2-nitrobenzonitrile

Add 498mg (3.0mmol) 2-nitrobenzaldehyde oxime and 548mg (3.6mmol) DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) DPPA, react at room temperature 25°C After 30 min, the reaction was monitored by TLC and concentrated under reduced pressure. The resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a brownish yellow solid with a yield of 68.5%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.39 (d, J=8.8 Hz, 2H), 8.19 (d, J=8.8 Hz, 2H). See attached drawing 2 for details.

The synthesis of embodiment 3 4-bromoxynil

Add 597mg (3.0mmol) of 4-bromobenzaldoxime and 548mg (3.6mmol) of DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) of DPPA, and react at room temperature for 1h at 25°C After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a white solid with a yield of 71.0%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.66 (d, J=7.6 Hz, 2H), 7.55 (d, J=7.6 Hz, 2H). See attached drawing 3 for details.

The synthesis of embodiment 4 4-cyanobenzoic acid methyl esters

Add 537mg (3.0mmol) 4-(hydroxyimino)methylbenzoate and 548mg (3.6mmol) DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) DPPA, Reaction at room temperature 25°C for 2h, after the completion of the reaction monitored by TLC, concentrated under reduced pressure, the obtained crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a light yellow solid, the yield was 66.2 %. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.16 (d, J=7.5Hz, 2H), 7.77 (d, J=7.5Hz, 2H), 3.98 (s, 3H). See attached drawing 4 for details.

The synthesis of embodiment 5 4-propoxybenzonitrile

Add 537mg (3.0mmol) of 4-propoxybenzaldehyde oxime and 548mg (3.6mmol) of DBU into a reaction flask of chloroform (4mL), stir well, then slowly add 908mg (3.3mmol) of DPPA, at room temperature 25°C After reacting for 30 minutes, TLC monitored the completion of the reaction, and concentrated under reduced pressure. The resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a light yellow liquid with a yield of 80.7%. ¹ H NMR (400MHz, DMSO-d ₆ )δ: 7.75(dd, J=9.2, 2.2Hz, 2H), 7.12-7.06(m, 2H), 4.01(t, J=6.5Hz, 2H), 1.78- 1.66 (m, 2H), 0.97 (t, J = 7.4Hz, 3H). See attached drawing 5 for details.

The synthesis of embodiment 6 4-butoxybenzonitrile

Add 579mg (3.0mmol) 4-butoxybenzaldehyde oxime, 548mg (3.6mmol) DBU in the reaction bottle of dichloromethane (4mL), after stirring evenly, then slowly add 908mg (3.3mmol) DPPA, at room temperature 25 After reacting at ℃ for 45 min, TLC monitored the completion of the reaction, concentrated under reduced pressure, and the obtained crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a light yellow liquid with a yield of 78.3%. ¹ H NMR (400MHz,DMSO-d ₆ )δ:7.81-7.68(m,2H),7.76-7.70(m,2H),7.14-7.02(m,2H),7.10-7.04(m,2H),4.03 (t, J = 6.5Hz, 2H), 1.69 (dt, J = 14.4, 6.5Hz, 2H), 1.47-1.34 (m, 2H), 0.91 (t, J = 7.4Hz, 3H). See attached drawing 6 for details.

The synthesis of embodiment 7 4-benzyloxybenzonitrile

Add 681mg (3.0mmol) of 4-benzyloxybenzaldehyde oxime and 548mg (3.6mmol) of DBU into a reaction flask of acetonitrile (4mL). The reaction was carried out for 30 minutes. After the reaction was monitored by TLC, it was concentrated under reduced pressure. The resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a white solid with a yield of 82.2%. ¹ H NMR (400MHz,DMSO-d ₆ )δ:7.83-7.75(m,2H),7.49-7.44(m,2H),7.44-7.38(m,2H),7.37(dd,J＝6.4,2.0Hz ,1H), 7.23-7.15(m,2H), 5.21(s,2H). See attached drawing 7 for details.

Example 8 Synthesis of 2,4-dimethoxybenzonitrile

Add 543mg (3.0mmol) of 2,4-dimethoxybenzaldehyde oxime and 548mg (3.6mmol) of DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) of DPPA, and Reacted at 25°C for 30 min. After the reaction was monitored by TLC, it was concentrated under reduced pressure. The resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a light yellow liquid with a yield of 81.4%. 1H NMR (400MHz, DMSO-d ₆ )δ: 7.50(d, J=8.4Hz, 1H), 6.54(d, J=8.5Hz, 1H), 6.48(s, 1H), 3.93(s, 3H), 3.88(s,3H). See attached drawing 8 for details.

The synthesis of embodiment 9 2-cyanopyridine

Add 366mg (3.0mmol) of pyridine-2-carbaldehyde oxime and 548mg (3.6mmol) of DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) of DPPA, and react at a temperature of 80°C After 1.5 min, the reaction was monitored by TLC and concentrated under reduced pressure. The resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 5:1) to obtain a reddish-brown liquid with a yield of 64.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 4.87 (s, 2H), 4.54 (s, 2H), 4.38 (s, 5H). See attached drawing 9 for details.

The synthesis of embodiment 10 (E)-cinnamonitrile

Add 441mg (3.0mmol) cinnamon aldoxime and 548mg (3.6mmol) DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) DPPA, react at 50°C for 1h, TLC After monitoring the reaction, it was concentrated under reduced pressure, and the obtained crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a light yellow liquid with a yield of 66.4%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.7-7.62 (m, 3H), 7.50-7.41 (m, 3H), 6.49 (d, J=16.8 Hz, 1H). See Figure 10 for details.

The synthesis of embodiment 11 (E)-4-chlorocinnamonitrile

Add 543mg (3.0mmol) 4-chlorocinnamic aldoxime and 548mg (3.6mmol) DBU into a reaction flask of acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) DPPA, and react at a temperature of 60°C After 1.5 h, after the reaction was monitored by TLC, it was concentrated under reduced pressure, and the resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 10:1) to obtain a light yellow liquid with a yield of 62.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.40 (s, 1H), 7.29 (t, J=3.8Hz, 4H), 5.89 (d, J=16.7Hz, 1H). See attached drawing 11 for details.

The synthesis of embodiment 12 (E)-2-benzylidene heptanonitrile

Add 651mg (3.0mmol) ɑ-amylcinnamic aldoxime and 548mg (3.6mmol) DBU into acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) DPPA, react at 50°C for 1.5h After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 5:1) to obtain a colorless liquid with a yield of 58.4%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.49-7.38(m, 6H), 2.46(t, J=7.7Hz, 2H), 1.61-1.52(m, 2H), 1.31-1.24(m, 4H ), 0.84 (t, J=6.8Hz, 3H). See attached drawing 12 for details.

The synthesis of embodiment 13 (E)-3-(furan-2-yl) acrylonitrile

Add 411mg (3.0mmol) of 3-(2-furyl)acryl aldoxime and 548mg (3.6mmol) of DBU into acetonitrile (4mL), stir well, then slowly add 908mg (3.3mmol) of DPPA, at 50°C The reaction was carried out for 2 hours. After the reaction was monitored by TLC, it was concentrated under reduced pressure. The resulting crude product was separated by column chromatography (eluent V _{petroleum ether} : V _{ethyl acetate} = 5:1) to obtain a brownish yellow solid with a yield of 63.6%. ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.52(s, 1H), 7.14(d, J=16.3Hz, 1H), 6.65(s, 1H), 6.53(s, 1H), 5.79(d, J=16.2 Hz, 1H). See Figure 13 for details.

用ω-2θ扫描方式收集衍射点，数据的处理采用SHELXL-97程序直接解出晶体结构。Dissolve (E)-3-(furan-2-yl)acrylonitrile in a mixed solvent of dichloromethane and methanol, and volatilize naturally at room temperature. After about 5 days, ^a colorless crystal is obtained. Crystal, the data collected by APEX II CCD X-ray single crystal diffractometer adopts graphite monochromatic MoKɑ ray

The diffraction points were collected by ω-2θ scanning, and the data was processed by SHELXL-97 program to directly solve the crystal structure.

ɑ＝γ＝90.00°，β＝102.59(4)°，/>

Z＝4，T＝170.0K，Dc＝1.314g/cm3，μ＝0.09mm^-1，F(000)＝248。通过X-ray单晶衍射可以看到产物1q的立体结构，具体见附图14。The crystal structure of the product (E)-3-(furan-2-yl)acrylonitrile (1q) belongs to the monoclinic system, as shown in Table 1, P2 ₁ /n space group, unit cell parameters

ɑ=γ=90.00°, β=102.59(4)°, />

Z=4, T=170.0K, Dc=1.314g/cm3, μ=0.09mm ^-1 , F(000)=248. The three-dimensional structure of the product 1q can be seen through X-ray single crystal diffraction, see Figure 14 for details.

Table 1 Crystal data and structure refinement of product (E)-3-(furan-2-yl)acrylonitrile (1q)

It should be noted that when the present invention involves a numerical range, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods adopted are the same as those in the embodiments, in order to avoid repeating , the invention describes preferred embodiments. While preferred embodiments of the present invention have been described, additional changes and modifications can be made to these embodiments by those skilled in the art once the basic inventive concept is appreciated. Therefore, it is intended that the appended claims be construed to cover the preferred embodiment as well as all changes and modifications which fall within the scope of the invention.

Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations.

Claims (4)

1. a kind of preparation method of nitrile compounds, it is characterized in that, take aldoxime derivative as raw material, add diphenyl phosphoric azide and 1,8-diazabicycloundec-7-ene, in organic Reaction in solvent, one-step preparation obtains nitrile compound, and its synthetic route is as follows:

Described nitrile compound is 2-nitrobenzonitrile, 4-bromobenzonitrile, methyl 4-cyanobenzoate, 4-propoxybenzonitrile, 4-butoxybenzonitrile, 4-benzyloxybenzene Nitrile, 2,4-dimethoxybenzonitrile, 2-cyanopyridine, (E)-cinnamonitrile, (E)-4-chlorocinnamonitrile, (E)-2-benzylideneheptanonitrile and (E )-3-(furan-2-yl)acrylonitrile; The molar ratio of diphenylphosphoryl azide, 1,8-diazabicycloundec-7-ene and aldoxime derivatives is 1.2:1.1:1; The reaction time is 0.5-2h; The temperature of the reaction is 25-80°C; The organic solvent is one of acetonitrile, methylene chloride and chloroform. 2. the preparation method of nitrile compound according to claim 1, is characterized in that, described nitrile compound comprises the following steps of preparation: in reaction flask, adds organic solvent, then adds aldoxime derivative and diphosphoric acid diazide successively Phenyl ester, after stirring evenly, slowly add 1,8-diazabicycloundec-7-ene, react at room temperature and concentrate under reduced pressure to obtain crude nitrile compounds, which are then separated by chromatography. 3. the preparation method of nitrile compound according to claim 2 is characterized in that, adopts thin-layer chromatography to detect whether reaction is complete, stops reaction after reaction is complete. 4. the preparation method of nitrile compounds according to claim 3, is characterized in that, the eluent of described chromatographic separation is sherwood oil and ethyl acetate, and the volume ratio of sherwood oil and ethyl acetate is 2-10 :1.

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