A method for reducing amidation of triazine esters and nitroaromatic hydrocarbons

Abstract

The invention discloses a method for reducing amidation of triazine ester and nitroaromatic hydrocarbons, and belongs to the technical field of organic compound synthesis. The method of the invention reacts triazine ester and nitroaromatic hydrocarbons in a solvent under the action of TMSCl and a metal reducing agent to obtain a target compound. The reaction is carried out under the condition of iron powder as a reducing agent and trimethylchlorosilane as an additive, without the need for a catalyst and a ligand, and amide compounds with diverse structures are obtained with a medium to good yield. The preparation method of the invention has mild reaction conditions, simple post-processing, green steps, low pollution, high economic benefits, and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and specifically relates to a method for reducing amidation of triazine ester and nitro aromatic hydrocarbon. Background Art

[0002] Amides are an important class of molecules that are not only widely present in natural products, bioactive molecules and functional materials, but also an important part of synthetic organic chemistry. Traditionally, amides can be synthesized by coupling carbonyl compounds (such as carboxylic acids and esters) with amines. In recent decades, the use of nitroaromatics as an attractive nitrogen source to couple with esters to synthesize amides has attracted widespread attention because nitroaromatics are more readily available and more stable than aromatic amines. Triazine esters, as a readily available and stable acylating agent, have been shown to be an alternative to traditional esters and can participate in a series of organic reactions such as Suzuki reaction, Kumada reaction, Sonogashira reaction, reduction reaction, Catellani reaction, etc. Although different carboxylic acid derivatives (such as esters and amides) have been used to couple with nitroaromatics to synthesize amides, the use of triazine esters as acylating agents to react with nitroaromatics under reducing conditions to obtain amides has not been developed.

[0003] Previously developed methods require the use of relatively expensive and more reactive metals (e.g., Mg, Zn, Mn) in the presence or absence of transition metal catalysts (e.g., Ni, Cr). Iron metal is undoubtedly the most abundant and cheapest metal on Earth. In order to study Fe(0)-mediated organic transformations and reductive cross-coupling reactions, we therefore consider the iron-mediated reductive amidation of triazine esters with nitroaromatics to provide a new method for the synthesis of amides. Summary of the invention

[0004] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0005] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0006] One of the objects of the present invention is to provide a method for the reductive amidation of triazine esters with nitroaromatic hydrocarbons, which uses cheap and readily available nitroaromatic hydrocarbons as nitrogen sources and uses iron, the most abundant and cheapest metal on earth, as a reducing metal.

[0007] In order to solve the above technical problems, the present invention provides the following technical solution: a method for reducing amidation of triazine ester and nitroaromatic hydrocarbon, comprising:

[0008] The triazine ester represented by formula I and the nitroaromatic hydrocarbon represented by formula II are reacted in a solvent under the action of TMSCl and a metal reducing agent to obtain a compound represented by formula III;

[0009]

[0010] Wherein, Ar includes one of phenyl, trifluoromethyl substituted phenyl, ester substituted phenyl, halogen substituted phenyl, tert-butyl substituted phenyl, methyl substituted phenyl, methoxy substituted phenyl, phenyl substituted phenyl, naphthalene substituted, and thiophene substituted;

[0011] Ar' includes one of phenyl, trifluoromethyl substituted phenyl, ester substituted phenyl, trifluoromethoxy substituted phenyl, halogen substituted phenyl, methyl substituted phenyl, methoxy substituted phenyl, pyridine substituent, and carbazole substituent.

[0012] As a preferred embodiment of the method for reductive amidation of triazine ester with nitro aromatic hydrocarbon of the present invention, the molar ratio of the nitro aromatic hydrocarbon to the triazine ester is 1:1.5-2.5.

[0013] As a preferred embodiment of the method for reductive amidation of triazine ester with nitro aromatic hydrocarbon of the present invention, the molar ratio of the nitro aromatic hydrocarbon to the triazine ester is 1:2.5.

[0014] As a preferred embodiment of the method for reductive amidation of triazine ester with nitro aromatic hydrocarbon of the present invention, the molar ratio of the nitro aromatic hydrocarbon to the iron powder is 1:1-4.

[0015] As a preferred embodiment of the method for reductive amidation of triazine ester with nitroaromatic hydrocarbon of the present invention, the molar ratio of the nitroaromatic hydrocarbon to the iron powder is 1:4.

[0016] As a preferred embodiment of the method for reductive amidation of triazine ester with nitroaromatic hydrocarbon of the present invention, the metal reducing agent comprises one of zinc, iron, manganese and tin.

[0017] As a preferred embodiment of the method for reductive amidation of triazine ester with nitroaromatic hydrocarbon of the present invention, the metal reducing agent is iron powder.

[0018] As a preferred embodiment of the method for reductive amidation of triazine ester with nitroaromatic hydrocarbons of the present invention, the solvent comprises one of N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

[0019] As a preferred embodiment of the method for reductive amidation of triazine ester with nitroaromatic hydrocarbon of the present invention, the reaction temperature is not less than 60°C; preferably, the reaction temperature is 120°C.

[0020] As a preferred embodiment of the method for reductive amidation of triazine ester with nitroaromatic hydrocarbon of the present invention, it further comprises a step of purifying the target product.

[0021] In summary, the chemical equation for the optimal reaction conditions of the present invention is as follows:

[0022]

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention provides a novel method for the reductive amidation of triazine esters and nitroaromatics, wherein the reaction uses cheap and readily available nitroaromatics as a nitrogen source and uses the most abundant and cheapest iron on earth as a reducing metal. The preparation method of the present invention has the characteristics of simple reaction conditions, convenient post-treatment, green steps, low pollution, high economic benefits, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0026] Figure 1 is the hydrogen spectrum of the target product of Example 1 of the present invention;

[0027] Figure 2 The carbon spectrum of the target product of Example 1 of the present invention;

[0028] Figure 3 is the hydrogen spectrum of the target product of Example 2 of the present invention;

[0029] Figure 4 The carbon spectrum of the target product of Example 2 of the present invention;

[0030] Figure 5 is the hydrogen spectrum of the target product of Example 3 of the present invention;

[0031] Figure 6 The carbon spectrum of the target product of Example 3 of the present invention;

[0032] Figure 7 is the hydrogen spectrum of the target product of Example 4 of the present invention;

[0033] Figure 8 This is the carbon spectrum of the target product of Example 4 of the present invention. DETAILED DESCRIPTION

[0034] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0035] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0036] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0037] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0038] Sources of raw materials used in the examples: The triazine esters used in the examples were synthesized from different carboxylic acids and 2-chloro-4,6-dimethoxy-1,3,5-triazine under the action of N-methylmorpholine, and were prepared in the laboratory with reference to the following literature:

[0039] [1] Luca, LD; Giacomelli, G.; Tadde, MJ Org. Chem. 2001, 66, 2534-2537.

[0040] [2] Yu, B.; Sun, H.; Xie, Z.; Zhang, G.; Xu, L.-W.; Zhang, W.; Gao, Z. Org. Lett.2015, 17, 3298-3301.

[0041] The raw materials and nitroaromatic hydrocarbons for preparing triazine esters are all purchased commercially.

[0042] Example 1

[0043] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and plug it with a rubber stopper and a nitrogen balloon while it is still hot; then weigh iron powder (89.4 mg, 1.6 mmol, 4 equiv.) and 4,6-dimethoxy-1,3,5-triazine-2-yl-benzoate (261.2 mg, 1 mmol, 2.5 equiv.) and add them to the sealed tube; add 1 mL of ultra-dry N,N-dimethylformamide, and then replace the nitrogen gas in the sealed tube three times. Then add nitrobenzene (49.2 mg, 0.4 mmol, 1 equiv.) and TMSCl (467.6 mg, 0.8 mmol, 2 equiv.) to the sealed tube respectively; stir the mixture at 120°C for 24 hours;

[0044] (2) Then, 1M HCl solution was used for quenching and ethyl acetate was used for extraction; the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:8-10. Finally, 67.3 mg of the target product N-phenylbenzamide was obtained. The structural formula of the compound is:

[0045]

[0046] The above N-phenylbenzamide was characterized as Figure 1 and 2 As shown, the result is: white solid; 1 HNMR (400MHz, CDCl 3 ):7.92–7.81(m,3H),7.65(d,J=7.8Hz,2H),7.59–7.52(m,1H),7.49(t,J=7.5Hz,2H),7.38(t,J=7.9Hz,2H),7.16(t,J=7.4Hz,1H)ppm. 13 CNMR (100MHz, CDCl 3 ):δ165.7,137.9,134.9,131.9,129.1,128.8,127.0,124.6,120.2ppm.HRMS(m / z):calcdforC 13 H 12 NO[M+H] + 198.0913,found:198.0916.IR(KBr,neat):ν3344,3052,3026,1656,1533,1439,1260,1177,910,750cm -1 .

[0047] According to the characterization data, the obtained reaction product is N-phenylbenzamide (purity>98%); the product yield is calculated and the result is 85%.

[0048] Example 2

[0049] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and plug it with a rubber stopper and a nitrogen balloon while it is still hot; then weigh iron powder (89.4 mg, 1.6 mmol, 4 equiv.) and 4,6-dimethoxy-1,3,5-triazine-2-yl-(4-methoxycarbonyl)benzoate (319.3 mg, 1 mmol, 2.5 equiv.) and add them to the sealed tube; add 1 mL of ultra-dry N,N-dimethylformamide, and then replace the nitrogen gas in the sealed tube three times. Then add nitrobenzene (49.2 mg, 0.4 mmol, 1 equiv.) and TMSCl (467.6 mg, 0.8 mmol, 2 equiv.) to the sealed tube respectively; stir the mixture at 120°C for 24 hours;

[0050] (2) Then, 1M HCl solution was used for quenching and ethyl acetate was used for extraction; the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:8-10. Finally, 53.5 mg of the target product N-phenyl-4-(methoxycarbonyl)benzamide was obtained. The structural formula of the compound is:

[0051]

[0052] The above N-phenyl-4-(methoxycarbonyl)benzamide was characterized, as Figure 3 and 4 As shown, the result is: white solid; 1 HNMR (400MHz, CDCl 3 ): δ8.20–8.11(m,2H),7.98–7.80(m,3H),7.65(d,J=7.7Hz,2H),7.44–7.34(m,2H),7.22–7.14(m,1H),3.96(s,3H)ppm. 13 CNMR (100MHz, DMSO-d 6 ): δ166.3,165.5,139.4,139.1,132.5,129.7,129.2,128.5,124.7,121.1,53.0ppm.HRMS(m / z,neat):calcdforC 15 H 14 NO3 [M+H] + 256.0968,found:256.0966.IR(KBr):ν=3367,3056,2923,1717,1660,1534,1439,1279,1119,757cm -1 .

[0053] According to the characterization data, the obtained reaction product is N-phenyl-4-(methoxycarbonyl)benzamide (purity>98%); the product yield is calculated and the result is 52%.

[0054] Example 3

[0055] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and plug it with a rubber stopper and a nitrogen balloon while it is still hot; then weigh iron powder (89.4 mg, 1.6 mmol, 4 equiv.) and 4,6-dimethoxy-1,3,5-triazine-2-yl-benzoate (261.2 mg, 1 mmol, 2.5 equiv.) and add them to the sealed tube; add 1 mL of ultra-dry N,N-dimethylformamide, and then replace the nitrogen gas in the sealed tube three times. Then add 2-bromo-4-methoxynitrobenzene (92.8 mg, 0.4 mmol, 1 equiv.) and TMSCl (467.6 mg, 0.8 mmol, 2 equiv.) to the sealed tube respectively; stir the mixture at 120°C for 24 hours;

[0056] (2) Then, 1M HCl solution was used for quenching and ethyl acetate was used for extraction; the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:8-10. Finally, 67.0 mg of the target product N-(2-bromo-4-methoxyphenyl)benzamide was obtained. The structural formula of the compound is:

[0057]

[0058] The above N-(2-bromo-4-methoxyphenyl)benzamide was characterized as Figure 5 and 6 As shown, the result is: yellow solid; 1HNMR (400MHz, CDCl3): δ8.48 (brs, 1H), 8.30 (d, J = 3.0Hz, 1H), 7.98–7.90 (m, 2H), 7. 63–7.49(m,3H),7.43(d,J=8.9Hz,1H),6.61(dd,J=8.9,3.0Hz,1H),3.85(s,3H)ppm. 13 CNMR(100MHz, CDCl3): δ165.3,159.7,136.5,134.5,132.3,129.0,127.0,112.1,106.4,103.8,55.6ppm.HRMS(m / z):calcdfor C 14 H 13 BrNO 2 [M+H]+306.0124,found:306.0124.IR(KBr,neat):ν3207,3013,2927,1636,1578,1516,1474,1289,1170,717cm -1 .

[0059] According to the characterization data, the obtained reaction product is N-(2-bromo-4-methoxyphenyl)benzamide (purity>98%); the product yield is calculated to be 55%.

[0060] Example 4

[0061] (1) Place the sealed tube equipped with a magnetic stirrer in an oven to dry for one hour, take it out and plug it with a rubber stopper while it is still hot and insert a nitrogen balloon; then weigh iron powder (89.4 mg, 1.6 mmol, 4 equiv.) and 4,6-dimethoxy-1,3,5-triazine-2-yl-(4-chloro)benzoate (295.7 mg, 1 mmol, 2.5 equiv.) and add them to the sealed tube; add 1 mL of ultra-dry N,N-dimethylformamide, and then replace the nitrogen gas in the sealed tube three times. Then add nitrobenzene (49.2 mg, 0.4 mmol, 1 equiv.) and TMSCl (467.6 mg, 0.8 mmol, 2 equiv.) to the sealed tube respectively; stir the mixture at 120°C for 24 hours;

[0062] (2) Then, 1M HCl solution was used for quenching and ethyl acetate was used for extraction; the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the extract was removed by rotary evaporation. The crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: the stationary phase was 200-300 mesh silica gel powder, and the mobile phase was petroleum ether / ethyl acetate 200:8-10. Finally, 64.2 mg of the target product N-phenyl-(4-chloro)benzamide was obtained. The structural formula of the compound is:

[0063]

[0064] The above N-phenyl-(4-chloro)benzamide was characterized, as Figure 7 and 8 As shown, the result is: white solid; 1 HNMR (400MHz, DMSO-d6): δ10.32(brs,1H),8.05–7.92(m,2H),7.82–7.70(m,2H),7.67–7.54(m,2H),7.42–7.31(m,2H),7.18–7.05(m,1H)ppm. 13 CNMR(100MHz,DMSO-d6):δ164.5,139.0,136.4,133.7,129.7,128.7,128.5,123.9,120.5ppm.HRMS(m / z):calcdforC 13 H 11 ClNO[M+H]+232.0524,found:232.0526.IR(KBr):ν=3350,3057,2923,1654,1599,1530,1440,1326,1093,759cm -1 .

[0065] According to the characterization data, the obtained reaction product is N-phenyl-(4-chloro)benzamide (purity>98%); the product yield is calculated and the result is 69%.

[0066] Example 5

[0067] Example 5 is basically the same as Example 1, except that the equivalent of 4,6-dimethoxy-1,3,5-triazine-2-yl-benzoate (2a) is different, the metal reducing agent and its equivalent are different, the solvent is different, and the reaction temperature is different, as shown in Table 1 below:

[0068] Table 1

[0069]

[0070]

[0071] It can be seen from numbers 1 to 3 in Table 1 that, under the same conditions, for different equivalents of 2a, such as 1.5, 2, and 2.5 equivalents, the yield increases with the increase of 2a equivalents, and 2.5 equivalents has the best effect, with the highest yield being 85%.

[0072] From the numbers 3 to 11 in Table 1, it can be seen that under the same conditions, for different metal reducing agents, such as iron, zinc, manganese, tin, lead, bismuth, copper, indium, and stannous chloride, iron has the best effect, with the highest yield of 85%.

[0073] It can be seen from the numbers 3, 12 to 14 in Table 1 that, under the same conditions, for different equivalents of iron, such as 4, 3, 2, and 1 equivalents, the yield decreases as the iron powder equivalent decreases, and 4 equivalents of iron powder has the best effect, with the highest yield of 85%.

[0074] It can be seen from No. 3, 15 to 20 in Table 1 that under the same conditions, for different solvents, such as N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, ethanol, and water, the reaction can only be carried out in amide solvents, and N,N-dimethylformamide has the best effect, with the highest yield of 86%.

[0075] It can be seen from numbers 15, 21 to 23 in Table 1 that, under the same conditions, for different reaction temperatures, such as 120°C, 100°C, 180°C, and 60°C, as the temperature decreases, the yield gradually decreases, and the best effect is achieved at 120°C, with the highest yield being 86%.

[0076] Example 6

[0077] Example 6 is basically the same as Example 1, except that in step (1), the triazine ester and the nitroaromatic hydrocarbon are different, as shown in Table 2 below:

[0078] Table 2

[0079]

[0080]

[0081]

[0082] The invention provides a reductive amidation reaction of triazine ester and nitroaromatic hydrocarbon, wherein the reaction is carried out with iron powder as a reducing agent and trimethylchlorosilane as an additive, without the need for a catalyst and a ligand, and amide compounds with various structures are obtained with a medium to good yield. The preparation method of the invention has mild reaction conditions, simple post-treatment, green steps, low pollution, high economic benefits, and the like.

[0083] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for the reductive amidation of triazine esters and nitroaromatics, characterized in that: include, The triazine ester represented by formula I and the nitroaromatic hydrocarbon represented by formula II are reacted in a solvent under the action of TMSCl and a metal reducing agent to obtain a compound represented by formula III; (Formula I); (Formula II); (Formula III); Wherein, Ar includes one of phenyl, naphthyl, thienyl, trifluoromethyl substituted phenyl, ester substituted phenyl, halogen substituted phenyl, tert-butyl substituted phenyl, methyl substituted phenyl, methoxy substituted phenyl, and phenyl substituted phenyl; Ar' includes one of phenyl, pyridyl, carbazolyl, trifluoromethyl substituted phenyl, ester substituted phenyl, trifluoromethoxy substituted phenyl, halogen substituted phenyl, methyl substituted phenyl, and methoxy substituted phenyl; Wherein, the metal reducing agent is iron powder; The solvent is selected from one of N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide; The reaction temperature is not less than 60°C.

2. The method for reductive amidation of triazine esters and nitroaromatics according to claim 1, characterized in that: The molar ratio of the nitroaromatic hydrocarbon to the triazine ester is 1:1.5-2.

5.

3. The method for reductive amidation of triazine esters and nitroaromatics as claimed in claim 2, characterized in that: The molar ratio of the nitroaromatic hydrocarbon to the triazine ester is 1:2.

5.

4. The method for reductive amidation of a triazine ester with a nitroaromatic hydrocarbon according to any one of claims 1 to 3, characterized in that: The molar ratio of the nitroaromatic hydrocarbon to the iron powder is 1:1-4.

5. The method for reductive amidation of triazine ester with nitroaromatic hydrocarbons according to claim 4, characterized in that: The molar ratio of the nitroaromatic hydrocarbon to the iron powder is 1:

4.

6. The method for reductive amidation of a triazine ester with a nitroaromatic hydrocarbon as claimed in any one of claims 1 to 3 and 5, characterized in that: The method also includes a step of purifying the target product.

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