A method for preparing an N,N-diaryl urea compound

Abstract

The application discloses a preparation method of N,N-diaryl urea compounds, which couples aromatic amine compounds into N,N-diaryl urea compounds through carbonylation. The application uses formic acid as a carbonyl source, copper acetate as an oxidant, palladium acetate as a catalyst, 1,4-dioxane as a solvent, and performs a reflux reaction at 120 DEG C. The method has good safety and high yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing N,N-diarylurea compounds. Background Technology

[0002] N,N-Diarylurea compounds are important organic intermediates used in the synthesis of herbicides, insecticides, and sulfonamides. They are intermediates in the non-phosgene synthesis of isocyanates and can also be used as plant growth regulators. They are primarily used as intermediates for sulfanilamide, and their chlorosulfonation product can be used as a major raw material for sulfamethoxazole. Current synthetic methods use highly toxic substances such as carbon monoxide as raw materials, posing a significant risk.

[0003] Therefore, establishing a safe and efficient synthetic method for N,N-diarylurea compounds is of great significance to human health and environmental protection. Summary of the Invention

[0004] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

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

[0006] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing N,N-diarylurea compounds.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: including,

[0008] In the presence of a catalyst, aromatic amine compounds are carbonylated and coupled using a carbonyl source and an oxidant to obtain N,N-diarylurea compounds.

[0009] The aromatic amine compounds have a structure as shown in general formula (I).

[0010]

[0011] In the formula, R is selected from any one of H, CH3, Cl, Br, and methoxy.

[0012] As a preferred embodiment of the method for preparing the N,N-diarylurea compounds of the present invention, wherein: the aromatic amine compound represented by formula (Ⅰ) is selected from one of the following structural formulas;

[0013]

[0014] In a preferred embodiment of the method for preparing the N,N-diarylurea compounds of the present invention, the carbonyl source includes formic acid.

[0015] In a preferred embodiment of the method for preparing the N,N-diarylurea compounds of the present invention, the oxidant includes copper acetate.

[0016] As a preferred embodiment of the method for preparing the N,N-diarylurea compounds of the present invention, the method specifically includes:

[0017] An aromatic amine compound, Cu(OAc)2, and palladium acetate were slowly added sequentially to a solution of formic acid and 1,4-dioxane to obtain a reaction mixture.

[0018] The reaction mixture was heated to reflux and stirred, while the reaction was detected by thin-layer chromatography.

[0019] After the reaction was completed, the reaction mixture was diluted with ethyl acetate, washed with water, dried with anhydrous sodium sulfate, and then evaporated under reduced pressure.

[0020] The residue was then purified by flash chromatography using ethyl acetate and petroleum ether as eluents to obtain N,N-diarylurea compounds.

[0021] In a preferred embodiment of the preparation method of the N,N-diarylurea compounds of the present invention, the stirring reaction time is 18-24 h.

[0022] In a preferred embodiment of the preparation method of the N,N-diarylurea compounds of the present invention, the temperature of the stirring reaction is 100-140°C.

[0023] In a preferred embodiment of the preparation method of the N,N-diarylurea compounds of the present invention, the ratio of ethyl acetate to petroleum ether in the eluent is 1:3 to 5.

[0024] In a preferred embodiment of the preparation method of the N,N-diarylurea compounds of the present invention, the N,N-diarylurea compounds have a structure as shown in general formula (II).

[0025]

[0026] Beneficial effects of this invention:

[0027] Compared with the prior art, the present invention uses aromatic amine compounds as raw materials, formic acid as carbonyl source, copper acetate as oxidant, and palladium acetate as catalyst for reaction, which has good safety and high yield. Detailed Implementation

[0028] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0029] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0030] 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 phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0031] Unless otherwise specified, all raw materials used in this invention are commercially available.

[0032] Example 1

[0033] This embodiment provides a method for preparing N,N-diarylurea compounds, specifically as follows:

[0034] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4,dioxane solution. Then, 1 mmol aniline, 1.5 mmol copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0035]

[0036] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give N,N-diphenylurea as a white solid in 91% yield.

[0037] 1 HNMR (500MHz, DMSO-d) 6 )δ8.68(s,2H),7.48-7.46(d,J=7.6Hz,4H),7.32-7.28(t,J=7.2Hz,4H),7.00-6.97(t,J=7.6Hz,2H).

[0038] 13 CNMR (126MHz, DMSO-d)6 )δ153.0,140.1,129.3,122.3,118.7.

[0039] The comparison showed that it was consistent with existing N,N-diphenylurea, indicating that the target product was successfully prepared.

[0040] Example 2

[0041] The difference between this embodiment and Example 1 is that the raw material aniline is changed to 3-methylaniline, specifically:

[0042] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4,dioxane solution. Then, 1 mmol 3-methylaniline, 1.5 mmol copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0043]

[0044] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-di-m-tolylurea as a white solid in 85% yield.

[0045] 1 H NMR (500MHz, DMSO-d) 6 )δ8.60(s,2H),7.34(s,2H),7.26-7.24(d,J=6.0Hz,2H),7.19-7.15(m,2H),6.81-6.79(d,J=7.6Hz,2H),2.29(s,6H).

[0046] 13 CNMR (126MHz, DMSO-d) 6 )δ153.0,140.2,138.4,129.1,123.0,119.1,115.8,21.7.

[0047] The product was found to be consistent with existing 1,3-di-m-tolylurea, indicating that the target product was successfully prepared.

[0048] Example 3

[0049] The difference between this embodiment and Example 1 is that the raw material aniline is changed to 2-methylaniline, specifically:

[0050] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4,dioxane solution. Then, 1 mmol 2-methylaniline, 1.5 mmol copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0051]

[0052] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-di-o-tolylurea as a white solid in 87% yield.

[0053] 1 H NMR (500MHz, DMSO-d) 6 )δ8.24(s,2H),7.81-7.80(d,J=7.6Hz,2H),7.19-7.13(m,4H),6.96-6.94(t,J=7.2Hz,2H),2.27(s,6H).

[0054] 13 C NMR (126MHz, DMSO-d) 6 )δ153.4,138.0,130.7,128.2,126.6,123.2,122.0,18.5.

[0055] The product was found to be consistent with existing 1,3-di-o-tolylurea, indicating that the target product was successfully prepared.

[0056] Example 4

[0057] The difference between this embodiment and Example 1 is that the raw material aniline is changed to p-methylaniline, specifically:

[0058] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4-dioxane solution. Then, 1 mmol of p-methylaniline, 1.5 mmol of copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0059]

[0060] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give N,N'-bis(p-tolyl)urea as a white solid in 92% yield.

[0061] 1 H NMR (500MHz, DMSO-d) 6 )δ8.52(s,2H),7.36-7.34(d,J=8.0Hz,4H),7.10-7.08(d,J=8.4Hz,4H),2.26(s,6H).

[0062] 13 C NMR (126MHz, DMSO-d) 6 )δ153.1,137.7,130.8,129.7,118.7,20.8.

[0063] Comparison revealed that it was consistent with existing N,N'-bis(p-tolyl)urea, indicating that the target product was successfully prepared.

[0064] Example 5

[0065] The difference between this embodiment and Example 1 is that the raw material aniline is changed to 2-methoxyaniline, specifically:

[0066] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4,dioxane solution. Then, 1 mmol 2-methoxyaniline, 1.5 mmol copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0067]

[0068] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-bis(2-methoxyphenyl)urea as a white solid in 86% yield.

[0069] 1 H NMR (500MHz, DMSO-d) 6 )δ8.91(s,2H),8.12-8.11(t,J=6.4Hz,2H),7.01-6.87(m,6H),3.86(s,6H).

[0070] 13C NMR (126MHz, DMSO-d) 6 )δ153.2,148.7,130.7,129.3,122.4,120.9,111.3,56.2.

[0071] The comparison showed that it was consistent with the existing 1,3-bis(4-chlorophenyl)urea, indicating that the target product was successfully prepared.

[0072] Example 6

[0073] The difference between this embodiment and Example 1 is that the raw material aniline is changed to m-aminoanisole, specifically:

[0074] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4-dioxane solution. Then, 1 mmol m-aminoanisole, 1.5 mmol copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0075]

[0076] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-bis(3-methoxyphenyl)urea as a white solid in 83% yield.

[0077] 1 H NMR (500MHz, DMSO-d) 6 )δ8.66(s,2H),7.19-7.16(m,4H),6.95-6.93(d,J=6.0Hz,2H),6.67-6.55(d,J=7.6Hz,2H),3.74(s,6H).

[0078] 13 CNMR (126MHz, DMSO-d) 6 )δ160.1,152.9,141.3,130.0,111.0,107.7,104.4,55.4.

[0079] The comparison showed that it was consistent with the existing 1,3-bis(3-methoxyphenyl)urea, indicating that the target product was successfully prepared.

[0080] Example 7

[0081] The difference between this embodiment and Example 1 is that the raw material aniline is changed to p-aminoanisole, specifically:

[0082] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4-dioxane solution. Then, 1 mmol of p-aminoanisole, 1.5 mmol of copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0083]

[0084] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-bis(4-methoxyphenyl)urea as a white solid in 92% yield.

[0085] 1 H NMR (500MHz, DMSO-d) 6 )δ8.38(s,2H),7.36-7.34(d,J=9.2Hz,4H),6.87-6.85(d,J=8.4Hz,4H),3.71(s,6H).

[0086] 13 C NMR (126MHz, DMSO-d) 6 )δ154.8,153.4,133.4,120.4,114.4,55.6.

[0087] The comparison showed that it was consistent with the existing 1,3-bis(4-methoxyphenyl)urea, indicating that the target product was successfully prepared.

[0088] Example 8

[0089] The difference between this embodiment and Example 1 is that the raw material aniline is changed to m-chloroaniline, specifically:

[0090] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1,4,dioxane solution. Then, 1 mmol m-chloroaniline, 1.5 mmol copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0091]

[0092] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-bis(3-chlorophenyl)urea as a white solid in 50% yield.

[0093] 1 H NMR (500MHz, DMSO-d) 6 )δ8.99(s,2H),7.71(s,2H),7.31-7.27(m,4H),7.04-7.03(d,J=6.0Hz,2H).

[0094] 13 C NMR (126MHz, DMSO-d) 6 )δ152.7,141.5,133.7,130.9,122.2,118.2,117.3.

[0095] Comparison with existing 1,3-bis(3-chlorophenyl)urea indicates that the target product was successfully prepared.

[0096] Example 9

[0097] The difference between this embodiment and Example 1 is that the raw material aniline is changed to p-chloroaniline, specifically:

[0098] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1-4,dioxane solution. Then, 1 mmol of p-chloroaniline, 1.5 mmol of copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0099]

[0100] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-bis(4-chlorophenyl)urea as a white solid in 75% yield.

[0101] 1 H NMR (500MHz, DMSO-d) 6 )δ8.86(s,2H),7.49-7.47(d,J=8.8Hz,4H),7.36-7.32(d,J=8.8Hz,4H).

[0102] 13 C NMR (126MHz, DMSO-d) 6 )δ152.8,139.0,129.1,126.0,120.3.

[0103] The comparison showed that it was consistent with the existing 1,3-bis(4-chlorophenyl)urea, indicating that the target product was successfully prepared.

[0104] Example 10

[0105] The difference between this embodiment and Example 1 is that the raw material aniline is changed to p-bromoaniline, specifically:

[0106] At room temperature, 0.25 mmol formic acid was dissolved in 20 ml of 1-4,dioxane solution. Then, 1 mmol of p-bromoaniline, 1.5 mmol of copper acetate, and 5 mol% palladium acetate were slowly added sequentially. The mixture was stirred at 120 °C for 24 h under reflux. The reaction equation is as follows:

[0107]

[0108] The reaction was monitored by thin-layer chromatography. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was purified by recrystallization (dichloromethane:ethyl acetate = 4:1) to give 1,3-bis(4-bromophenyl)urea as a white solid in 56% yield.

[0109] 1 H NMR (500MHz, DMSO-d) 6 )δ8.89(s,2H),7.46-7.42(q,8H).

[0110] 13 C NMR (126MHz, DMSO-d) 6 )δ152.7,139.4,132.0,120.7,113.9.

[0111] The comparison showed that it was consistent with the existing 1,3-bis(4-bromophenyl)urea, indicating that the target product was successfully prepared.

[0112] Example 11

[0113] The difference between this comparative example and Example 1 is that the preparation temperature was adjusted to 110°C, while the rest of the preparation process was the same as in Example 1, to prepare N,N-diphenylurea.

[0114] The yield was 84%.

[0115] Example 12

[0116] The difference between this comparative example and Example 1 is that the preparation temperature was adjusted to 130°C, while the rest of the preparation process was the same as in Example 1, to prepare N,N-diphenylurea.

[0117] The yield was 87%.

[0118] Example 13

[0119] The difference between this comparative example and Example 1 is that the preparation temperature was adjusted to 140°C, while the rest of the preparation process was the same as in Example 1, to prepare N,N-diphenylurea.

[0120] The yield was 85%.

[0121] Comparative Example 1

[0122] This comparative example provides a conventional method for preparing N,N-diarylurea compounds, specifically as follows:

[0123] At room temperature, a mixture of 2 mmol amine, 1 mg Pd-610, 5 mol% KI, and 2 ml dioxane was added to a glass tube and placed in an 80 ml autoclave. The autoclave was then cleaned and purged with CO and O2 (CO:O2 = 35:5 bar). The reaction mixture was stirred at 130 °C for 24 h. The reaction equation is as follows:

[0124]

[0125] However, such methods use gaseous CO as a carbonyl source, which is a flammable and toxic gas. Therefore, it is crucial to use a safe carbonyl source to prepare N,N-diarylurea compounds.

[0126] Comparative Example 2

[0127] The difference between this comparative example and Example 1 is that the solvent was changed to dimethylformamide, while the rest of the preparation process was the same as in Example 1. N,N-diphenylurea was prepared, but the reaction could not occur.

[0128] Comparative Example 3

[0129] The difference between this comparative example and Example 1 is that the solvent was changed to dimethyl sulfoxide, while the rest of the preparation process was the same as in Example 1. N,N-diphenylurea was prepared, but the reaction could not occur.

[0130] Comparative Example 4

[0131] The difference between this comparative example and Example 1 is that the solvent was changed to toluene, while the rest of the preparation process was the same as in Example 1. N,N-diphenylurea was prepared, but the reaction did not occur.

[0132] Comparative Example 5

[0133] The difference between this comparative example and Example 1 is that the solvent was changed to tetrahydrofuran, while the rest of the preparation process was the same as in Example 1. N,N-diphenylurea was prepared, but the reaction could not occur.

[0134] Comparative Example 6

[0135] The difference between this comparative example and Example 1 is that the solvent was changed to dichloroethane, while the rest of the preparation process was the same as in Example 1. N,N-diphenylurea was prepared, but the reaction did not occur.

[0136] Comparative Example 7

[0137] The difference between this comparative example and Example 1 is that the oxidant was changed to CuCl2, while the rest of the preparation process was the same as in Example 1. N,N-diphenylurea was prepared, but the reaction could not occur.

[0138] Comparative Example 8

[0139] The difference between this comparative example and Example 1 is that the catalyst was changed to PdCl2, while the rest of the preparation process was the same as in Example 1, to prepare N,N-diphenylurea.

[0140] The yield was 26%.

[0141] In summary, the present invention provides a method for carbonylating and coupling aromatic amine compounds into N,N-diarylurea compounds. The present invention uses formic acid as a carbonyl source, copper acetate as an oxidant, palladium acetate as a catalyst, and 1,4-dioxane as a solvent. The reaction is carried out under reflux at 120°C for 24 hours. The method has good safety and high yield.

[0142] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing an N,N-diarylurea compound, characterized in that: include, In the presence of a catalyst, aromatic amine compounds are carbonylated and coupled using a carbonyl source and an oxidant to obtain N,N-diarylurea compounds. The aromatic amine compounds have a structure as shown in general formula (I). The N,N-diarylurea compounds have the structure shown in general formula (II). In formulas (I) and (II), R is selected from any one of H, CH3, Cl, Br, and methoxy groups; The carbonyl source is formic acid; The oxidant is copper acetate; The catalyst is palladium acetate.

2. The method for preparing N,N-diarylurea compounds as described in claim 1, characterized in that: The aromatic amine compounds represented by formula (Ⅰ) are selected from one of the following structural formulas.

3. The method for preparing N,N-diarylurea compounds according to any one of claims 1 to 2, characterized in that: The method specifically includes: An aromatic amine compound, Cu(OAc)2, and palladium acetate were slowly added sequentially to a solution of formic acid and 1,4-dioxane to obtain a reaction mixture. The reaction mixture was heated to reflux and stirred, while the reaction was detected by thin-layer chromatography. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, washed with water, dried with anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was then purified by flash chromatography using ethyl acetate and petroleum ether as eluents to obtain N,N-diarylurea compounds.

4. The method for preparing N,N-diarylurea compounds as described in claim 3, characterized in that: The stirring reaction time is 18–24 hours.

5. The method for preparing N,N-diarylurea compounds as described in claim 3, characterized in that: The temperature of the stirring reaction is 100–140°C.

6. The method for preparing N,N-diarylurea compounds as described in claim 3, characterized in that: The ratio of ethyl acetate to petroleum ether in the eluent is 1:3 to 5.

Images