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Communication

Amide-Assisted Rearrangement of Hydroxyarylformimidoyl Chloride to Diarylurea

by
Xizhong Song
1,2,
Xiaoyu Liu
1,
Wei Yu
3,* and
Yi Jin
1,*
1
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
2
Jianxi Nafutang Pharmaceutical Co., Ltd., Zhangshu 331200, China
3
920th Hospital of Joint Logistics Support Force, PLA, Kunming 650118, China
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(21), 6437; https://doi.org/10.3390/molecules26216437
Submission received: 27 September 2021 / Revised: 20 October 2021 / Accepted: 22 October 2021 / Published: 25 October 2021
(This article belongs to the Section Organic Chemistry)
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Abstract

A novel amide-assisted rearrangement reaction of hydroxybenzimidoyl chloride has been established for the efficient synthesis of 1,3-diphenylurea derivatives. A variety of electronically and sterically different 1,3-diphenylurea derivatives can be obtained in good to excellent yields, and a proposed reaction mechanism is also presented.

Graphical Abstract

1. Introduction

Urea derivatives have a myriad of applications in biological studies, analytical chemistry, pharmaceuticals, polymer sciences, and agrochemicals [1,2,3,4,5,6,7,8]. N, N′-disubstituted urea exhibits a wide range of potent biological properties in bioactive and pharmacologically impressive structures [9,10,11,12,13,14]. For instance, many urea-containing compounds have been used to cure human diseases (Figure 1) [15,16,17,18].
Given the medicinal and biological properties of N, N′-disubstituted urea, synthetic–organic chemists and medicinal chemists have shown considerable interest in the development of efficient methodologies for the synthesis of this structure. The traditional methods of synthesizing urea involve the condensation reaction between an amine and active carbonyl compounds, such as isocyanate [19,20,21,22], chloroformate [23], and carbonyl di-imidazole [24,25] (Scheme 1a). Also, the Curtius rearrangement provides an effective method for preparing urea from an arylformyl chloride substrate (Scheme 1b) [26,27,28]. These methods have been extensively studied and applied in actual production, but the development of novel methods for the preparation of urea is still in high demand.
Aromatic oxime is a vital precursor and intermediate in organic synthesis [29,30,31]. The typical Beckman rearrangement reaction can achieve the conversion of ketoxime to amide products under strong acid conditions [32,33]. Since the hydrogen-atom migration of aldoxime is difficult, metal catalysts are usually required in order to carry out the Beckmann rearrangement of aldoxime [34,35,36,37]. Therefore, it is still challenging to achieve a metal-free aldoxime rearrangement. The amides have been widely used as directing groups to activate C‒H bonds and facilitate the conversion of multiple functional groups [38,39,40,41,42]. To date, there have been no reports of amide-assisted rearrangement reactions. We envision that the amide can utilize the hydrogen bond to bind with the hydroxyl group of hydroxyarylformimidoyl chloride, thereby activating the N‒O bond, which is conducive to the departure of the hydrated positive ion and allows the rearrangement of aldoxime.
Herein, we have developed a smooth and efficient synthesis of 1,3-diphenylurea derivatives from hydroxybenzimidoyl chloride under mild conditions with amides as additives.

2. Results and Discussion

In our initial studies, N-hydroxybenzimidoyl chloride (1a) was reacted with benzamide using N, N-dimethylformamide (DMF) as the solvent, and the desired product 2a was obtained in medium yields (31%, Table 1, entry 1). Different solvents, such as methanol, ethanol, 1,4-dioxane, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), and dichloromethane (DCM), were screened at room temperature. The results indicate that the most efficacious reaction occurred with DMSO (yield 42%, Table 1, entry 8). Encouraged by this result, we sought to enhance the yield of this reaction and carried out a screening of bases, such as K2CO3, Et3N, DMAP, DBU, and t-BuOK (Table 1, entries 10–14). The experimental data showed that the reaction proceeded with good yield (42%, Table 1, entry 8) when Cs2CO3 was used, while the other bases were not as effective. The reaction could not be carried out in the absence of a base (Table 1, entry 15). Additionally, increasing temperature is beneficial to the reaction, since higher yields were obtained at 120 °C (87%, Table 1, entry 21). Under these conditions, increasing the reaction time did not affect the yield (87%, Table 1, entry 23). Subsequently, we selected acetamide, propionamide, 2-phenylacetamide, and 4-chlorobenzamide to screen the additives. The results show that the effect of using benzamide is still more potent than the other amides. Simple amides, such as acetamide and propionamide, are also effective, but 2-phenylacetamide and 4-chlorobenzamide are not as effective (Table 1, entries 24–27). Notably, without the addition of the amide reagents, the reactions described herein will not occur (Table 1, entries 28). Therefore, under optimized conditions (using DMSO as the solvent with Cs2CO3 as the base at 120 °C for 5 h), different N-hydroximoyl chlorides were selected in order to prepare products 2a–2l (yield: 71–87%, Table 2). Reducing the amount of benzamide will significantly reduce the reaction yield (Table 1, entries 29–30), although the reaction yield did not increase significantly with an increase in the amount of benzamide, (Table 1, entries 31).
In Table 2, the results show that N-hydroxybenzimidoyl chloride (1) substrates that bore electron-donating groups (such as methoxy or methyl) as the R substituents were well-tolerated at good yields (2e, 83%, 2f, 80%, 2h, 84%, 2j, 86%). In addition, electron-withdrawing substituents (such as chloro-, fluoro- or trifluoromethyl) are also usable in the reaction, but the reaction yield is reduced (2c, 72%, 2i, 76%, 2k, 71%, 2l, 73%). Furthermore, the yield of para-containing substituents is higher than the yield of meta-containing substituents (2c, 72%, 2i, 76%). Finally, the reaction yield of a substrate that contains two groups is not as high as a substrate that contains one group (2b, 77%, 2j, 86%). Unfortunately, no corresponding products were obtained using other heteroaromatic substrates (1), such as pyridine, furane or thiophene.
The chemical structures of the 1,3-diphenylurea derivatives were examined by 1H NMR, 13C NMR, and HRMS analyses (see Supplementary Materials). The structure of 2a was unambiguously confirmed by single-crystal X-ray analysis [43], as shown in Figure 2.

3. Conclusions

In summary, an amide-assisted rearrangement reaction of hydroxybenzimidoyl chloride has been developed for the preparation of 1,3-diphenylurea derivatives. This highly effective reaction proceeds well to afford 1,3-diphenylurea derivatives without metal catalysts under mild conditions and shows good functional-group tolerance. A proposed reaction mechanism has been presented, suggesting that the reaction went through a novel rearrangement process. We believe that the findings of this study promote the rapid synthesis of novel diphenylurea compounds exhibiting crucial biological activity.

Supplementary Materials

The following are available online, X-ray crystallography data of compounds: 2a, Characterization data and copies of 1H and 13C NMR spectra for all new compounds.

Author Contributions

Writing—original draft, X.S. and X.L.; writing—review and editing, W.Y. and Y.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by NSFC, grant number 22067020 and Yunnan Fundamental Research Projects (202101AS070034 and 202001BB050009) and the Program for Excellent Young Talents, Yunnan University, China.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data generated during the present study are available from the corresponding author on reasonable request.

Acknowledgments

This research was funded by NSFC, grant number 22345323 and Yunnan Fundamental Research Projects (202101AS070034 and 202001BB050009) and the Program for Excellent Young Talents, Yunnan University, China.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of all the compounds are available from the authors.

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Molecules 26 06437 g001
Figure 1. Representative biological urea derivatives.
Figure 1. Representative biological urea derivatives.
Molecules 26 06437 g001
Molecules 26 06437 sch001
Scheme 1. Preparation methods of N, N′-disubstituted urea.
Scheme 1. Preparation methods of N, N′-disubstituted urea.
Molecules 26 06437 sch001
Molecules 26 06437 g002
Figure 2. Crystal structure of 2a.
Figure 2. Crystal structure of 2a.
Molecules 26 06437 g002
Table 1. Optimization of experimental conditions a,c.
Table 1. Optimization of experimental conditions a,c.
Molecules 26 06437 i001
EntryBaseSolventAdditiveTime (h)t [°C] bYield (%)
1Cs2CO3DMFBenzamide5rt b31
2Cs2CO3MeOHBenzamide5rt bnr
3Cs2CO3EtOHBenzamide5rt bnr
4Cs2CO3DCMBenzamide5rt bnr
5Cs2CO3TolueneBenzamide5rt b8
6Cs2CO3THFBenzamide5rt bnr
7Cs2CO3DioxaneBenzamide5rt b11
8Cs2CO3DMSOBenzamide5rtb42
9Cs2CO3AcetoneBenzamide5rt bnr
10K2CO3DMSOBenzamide5rt b25
11Et3NDMSOBenzamide5rt b27
12DMAPDMSOBenzamide5rt b22
13DBUDMSOBenzamide5rt b19
14tBuOKDMSOBenzamide5rt b34
15NoneDMSOBenzamide5rt bnr
16Cs2CO3DMSOBenzamide53045
17Cs2CO3DMSOBenzamide54558
18Cs2CO3DMSOBenzamide56061
19Cs2CO3DMSOBenzamide57566
20Cs2CO3DMSOBenzamide59073
21Cs2CO3DMSOBenzamide512087
22Cs2CO3DMSOBenzamide5reflux87
23Cs2CO3DMSOBenzamide1012087
24Cs2CO3DMSOAcetamide512071
25Cs2CO3DMSOPropionamide512062
26Cs2CO3DMSOPhenylacetamide512039
27Cs2CO3DMSOChlorobenzamide5120trace
28Cs2CO3DMSONone10120nr
29Cs2CO3DMSOBenzamide (0.2 mmol)1012063
30Cs2CO3DMSOBenzamide (0.1 mmol)1012046
31Cs2CO3DMSOBenzamide (0.5 mmol)1012088
a Reagents and conditions: N-hydroxybenzimidoyl chloride (1a, 1.0 mmol), benzamide (0.4 mmol), base (2.2 mmol), solvent (20 mL). b rt = room temperature. c Isolated yield based on 1a.
Table 2. Synthesis of 1,3-diphenylurea derivatives a,b.
Table 2. Synthesis of 1,3-diphenylurea derivatives a,b.
Molecules 26 06437 i002
Molecules 26 06437 i003
a General conditions: N-hydroxybenzimidoyl chloride (1a, 1.0 mmol), benzamide (0.4 mmol), Cs2CO3 (2.2 mmol), DMSO (20 mL). b Isolated yield based on 1.
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MDPI and ACS Style

Song, X.; Liu, X.; Yu, W.; Jin, Y. Amide-Assisted Rearrangement of Hydroxyarylformimidoyl Chloride to Diarylurea. Molecules 2021, 26, 6437. https://doi.org/10.3390/molecules26216437

AMA Style

Song X, Liu X, Yu W, Jin Y. Amide-Assisted Rearrangement of Hydroxyarylformimidoyl Chloride to Diarylurea. Molecules. 2021; 26(21):6437. https://doi.org/10.3390/molecules26216437

Chicago/Turabian Style

Song, Xizhong, Xiaoyu Liu, Wei Yu, and Yi Jin. 2021. "Amide-Assisted Rearrangement of Hydroxyarylformimidoyl Chloride to Diarylurea" Molecules 26, no. 21: 6437. https://doi.org/10.3390/molecules26216437

APA Style

Song, X., Liu, X., Yu, W., & Jin, Y. (2021). Amide-Assisted Rearrangement of Hydroxyarylformimidoyl Chloride to Diarylurea. Molecules, 26(21), 6437. https://doi.org/10.3390/molecules26216437

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