Amide-Assisted Rearrangement of Hydroxyarylformimidoyl Chloride to Diarylurea

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.

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.

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 K 2 CO 3 , Et 3 N, DMAP, DBU, and t-BuOK (Table 1, entries [10][11][12][13][14]. The experimental data showed that the reaction proceeded with good yield (42%, Table 1, entry 8) when Cs 2 CO 3 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][25][26][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 Cs 2 CO 3 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 ( 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, electronwithdrawing 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 metacontaining 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 1 H NMR, 13 C 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.

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 1 H and 13 C 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.

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