Urea Synthesis from Isocyanides and O-Benzoyl Hydroxylamines Catalyzed by a Copper Salt

In the presence of CuOAc, a series of unsymmetric ureas can be generated in moderate to good yields under mild reaction conditions (10 mol% of CuOAc, 2 equiv t-BuONa or PhONa, 30 °C), using aryl isocyanides and O-benzoyl hydroxylamines as the readily accessible starting materials. The reactions might undergo a cascade process involving isocyanide insertion into the N-O bond and Mumm-type rearrangement. This work represents a rare example of isocyanide insertion into N-O bonds, which would extend isocyanide insertion chemistry.


Introduction
Ureas are common core structures of a wide variety of pharmaceuticals, agrochemicals, and functional materials. For example, compounds containing the urea substructure include an effective herbicide (Diuron, A) [1], CCR1 antagonist (B) [2], and HIV protease inhibitor (C) (Scheme 1) [3]. Ureas also provide useful synthons for the construction of a vast majority of valuable compounds [4,5]. Moreover, they are potential organocatalysts by serving as hydrogen-bond donors [6] and ligands for transition metals [7]. Therefore, numerous methods have successfully been explored to synthesize ureas, such as the addition of amines to isocyanates or to carbonyldiimidazole (Scheme 2a) [8,9], direct carbonylation of primary amines with carbon monoxide (Scheme 2b) [10], and transition metal-catalyzed cross-coupling of aryl chlorides with sodium cyanate (Scheme 2c) [11]. Despite these achievements, these approaches have several limitations, including the use of toxic reagents and/or the requirement of high temperature and pressure, which results in limited reaction types and substrate scope, poor functional group tolerance, and/or structural diversity of the obtained ureas. Consequently, the development of a concise and new method for the preparation of ureas is highly desirable. Isocyanides are a class of synthetically useful synthons [12] that can participate in a series of transformations, such as multicomponent reactions [13], cycloaddition reactions [14,15], and insertion reactions [16]. Among insertion reactions, it is known that isocyanides can insert into heteroatom/C-H and C-heteroatom/metal bonds for the preparation of valuable compounds. Compared to these reactions, examples of isocyanide insertion into N-O bonds are rare. It is noteworthy that N-O bonds exist in a large number of organic molecules. As such, the application of N-O bond-containing molecules in isocyanide insertion reactions would provide many opportunities for the construction of valuable compounds, particularly N-containing molecules. For instance, Jiang and Wang independently developed Pd-catalyzed reactions of oximes of isocyanides for the synthesis of N-heterocycles (Scheme 3a) [17,18]. In addition, we recently reported Ag-and Cu-catalyzed difunctionalization of the isocyano group, involving isocyanide insertion into the N-O bond, for the rapid generation of pyrimidinediones [19] and dihydroquinolinones [20], respectively (Scheme 3b,c). Based on these studies and our continuous interest in N-O bond transformations [21][22][23], we wished to develop more methods regarding isocyanide insertion into N-O bonds for the synthesis of N-containing compounds. Herein, we describe a Cu-catalyzed method for the rapid assembly of ureas using aryl isocyanides and O-benzoyl hydroxylamines as readily accessible starting materials (Scheme 3d). The reactions occur under mild reaction conditions and generated various new structures of unsymmetric ureas. at all (entries [1][2][3][4][5]. Pleasingly, we found that the reaction could generate urea (3a) in the presence of PhONa or t-BuONa as the base, and the latter promoted the transformation with 86% yield (entries 6 and 7). These results indicated that the bases were significant for the reaction. CuI and CuBr 2 also catalyzed the reaction, albeit lower yields were obtained (entries 8 and 9). In addition, the reaction failed with FeCl 2 as the catalyst (entry 10). Copper salt was essential for the reaction, as no product was formed in the absence of CuOAc (entry 11). Transformation 3a delivered very low yields with DMSO or MeCN as the solvent (entries 12 and 13).

Substrate Scope
With the optimized reaction conditions in hand, we next probed the substrate scope with regard to the isocyanides (Scheme 4). A wide range of aryl isocyanides were amenable to this method, and a series of functional groups were tolerated, including methyl (3b, 3g, 3h, and 3k), ester (3c and 3i), cyano (3d and 3j), phenyl (3e), methoxy (3f), fluoro (3h), bromo (3i and 3j), and chloro groups (3k). Moreover, isocyanides bearing naphthyl (3l) and isoquinoline (3m) moieties also took part in the reaction to deliver the corresponding products with 61% and 79% yield, respectively. For reactions producing ureas in moderate yields, anilines were detected as the main by-products.
We proposed a reaction mechanism for the reaction of 1a with 2a, based on the experimental results and some previous work related to Cu-mediated amination reactions with O-benzoyl hydroxylamines as the aminating source [24][25][26][27][28]. As displayed in Scheme 6, first, Cu(I) salt reacted with 2a to form the aminocopper intermediate A through oxidative addition, which then reacted with 1a to produce copper species B or B' via isocyanide insertion into the Cu-N or Cu-O bond, respectively. Subsequently, C-O or C-N reductive elimination delivered imidate C, which would undergo Mumm-type rearrangement to generate species D and an acyl cation [29]. The final product 3a was formed after protonation during quenching of the reaction. Notably, the acyl cation could be trapped by AcO − or t-BuO − to yield the corresponding anhydride or ester, which was observed by GC-MS analysis. Scheme 6. Hypothesis for Cu-catalyzed urea synthesis.

Materials and Methods
All reactions dealing with air-and moisture-sensitive compounds were carried out in dry reaction vessels under a nitrogen atmosphere. 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 600 MHz NMR spectrometer. 1 H and 13 C NMR spectra are reported in parts per million (ppm) downfield from an internal standard (Supplementary Materials), tetramethylsilane (0 ppm) and CHCl 3 (77.0 ppm), respectively. HRMS (m/z) was recorded using ESI (Q-TOF) mode. Melting points were determined using a capillary melting point apparatus and are uncorrected. Unless otherwise noted, materials were purchased from commercial suppliers and were used as received. Anhydrous tetrahydrofuran was distilled over Na and stored under N 2 .

Preparation of Substrates
All O-benzoyl hydroxylamines and isocyanides were synthesized according to the literature [20].

Preparation of Isocyanides (1) N-Formylation
Acetyl formyl anhydride (prepared by stirring 2.5 equiv acetic anhydride and 2.5 equiv formic acid at 55 • C for 2 h) was added dropwise at 0 • C to a stirred solution of aniline (9 mmol) in THF (15 mL), and the mixture was stirred for 2 h at room temperature. Then, the saturated solution of NaHCO 3 was added, and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over mgSO 4 and concentrated by rotary evaporation. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the N-formylated products.

Dehydration
To a solution of the N-formylated products (5 mmol) and Et 3 N (2.1 mL, 15 mmol) in CH 2 Cl 2 (10 mL) at 0 • C was added triphosgene (0.74 g, 2.5 mmol) in CH 2 Cl 2 (10 mL). The solution was stirred at 0 • C for 3 h. Then, methanol was added to the suspension solution, and the solution was concentrated by rotary evaporation. The residue was purified by column chromatography (petroleum ether) to give the isocyanides.

Preparation of O-Benzoyl Hydroxylamines (2)
A 100 mL flask was charged with benzoyl peroxide (2 mmol), dipotassium hydrogen phosphate (3 mmol), and N,N -dimethylformamide. The amine starting material (3 mmol) was added dropwise at room temperature. The suspension was stirred at ambient temperature for the indicated reaction time. The reaction was quenched with water (10 mL), and the contents were vigorously stirred for several minutes until all solids were dissolved. The reaction mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was collected and washed with two 25 mL portions of saturated aq. NaHCO 3 solution, followed by 25 mL of brine, and then dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the desired product.

General Procedures for Ureas
A 10 mL Schlenk tube equipped with a stir bar was charged with isocyanides (0.2 mmol), O-benzoyl hydroxylamines (0.3 mmol), CuOAc (10 mol%), and t-BuONa (0.4 mmol). Then, the Schlenk tube was quickly evacuated and refilled with N 2 three times, followed by the addition of THF (2 mL). The Schlenk tube was sealed with a Teflon screwcap under N 2 flow, and the reaction mixture was stirred at 30 • C for 12 h. Upon cooling to room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate and filtered through a pad of silica gel, followed by washing the silica gel pad with ethyl acetate (20 mL). Subsequently, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford the desired products.