Effective approach to ureas through organocatalyzed one-pot process
Graphical abstract
Introduction
The discovery of convenient methods for the formation of carbon-nitrogen bond has always been a focused area in synthetic organic chemistry, due to wide application in both natural product synthesis and industrial research and production.1 As a prime instance, efficient methods toward preparation of urea and its analogous are very important in synthetic and medicinal chemistry, because these chemical subunits serve as substructures for numerous pharmaceuticals,2 agrochemicals,3 as well as materials science.4 For example, the urea units are present in PI3K inhibitors (BEZ235, PKI-587)5, VEGFR inhibitors (Sorafenib, ABT-869, Lenvatinib, PD173074),6 TRPV antagonists (SB705498),7 and p38-MAP kinase inhibitors (BIBR796)8 (Fig. 1). Moreover, urea-containing scaffolds are frequently used in the design of bifunctional organocatalysts.9 Accordingly, tremendous efforts have been devoted to developing methods for the construction of urea motifs, and a number of powerful approaches have been reported.10, 11, 12, 13, 14, 15, 16, 18 However, most of the traditional methods for the preparation of urea or its derivatives involve the use of phosgene,10 metal-catalysts,11 isocyanate,12 azide,13 carbonyl imidazole derivatives14 and microwave-accelerated conditions,15 which are highly toxic, unstable, or challenging for large scale application. To pursue green processes, several methods through transition metal-catalyzed oxidative carbonylation of amines with CO16 or direct carbonylation of amine by CO217 are developed in recent years. However, the use of high pressure of CO/CO2 gas still limits lab-scale application in medicinal chemistry.
With continuous focus in exploring practical synthetic methods for the synthesis of natural products and compounds with medicinal interests,18 we decided to develop a convenient method for the construction of urea scaffolds. The most straightforward urea synthesis uses activated carbamates as the starting materials or key intermediates. For example, very recently, Me3SiCl, SiI2H2 or Tf2O/Base were reported to activate the Boc-protected amines19 (Fig. 2. Eq. 1). Starting from unprotected amines, urea formation can also be achieved with the promotion of 4-dimethylaminopyridine (DMAP) in the presence of Boc anhydride20 (Fig. 2. Eq. 2). Herein, we present efficient approach to obtain ureas with catalytic amount of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (Fig. 2. Eq. 3) or 1,4-Diazabicyclo[2.2.2]octane;triethylenediamine (DABCO) (Fig. 2. Eq. 4).
Section snippets
Results and discussion
As shown in Table 1, the reaction of Boc-protected 3-bromoaniline (7a) with benzylamine was used as the template for our investigation. Firstly, at room temperature, in DCM or acetonitrile as the solvent, only trace amount (≤5%) of urea product 9a was observed with 10% TBD, while no reaction can be detected with catalytic amount of DMAP or DABCO (Table 1, entries 1–4). When the reaction mixture was heated at 60 °C, the desired 9a was obtained in 65% yield (Table 1, entry 5). The reaction was
Conclusions
In summary, we established an efficient method to prepare N, N’-unsymmetrically substituted ureas 9 through the ammonolysis of N-Boc protected anilines 7 with amines prompted by TBD. Furthermore, one-pot approach, for the preparation of symmetric N, N'-substituted ureas 12 by the diammonolysis process of Boc2O with 2 equivalents of amines, was also achieved, catalyzed by DABCO. The methods for the urea formation reported in this study are convenient, practicable and efficient. It can be applied
Acknowledgments
We thank the National Natural Science Foundation of China (No. 81673297), the Shanghai Municipal Committee of Science and Technology (No. 17431902500, 17JC1400200 and 15ZR1449000). We also thank Dr. Chang-Mei Si (School of Pharmacy, Fudan University) for helpful in preparation of manuscript.
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