Expedient phosgene-free synthesis of symmetrical diarylureas from carbamates

A convenient method for synthesis of symmetrical diarylureas from carbamtes is reported. The diarylureas were obtained in excellent yield when carbamates were boiled at reflux in dry benzene in the presence of sodium hydride as a catalyst and 1 8 -Crown- 6 ( 18 C 6 ) as a co-catalyst. A plausible mechanism explains the formation of 1,3-diarylureas from carbamates in the presence of basic catalyst is reported. The chemical structure of the diarylureas was confirmed by spectroscopic techniques and compared with an authentic sample prepared using previously reported methods


Introduction
Urea (carbamide) and its derivatives are interesting organic compounds, which have a unique chemical structure and numerous applications in a variety of fields.For example, in the field of biochemicals and pharmaceuticals, urea is applied directly as an active component or intermediate for treatment of many health disorder and some chronic diseases.Sorafenib (Nexavar ® ) and Regorafenib (Stivarga ® ) are both derivatives of diarylureas.][3] Imatinib (Gleevec ® ) is another example of the same scaffold, which has proved to be a breakthrough in treatment of chronic leukemia. 46][7] In another pharmaceutical application, diarylurea derivatives were exhibited an excellent anti-inflammatory effect via selective inhibition of COX2 over COX1 isoenzyme. 8,9Additionally, diarylurea derivatives act as intermediates in the synthesis of different biologically active compounds.1][12][13] Also, diarylureas were used as catalyst or cocatalyst in some chemical transformations.For example, diarylureas were applied as catalyst for specific epoxidation of alkenes and as cocatalyst for asymmetric aziridination reactions. 14,15 nsiderable attention was paid toward the accessibility of the diarylurea derivatives from either natural sources or chemical transformations with low hazardous reaction conditions.The 1, 3-disubstituted ureas were isolated in low quantities from various natural sources.For example, four different N,N'-disubstituted urea derivatives were isolated from the roots of evergreen shrub of Pentadiplandra brazzeana. 16Since the first synthesis of urea, from cyanic acid, by Friedrich Wöhler in 1828, which is considered as a major mile stone in the history of organic chemistry, many methods and approaches for synthesis of urea and its derivatives were reported in literature.
Furthermore, carbamates have been used for the synthesis of different symmetrical or asymmetrical 1,3disubstituted ureas, by aminolysis reaction with primary or secondary amines in the presence of different catalysts.For example, series of substituted ureas were prepared from different carbamates when treated with amines in the presence of ethylmagnesium bromide (EtMgBr), 32 bis(trimethylaluminum)-1,4-diazabicyclo [2.2.2]octane adduct (DABAL-Me3), 33 or 2-chloropyridine/Tf2O, 34 aluminium trimethyl((AlMe3)/toluene mixture. 35All these approaches involve reaction of carbamates with a primary or a secondary amine to produce the required 1,3-disubstituted ureas.Recently, triethylamine and dimethylformamide (DMF) were used with some limitations for synthesis of particular 1,3-disubstituted phenyl ureas. 368][39] For example, diarylureas were unexpectedly synthesized from the reaction of nicotinic acids and ethylchloroformate with a moderate yield (60-65%). 40Moreover, diaryl ureas were obtained via C-N cross coupling reaction of the N-aryl urea with the aryl halides in presence of Pd. 41

Results and Discussion
In this work, we report an expedient phosgene-free method for synthesis of symmetrical diaryl ureas from carbamates.In a typical procedure, when a solution of carbamate (1) 42 in dry benzene, under argon atmosphere, was heated to boiling reflux in the presences of sodium hydride and catalytic amount of crown ether ( 18 C6) as a co-catalyst, after the reaction work-up, the diaryl ureas (2) were obtained in an excellent yield (85-90%) (Scheme 2, Table 1).It is worthy to mention that, when the reaction was conducted in absence of crown ether ( 18 C6), no diaryl urea was detected or isolated from the reaction even after long period of boiling reflux.In order to assess other basic conditions, sodium ethoxide was used as a catalyst and ethanol as a solvent.When the sodium ethoxide was used in a 1:1 molar ratio (ethoxide/carbamate) the diaryl urea was not isolated after the final work-up of the reaction.However, the product was formed only when the sodium ethoxide was used in a molar ratio of 4:1 (ethoxide/carbamate).The reactions were completed after 1 hour heating under reflux and the products were isolated in good yields, ranging from 55 to 60 %. (   A plausible mechanism that explains the formation of the products is depicted in scheme 3. The reaction starts by basic abstraction of hydrogen from the amidic nitrogen in the carbamate molecules 1 to produce a carbamate anion 3. The formation of this anion is favored because it is stabilized by resonance and delocalization of the negative charge due to the carbonyl group and the aromatic ring.Then, the carbamate anion undergoes a further stabilization via an intramolecular rearrangement, under the reaction conditions, to produce the isocyanate 4 after removal of alkoxy group (OR) as a good leaving group. 45,46Subsequently, the carbamate anion (3) acts as a nucleophile and attack the isocyanate 4 (addition-elimination reaction, similar to the reaction of amine with isocyanate) to form the four-membered ring diamide intermediate 6 (1,3diazetidine-2,4-diones often simply called uretidine diones or uretediones) via addition intermediate 5. 44 Alternatively, the four-membered ring intermediate 6 could be formed via dimerization of isocyanate 4 under the reaction conditions. 47Then, reaction proceeds analogously to the previously reported mechanism for conversion of isocyanate to 1,3-disubstituted urea in basic medium. 44Therefore, ring opening by hydrolysis of the cyclic diamide 6 would produce carbamic acid intermediate 7. The elimination of carbon dioxide with hydrogen shift in the later intermediate would produce the desired 1,3-symmetrical disubstituted urea 2.
The chemical structure of the products were confirmed by spectroscopic techniques and by comparison with authentic samples prepared using previously reported methods. 44age 88 © ARKAT USA, Inc

Conclusions
In conclusion, a series of diarylurea derivatives were successfully synthesized with high yields, >80%, by refluxing carbamates in benzene for three hours in the presence of sodium hydride as a catalyst and 18 C6 as a co-catalyst catalyst.The diarylureas were not formed in the absence of 18 C6 , even after a long time of heating under reflux, indicating the key role of it in the synthesis process.Alternatively, the same products were prepared, in lower yield (<60%) when four fold of sodium ethoxide was used as a catalyst in boiling ethanol.A plausible mechanism has been suggested to explain the formation of 1,3-diarylureas from carbamates in the presence of basic catalyst.The structure of the synthesized compounds was confirmed by spectroscopic techniques.IR (cm -1 ) 3285.9 (NH), 1632.3 (C=O amide). 1 H NMR (DMSO-d6, ppm) δ: 8.85 (s, 2H), 7.52 (s, 2H), 7.12 (s, 2H). 13C NMR (DMSO-d6, ppm): δ 148.9, 138.7, 132.5, 129.9, 120.1, 118.2.