Microwave-mediated and Customery Synthesis of N-benzoyl-or N-Substituted Benzoyl-N , N ′-Dialkylureas from Arylcarboxylic Acids and N , N ′-Disubstituted Carbodiimides under Solvent-free Conditions

Uma síntese fácil, eficiente e rápida de N-benzoil-(e benzoil N-substituída)-N,N′-dialquiluréias foi realizada com bons rendimentos em condições livre de solvente. Primeiramente, a reação entre um ácido carboxílico e uma carbodiimida dissubstituída foi feita empregando radiação de microondas, e depois a mesma reação foi realizada sob aquecimento convencional. Os rendimentos são comparáveis em ambos os casos.


Introduction
4][5] The synthesis of cabergoline, an N-acylurea and a potent prolactin inhibitor, has been reported by Ashford et al. in 2002, 6 and in the same year, its effectiveness in treating acromegaly has also been announced. 7Furthermore, some acylureas have found application in agriculture because they hamper the growth and reproduction of the fall armyworm and house fly. 8In fact, these ureas also serve as intermediates for their transformation into amides and esters. 9Because of these properties, N-acylureas are of interest as potential drugs, and also as starting intermediates for the preparation of amides and esters, hence our interest in synthesizing such compounds.
Discovering new high-yielding, selective reactions is vital for the advancement of synthetic organic chemistry.Reactions that generate products with a minimum of operations are not only noteworthy but are fundamental for synthesizing new compounds in a shorter time.For achieving this goal, microwavemediated reaction has great advantage, and during the last decade this technique experienced tremendous growth and development. 10Because of its cleanliness and reduced work-up, we decided to examine the reaction of benzoic acid and substituted benzoic acids with N,N′-dicyclohexyl-and N,N′diisopropylcarbodiimides employing microwave radiation.
A literature pursuit revealed the existence of a sole example involving the preparation of 1-benzoyl-1,3diisopropylurea employing benzoic acid and N,N′diisopropylcarbodiimide in a mixture of CH 2 Cl 2 / DMF (9:1), containg DMAP as a catalyst, under microwave radiation for 60 min. 11This reaction was performed in a sealed tube having a pressure of 3.0 bar and at 90 o C. The usual method for synthesizing N-acylureas involves: i) reactions between N-substituted amides and isocyanates in refluxing toluene for 24h; 12 ii) benzoyl peroxide and dicyclohexylcarbodiimide in methanol again at reflux temperature for 12h, 13 and iii) carboxylic acids and N,N′disubstituted carbodiimides in solution. 14In 1991, Corriu et al. 15 reported that N-acylureas can also be obtained from pentacoordinated silicon hydride and N, N′-dialkylcarbodiimides in two steps.In this article, we wish to describe two methods, one by microwave irradiation and the other by dry heating, both without the use of any solvent.None of these procedures have been found in the literature.These protocols are speedy, eco-friendly and involve simple purification of the products.Therefore, this type of reaction can be considered as a part of green chemistry.

Results and Discussion
In the present work, N,N′-dicyclohexyl-and N,N′diisopropylcarbodiimides have been allowed to react with aromatic carboxylic acids under the influence of microwave irradiation using a domestic oven (Scheme 1). 16n general, it took from 5-12 min.for completion of the reaction and the temperature varied between 100-114 o C. In each case the reaction between the reagents cited above furnished mainly the desired N-aroylureas, acid anhydrides and N,N′-disubstituted ureas.
The formation of such products by the reaction of an acid and a carbodiimide employing usual methods has been known since 1962. 17We observed the reaction rate enhancement when the phenyl ring of the acid carried an electron-withdrawing group.Increased reaction rate has also been reported earlier by Šlebioda. 18He studied the substituent effect in the reaction of dicyclohexylcarbodiimide with substituted benzoic acids in buffered solution and found the velocity increment of the reaction containing electron-withdrawing substituent in the phenyl ring.
In order to compare the results described above, the reactants were mixed and heated in a glass tube in solventless condition without microwaves.The reaction took place at 110 o C, but required a little longer time for its completion (see Table 1).With this, it is concluded that N-benzoyl-or substituted aroylureas can easily be obtained either from benzoic acid and substituted benzoic acids and a diimide.There is no report in the literature regarding the dry conventional heating for obtaining N-acylureas.Table 1 contains, besides other details, the yields of our two methods and their comparison with the literature values.
Separation of compounds 3a-i and 4a-g was achieved by liquid chromatography over silica gel.The yields of the chromatographically pure products are provided in the experimental section.The infrared and NMR spectra of the isolated substances agreed with the structure.

Conclusions
In summary, this study has highlighted the ready generation of N-aroyl-N,N′-disubstituted ureas from benzoic and substituted benzoic acids and N,N′disubstituted carbodiimides under solvent-free conditions in a domestic microwave oven.This opens up the scope for synthesizing a variety of acylureas using such radiation technique.Also, the classical method for the above-cited preparation by dry heating is an achievement.

General experimental procedures
Melting points were determined on an Electrothermal (Mel-Temp) apparatus (Model No. 1002D) and are Scheme 1.
uncorrected.All reactions were monitored by TLC analysis (TLC plates contained GF 254 , Merck).IR spectra were measured with a IFS66 Bruker spectrometer employing either a KBr disc or a nujol mull. 1 H NMR spectra were recorded with a Varian unity plus 300 MHz spectrometer using CDCl 3 as solvent and SiMe 4 as an internal standard.All reactions were conducted in a domestic microwave oven Model Sanyo EM-300B, 220/ 650W/2450 MHz.

Synthesis of N-benzoyl-or N-substituded benzoyl-N,N′dialkylureas
A suitable aromatic carboxylic acid 1a-g (1.0 mmol) and an appropriate carbodiimide (1.1 mmol of DCC and 2.0 mmol of DIC. 23were well triturated and placed in a small glass test tube.Two separate experiments were carried out.(i) microwave irradiation: the mixture was irradiated between 5-12 min.in an unmodified domestic microwave oven (100% potency, 650W), cooled and the components were purified by chromatography.(ii) Conventional heating experiments: the mixture was heated in a preheated oil bath maintained at 110 °C for a certain length of time and cooled.In both cases the crude product was treated with chloroform and filtered to remove the insoluble urea.Chloroform: ethyl acetate (8.0:2.0) for entries 1-7 and chloroform: ethyl acetate (9.0:1.0) for entries 8 and 9 were used to develope the tlc plates followed by their revelation under ultraviolet light.Two spots were observed -one due symmetrical anhydrides with R f values ≈ 0.60 and N-acyl ureas having R f values ≈ 0.43.The chloroform solution of the products was applied to a thick-layer chromatographic plate and developed using the above-mentioned solvent system.Work-up furnished chromatographically pure N-acyl ureas 3a-i and symmetrical anhydrides 4a-g.