An eco-friendly approach for the synthesis of 1,2,5-trisubstituted and 4-amino-1,2,5-tetrasubstituted imidazoles via a multi-component condensation

The synthesis of 1,2,5-trisubstituted and 4-amino-1,2,5-tetrasubstituted imidazoles was demonstrated via a two-step cyclo-condensation reaction of aryl amines, carbonitriles, and ethyl bromopyruvate or aryl amines and arylglyoxals in ethanol heated under reﬂux in the presence of iron (III) chloride (FeCl 3 ), and disodium phosphate (Na 2 HPO 4 ) as catalysts, respectively. All the products were obtained in good to excellent yields and their structures were established from their spectroscopic data.

With this in mind, and in continuation of our current studies on the development of new approaches for the synthesis of multi-substituted imidazoles, [38][39][40] herein, we describe a facile and efficient protocol for the synthesis of 4-amino-1,2,5-tetrasubstituted and 1,2,5-trisubstituted imidazoles via a two-step, four or three-component reaction of aryl amines, carbonitriles, and aryl amines with arylglyoxals or ethyl bromopyruvate in the presence of disodium phosphate (Na2HPO4), and iron (III) chloride (FeCl3) as a catalyst, respectively.

Results and Discussion
To initiate our study, the arylamidine 3 was prepared via the reaction of aniline 1 with carbonitrile 2 in the presence of AlCl3 at 120 o C for 1 h under solvent-free conditions.The arylamidine compounds were identified by the comparison of their physical and spectral data with those of authentic samples. 41Then, the optimised conditions for the condensation were established, using model compounds, arylamidine 3 (1 mmol), and electrophiles such as iminone resulting from aniline 4 (1 mmol) with arylglyoxal 5 (1 mmol) or ethyl bromopyruvate (7) (1 mmol) in the presence of Na2HPO4 (20 mol%), and FeCl3 (20 mol%) as catalysts in ethanol heated at reflux for 12 h.The optimized reaction conditions were then used to synthesize and explore the scope of this novel transformation to give two series of 4-amino-1,2,5-tetrasubstituted imidazoles 6, and 1,2,5-trisubstituted imidazoles 8.As can be seen from Table 1, the nature of the electrophilic component affects the type of products formed: when the electrophile is an iminone resulting from aniline 4 with arylglyoxal 5 then product 6 is formed, but when the electrophile is ethyl bromopyruvate (7) then product 8 is formed.Also, the catalysts affect the product yields: in the presence of both Na2HPO4 and FeCl3 as catalysts, Table 1.Synthesis of 4-amino-1,2,5-tetrasubstituted imidazoles 6, and 1,2,5-trisubstituted imidazoles 8.
a Isolated yields.b Reaction time was 13 h.
a higher yield of the products 6 and 8 were obtained, respectively.Moreover, electronic effects and the nature of substituents on the aniline, the carbonitrile, and the arylglyoxal led to products with different reaction yields.When anilines containing electron-donating groups, were reacted with carbonitriles and the arylglyoxals containing electron-withdrawing groups, higher yields were obtained (Table 1).
To the best of our knowledge, all the synthesized compounds were new, as such, they were characterized by 1 H and 13 C NMR, IR, CHN analysis and melting points.For instance, the 1 H NMR spectrum of the compound 6a consisted of two singlets at δH 3.59 and 3.73 for the methoxy groups in the product.The aromatic protons resonated in the region δH 6.45-7.91 and a broad singlet signal at δH 7.44 for the proton of the nitrogen group were also observed.The 13 C NMR spectrum of compound 6a exhibited 21 distinct signals in agreement with the proposed structure.In the IR spectrum, the NH and C═N groups absorption were observed at 3409 and 1608 cm −1 .Partial assignments of these resonances for the other products are given in the experimental section.
A proposed mechanism for the formation of 4-amino-1,2,5-tetrasubstituted imidazoles 6 and 1,2,5trisubstituted imidazoles 8 is described in Scheme 1.The nature of the electrophile was different, so that: 4amino-1,2,5-tetrasubstituted imidazoles 6 formed via four steps; at first, based on the result in the current study and our previous report, 40 arylamidine 3 is formed by the addition of the aniline 1 to the carbonitrile 2 at 120 o C for 1 h under solvent-free conditions.Also, iminone A is formed through Knoevenagel condensation of the aniline 4 to the arylglyoxal 5, in agreement with our previous report. 424][45] Firstly, arylamidine 3 is formed by the addition of the aniline 1 to the carbonitrile 2 at 120 o C for 1 h under solventfree conditions.Then, on addition of arylamidine 3, the formation of intermediate C occurred via a nucleophilic addition reaction of the nitrogen to methylene group in ethyl bromopyruvate (7) followed by the elimination of HBr.In the last step, intermediate C undergoes intramolecular nucleophilic addition the second nitrogen to the carbonyl group and elimination of H2O to form the 1,2,5-trisubstituted imidazole 8.

Conclusions
In summary, we have successfully described a convenient and efficient protocol for the synthesis of two series of 4-amino-1,2,5-tetrasubstituted and 1,2,5-trisubstituted imidazoles via a two-step, four or three-component reaction of aryl amines, carbonitriles, and aryl amines with arylglyoxals or ethyl bromopyruvate in the presence of disodium phosphate, and iron (III) chloride as catalyst, respectively.The catalysts are readily available and inexpensive and can conveniently be handled and removed from the reaction mixture.The notable features offered by this method are the environmentally friendly procedure, readily available starting materials, easy workup, and good to high product yields.

Experimental Section
General.All chemicals were purchased from Aldrich and Merck with high-grade quality, and used without any purification.All melting points were obtained by Barnstead Electrothermal 9200 apparatus and are uncorrected.The reactions were monitored by TLC and all yields refer to isolated products.NMR spectra were obtained on a Varian 500 MHz spectrometer ( 1 H NMR at 500 MHz, 13 C NMR at 125 MHz) using TMS as an internal standard; coupling constants are measured in Hz.Infrared spectra were recorded on a Bruker FT-IR Equinax-55 spectrophotometer in KBr with absorption in cm -1 .Elemental analyses were performed using a Carlo Erba EA 1108 instrument.All products were characterized by their spectral and physical data.

General procedure for the synthesis of arylamidine (3).
The mixture of aryl amine 1 (1.2 mmol), carbonitrile 2 (1.0 mmol), and AlCl3 (1.0 mmol) was charged to a round bottom flask.The mixture was stirred at 120 °C for 1 h, then ice water (20 mL) was added to round bottom flask heat mixture, after 10% sodium hydroxide solution was added with a mixture of reaction to obtain pH = 14, and the precipitate was extracted with CHCl3 (3 × 7 mL), dried (MgSO4), and the solvent evaporated.The colorless crude product was crystallized from toluene.General procedure for the synthesis of compounds 6a-h.A mixture of arylamine 4 (1.0 mmol) and arylglyoxal 5 (1.0 mmol) was stirred in EtOH (15 mL) heated at reflux for 2 h to give iminone.Then, arylamidine 3 (1.0 mmol) was added in the presence of disodium phosphate (20 mol%) under reflux conditions for 10 h.After completion of the reaction (TLC), the solvent was removed under reduced pressure, and the resulting crude product was purified by washing with EtOH to give the pure compounds 6a-h (68-82%).General procedure for the synthesis of compounds 8a-d.A mixture of arylamidine 3 (1.0 mmol) and ethyl bromopyruvate (7) (1.0 mmol) was stirred in EtOH (15 mL) in the presence of iron (III) chloride (20 mol%) heated at reflux for 12 h.After completion of the reaction (TLC), the solvent was removed under reduced pressure, and the viscous residue was purified by plate chromatography (20 × 20 cm) using n-hexane/EtOAc (25:75) as eluent to give the pure compounds 8a-d (56-62%).