Appel reagent as novel promoter for the synthesis of polysubstituted imidazoles

Abstract We present an efficient method for the synthesis of polysubstituted imidazoles in the presence of Appel reagent (Ph3P/CCl4). Tri-substituted imidazoles is synthesized via condensation of aldehydes, benzil and ammonium acetate, and tetra-substituted imidazole is prepared via condensation of aldehydes, benzil, ammonium acetate and primary amines. These protocols allow the simple preparation of the desired products using readily available reagent instead of complex, expensive and toxic reagents under mild reaction conditions in excellent yields.


Introduction
Imidazole and its derivatives are important class of N-heterocycles that occupies a significant place in synthetic and medicinal chemistry.These compounds act as organic catalysts, 1 precursors of ionic liquids 2 and carbene ligands, 3 building blocks of complex meaningful molecules and natural products, 4 and ligands in metalloenzymes. 5The imidazole core exists in many compounds with pharmaceutical and biological activity such as losartan, eprosartan, carnosinemia, histamine, and histidine. 6The imidazole-containing compounds have also other useful activities such as anthelmintic, 7 antifungal, 8 antiviral activities, 9 antitubercular, 10 antitumor, 11 analgesic, 12 anti-inflammatory, 13 and antibacterial activity.Although the broad variety of synthetic routes have been reported to synthesize imidazole derivatives, 15,16 there are few protocols for preparation of polysubstituted imidazoles.The well-known route for preparation of polysubstituted imidazoles is one-pot reaction between aldehydes, benzil, ammonium acetate and primary amines catalyzed by various catalysts such as FeCl3•6H2O, 17 silica gel/NaHSO4, 18 PPA-SiO2, 19 BF3•SiO2,20 silica gel or HY zeolite, 21 heteropolyacids, 22 HOAc, 23 L-proline, 24 InCl3•3H2O, 25 nanocrystalline sulfated zirconia, 26 1,4diazabicyclo[2,2,2]octane (DABCO), 27 K5CoW12O40•3H2O, 28 alumina, 29 ionic liquids, 30 HClO4-SiO2, 31 silicabonded propylpiperazine N-sulfamic acid,32 and Zr(acac)4. 33However, some of these methods involve the use of toxic and expensive catalysts or media, and have notable disadvantages such as harsh reaction conditions, long reaction times, and moderate yields.Therefore, the development of novel and efficient approaches to generate polysubstituted imidazoles is still desirable.
Due to the chemical and pharmacological significance of imidazoles, we sought to develop a one-pot protocol for the efficient formation of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles through the addition reaction between aldehydes, benzil, ammonium acetate and primary amines in the presence of Ph3P and CCl4 which known as the Appel reagent.Although, the Appel reagent converts an alcohol into the corresponding alkyl halide, we believed that this reagent can be promoted the synthesis of the desired imidazoles.

Results and Discussion
To synthesize the 2,4,5-trisubstituted imidazoles, the reaction between 4-methoxybenzaldehyde 1a, benzil 2 and ammonium acetate 3, as a model reaction, was investigated in the presence of various amounts of Ph3P and CCl4, at different temperatures.As shown in table 1, the best yield of tri-substituted imidazole 4a was obtained in the presence of 1.1 equiv. of Ph3P at 55 °C in 1 mL of CCl4 as reactive solvent after 1.5 h (Table 1, entry 9, 95%).In addition, we examined the reaction in various additional solvents such as CHCl3, CH2Cl2, toluene, DMF, THF, DMSO, and it was found that although the reaction led to approximately acceptable yields in these solvents, the addition of these solvents did not give the better yield of product (Table 1, entries 10-15).In continuous, we examined the reaction of 4-methoxybenzaldehyde 1a, benzil 2, ammonium acetate 3, and benzylamine 5a in the presence of various amount of Ph3P and CCl4 under several reaction conditions to generate 1,2,4,5-tetrasubstituted imidazole 6a.As shown in table 2, the best yield of tetra-substituted imidazole 6a was obtained in the presence of 1.1 equiv. of Ph3P at 60 °C in 1 mL of CCl4 as reactive solvent after 1 h (Table 2, entry 8, 92%).Also, we found that the addition of various solvents such as CHCl3, CH2Cl2, toluene, DMF, THF, DMSO in the reaction mixture, did not lead to better yield of product (Table 2, entries 9-14).In order to show the generality and scope of these new protocols, the reactions were performed using various aldehydes 1 and primary amines 5 in the presence of 1.1 equiv.Ph3P in 1mL CCl4 at convenient temperatures to produce the corresponding polysubstituted imidazoles 4 and 6 (Table 3).All the reactions reached to completion within 1.5 h for 2,4,5-trisubstituted imidazoles 4 and 1 h for 1,2,4,5-tetrasubstituted imidazoles 6. 1 H NMR analysis of the reaction mixtures clearly indicated formation of the polysubstituted imidazoles 4 and 6 in excellent yields.The structures of the polysubstituted imidazoles 4 and 6 were deduced by melting point determination and from 1 H and 13 C NMR spectral data.
A proposed mechanism for the formation of the polysubstituted imidazoles 4 and 6 is depicted in Scheme 1.On the basis of the Appel reaction, 41 the treatment of triphenylphosphine with carbon tetrachloride leads to form phosphonium ion 7, that reacts with aldehydes 1 to form the oxyphosphonium intermediates 8.The generation of the oxyphosphonium intermediates 8 promotes the nucleophilic addition of ammonium acetate 3 via removal of triphenylphosphine oxide and chloride anion to generate the iminium ions 10.The addition of another ammonium acetate on the iminium ions 10 gives the intermediates 11.Then, the condensation of intermediates 11 with benzil 2 produces trisubstituted imidazoles 4 by removal of 2 water molecules.In similar pathway, the addition of primary amines 5 onto iminium ions 10 forms intermediates 14 which produces tetrasubstituted imidazol 6 via condensation with benzil. (2)

Conclusions
In conclusion, we have developed a one-pot and multicomponent reaction between aldehydes, benzil, ammonium acetate and primary amines in the presence of Ph3P and CCl4 which known as Appel reagent.The reactions were carried out under mild reaction conditions and without the use of very high temprature, and complex, toxic and expensive reagents to prepare the polysubstituted imidazoles which are of potential synthetic and pharmacological interest.Use of simple materials, relatively short reaction times, and high yield of the products are the other advantages of our protocol.We believe that the success in this process could open the door to the design of diverse reactions and the generation of interesting organic compounds based on treatment of carbonyl groups with Appel reagent.

Experimental Section
Ammonium acetate, benzil, aldehydes, primary amines, triphenylphosphine and carbon tetrachloride were obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification.Progress of the reactions was monitored by thin layer chromatography (TLC).Melting points were measured on an Electrothermal 9100 apparatus.After completion of the reaction, the solvent was removed and the residue was purified by column chromatography using n-hexane-EtOAc (4:1) as eluent.The solvent was removed to afford the pure product 6a as pale yellow solid.The spectral data of some 1,2,4,5-tetrasubstituted imidazoles 6 are given next.

Figure 1 .
Figure 1.Some examples of pharmaceutical and biological active imidazoles.