An Efficient Synthesis of 2,4,5-Trisubstituted and 1,2,4,5-Tetrasubstituted-1H-imidazoles

Abstract

Since the appearance of the first paper on the application of microwave irradiation in the chemical synthesis the approach has blossomed into a useful technique for a variety of applications in organic synthesis and functional group transformations. In moving towards sustainable technologies the focus has now shifted to less cumbersome solventless methods wherein solid supported microwave synthesis has played an important role. This technique eliminates the use of solvent during the reaction stage but requires an appreciable amount of solvent for the adsorption of reagents and elution of product. The emergence of neat reaction is a recent approach under the new paradigm of green chemistry where the neat reactants undergo facile reaction to provide high yield of pure products thus eliminating or minimizing the use of organic solvents. These no solvent reactions are not only advantageous for environmental reasons but also offer benefits of enhanced reaction rates, greater selectivity and experimental ease of manipulation. The imidazole ring system is of particular interest as it is a component of histidine that produces histamine in metabolic process. The potency and wide applicability of the imidazole pharmacophore can be attributed to its hydrogen bond donor-acceptor capability as well as its high affinity for metals which are present in many protein active sites (eg. Zn, Fe, Mg). Triaryl imidazoles are used in photography as photosensitive compounds. In addition, they are of interest because of their herbicidal, analgesic, fungicidal, antiinflammatory and antithrombotic activities. The original synthesis of imidazole utilized glyoxal, formaldehyde and ammonia and established that the formation of four N–C bonds was a viable route. Although classical methods were derived from this early success, the reactions suffered low yields, mixture of products and lack of generality. Synthetic methodology alternatives are many and varied and have resorted to harsh conditions (eg. the formamide synthesis, which requires excess reagents, H2SO4 as a condensing agent, 150-200 °C, 4-6 h, 40-90%). Also, reagents for these procedures are not readily available, a key deficiency for library synthesis. In continuation to our endeavour towards green chemistry and the biological importance of substituted imidazole derivatives we have developed an ecologically safe strategy for the synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazole derivatives employing neat reaction conditions using MWI. Results and Discussion