Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives

Abstract

A novel multicomponent reaction involving o-phenylenediamines, aldehydes and p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of a base leading to the formation of quinoxalines in very good yields is described.Quinoxalines are widely used as intermediates in medicinal chemistry, 1,2 since they exhibit a wide range of biological activities, such as antiviral, antibacterial, antiinflammatory and kinase inhibitor properties. 3-10 The echinomycin 11 and the triostins 12 are well-known antibiotic families of quinoxaline derivatives. Furthermore, they have found applications as dyes, 13a efficient electroluminescent materials, 13b organic semiconductors, 13c dehydroannulenes, 13d cavidands 13e and chemically controllable switches. 13f Thus, a number of methods have been developed for the synthesis of substituted quinoxalines involving condensation of 1,2-phenylenediamines with adiketones, also under microwave irradiation, 14 1,4-addition of 1,2-diamines to diazenylbutenes, 15 oxidation trapping of a-hydroxyketones with 1,2-diamines, 16 oxidative cyclization of phenacyl bromides 17 or vicinal diols with ophenylenediamines, 18 oxidative coupling of epoxides 19 or ketones 20 with 1,2-diamines. Very recently, quinoxalines were also synthesized in 33-55% yield, through a twostep reaction sequence, the first step involving a multicomponent reaction between o-phenylenediamines, aldehydes and isonitriles in hydrochloric methanolic solution, whereas in the second step a DDQ oxidation of the isolated dihydroquinoxalines was involved. 21 Sequential transformations and one-pot multicomponent reactions (MCRs) offer significant advantages over conventional linear step syntheses, by reducing time and saving money, energy and raw material thus resulting in both economic and environmental benefits. 22 Moreover, multicomponent synthesis has been established as a valuable tool to the pharmaceutical industry for construction of low molecular weight compound libraries through combinatorial strategies and parallel synthesis. 23 Although p-toluenesulfonylmethyl isocyanide (TosMIC) is a versatile, widely applicable reagent that constitutes a densely functionalized building block bearing an active methylene group apart from its inherent advantage of possessing also an isonitrile functionality, which can serve as a handle for further manipulation, the possibility of its use in multicomponent reactions has not been greatly appreciated. TosMIC has most commonly been used in heterocyclic ring construction, 24 in particular, of oxazole and pyrrole moieties, but comparatively rarely in multicomponent reactions. 25 Since the reaction between imines and TosMIC in basic media constitutes a trusted method for the synthesis of 1,5-disubstituted imidazoles 26 and in continuation to our previous work 27 we speculated that formation of quinoxalines would be possible, through a multicomponent reaction, by using o-phenylenediamines with equimolar amounts of an aldehyde and TosMIC.Initially, a three-component reaction was performed between o-phen...