A Multicomponent Domino Reaction and in situ Aerobic Oxidation Sequence for the First One-Pot Synthesis of Polycyclic Benzimidazoles from 1,3-Dicarbonyl Derivatives

Abstract

A facile one-pot synthesis of functionalized pyrido[1,2-a]benzimidazoles is described via a molecular-sieves-promoted three-component domino reaction and in situ aerobic oxidation sequence from 1,3-dicarbonyls, aromatic o-diamines and unsaturated aldehydes. This environmentally friendly sequence does not require any harmful reagents, and liberates water as the only by-product. The desired products are obtained in good to excellent yields and generally with high purity, after simple filtration. Development of new multicomponent reactions 1 involving domino processes (MCRs), 2 combining at least three different substrates in a one-pot operation, constitutes nowadays a central academic and industrial investigation domain 3 in diversity-oriented synthesis 4 of functionalized heterocycles. These very efficient atom-5 and stepeconomic 6 transformations also combine increase in molecular and functional complexity with practical and environmental concerns, 7 approaching quite closely the concept of an ideal synthesis. 8 Although isonitriles became one of the most popular reactant in MCRs, 9 especially as a key component in the well-known Passerini 10 and Ugi 11 reactions, the reactivity of 1,3-dicarbonyls, proposed as early as 1882 by Hantzsch, 12 proved to be highly efficient but have been relatively unexplored until recently. 13 As part of our efforts to develop new efficient one-pot methodologies to access novel heterocyclic structures, we have recently reported molecular-sieves-promoted multicomponent domino transformations of b-keto esters, b-diketones and b-keto amides in the presence of unsaturated aldehydes and functionalized primary amines for the stereoselective synthesis of polycyclic N/O-, N/Sand N/N-aminals 14 or polyfunctionalized 2,6-diazabicyclo[2.2.2] octane cores 15 (Figure 1).Interestingly, in both approaches, although usually fused derivatives were obtained with simple aliphatic amines (Figure 1, compounds A-C), using o-hydroxyaniline resulted in the exclusive formation of spiro-type structures ( Figure 1, compounds D or E). On the contrary, a preliminary experiment indicated that the use of o-aminoaniline 3 led regioselectively to the corresponding fused polyheterocycles. As illustrated in Scheme 1, under standard conditions, reaction of b-keto ester 1a with acrolein 2a and 1,2-diaminobenzene 3 gave a 88% yield of a unexpected mixture of fused tricyclic aminal 4a and the corresponding benzimidazole 5a in a 1:1 ratio. Subsequent treatment of the crude mixture with CAN or MnO 2 afforded the oxidized compound 5a as a single product, opening a potential new way for the facile one-pot construction of benzimidazole nucleus. Scheme 1In this communication, we report a new and versatile multicomponent domino reaction and in situ aerobic oxidation sequence for the clean and efficient one-pot synthesis of functionalized polycyclic benzimidazole skeletons. Our approach is based on the peculiar selective reactivity of aromatic o-diamines which allows the exclusive formation of fused benzimidazoles by in situ o...