Expedient Entry into 1,4-Dihydroquinoxalines and Quinoxalines via a Novel Variant of Isocyanide-Based MCR

Abstract

A novel multicomponent reaction of o-phenylenediamines with aldehydes and isonitriles yields 1,4-dihydroquinoxalines. These intermediates are unstable under reaction conditions. They undergo oxidation with DDQ to furnish 33-54% isolated yields of the respective quinoxalines. This reaction is general for aromatic 1,2-diamines. Monoalkylated aryl 1,2-diamines lead to stable 1,4-dihydroquinoxalines.

General Multicomponent Strategy for the Synthesis of 2‐Amino‐1,4‐diazaheterocycles: Scope, Limitations, and Utility

“…It should be noted in this context that the same oxidative side reactions were observed in the HCl-promoted IMCRs of 1,2-phenylenediamine with aldehydes. [18] Nevertheless, those authors were able to isolate 3-arylquinoxalin-2-amines in moderate yields through the employment of an IMCR/2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) oxidation sequence in one-pot mode. In view of this, the most recently published results [32] appear unexpected: the same reaction in the presence of catalytic amounts (20 mol-%) of Fe(ClO 4 ) 3 , which is a strong oxidizing agent, led directly to aromatic 3-arylquinoxalin-2-amines in excellent isolated yields (91-93 %).…”

“…It should be noted that, simultaneously with our publications, TsOH-catalyzed MCRs of 2,3-diaminomaleonitrile with ketones and isocyanides were proposed for the synthesis of 6,6-disubstituted 1,6-dihydropyrazin-2,3-dicarbonitriles. [17] In addition, two more publications [18,19] describing Brønsted-acid-catalyzed IMCRs of 1,2-phenylenediamines with carbonyl compounds appeared while this manuscript was in preparation. In view of the growing synthetic interest in IMCRs of diamines, and of the opportunities that these IMCRs might provide as a promising strategy for the synthesis of privileged heterocycles containing 2-aminopyrazine, [20][21][22] 2-aminoquinoxaline, [23] and other related aminoazaheterocyclic cores, we report here the scope, limitations, extensions, and some subsequent applications of the discovered IMCRs.…”

BF3·OEt2-promoted reaction of isocyanides with o-aminobenzophenones

“…This was recently exemplified by the synthesis of 1,6-dihydropyrazine-2,3-dicarbonitriles from 2,3-diaminomalonitrile, 4 efficient assembly of 3,4,5,6-tetrahydropyrazine-2-amines from ethylenediamine, 5 and by the preparation of (1,4-dihydro)quinoxaline derivatives from o-phenylenediamines. 6 In such processes, both introducing an alternative nucleophile and exploiting the bifunctional character of the intermediate 'iminoamine' led to a reaction design that is quite novel, yet conceptually linked to the Ugi process (Scheme 1).…”

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

“…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.…”