Recyclization of Maleimides by Binucleophiles as a General Approach for Building Hydrogenated Heterocyclic Systems

Abstract

The building of heterocyclic systems containing hydrogenated fragments is an important step towards the creation of biologically-active compounds with a wide spectrum of pharmacological activity. Among the numerous methods for creating such systems, a special place is occupied by processes using N-substituted maleimides as the initial substrate. This molecule easily reacts in Diels-Alder/retro-Diels-Alder reactions, Michael additions with various nucleophiles, and co-polymerization processes, as have been described in numerous detailed reviews. However, information on the use of maleimides in cascade heterocyclization reactions is currently limited. This study is devoted to a review and analysis of existing literature data on the processes of recyclization of N-substituted maleimides with various C,N-/N,N-/S,N-di- and polynucleophilic agents, such as amidines, guanidines, diamines, aliphatic ketazines, aminouracils, amino- and mercaptoazoles, aminothiourea, and thiocarbomoyl pyrazolines, among others. The significant structural diversity of the recyclization products described in this study illustrates the powerful potential of maleimides as a building block in the organic synthesis of biologically-active compounds with hydrogenated heterocyclic fragments.

New Aspects of the Reaction of Thioacetamide and N-Substituted Maleimides

“…In the reactions of N-arylmaleimides with thiourea and its derivatives, five-and sixmembered heterocycles are usually formed: thiazoles B [1,7,[13][14][15][16][17][18] and thiazines C [20]. Reactions of N-arylmaleimides with polynucleophilic reagents, such as amidinothiourea and thiosemicarbazones proceed at 1,3-S,N-binucleophilic centers with the formation of the corresponding thiazolines [2,3,21,22].…”

“…Reactions of N-arylmaleimides with polynucleophilic reagents, such as amidinothiourea and thiosemicarbazones proceed at 1,3-S,N-binucleophilic centers with the formation of the corresponding thiazolines [2,3,21,22]. The reaction of N-arylmaleimides with heterocyclic 1,3-N,S-binucleophiles (for example, 2-thioquinazolines [7] and 2-mercapto-1,2,4-triazoles [5]) leads to the formation of condensed systems, such as thiazolo [2,3-b]quinazolines and thiazolo [3,2-b] [1,2,4]triazoles, respectively. Thioethers-products of sulfur atom addition to the double bond of N-arylmaleimides by the Michael reaction type were isolated for 2-mercapto-1,2,4-triazole [6].…”

“…N-substituted maleimides are promising organic substrates that are used to build a wide range of fused and linearly linked heterocyclic scaffolds with biologically active properties [1][2][3][4][5][6][7][8][9]. The reactive feature of maleic acid imides is their ability to enter into 1,3-dipolar addition reactions [8][9][10][11][12] and into recyclization reactions under the action of binucleophilic reagents-in particular, 1,3-S,N-binucleophiles [1][2][3][4][5][6][7][13][14][15][16][17][18][19][20][21][22][23].…”

“…N-substituted maleimides are promising organic substrates that are used to build a wide range of fused and linearly linked heterocyclic scaffolds with biologically active properties [1][2][3][4][5][6][7][8][9]. The reactive feature of maleic acid imides is their ability to enter into 1,3-dipolar addition reactions [8][9][10][11][12] and into recyclization reactions under the action of binucleophilic reagents-in particular, 1,3-S,N-binucleophiles [1][2][3][4][5][6][7][13][14][15][16][17][18][19][20][21][22][23]. In such reactions, the addition of a more nucleophilic sulfur atom to the activated double bond of N-substituted maleimide usually occurs at the first stage, and the recyclization of the succinimide ring under the action of the nucleophilic nitrogen atom occurs at the second stage [19,21] (Scheme 1, adduct A).…”