2-Imidazolidinone benzofurans as unexpected outcome of the Lewis acid mediated Nenitzescu reaction

Abstract

The Lewis acid mediated Nenitzescu reaction with piperazinone enaminoesters surprisingly afforded rearranged 2-imidazolidinone 5-hydroxybenzofurans. The reaction was optimised and a scope study was performed. A one-pot two-step procedure was realised...

Exploration of the Divergent Outcomes for the Nenitzescu Reaction of Piperazinone Enaminoesters

“…These classes of compounds exhibit promising activities for a variety of pharmaceutic applications, e.g., as antiviral agents [3][4][5][6][7][8][9][10], anti-inflammatory drugs [11][12][13][14], anticancer agents [15][16][17], and anti-arrhythmic agents [18]. This research fits within the research interests of the laboratory of organic synthesis at the Department of Chemistry at KU Leuven concerning the condensation reactions of quinones [19][20][21][22][23].…”

“…O-acylated 4,5-dihydroxyindoles are Besides 5-hydroxyindoles and benzofurans, a diverse range of alternative reaction products, including 6-hydroxyindoles [32][33][34], O-acylated 4,5-dihydroxyindoles [33,[35][36][37][38], pyrroloindoles [39], furo [2,3-f ]benzofurans [40], and dimeric indoles [35], have been isolated (Scheme 2). Moreover, 6-hydroxyindoles are formed in the so-called 'anti-Nenitzescu reaction' which occurs via a 1,2-addition followed by an intramolecular Michael addition [15,23]. Especially, reactions of N-aryl-substituted enaminoesters at low temperatures are known to generate 6-hydroxyindoles [41].…”

“…Besides rearranged benzofurans, enamino quinones and 5-hydroxyindoles were observed under certain conditions, for example, in Et2O as solvent or when using 2,5-dimethyl-p-benzoquinone or tert-butyl-p-benzoquinone under the optimized conditions [23]. Scheme 3.…”

“…Scheme 3. (A) Parr and Reiss, the condensation of a cyclic enamine and p-benzoquinone, data from [44]; (B) Unexpected formation of a rearranged benzofuran, data from [23]. Recently, our research group investigated the Nenitzescu reaction of piperazinone enaminoesters [27,43].…”

“…This research was inspired by earlier work conducted by Parr and Reiss, who obtained enamino quinone 13 from the condensation of enamine 12 and p-benzoquinone, and O-acylated 4,5-dihydroxyindole 14 upon heating in acetic acid [44] (Scheme 3A). Our research group hypothesized that by replacing acetic acid (AcOH) with trifluoroacetic acid (TFA), thus lowering the nucleophilicity of the acetate, the formation of the O-acylated indole could be suppressed allowing the synthesis of a 5-hydroxyindole [23]. Interestingly, the reaction produced an unexpected rearranged 2-imidazolidinonebenzofuran 16 and not the anticipated 5-hydroxyindole (Scheme 3B).…”