Beobachtungen zum mechanismus der nenitzescu-reaktion—III acylwanderungen—I

Nenitzescu Indole Synthesis: 1929-2019 Unexpected Formation of a Pyrrole-Azepine Hybrid in the Nenitzescu Indole Synthesis: A Reinvestigation

“…The reaction mechanism for the formation of 5-hydroxyindoles is complex and the role of intermediate 4 (Scheme 2) in the formation of 5-hydroxyindoles was proposed by its discoverer in 1929 and confirmed initially on the basis of experiments performed by Raileanu and Nenitzescu in 1965 [2] and then in 1971 [3]. A similar mechanism was proposed by Allen in 1966 [21] and substantiated by evidence emanating from further research studies made in this field [21][22][23][24][25][26][27]. The generally accepted mechanism for the formation of 5-hydroxyindoles, the so-called Nenitzescu-Allen mechanism, includes, in the first step, the Michael addition of the enamine 2 to the C=C bond of 1,4benzoquinone 1.…”

Nenitzescu 5‐Hydroxyindole Synthesis

“…Even though the proposed mechanism does not preclude formation of 4-alkyl-5-hydroxyindoles, no examples were known until Allen and Weiss isolated ethyl 4-carbomethoxy-5-hydroxy-2-methylindole-3-carboxylate (22) from the reaction of 2-carbomethoxy-1,4-benzoquinone (20) with ethyl 3-aminocrotonate, following treatment of the initially formed, and isolated, Michael adduct 21 with acetic acid and 0.18 equivalents of quinone 20 (Scheme 4, equation 1) [13]. These conditions presumably isomerize 21 to the E-isomer that would lead to cyclization and completion of the Nenitzescu indole synthesis.…”

“…In a series of papers, Kuckländer has provided additional evidence for the Nenitzescu-Allen mechanism, in particular the D → E → F → G transformation [18][19][20]. For example, isolated carbinolamine 35 gives byproducts 36-38 in addition to indole 39 (Scheme 7, equation 1) [18].…”

“…For example, isolated carbinolamine 35 gives byproducts 36-38 in addition to indole 39 (Scheme 7, equation 1) [18]. The formation of 36 presumably involves reaction of iminium ion 40 with acetate and rearrangement of 41 to 36 as shown (Scheme 7, equation 2) [20]. Kuckländer and Hühnermann found that benzoquinone reacts with β-arylaminocrotonates in propionic acid to afford 6-hydroxyindoles 42 (10%-30%) (equation 3), along with the byproducts 5-acyloxy-4hydroxyindoles (20%-35%) and arylaminobenzofurans (10%-15%) [21].…”

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

“…Especially, reactions of N-aryl-substituted enaminoesters at low temperatures are known to generate 6-hydroxyindoles [41]. 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].…”