Cyclization of aniline-acetylenedicarboxylate adducts. A modified Conrad-Limpach method for the synthesis of potential antimalarials

Synthesis and Pharmacological Evaluation of Some 4‐Oxo‐quinoline‐2‐carboxylic Acid Derivatives as Anti‐inflammatory and Analgesic Agents

“…Traditionally, synthesis of 2‐[(4'‐substituted‐phenyl)‐amino]‐2‐butenedioates 1a–4a has been achieved using the method of Conrad and Limpach 23, 24, involving the reaction between anilines and acetylenedicarboxylate, followed by cyclization in diphenylether at ∼250°C, affording compounds 1b–4b . Aroylation of the nitrogen of quinolones in dichloromethane at room temperature afforded compounds 5–15 in good yields (Scheme and Table 1).…”

4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities

“…The N -oxide of 7 was the second compound displaying in vivo activity in the same malaria model confirming the initial assumption that the poor bioavailability of compund limited its use in mammals. It is also noteworthy that in 1968 Lemke and co-workers reported a series of 3-unsubstituted 4(1 H )-quinolone-2-carboxylates which were inactive against P.berghei in a murine model [48]. …”

Study of the Hydroamination Reaction of Methyl Acetylenedicarboxylate with Aromatic Amines and its Heterocyclization Products

“…Thus, this aza‐Michael‐type reaction, leads to alkyl N ‐alkyl‐2‐phenylamino‐2‐butenedioates ( 3 ), which are important intermediates in the synthesis of various heterocyclic compounds with broad biological activity [3,11–15] . Literature shows ambiguity in the 1 H‐NMR spectroscopic assignment of enamines 3 a and 3 b , and therefore of their configuration, leading to confusing or contrary conclusions regarding their structural configuration [6,9,16–23] . Subsequent treatment of compounds 3 with a cyclizing agent such as polyphosphoric acid (PPA) at 130 °C, yields 2‐alkoxycarbonyl‐4‐quinolinones 4 (Scheme 1) via an intra‐molecular Friedel‐Crafts reaction [6,9,11,14,16–20] …”

“…Attempts to obtain the N ‐benzyl and N ‐phenyl derivatives ( 3 b ) were unsuccessful. Subsequently, the synthesis of N ‐aryl derivatives was reported through the use of Cu(OTf) 2 as a catalyst, obtained as a pale yellow liquid instead a characteristic solid like most 4‐quinolones‐2‐carboxylic acid derivatives, [5,6,9,10,12,19,22] but their spectroscopic characterization is doubtful [15] …”

“…[3,[11][12][13][14][15] Literature shows ambiguity in the 1 H-NMR spectroscopic assignment of enamines 3 a and 3 b, and therefore of their configuration, leading to confusing or contrary conclusions regarding their structural configuration. [6,9,[16][17][18][19][20][21][22][23] Subsequent treatment of compounds 3 with a cyclizing agent such as polyphosphoric acid (PPA) at 130°C, yields 2-alkoxycarbonyl-4quinolinones 4 (Scheme 1) via an intra-molecular Friedel-Crafts reaction. [6,9,11,14,[16][17][18][19][20] Recently, it has been reported the directly obtainment of a variety of 4-quinolones via a one-pot cascade reaction using PPA as a cycling agent.…”