RESUMEN
Presented herein is a novel synthesis of new 2-(quinolin-4-yl)-1,4-dihydroquinazoline systems 8, in which the acid-catalyzed rearrangement of spiro[benzo[e][1,4]diazepine-3,4'-quinolin]-2(1H)-ones generated in situ from 3-(2-aminophenyl)-5H-benzo[e][1,4]diazepin-2(1H)-ones 6 with acetone and alkylmethyl ketones has been realized as an important step. An attempt to synthesize isomeric 2-(2-aminophenyl)-5H-benzo[e][1,4]diazepin-3(4H)-one 6'a by hydrolysis of the corresponding N-{2-[5H-benzo[e][1,4]diazepin-3(4H)-on-2-yl]phenyl}acetamide 5'a led to a new heterocyclic system, 6-methyl-8,13-dihydro-13aH-quinazolino[4,3-b]quinazolin-5-ium 13a-carboxylate 14, as a result of an unexpected rearrangement. In addition, it is noteworthy that during the hydrolysis of N-{2-[5H-benzo[e][1,4]diazepin-2(1H)-on-3-yl]phenyl}acetamides 5, the not previously described 14-dihydro-5H-14,5a-(epimino[1,2]benzo)benzo[5,6][1,4]diazepin[2,1-b]quinazolin-6(7H)-ones 7 were unexpectedly obtained.
RESUMEN
A facile and direct intramolecular indolinone-quinolone rearrangement was developed for the synthesis of quinolino[3,4-b]quinoxalin-6-ones from spiro[indoline-3,2'-quinoxaline]-2,3'-diones, which are readily available with use of isatines, malononitrile, and 1,2-phenylenediamines under quite mild conditions. This efficient approach provides excellent yields and could potentially be used for the construction of a diverse library of quinolino[3,4-b]quinoxalin-6-ones for high-throughput screening in medicinal chemistry. The reaction mechanism is explored by extensive DFT calculations.
RESUMEN
Herein, we report a polyphosphoric acid (PPA)-mediated divergent metal-free operation to access a diverse collection of 3-(indol-2-yl)quinoxalin-2-ones and 4-(benzimidazol-2-yl)-3-methylcinnolines in moderate to excellent overall yields. The described process involves two distinct, and competing rearrangements of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, namely [3,3]-sigmatropic Fischer rearrangement with the formation of an indole ring to produce 3-(indol-2-yl)-quinoxalin-2-ones, and Mamedov rearrangement with simultaneous construction of benzimidazole and cinnoline rings to form the new biheterocyclic systemâ4-(benzimidazol-2-yl)-3-methylcinnolines. The reaction mechanism of both rearrangement channels is explored by extensive dispersion-corrected DFT calculations. It is partcularly remarkable that when 3-(aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones is used, instead of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, reactions proceed regioselectively with the formation of only rearrangement productsâ4-(benzimidazol-2-yl)-3-arylcinnolines with high yields. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the new rearrangement found features a promising approach for the design of unique compound libraries for drug design and discovery programs.
RESUMEN
A novel and efficient protocol for the synthesis of diversely substituted 2,2'-bibenzimidazoles from the reaction of 3-cyanoquinoxalin-2(1H)-ones with 1,2-diaminobenzenes has been developed, which proceeds through sequential nucleophilic addition and electrophilic substitution followed by a Mamedov rearrangement. The synthetic utility of this strategy was illustrated by the concise, one-pot synthesis of 5,5'-bi(2,2'-bibenzimidazoles) and aza-analogues of 2,2'-bibenzimidazole.
RESUMEN
A facile approach to a range of substituted 7-(benzimidazol-2-yl)thioxolumazines [7-(benzimidazol-2-yl)-2-thioxo-2,3-dihydropteridin-4(1 H)-ones] and 7-(benzimidazol-2-yl)lumazines [7-(benzimidazol-2-yl)pteridine-2,4(1 H,3 H)-diones] is described. These new biheterocyclic systems are obtained via H2SO4-catalyzed rearrangement of quinoxalin-2-ones in the presence of 5,6-diamino-2-mercapto- and 2,5,6-triaminopyrimidin-4-ols. Thus, benzimidazole and pteridine rings are constructed in one synthetic step. A plausible ANRORC ( addition of nucleophile, ring opening and ring closure)-type reaction mechanism is proposed. Applying the rearrangement to the aza-analogue of 3-benzoylquinoxalin-2(1 H)-one-i.e., 3-benzoylpyrido[2,3- b]pyrazin-2(1 H)-one-with 5,6-diamino-2-mercaptopyrimidin-4-ol makes it possible to synthesize inaccessible 7-(1 H-imidazo[4,5- b]pyridin-2-yl)-6-phenyl-2-thioxo-2,3-dihydropteridin-4(1 H)-one. 7-(Benzimidazol-2-yl)-6-(2-fluorophenyl)-2-thioxo-2,3-dihydropteridin-4(1 H)-ones undergoes intramolecular nucleophilic substitution of fluorine by a nitrogen of the benzimidazole fragment with the formation of benzo[4',5']imidazo[1',2':1,2]quinolino[4,3- g]pteridine-2,4(1 H,3 H)-diones as new heterocyclic systems.
RESUMEN
The new efficient synthesis of biologically important 3-hydroxy-4-arylquinolin-2-ones through the Darzens condensation (epoxidation) of dichloroacetanilides with aromatic aldehydes followed by one-pot dechlorative epoxide-arene cyclization is described. This methodology has been utilized for the synthesis of naturally occurring viridicatol, a fungal metabolite isolated from the penicillium species.
RESUMEN
The reaction of 3-benzoylquinoxalin-2(1H)-ones with enamines (generated in situ from ammonium acetate and the corresponding methylaryl(hetaryl)ketones) proceeds smoothly to give the corresponding substituted 1-(pyrrolyl)benzimidazolone derivatives in moderate yields through the novel rearrangement of 3-benzoylquinoxalin-2(1H)-ones involving a dual cleavage of the C3âN4 and C2-C3 bonds under mild conditions.
Asunto(s)
Acetatos/química , Aminas/química , Bencimidazoles/química , Bencimidazoles/síntesis química , Cetonas/química , Quinoxalinas/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
A synthetically useful protocol has been developed for the preparation of highly functionalized N-pyrrolylbenzimidazol-2-ones. The reaction of variously substituted 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with commercially available enamines in acetic acid results in a rapid rearrangement and formation of N-pyrrolylbenzimidazol-2-ones in modest to excellent yields. The key step of the rearrangement involves the novel ring contraction of 3-aroyl- and 3-alkanoylquinoxalin-2(1H)-ones with enamines. In this case, the atom of carbon which is displaced from the pyrazine ring of quinoxalin-2(1H)-one becomes the fourth carbon atom of the newly formed pyrrole ring. The method is applicable for the aza analogues of quinoxalin-2(1H)-ones.
Asunto(s)
Compuestos Aza/química , Bencimidazoles/síntesis química , Piridonas/síntesis química , Quinoxalinas/química , Bencimidazoles/química , Estructura Molecular , Piridonas/química , Relación Estructura-ActividadRESUMEN
A novel series of 2-(benzimidazol-2-yl)quinoxalines with three types of pharmacophore groups, namely, piperazine, piperidine, and morpholine moieties, which are part of known antitumor drugs, was designed and synthesized. The compounds have been characterized by NMR and IR spectroscopy, high- and low-resolution mass spectrometry, and X-ray crystallography. 2-(Benzimidazol-2-yl)quinoxalines with N-methylpiperazine substituents showed promising activity against a wide range of cancer lines, without causing hemolysis and showing little cytotoxicity against normal human Wi-38 cells (human fetal lung). A mixture of regioisomers 2-(benzimidazol-2-yl)-3-(4-fluorophenyl)-6(and 7)-(4-methylpiperazin-1-yl)quinoxalines (mri BIQ 13da/14da) showed a highly selective cytotoxic effect against human lung adenocarcinoma (cell line A549) with a half-maximal inhibitory concentration at the level of doxorubicin with a selectivity index of 12. The data obtained by flow cytometry, fluorescence microscopy, and multiparametric fluorescence analysis suggested that the mechanism of the cytotoxic effect of the mri BIQ 13da/14da on A549 cells may be associated with the stopping of the cell cycle in phase S and inhibition of DNA synthesis as well as with the induction of mithochondrial apoptosis. Thus, mri BIQ 13da/14da can be considered as a leading compound deserving further study, optimization, and development as a new anticancer agent.