Electrophilic substitution in 3- and 4-methyl-2(1h)quinolinone through metallated species

Martín, Olga Buitrago; Cuesta, Elena de la; Avendaño, Carmen

doi:10.1016/0040-4020(95)00377-k

Cited by 16 publications

(4 citation statements)

References 24 publications

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“…Known 4-methylquinolone ( 15 ) was transformed into the pent-4-enyl substituted quinolone 9 by deprotonation and subsequent electrophilic attack by but-3-enyl bromide as an alkylating agent. Amine 17 was prepared by nucleophilic displacement of the triflate group in quinolone 16 with N -but-3-enylamine .…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a Hydrogen-Bonding Motif

et al. 2011

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Six 2-quinolones, which bear a terminal alkene linked by a three- or four-membered tether to carbon atom C4 of the quinolone, were synthesized and subjected to an intramolecular [2 + 2]-photocycloaddition. The reaction delivered the respective products in high yields (78-99%) and with good regioselectivity in favor of the straight isomer. If conducted in the presence of a chiral hydrogen-bonding template (2.5 equiv) at low temperature in toluene as the solvent, the reaction proceeded enantioselectively (83-94% ee). An organocatalytic reaction was achieved when employing a chiral hydrogen-bonding template with an attached sensitizing unit (benzophenone or xanthone). The xanthone-based organocatalyst proved to be superior as compared to the respective benzophenone. Closer inspection revealed that the reaction of 4-(pent-4-enyloxy)quinolone leading to a six-membered ring, annelated to the cyclobutane, was less enantioselective (up to 41% ee with 30 mol % catalyst) than the reaction of 4-(but-3-enyloxy)quinolone leading to a five-membered ring (90% ee with 5 mol % and 94% ee with 20 mol % catalyst). Photophysical data (emission spectra, laser flash photolysis experiments) proved that the latter photocycloaddition was significantly faster, supporting the idea that the dissociation of the substrate from the catalyst prior to the photocycloaddition is responsible for the decreased enantioselectivity. Under optimized conditions, employing 10 mol % of the xanthone-based organocatalyst at -25 °C in trifluorotoluene as the solvent, three of the other four substrates gave the intramolecular [2 + 2]-photocycloaddition products with high enantioselectivities (72-87% ee). In all catalyzed reactions, the yields based on conversion were moderate to good (40-93%).

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Section: Resultsmentioning

confidence: 99%

Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a Hydrogen-Bonding Motif

et al. 2011

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“…quinone motif, namely lithiation at C-3 assisted by the neighboring carbonyl group, as shown in structure 6 (Figure 2), 10 and lithiation of the C-4 methyl assisted by the neighboring C-5 methoxy group (structure 7). 11…”

Section: Methodsmentioning

confidence: 99%

“…Although both modes of lithiation are known in the literature, the first has been more extensively studied, 10 while lithiation at C-4 has been primarily exploited for the creation of carbon-heteroatom bonds. 11 In order to establish more clearly the precedence between these two potential lithiation sites and also to facilitate comparison with our subsequent results, we decided to extend the scope of this reaction by examining its general application to the generation of C-C bonds. As shown in Scheme 3 and Table 1, treatment of 4-methyl-5,8-dimethoxy-2(1H)-quinolinone (8) with 2.2 equivalents of BuLi followed by addition of an identical excess of an alkyl halide led to excellent yields of the products substituted at the C-4 methyl, which were obtained with complete regioselectivity regardless of the nature of the halide employed (entries 1-4).…”

Section: Figurementioning

confidence: 99%

The Directed Lithiation Route to 2-Amino-3-alkylquinones: Highly Regioselective Introduction of Electrophiles at the C-7 Position of 2(1H)-Quinolinones

Sánchez¹,

Cledera²,

Perumal³

et al. 2007

Synlett

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An ortho-directed lithiation strategy starting from 2-amino-1,4-dimethoxybenzene derivatives allowed the efficient preparation of 2-amino-3-alkylbenzoquinone derivatives. This method was also successful in the case of 6-pivaloylamino-4-methyl-5,8-dimethoxycarbostyril derivatives, in spite of the fact that two other modes of lithiation are possible, and allowed the preparation of derivatives containing alkyl chains or functional groups at the highly hindered C-7 position. A reaction starting from 4-methyl-5,8-dimethoxy-2-pivaloyloxyquinoline was regioselectively directed to the C-4 methyl group.A number of natural heterocyclic quinones with antitumor properties, most notably some members of the mitomycin family, contain a 2-amino-3-alkyl-1,4-benzoquinone fragment (1, Figure 1). Compounds with this structure can also be considered as useful potential synthons for the preparation of other biologically active natural products like the sebastianins, 2 a group of cytotoxic marine alkaloids belonging to the pyridoacridine family. 3 Figure 1Previous work related to the synthesis of structures 1 has normally involved the construction of 2-methoxy-3-aminobenzoquinone moieties, followed by the displacement of the methoxy group by ammonia, but the preparation of these starting materials involves lengthy routes. 4 We describe in this communication some results related to the development of a directed-metalation-based strategy 5 for the synthesis of compounds 1, as summarized in Scheme 1. This strategy is simpler, and therefore potentially more efficient than previous methods in that it avoids the difficulties associated with the preparation of 1,2,3,4-tetrasubstituted benzene derivatives as starting materials. It also avoids issues of regioselectivity at the oxidation stage due to the presence of a 2-methoxy group, which facilitates ortho-quinone synthesis. In connection with this strategy, we report here our results on the preparation of a simple quinone containing the desired substitution pattern and the subsequent application of the directed lithiation strategy to 4-methylcarbostyril, a challenging system where two additional modes of lithiation are possible. Scheme 1Our initial studies were aimed at the preparation of the 3-methyl-5,6-unsubstituted compound 5, an acyl derivative of the simplest possible compound with structure 1, namely the benzoquinone derivative. As shown in Scheme 2, directed ortho-lithiation of 2,5-dimethoxy-N-pivaloylaniline 2 proceeded very efficiently by its treatment with 2.5 equivalents of BuLi to give the nonisolated dilithio species 3, which was trapped with methyl iodide to afford compound 4 in 94% yield. 6 Oxidative demethylation of 4 to 5 was carried out in 45% yield under standard conditions, by treatment of 4 with ceric ammonium nitrate in acetonitrile-water at room temperature. 7Having proved the feasibility of the ortho-metalation strategy, we decided to test its scope by applying it to a more complex case. We chose the 2(1H)-quinolinone (carbostyril) system to this effect, prompted by t...

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“…Direct ring metallation for the introduction of carbon substituents onto a preformed pyridone has been studied [42][43][44]. Regioselective electrophilic substitutions are obtained with irregular results, better the ring construction bearing the substitution required in the final product and is Recently, a direct arylation of 2-pyridone by photostimulated S RN 1 reaction between cesium phenoxides and chloro-2-pyridones has been described with yields no better than 50% for the Csubstitution product (Scheme (2)) [45].…”

Section: -Pyridones As Building Blocks In Synthesismentioning

confidence: 99%

New Synthetic Methods to 2-Pyridone Rings

Torres¹,

Gil²,

Parra

2005

COC

203

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The synthesis of a substituted 2-pyridone ring is a topical area of continuing interest due to the number of biologically active molecules containing this moiety. Over the last decade, natural compounds with this structure have emerged as potent antitumor antiviral and attention, because those compounds may be studied as a simple model for investigating mechanisms of some enzymatic reactions or for discerning the behavior of nucleic acids bases in connection with mutation due to base mispairing or other mistaken helices. Recent studies have shown the usefulness of 2-pyridones as intermolecular connectors between building blocks in material science. Thus, despite the large number of methods known for their synthesis, new procedures are continuously being developed. Two main synthetic approaches can be found in the literature: from other heterocycles systems or condensation of acyclic systems. The latter can be further classified depending on the bond formed in the cyclization step: by C-C or C-N bond generation. The latter can be subclassified depending on the first condensation step. This is a review of new or improved methods for constructing 2-pyridone rings. This article will be restricted to ring formation, which can be included in the total synthesis of several compounds with specific biological or material properties.The pursuit of these properties requires efficient synthetic routes that allow rapid assembly and variation of multiple pendant substituents on the heteroaromatic case, which permits rapid analogsynthesis (RAS) [1].

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Electrophilic substitution in 3- and 4-methyl-2(1h)quinolinone through metallated species

Cited by 16 publications

References 24 publications

Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a Hydrogen-Bonding Motif

Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a Hydrogen-Bonding Motif

The Directed Lithiation Route to 2-Amino-3-alkylquinones: Highly Regioselective Introduction of Electrophiles at the C-7 Position of 2(1H)-Quinolinones

New Synthetic Methods to 2-Pyridone Rings

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