The diels-alder chemistry of 1-vinyl-2-pyridones

The Diels-Alder chemistry of a series of 1-vinyl-2-pyridones using a variety of dienophilic species including dimethyl acetylenedicarboxylate, benzyne, maleic anhydride and methyl vinyl ketone has been explored in order to determine the generality of this method for generation of N-vinylisoquinuclidines. In general, the cycloaddition reactions lead to modestly high yeilds of the azabicyclooctane products. In the course of these studies, we noted that retro-Diels-Alder reactions of N-vinylisoquinuclidienones lead to generation of N-vinylisocyanates and a benzene fragment while the corresponding mono-unsaturated isoquinuclidenones form the corresponding pyridones by elimination of an ethylene unit. Lastly, the regio- and stereochemical courses for the π2+ π4 addition reactions of methyl vinyl ketone and 1-vinyl-2-pyridones were investigated. The major products from these reactions appear to result from reaction pathways predicted to be of low energy using first-order molecular orbital methods.     

General synthetic methods for the preparation of 1-substituted-vinyl-2-pyridones

General methods for the preparation of a variety of 1-substituted vinyl-2-pyridones are described. Synthetic routes followed involve (1) nucleophilic substitution reaction of the 2-hydroxy-pyridyl anion of haloolefins containing β-activating groups, such as carbonyl and phenyl, (2) elimination reactions of ester derivatives of 1-pyridonyl-2-ethanols and (3) base catalyzed isomerizations of 1-allyl-2-pyridones. The details involved with each of the synthetic methods and purification of the derived 1-vinyl-2-pyridones are described. Additionally important spectroscopic properties of compounds in this series are discussed in terms of preferred conformations about the nitrogen-exocyclic vinyl carbon bond.     

Diels-Alder reactions of nitro-2(1H)-pyridones with 2,3-dimethyl-1,3-butadiene

Diels-Alder (DA) reactions of 3- or 5-nitro-2(1H)-pyridones and nitro-2(1H)-pyridones containing a methoxycarbonyl group with 2,3-dimethyl-1,3-butadiene were examined. The DA reactions of 3-nitro-2(1H)-pyridones in this paper represent, to the best of our knowledge, the first report of DA reactions of 3-substituted 2(1H)-pyridones and consequent production of isoquinolones. Performing the same reactions with 5-nitro-2(1H)-pyridones yielded quinolones. DA reactions of 2(1H)-pyridones with nitro and methoxycarbonyl groups produced isoquinolones, quinolones and phenanthridones (the double DA adducts), aromatized or hydrogenated. The substituent effect was evaluated by calculating the activation energy, using the ab initio MO method.     

Reactions of ketene silyl acetals with imine-complexes of titanium tetrachloride. New and convenient routes to 5,6-dihydro-2-pyridones and 5-amino-2-alkenoates

The reactions of vinylketene silyl acetals (VKSAs) with imine complexes of TiCl₄ give the corresponding 5,6-dihydro-2-pyridones and/or 5-amino-2-alkenoates in good to excellent yields. It is suggested that an addition-cyclization mechanism is operative for the formation of 5,6-dihydro-2-pyridones in this formal cyclocondensation reaction.     

Enantioselective photochemical reactions of 2-pyridones in solution

[reaction: see text] Two key photochemical reactions of prochiral 2-pyridones were studied in the presence of a chiral host. The [4 + 4]-photocycloaddition with cyclopentadiene (CpH) proceeded smoothly and with high enantioselectivity (84-87% ee). The absolute configuration of the endo-diastereoisomer was established by X-ray crystallography. The electrocyclic [4pi]-ring closure to 3-oxo-2-azabicyclo[2.2.0]-5-hexenes occurred with lower enantioselectivity (20-23% ee at -20 degrees C). The velocity of the latter reaction slowed significantly with decreasing temperature.     

Regio- and selective synthesis of 4,6-disubstituted-2-pyridones

Palladium catalysed regio- and stereoselective annulation of allenyl stannanes by β-iodo vinylic amides gives good yields of the corresponding 2-pyridones. This annulation probably occurs via a Stille reaction/cyclisation sequence.     

An improved Ullmann-Ukita-Buchwald-Li conditions for CuI-catalyzed coupling reaction of 2-pyridones with aryl halides

An effective CuI-trans-N,N′-dimethylcyclohexane-1,2-diamine (DMCDA)-K₂CO₃-catalyzed coupling reaction of 2-pyridones with aryl halides is described. Under our conditions, DMCDA was found to be an effective catalyst that facilitates the coupling reactions even in toluene, a common industrial solvent. In addition, 3-bromopyridine could also be coupled effectively under these conditions, indicating that the catalytic reactivity of this system is high. The reaction could be applied for polymer modification and iterative oligo-pyridone synthesis.     

Novel and efficient synthesis of 4-sulfonyl-2-pyridones

Heterocyclic 4-sulfonyl-2-pyridones represent useful scaffolds for drug discovery, and are also versatile synthetic building blocks. Herein, we describe a novel and efficient synthesis of this heterocyclic ring system utilizing an acid-mediated cyclo-condensation reaction. This synthetic method affords convenient access to structurally diverse N-substituted 4-sulfonyl-2-pyridones in moderate to good yields.     

A simple synthesis of novel 2-pyridones from chalcones

Several novel 2-pyridones were synthesized in good yields from a simple one-pot reaction by the condensation of different substituted chalcones and malonamide using sodium ethoxide in ethanol at room temperature. The structures of these 2-pyridones were elucidated from their ¹H, ¹³C and infrared spectral data as well as their elemental analysis. Different 2-pyridones tautomers were obtained as the solvent of crystallization changes.     

An efficient organocatalytic method for tandem synthesis of functionalized 2-pyridones

Highly functionalized 2-pyridones are obtained via a tandem reaction between primary amines and acetylenic esters in the presence of N-methylimidazole as an organocatalyst.     

Synthesis of new potentially bioactive bicyclic 2-pyridones

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target bicyclic 2-pyridones in good to excellent yields.     

Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones

By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave irradiation proved to be superior to traditional conditions and the primary amines were obtained in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-93% yields.     

The diene synthesis reaction and substitutive addition with 2-pyridones and their thio analogs (review)

The literature on the reactions of 2-pyridones and their thio analogs with unsaturated compounds taking place by a mechanism of diene synthesis or of substitutive addition, depending on the structure of the initial components, has been systematized. The basic synthetic directions of the use of these reactions and also the stereochemistry of the diene synthesis with 2-pyridones and 2-thiopyridones are considered.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 3–20, January, 1984.     

2-pyridones from cyanoacetamides and enecarbonyl compounds: application to the synthesis of nothapodytine B

The condensation of an enone or enal with cyanoacetamide derivatives and t-BuOK furnishes either 3-cyano-2-pyridones or 3-unsubstituted-2-pyridones, depending on whether the reaction is carried out in the presence or in the absence of O(2). In the first case, in situ oxidation of Michael-type intermediates takes place; in the second case, the products result from "decyanidative aromatization" of such intermediates. A one-step synthesis of 3-alkyl-2-pyridones has been devised on the basis of decyanative union of an enone/enal and a 2-alkylcyanoacetamide. The new reaction forms the centerpiece of an unusually concise synthesis of nothapodytine B (mappicine ketone).     

Versatile synthesis of 3,5-disubstituted 2-fluoropyridines and 2-pyridones

5-bromo-2-fluoro-3-pyridylboronic acid (3) was prepared in high yield by ortho-lithiation of 5-bromo-2-fluoropyridine (1), followed by reaction with trimethylborate. Suzuki reaction of 3 with a range of aryl iodides gave 3-monosubstituted 5-bromo-2-fluoropyridines 4 in excellent yields. A second Suzuki reaction utilizing the bromo constituent of 4 with aryl and heteroaryl boronic acids provided 3,5-disubstituted 2-fluoropyridines 5, which in turn could be converted to the corresponding 2-pyridones 6.     

Improved procedure for the enantioselective synthesis of dihydrooxazolo and dihydrothiazolo ring-fused 2-pyridones

Improved procedures to synthesize enantioselectively analogues of a peptidomimetic scaffold with high biological relevance have been developed. Experimental design led to a general method for the preparation of dihydrooxazolo ring-fused 2-pyridones in good yields and high enantiomeric purity. The knowledge gained from this was also used to improve the microwave-accelerated synthesis of dihydrothiazolo ring-fused 2-pyridones to give complete stereo retention and high yields.     

Diene synthesis with 2-pyrones and 2-pyridones XIV. 1,4-Cycloadducts of 1-alkyl-2-pyridones with N-phenylmaleinimide and maleinimide

1-Alkyl-2-pyridones react with N-phenylmaleinimide and maleinimide stereoselectively via the scheme of the diene synthesis to give imides of 8-alkyl-8-azabicyclo[2.2.2]-4-octen-7-one-1,2-dioic acid. 3-Unsubstituted 2-pyridones form adducts with an endo configuration, whereas 1,3-dimethyl-2-pyridone gives an exo adduct under the same conditions. The endo- and exo-bridge adducts readily undergo retrograde diene disintegration on heating.     

Diels-alder reaction of 2(1H)-pyridones acting as dienes

Diels-Alder reactions between N-phenylmaleimide, acting as the dienophile, and 2(1H)-pyridones having a methoxy or a chloro substituent, were carried out, under atmospheric and high pressure conditions, to give the corresponding isoquinuclidine derivatives. Stereoselectivity of the Diels-Alder reactions was studied using molecular orbital calculations.     

A novel synthesis of 5-aryl-3-cyano-2-pyridones by using vinamidinium salts

A variety of vinamidinium salts were condensated with cyanoacetamide in refluxing methanol that contained sodium methoxide to produce 5-aryl-3-cyano-2-pyridones in good yield.Simple experimental conditions were used to prepare ten different 5-aryl-3-cyano -2-pyridones,four of which are new compounds.     

Retro-ene reactions in heterocyclic synthesis. II. A facile synthetic method for 4-hydroxy-2-pyridones

Schiff's bases 1 derived from ketones and t-butylamine reacted with diphenyl malonate, diphenyl methyl-malonate and diphenyl phenylmalonate to give 4-hydroxy-2-pyridones 4–6 . Schiff's bases b on reaction with trimethyl methanetricarboxylate afforded 4-hydroxy-3-methoxycarbonyl-2-pyridones 12 .