Regioselective synthesis of two types of highly substituted 2-pyridones through similar multicomponent reactions

The refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary monoamines in ethanol produces highly substituted 2-amino-6-pyridones such as 2-amino-1-(alkyl)-5-cyano-6-oxo-4-(aryl)-1,6-dihydropyridine-3-ethylcarboxylates in one-pot. On the other hand the refluxing of a mixture of ethylcyanoacetate, aromatic aldehydes, and primary diamines (1,2-ethylenediamine/1,3-propylenediamine) in ethanol furnishes symmetrical zwitterionic 2-pyridones such as 1-(2-amino-ethyl/3-amino-propyl)-6-hydroxy-2-oxo-4-(aryl)-1,2-dihydropyridine-3,5-dicarbonitriles. The result shows that primary diamines and monoamines react differently in the reactions, which provides new mechanistic insight into the regioselective synthesis of these biologically important compounds.     

Microwave-assisted solvent-free synthesis of substituted 2-quinolones

A rapid and efficient method for the preparation of a variety of substituted 2-quinolones has been developed through the reactions of o-aminoarylketones with ester compounds containing a reactive α-methylene moiety in the presence of a catalytic amount of cerium chloride heptahydrate under solvent-free conditions in high yields. The rate and yield of the reaction are considerably improved by employing microwave irradiation.     

Transition-metal-free highly efficient synthesis of 2-pyridones from β-keto amides and ynals

A convenient and efficient annulation reaction was developed, affording 2-pyridones in good to excellent yields. A variety of substituted β-keto amides and ynals were well tolerated, and especially the transformation produced water as only by-product under transition-metal-free conditions. Furthermore, the conjugated enyneamides were achieved from β-cyano amides and ynals in high yields.     

Microwave-assisted synthesis of substituted fluoroazines using KF·2H2O

This Letter describes a new microwave-assisted fluorination of azines using hydrated potassium fluoride in untreated DMSO under atmospheric conditions. It is thought that microwave irradiation promotes desolvation of the fluorine anion leading to halide nucleophilic substitution.     

Microwave-assisted synthesis of new substituted anilides of quinaldic acid

In this study a one step method for the preparation of substituted anilides of quinoline-2-carboxylic acid was developed. This efficient innovative approach is based on the direct reaction of an acid or ester with substituted anilines using microwave irradiation. The optimized method was used for the synthesis of a series of eighteen substituted quinoline-2-carboxanilides. The molecular structure of N-(4-bromophenyl)quinoline-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. It crystallizes in the monoclinic space group with four molecules within the unit cell and the total structure of the compound can be described as "a slightly screwed boat".     

One-pot synthesis of highly substituted indolines

A general and convenient one-pot synthesis of highly substituted indolines from arylhydrazines and aldehydes is reported. This synthesis allows introduction of substitution at essentially all positions of the indoline nucleus to achieve significant diversity in this biologically important template.     

Synthesis of substituted 2-pyridones and 4-aza-3-fluoridones

Substituted N-methyl-2-pyridones and N-methyl-4-aza-3-fluoridones, a previously unknown group of heterocyclic compounds, were obtained by oxidation of 3-methyl-2-phenylpyridine, 3-methyl-2-phenyl-5-(3-methyl-2-phenylpyridin-6-yl)pyridine iodomethylates, as well as of 4-aza-fluorenes substituted at the 9-position.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 939–942, July, 1986.     

Microwave-assisted zinc chloride-catalyzed synthesis of substituted pyrroles from homopropargyl azides

Ligand-free 5-endo-dig cyclization of 1,4- and 1,2,4-substituted but-3-yn-1-yl (homopropargyl) azides in the presence of zinc chloride (usually 20 mol %) in dichloroethane at elevated temperature provides 2,5-di- and 2,3,5-trisubstituted pyrroles in high to moderate yields (91-41%). Both conventional and microwave protocols furnished comparable results. A structure of 2-(4-fluorophenyl)-5-(4-methylphenyl)-1H-pyrrole was confirmed by X-ray crystallography.     

Microwave-assisted synthesis of substituted hexahydro-pyrrolo[3,2-c]quinolines

New compounds with the ethyl hexahydro-1H-pyrrolo[3,2-c]quinoline-2-carboxylate skeleton were prepared by microwave-assisted intramolecular 1,3-dipolar cycloaddition reactions. The reactions were carried out under solvent-free conditions and compared with the same reaction in the presence of a solvent and a catalyst. Steric effects on the selectivity of the reaction were noted and evaluated.     

Expedient synthesis of highly substituted fused heterocoumarins

[reaction: see text] Highly substituted fused coumarins can be prepared in two steps starting from the appropriate boronic acids and enol triflates. The synthesis of fused pyrano[2,3-d]pyrimidin-7-one (1) is a key example to demonstrate the potential of the method in the elaboration of new coumarin scaffolds.     

The synthesis of annelated 3-cyano-2-pyridones

Annelated tricyclic 3-cyano-2-pyridones were synthesized from cyanoacetamide adducts using a thermal cyclization process which had previously been reported to afford an annelated pyrimidone product.     

Synthesis of substituted 4-pyridones and 4-aminopyridinium salts via a one-pot pyridine synthesis

Synthesis of substituted 4-benzyloxypyridinium salts by the addition of Grignard reagents to pyridine N-oxides provides an efficient route for obtaining substituted 4-pyridones or 4-aminopyridinium salts.     

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.     

Microwave-assisted synthesis of highly functionalized guanidines on soluble polymer support

An efficient method for the N,N′-di(Boc)-protected guanidines containing piperazine and homopiperazine scaffolds has been developed under multi-step microwave irradiation. Followed by alkylation of carbamate-protected guanidines with various alkyl halides is also explored. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine by sodium hydride on soluble polymer support. In this manner, highly functionalized guanidines were obtained after cleavage from the support. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine components. In addition, the reaction is sufficiently simple workup by precipitation in each step to yield the substituted guanidines in high purity. In conjunction with microwave irradiation and soluble polymer support, this method provides an efficient route to access highly functionalized guanidines.     

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 rapid divergent synthesis of highly substituted delta-lactones

[reaction: see text] Nucleophilic 1,2-addition of (Z)-gamma-silyloxyvinylzinc reagents to ethyl glyoxylate followed by desilylation and cyclization affords 3,6-dihydro-3-hydroxypyran-2-ones in good chemical yields. In situ formation of allylic phosphates followed by reaction with RCu(CN)Li reagents affords substituted 5,6-dihydropyran-2-ones. The parent compound, 3,6-dihydro-3-hydroxypyran-2-one, undergoes allylic phosphate formation, cuprate-mediated allylic substitution, and 1,4-conjugate addition to afford trans-4,5-disubstituted tetrahydropyran-2-ones in a one-pot process.     

Regioselective and diastereoselective synthesis of highly substituted cyclopentanes

Highly substituted cyclopentane rings are present in a wide range of targets, and the efficient synthesis of such compounds constitutes a continuing challenge to organic synthesis. We present two complementary approaches to the regio- and diastereoselective synthesis of highly substituted cyclopentane structures. In both cases, a non-symmetrically disposed norbornene is employed as a common intermediate. One strategy relies on the Lewis acid-catalyzed ring opening of an anhydride, while the other employs production of a bicyclic lactone followed by its selective functionalization.