The Reaction of Fenchone and Camphor Hydrazones with 5-Acyl-4-Pyrones as a Method for the Synthesis of New Polycarbonyl Conjugates: Tautomeric Equilibrium and Antiviral Activity.

Selective synthesis of polycarbonyl conjugates of (+)-fenchone and (+)-camphor was carried out (44-91 % yields) via the ring-opening transformation of 5-acyl-4-pyrones with hydrazones of the corresponding monoterpenoids. A strong influence of the hydrazone fragment on the observed tautomeric equilibrium of the tricarbonyl system was shown. Although the major tautomer of the conjugates is the acyclic polycarbonyl form, the camphor-based conjugates undergo new type of ring-chain tautomerism, diketoenaminone-dihydropyridone equilibrium, and predominantly exist in the cyclic dihydropyridone form in DMSO-d.

Tunable Approach to Diverse Phenethylamines via Reduction of 5-Aryloxazolidines with Triethylsilane.

A rapid pathway for the synthesis of various β-phenethylamines from aromatic aldehydes has been developed. Initially, a wide range of 5-aryloxazolidines was prepared via the [3 + 2] cycloaddition reaction of -methylazomethine ylide derived from sarcosine and paraformaldehyde. The subsequent reduction of 5-aryloxazolidines with triethylsilane in trifluoroacetic acid yields three types of products: ,-dimethylphenylethanolamines, ,-dimethylphenethylamines, and tetrahydroisoquinolines, depending on the substituents in the aromatic ring and reaction conditions.

Tunable Zinc-Mediated Reductive Cyclization of Diastereomeric 3-Nitro-4-phenacyl-2-(trihalomethyl)chromanes to Fused Pyrroline -Oxides, Pyrrolines, and Pyrrolidines.

Reductive cyclization of trans,trans- and trans,cis-isomers of the 2-CF-substituted 3-nitro-4-phenacylchromanes with Zn-based reductive systems, depending on the conditions, affords 4-CF-substituted 1,3a,4,9b-tetrahydrochromeno[3,4-]pyrrole 3-oxides, 1,3a,4,9b-tetrahydrochromeno[3,4-]pyrroles, or 1,2,3,3a,4,9b-hexahydrochromeno[3,4-]pyrroles in good yields without changing the relative configuration of the pyran ring. A similar process involving the 2-CCl-substituted 3-nitro-4-phenacylchromanes is accompanied by reductive dehalogenation to form the corresponding 4-dichloromethyl-substituted fused chromanes along with the 3-(2-hydroxyaryl)-2-(2,2-dichlorovinyl)-5-phenyl-2-pyrroline 1-oxides as pyran ring opening products. The structure and relative configuration of the obtained products was reliably confirmed by X-ray diffraction analysis and 2D NMR spectroscopy.

Oxidative Ring-Opening Transformation of 5-Acyl-4-pyrones as an Approach for the Tunable Synthesis of Hydroxylated Pyrones and Furans.

A selective and tunable approach for oxidation of 4-pyrones has been developed ring-opening transformations leading to various hydroxylated oxaheterocycles. The first step of the strategy includes the base-catalyzed epoxidation of 5-acyl-4-pyrones in the presence of hydrogen peroxide for the effective synthesis of pyrone epoxides in high yields. The epoxides bearing the COEt group are reactive molecules that can undergo both pyrone and oxirane ring-opening deformylation to produce hydroxylated 2-pyrones or 4-pyrones.

The Construction of Polycyclic Pyridones via Ring-Opening Transformations of 3-hydroxy-3,4-dihydropyrido[2,1-][1,4]oxazine-1,8-diones.

This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-][1,4]oxazine-1,8-diones, their tautomerism, and reactivity towards binucleophiles. These molecules are novel and convenient building-blocks for the direct construction of biologically important polycyclic pyridones via an oxazinone ring-opening transformation promoted with ammonium acetate or acetic acid. In the case of -phenylenediamine, partial aromatization of the obtained heterocycles proceeded to form polycyclic benzimidazole-fused pyridones (33-91%).

2-(2-(Dimethylamino)vinyl)-4-pyran-4-ones as Novel and Convenient Building-Blocks for the Synthesis of Conjugated 4-Pyrone Derivatives.

A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring opening. This strategy includes selective transformations leading to conjugated and isoxazolyl-substituted 4-pyrone structures.

Different Behavior of 2-Substituted 3-Nitro-2-chromenes in the Reaction with Stabilized Azomethine Ylides Generated from α-Iminoesters.

The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2-chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of and ' isomers of the corresponding chromeno[3,4-]pyrrolidines in a ratio of 2.0-2.3:1 in 85-93% total yields as a result of a Michael addition/Mannich reaction sequence.

A novel strategy for the functionalization and design of 4-methylene-4-pyran merocyanines enamination and 1,8-conjugate addition.

4-Methylene-4-pyrans are popular merocyanine dyes, but their functionalization is limited by the Knoevenagel condensation with aromatic aldehydes. In this work, we developed a novel approach for the construction of a new class of pyran fluorophores based on enamination and subsequent nucleophilic substitution of the dimethylamino group 1,8-conjugate addition/elimination. This methodology includes selective transformations leading to previously unknown symmetrical and asymmetrical structures.

Green and Efficient Construction of Chromeno[3,4-]pyrrole Core via Barton-Zard Reaction from 3-Nitro-2-chromenes and Ethyl Isocyanoacetate.

A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene[3,4-]pyrroles in 63-94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or 2-phenyl-2-(trifluoromethyl)-3-nitro-2-chromenes and ethyl isocyanoacetate through the Barton-Zard reaction in ethanol at reflux for 0.5 h, using KCO as a base, has been developed.

Reactions of Trifluorotriacetic Acid Lactone and Hexafluorodehydroacetic Acid with Amines: Synthesis of Trifluoromethylated 4-Pyridones and Aminoenones.

Dehydroacetic acid and triacetic acid lactone are known to be versatile substrates for the synthesis of a variety of azaheterocycles. However, their fluorinated analogs were poorly described in the literature. In the present work, we have investigated reactions of trifluorotriacetic acid lactone and hexafluorodehydroacetic acid with primary amines, phenylenediamine, and phenylhydrazine.

5-Aryloxazolidines as Reagents for Double Alkylation of Arenes: A Novel Synthesis of 4-Aryltetrahydroisoquinolines.

5-Aryloxazolidines react with arenes under Lewis or Brønsted acid conditions via the Friedel-Crafts/Pictet-Spengler double alkylation sequence to give alkaloid-like 4-aryltetrahydroisoquinolines in 12-94% yields. Three approaches for the controlled insertion of substituents into the target molecules and application of oxazolidine derivatives such as 1-arylethanol-2-amines or 4-hydroxytetrahydroisoquinolines in the alkylation of arenes are also described. An unprecedented two-step easily scalable synthesis of the 4-aryltetrahydroisoquinoline core from aromatic aldehyde was achieved applying oxazolidine methodology.

2-Aryl-6-Polyfluoroalkyl-4-Pyrones as Promising R-Building-Blocks: Synthesis and Application for Construction of Fluorinated Azaheterocycles.

A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of oxidative cyclization of ()-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehydrobromination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were characterized.

2,6-Dicyano-4-pyrone as a Novel and Multifarious Building Block for the Synthesis of 2,6-Bis(hetaryl)-4-pyrones and 2,6-Bis(hetaryl)-4-pyridinols.

In this work, a three-stage and easily scalable synthesis of 2,6-dicyano-4-pyrone (overall yield of 45%) as a new convenient building block has been developed from diethyl acetonedioxalate. It was shown that the transformation with hydroxylamine and [3 + 2]-cycloaddition, in contrast to the reactions with hydrazines, selectively proceed through the attack at the cyano groups without the pyrone ring-opening to give symmetrical and unsymmetrical pyrone-bearing heterocyclic triads containing 1,2,4- and 1,3,4-oxadiazoles as well as tetrazole moieties. The reaction of 2,6-bis(hetaryl)-4-pyrones with ammonia afforded 2,6-bis(hetaryl)pyridines in 63-87% yields.

Catalyst-free Tandem 1,3-Dipolar Cycloaddition/Aldol Condensation: Diastereoselective Construction of the Azatetraquinane Skeleton.

The one-pot regioselective and diastereoselective method for the synthesis of 5-(het)aroyl-7-(het)arylhexahydrobenzo[4,5]pentaleno[1,6-](thia)pyrrolizine-6,12-diones from accessible 1,5-di(het)arylpent-4-ene-1,3-diones or curcuminoids in 38-98% yield was developed. This reaction proceeds as a sequence of 1,3-dipolar cycloaddition of azomethine ylide generated from ninhydrin and (thia)proline at the C═C bond of corresponding enedione, followed by spontaneous intramolecular aldol condensation and leads to the formation of an azatetraquinane scaffold.

Synthesis of 6,12-Methanodibenzo[,]azocines and 4-Aryltetrahydroisoquinolines from Aromatic Aldehydes.

A methodology for the synthesis of 7,12-dihydro-5-6,12-methanodibenzo[,]azocines from aromatic aldehydes and -(methoxymethyl)--(trimethylsilylmethyl)benzylamine using catalysis by trifluoroacetic and perchloric acids is described. The developed protocol was applied for the synthesis of -unsubstituted and -methyl-4-aryltetrahydroisoquinolines.

Self-Condensation of Enaminodiones as a Method for Benzene Ring Construction: Synthesis of Diacyl-Substituted Phenols and Catechols.

A novel transition metal-free approach for the construction of the benzene core has been developed through self-condensation of available enaminodiones. Functionalized acyl-substituted phenols and catechols were obtained in 29-97% yields with high chemoselectivity under mild conditions. This base-promoted formal [4+2] annulation proceeds via cyclohexanone formation and involves the cascade transformation based on double Michael addition and aromatization (retro-Claisen cleavage and amine elimination).

Synthesis of Multifunctionalized 2,3-Dihydro-4-pyridones and 4-Pyridones via the Reaction of Carbamoylated Enaminones with Aldehydes.

The novel and effective diastereoselective synthesis of multifunctionalized dihydropyridones, including CF-substituted derivatives, has been developed on the basis of the piperidine-promoted domino reaction of carbamoylated enaminones with aldehydes. The products have been prepared in 38-90% yields and can be easily isolated by crystallization. Tautomerism, epimerization, and atropisomerism of dihydropyridones have been studied.

Nonstabilized Azomethine Ylides in the Mannich Reaction: Synthesis of 3,3-Disubstituted Pyrrolidines, Including Oxindole Alkaloids.

Active methylene compounds react with in situ generated nonstabilized azomethine ylides via the domino Mannich reaction-dipolar cycloaddition to form 3,3-disubstituted pyrrolidines, including oxindole alkaloids. When the starting material possesses a single activated hydrogen, the reaction terminates at the Mannich base stage. The developed methodology was applied to a short and efficient synthesis of (±)-horsfiline and N-protected (±)-coerulescine.

Synthesis of Diketohexenoic Acid Derivatives by Alkenylation of Indoles and Pyrroles with 4-Pyrones.

A new synthesis of functionalized (Z)-6-hetaryl-2,4-dioxo-5-hexenoic acids based on acid-catalyzed alkenylation of indoles and pyrroles with derivatives of 5-substituted 4-pyrone-2-carboxylic acid in 37-82% yields has been developed. Coupling between isochelidonic acid and indoles followed by decarboxylation afforded biologically important (E)-6-indolyl-2,4-dioxo-5-hexenoic acids. These ring-opening reactions proceed with high regioselectivity through nucleophilic attack at the C-6 position of the pyrone ring.

Reagents for Storage and Regeneration of Nonstabilized Azomethine Ylides: Spiroanthraceneoxazolidines.

Nonstabilized azomethine ylides are easily trapped by anthraquinone to form stable spiro-oxazolidines, which have an unusual ability to undergo a cycloreversion in the presence of other dipolarophiles at 120-150 °C. All tested recycloadditions with carbonyl compounds and electron-poor alkenes occurred in moderate to high yields (41-92%). Moreover, increasing the reaction temperature to 210 °C made it possible to obtain adducts with low reactive dipolarophiles.

Synthesis of functionalized 2-salicyloylfurans, furo[3,2-b]chromen-9-ones and 2-benzoyl-8H-thieno[2,3-b]indoles by one-pot cyclizations of 3-halochromones with β-ketoamides and 1,3-dihydroindole-2-thiones.

Functionalized 2-salicyloylfurans and 2-benzoyl-8H-thieno[2,3-b]indoles were prepared under mild conditions by reaction of 3-halochromones with β-ketoamides and 1,3-dihydroindole-2-thiones, correspondently. The subsequent oxidative cyclization of the products resulted in formation of the corresponding furo[3,2-b]chromen-9-ones. These molecules could also be directly prepared from 3-halochromones using a one-pot protocol.

Synthesis and reactivity of 5-polyfluoroalkyl-5-deazaalloxazines.

Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, acetophenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives in good to excellent yields.

Reactions of 3-acylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone: one-pot synthesis of functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins.

Reactions of 3-methoxalyl-, 3-polyfluoroacyl- and 3-aroylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone in the presence of DBU proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent formal [3 + 3] cyclocondensation to functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins, depending on the substituent at the 3-position. An NMR study and X-ray crystallographic analysis are reported. The compounds synthesized can be considered as promising scaffolds for the design of the novel UV-A/B and UV-B filters.

One-pot, three-component synthesis of 7-azaindole derivatives from N-substituted 2-amino-4-cyanopyrroles, various aldehydes, and active methylene compounds.

An efficient and practical route to 7-azaindole framework has been developed by one-pot, three-component cyclocondensation of N-substituted 2-amino-4-cyanopyrroles, various aldehydes, and active methylene compounds in ethanol or acetic acid at reflux. Reactions involving tetronic acid, indane-1,3-dione, dimedone, and 5-phenylcyclohexane-1,3-dione gave carbocyclic fused 7-azaindoles, whereas Meldrum's acid, benzoylacetonitrile, and malononitrile resulted in the highly substituted 7-azaindole derivatives, making this strategy very useful in diversity-oriented synthesis (DOS).

2,3-unsubstituted chromones and their enaminone precursors as versatile reagents for the synthesis of fused pyridines.

A divergent and regioselective approach to fused pyridines was developed through formal [3 + 3] cyclocondensations from simple 2,3-unsubstituted chromones or their enaminone precursors.