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

A rapid pathway for the synthesis of various ß-phenethylamines from aromatic aldehydes has been developed. Initially, a wide range of 5-aryloxazolidines was prepared via the [3 + 2] cycloaddition reaction of N-methylazomethine ylide derived from sarcosine and paraformaldehyde. The subsequent reduction of 5-aryloxazolidines with triethylsilane in trifluoroacetic acid yields three types of products: N,N-dimethylphenylethanolamines, N,N-dimethylphenethylamines, and tetrahydroisoquinolines, depending on the substituents in the aromatic ring and reaction conditions. Moreover, an additional step of oxazolidine hydrolysis or ring-opening with hydrogen cyanide allowed us to synthesize N-methyl- or N-methyl-N-(cyanomethyl)phenethylamines.

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

Reductive cyclization of trans,trans- and trans,cis-isomers of the 2-CF3-substituted 3-nitro-4-phenacylchromanes with Zn-based reductive systems, depending on the conditions, affords 4-CF3-substituted 1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole 3-oxides, 1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrroles, or 1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrroles in good yields without changing the relative configuration of the pyran ring. A similar process involving the 2-CCl3-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-2H-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.

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-d6. The polyketones can undergo intramolecular cyclization to form N-amino-4-pyridones in high selectivity. In vitro screening for activity against the influenza virus H1 N1 and vaccinia virus was estimated for the obtained conjugates. The (+)-fenchone derivatives demonstrated the higher activity against vaccinia virus than camphor derivatives. The conjugate, which was prepared from diethyl isochelidonate and hydrazone (+)-fenchone, showed the highest activity against vaccinia virus (SI=17).

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 via 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 CO2Et group are reactive molecules that can undergo both pyrone and oxirane ring-opening via deformylation to produce hydroxylated 2-pyrones or 4-pyrones. The acid-promoted transformation led to 3-hydroxy-4-pyrones (24-76% yields), whereas the K2CO3-catalyzed ring-opening process of 2-carbethoxy-4-pyrone epoxides proceeded as an attack of alcohol at the C-3 position bearing the CO2Et group to give functionalized 6-acyl-5-hydroxy-2-pyrones (27-87% yields). The base-catalyzed reaction of 2-aryl-4-pyrone epoxides was followed by ring contraction and the dearoylation process to produce 3-hydroxyfuran-2-carbaldehydes in 42-80% yields. The transformation of 3-aroylchromone epoxides led to flavonols and 3-hydroxybenzofuran-2-carbaldehyde in the acidic and basic conditions, respectively. The prepared hydroxylated heterocycles demonstrated high reactivity for further transformations and low cytotoxicity and are promising fluorophores or UV filters.

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

4-Methylene-4H-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 via 1,8-conjugate addition/elimination. This methodology includes selective transformations leading to previously unknown symmetrical and asymmetrical structures. The dimethylaminovinyl-substituted pyrans are reactive intermediates and can be considered as a convenient synthetic tool for the construction of new merocyanines with tunable fluorescence (417-628 nm). The main strategies for the modification of the pyran moiety have been determined for the construction and targeted design of fluorophores. Pyrans bearing two enamine moieties demonstrate significant light extinction coefficients (up to 116 000 M-1 cm-1), high quantum yields (up to 69%) and large Stokes shifts (up to 152 nm) because of their strong push-pull nature. Density Functional Theory (DFT) calculations were performed for the explanation of the structural and photophysical features of the prepared merocyanines. The developed approach can be considered as a useful platform for further application of 4-methylene-4H-pyrans as promising fluorophores for sensors and solar cells, and in bioimaging.

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

This work describes the synthesis of 3-hydroxy-3,4-dihydropyrido[2,1-c][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 o-phenylenediamine, partial aromatization of the obtained heterocycles proceeded to form polycyclic benzimidazole-fused pyridones (33-91%).

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. While hexafluorodehydroacetic acid reacted the same way as non-fluorinated analog giving 2,6-bis(trifluoromethyl)-4-pyridones, trifluorotriacetic acid lactone had different regioselectivity of nucleophilic attack compared to the parent structure, and corresponding 3-amino-6,6,6-trifluoro-5-oxohex-3-eneamides were formed as the products. In the case of binucleophiles, further cyclization took place, forming corresponding benzodiazepine and pyrazoles. The obtained 2,6-bis(trifluoromethyl)-4-pyridones were able to react with active methylene compounds giving fluorinated merocyanine dyes.

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

A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene[3,4-c]pyrroles in 63-94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or 2-phenyl-2-(trifluoromethyl)-3-nitro-2H-chromenes and ethyl isocyanoacetate through the Barton-Zard reaction in ethanol at reflux for 0.5 h, using K2CO3 as a base, has been developed.

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

The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2H-chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of endo and endo' isomers of the corresponding chromeno[3,4-c]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. In a similar reaction involving 2-trifluoromethyl-3-nitro-2H-chromenes, only endo chromeno[3,4-c]pyrrolidines are formed in 85-94% yields. 3-Nitro-2-(trichloromethyl)-2H-chromenes under the same conditions react with these azomethine ylides to give the corresponding Michael adducts as individual anti-isomers with the cis,trans-configuration of the chromane ring in 40-67% yields. Some 4-CF3-substituted chromano[3,4-c]pyrrolidines exhibited high cytotoxic activity against HeLa human cervical carcinoma cells.

2-(2-(Dimethylamino)vinyl)-4H-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. The photophysical properties of the prepared 4-pyrones were determined in view of further design of novel merocyanine fluorophores. A solvatochromism was found for enamino-substituted 4-pyrones accompanied by a strong increase in fluorescence intensity in alcohols. The prepared conjugated structures demonstrated valuable photophysical properties, such as a large Stokes shift (up to 204 nm) and a good quantum yield (up to 28%).

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 RF-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 one-pot oxidative cyclization of (E)-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. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of biologically important CF3-bearing azaheterocycles, such as pyrazoles, pyridones, and triazoles.

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[1,6a-b](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 in situ 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.

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 CF3-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. The use of the resulting dihydropyridones in the synthesis of 1,2,6-trisubstituted 4-pyridone-3-carboxamides has been demonstrated via oxidative aromatization initiated by iodine.

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. Reactions of ethyl 6-indolyl-2,4-dioxo-5-hexenoate with nucleophiles are useful for the production of different ß-(indolyl)vinyl-containing azaheterocycles.

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

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

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. The 4-pyridone/4-pyridinol tautomerism of 2,6-bis(hetaryl)pyridinols and the influence of the nature of adjacent azolyl moieties on this equilibrium have been discussed.

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.