Divergent Transformations of 2-Nitro-1H-benzo[f]chromenes in Reactions with Alkylidenemalononitriles: Access to Naphtho[2,1-b]furans via Base-Mediated Pyran Ring Contraction.

The action of 2-(1-arylethylidene)malononitriles on 2-nitro-1H-benzo[f]chromenes in the presence of Et3N and MoO3·2H2O results in naphtho[2,1-b]furans containing an allylidenemalononitrile unit in the α-position. The reaction proceeds with contraction of the pyran ring via a cascade carba-Michael addition/retro-oxa-Michael reaction/tautomerization/SN2/oxidation process. In contrast, the reaction of 2-nitro-1H-benzo[f]chromenes with the cyclic Knoevenagel adduct derived from 1-indanone and malononitrile leads to dihydroindeno[1,2-c]xanthenes. The possibility of further transformations of naphtho[2,1-b]furan derivatives as useful precursors and their optical properties were also investigated.

Catalyst-free formal [3 + 2] cycloaddition of stabilized N,N-cyclic azomethine imines to 3-nitrobenzofurans and 3-nitro-4H-chromenes: access to heteroannulated pyrazolo[1,2-a]pyrazoles.

We have studied the [3 + 2]-cycloaddition of various N,N-cyclic azomethine imines to 3-nitrobenzofurans. This process is a rare example of their dearomatization. We have also extended this process to the related 3-nitro-4H-chromenes as dipolarophiles. Both reactions provide access to benzofuro- and chromeno-condensed pyrazolo[1,2-a]pyrazoles with 100% atom economy in a diastereoselective manner under mild eco-friendly conditions. Finally, on the basis of DFT calculations, the mechanistic insights into the mentioned [3 + 2]-cycloadditions and explanations of the experimentally determined limitations of the method are given. Hirshfeld atomic charge values of push-pull heterocycles were suggested as a criterion for a priori assessment of the possibility of their dipolar cycloaddition with N,N-cyclic azomethine imines.

Three-Component Condensation of Pyridinium Ylides, ß-Ketonitriles, and Aldehydes with Divergent Regioselectivity: Synthesis of 4,5-Dihydrofuran-3- and 2H-Pyran-5-carbonitriles.

A library of trans-4,5-dihydrofuran-3-carbonitriles was synthesized in a diastereoselective manner in good yields by the three-component reaction of ß-ketonitriles, carbonyl- and semistabilized pyridinium ylide precursors, and aldehydes in the presence of piperidine. This one-pot transformation generates two C-C and one C-O bond and proceeds through a cascade Knoevenagel condensation, a Michael addition, and intramolecular SN2 cyclization. Formation of cyclopropanecarbonitrile derivatives, which in some cases were obtained as major products, was found to be a competing reaction. The use of arylglyoxals changes regioselectivity and leads to 2-hydroxy-2H-pyran-5-carbonitriles.

Eco-friendly synthesis of fused pyrano[2,3-b]pyrans via ammonium acetate-mediated formal oxa-[3 + 3]cycloaddition of 4H-chromene-3-carbaldehydes and cyclic 1,3-dicarbonyl compounds.

Various substituted polycyclic pyrano[2,3-b]pyrans were synthesized via the condensation of 4H-chromene-3-carbaldehydes and their areno-condensed analogues with hetero- and carbocyclic 1,3-dicarbonyl compounds in acetic acid. Ammonium acetate was used as a green catalyst for the reaction. The process also involves the subsequent Knoevenagel condensation and 6π-electrocyclization of the 1-oxatriene intermediates formed. Fused pyridines were isolated as the products of the conjugated addition of ammonia to 1-oxatriene intermediates while using carbocyclic 1,3-dicarbonyl compounds and increasing the reaction time, indicating the reversibility of the electrocyclization stage. The calculated values of the Gibbs free energies and reaction rate constants for the 1-oxatriene - 2H-pyran equilibrium also testified to the irreversibility of pyrano[2,3-b]pyran formation in the case of using of heterocyclic 1,3-dicarbonyl compounds.

Synthesis, in vitro and in vivo evaluation of 2-aryl-4H-chromene and 3-aryl-1H-benzo[f]chromene derivatives as novel α-glucosidase inhibitors.

Herein we report a study of novel arylchromene derivatives as analogs of naturally occurring flavonoids with prominent α-glucosidase inhibitory properties. Novel inhibitors were identified via simple stepwise in silico screening, efficient synthesis, and biological evaluation. It is shown that 2-aryl-4H-chromene core retains pharmacophore properties while being readily available synthetically. A lead compound identified through screening inhibits yeast α-glucosidase with IC50 of 62.26 µM and prevents postprandial hyperglycemia in rats at 2.2 mg/kg dose.

An Inverse Electron Demand Azo-Diels-Alder Reaction of o-Quinone Methides and Imino Ethers: Synthesis of Benzocondensed 1,3-Oxazines.

We have studied the reactions of o-quinone methide precursors with imino ethers. The reaction provides a versatile route to substituted 1,3-benzoxazines. The proposed reaction mechanism involves the generation of the o-quinone methide intermediates, imino-Diels-Alder reaction, and elimination. This cascade process is a rare example of the participation of imino ethers as dienophiles.

Synthesis and biological evaluation of 2-acylbenzofuranes as novel α-glucosidase inhibitors with hypoglycemic activity.

A series of benzofuran derivatives was synthesized as analogues of known natural α-glucosidase inhibitors. Their activity was evaluated in enzymatic assay and in rat model of diabetes mellitus. Newly identified inhibitors demonstrate significant potency with IC50 values ranging from 6.50 to 722.2 µm, as well as hypoglycemic activity exceeding the reference drug acarbose. Docking simulations provided insight into structure-activity relationships to direct further development of these novel hypoglycemic agents.

Reaction of Push-Pull Enaminoketones and in Situ Generated ortho-Quinone Methides: Synthesis of 3-Acyl-4H-chromenes and 2-Acyl-1H-benzo[f]chromenes as Precursors for Hydroxybenzylated Heterocycles.

A simple and efficient method for the synthesis of 4H-chromenes and 1H-benzo[f]chromenes containing a trifluoroacetyl or aroyl group in the pyran ring from o-quinone methide precursors and push-pull enaminoketones has been developed. The chromenes are presumably formed through an initial oxa-Diels-Alder reaction, followed by an elimination of amine. The possibility of further transformations of given chromenes to o-hydroxybenzylated pyrazoles, isoxazoles, and pyridines has been demonstrated.

Potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent: access to 2-nitroarenofurans.

The first example of the use of potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine has been developed. The method tolerates a variety of functional groups on the starting quaternary ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of an o-quinone methide intermediate is postulated as a key to the mechanism of this cascade process.

Reactions of o-quinone methides with pyridinium methylides: a diastereoselective synthesis of 1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans.

A simple, general route to the 1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans substituted at C-2 by an acyl or aryl group, starting from phenolic Mannich bases and pyridinium ylides, has been developed. The mechanism of the reaction is believed to involve the formation of the o-quinone methide intermediate, Michael-type addition of the ylide to the o-quinone methide, followed by intramolecular nucleophilic substitution.

2-(4-Meth-oxy-phen-yl)-4H-1,3,2-benzoxathia-phosphinine 2-sulfide.

The asymmetric unit of the title compound, C(14)H(13)O(2)PS(2), contains two crystallographically independent mol-ecules, which differ in the conformation of the 1,3,2-benzoxathia-phosphinine moieties (screw boat in the first mol-ecule and envelope in the second mol-ecule). In the crystal, neither classical nor non-classical hydrogen bonds are found. Weak inter-actions (about 2.9-3.0 Å) between the lone pair of the terminal S atoms with H atoms occur. This compound was further characterized by (1)H NMR and IR spectroscopy.