Leonid L. Fershtat

Efficient assembly of mono- and bis(1,2,4-oxadiazol-3-yl)furoxan scaffolds via tandem reactions of furoxanylamidoximes

A general, facile, highly effective one-pot protocol for the synthesis of new types of heterocyclic systems incorporating mono- and bis(1,2,4-oxadiazol-3-yl)furoxan cores based on the tandem heterocyclization of furoxanylamidoximes with various aliphatic, aromatic, and heterocyclic carboxylic acid chlorides under very mild conditions (Cs2CO3, MeCN, 20 °C) has been developed. In addition, a solvent-free approach for the (1,2,4-oxadiazol-3-yl)furoxan synthesis by the reaction of furoxanylamidoximes with trimethyl orthoformate catalyzed by Sc(OTf)3 has been achieved. The advantages of step economy and scope make these reactions a powerful tool for assembling heterocyclic scaffolds of general chemistry and biomedical interest.

Synthesis of hetarylsulfanyl- and hetaryloxyfuroxans by nucleophilic substitution of nitro group in nitrofuroxans with heterocyclic thiol and hydroxy derivatives*

We report a general method for the synthesis of previously unknown heterocyclic systems containing furoxan and heterocyclic fragments linked by S- and О-bridges, based on nucleophilic substitution of nitro group in 4-nitrofuroxans with HetS and HetO groups introduced by reactions with hetarylthiols and hydroxy heterocycles in 1,8-diazabicyclo[5.4.0]undec-7-ene/МеCN system at room temperature. We showed that hetarylthiols reacted with 4-nitrofuroxans containing aliphatic, benzyl, and aromatic substituents at the ring С-3 atom, allowing to obtain a library of previously unknown hetarylsulfanylfuroxans, while the reaction with hydroxy heterocycles was successful only in the case of 4-nitro-3-phenylfuroxan, the rest of the nitrofuroxans showing low reactivity, and substitution products could be obtained only in certain cases. 4-Nitrofuroxans with electron-withdrawing substituents (NO2, CONH2) acted as oxidants, forming 1,2-di(hetaryl)disulfides.

Design of hybrid heterocyclic systems with a furoxanylpyridine core via tandem hetero-Diels–Alder/retro-Diels–Alder reactions of (1,2,4-triazin-3-yl)furoxans

Two convenient, facile, regioselective and highly effective one-pot protocols for the synthesis of previously unknown hybrid heterocyclic systems with the furoxanylpyridine core based on the tandem inverse-electron-demand hetero-Diels–Alder/retro-Diels–Alder reactions of the tailor-made (1,2,4-triazin-3-yl)furoxans with 1-(pyrrolidino)cyclohexene and norbornadiene have been developed. The methods comprise [4 + 2] cycloaddition of enamine or norbornadiene to the 1,2,4-triazine ring of (1,2,4-triazin-3-yl)furoxans followed by one-pot transformation of the formed intermediates and this affords an extensive series of polyheterocyclic ensembles combining furoxan and pyridine (tetrahydroisoquinoline, indenopyridine, terpyridine) rings in one molecule through a C–C bond in good to excellent yields.

An effective synthesis of (1Н-1,2,4-triazol-3-yl)furoxans

A general, simple, and effective method has been developed for the preparation of previously practically unknown (5-R-1Н-1,2,4-triazol-3-yl)furoxans with various substituents at the other carbon atom of furoxan ring, based on condensation of furoxanylamidrazones with electrophilic reagents (cyanogen bromide, acetic and trifluoroacetic anhydrides).

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

The molecular hybridization of different compounds with known pharmacological activity is a particularly prominent approach for the design of potential drugs with improved pharmacokinetic profiles. Much attention over the last decade has been focused on the synthesis of hybrid structures with a nitric oxide (NO)‐donor framework, as NO is a ubiquitous and crucial regulator of cellular metabolism, affecting various physiological and pathophysiological processes. 1,2,5‐Oxadiazole 2‐oxides (furoxans), which are capable of exogenous NO release in the presence of thiol cofactors, are an important class of prospective NO donors. As such, a wide range of hybrid compounds that combine a furoxan ring with various pharmacologically active structures have been created. This review focuses on recent results in the synthesis and pharmacological activity of furoxan‐based hybrids. Special attention is given to chemo‐ and regioselective methods used in the preparation of these hybrid structures, and the role of synergistic effects on their pharmacological activity, associated with the furoxan fragment.

Dinitrofuroxan cycloreversion as a novel general approach for the synthesis of nitroazoles

A novel general approach towards various nitroazoles via tandem process involving dinitrofuroxan cycloreversion followed by [3+2] cycloaddition of generated in situ nitroformonitrile oxide is developed. The reaction is promoted by addition of catalytic amounts of ionic liquids. Plausible mechanisms of the described processes based on quantum chemical calculations are proposed.

Effective synthesis of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines

A highly effective method for the preparation of 7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines was developed on the basis of condensation reaction between aryl(hetaryl) α-bromo ketones and commercially available thiocarbohydrazide, followed by treatment of the obtained 2-hydrazinyl-6H-1,3,4-thiadiazine hydrobromides with ortho esters in the presence of trifluoroacetic acid under mild conditions.