S. V. Kurbatov

Super-electrophilic 10π Heteroaromatics. New Mechanistic and Synthetic Applications

Nucleophilic aromatic substitutions (SNAr reactions) together with the formation of the related σ-anionic adducts are reactions of great importance in organic synthesis. 1 – 4 Scheme 1 describes a ...

The Stepwise Diels–Alder Reaction of 4-Nitrobenzodifuroxan with Danishefsky’s Diene

The Diels-Alder reaction of 4-nitrobenzodifuroxan (NBDF) with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene has been investigated experimentally and theoretically. Treatment of NBDF with excess diene in chloroform at room temperature was found to afford a single product that contained a carbonyl functionality. Based on an X-ray structure and NMR spectroscopic data, the product appeared to be a result of the hydrolysis of the OSiMe(3) moiety of the thermodynamically more stable endo [2+4] cycloadduct, characterized by a cis arrangement of the MeO and NO(2) functionalities. In situ NMR investigations of the interaction were carried out at room temperature in CDCl(3) and at -40 °C in deuterated acetonitrile. Calculations at the B3LYP/6-31G* level in the gas phase and in acetonitrile were carried out under the assumption that the most stable cis conformation of the diene is also the most reactive in the interaction. The analysis revealed the NBDF/cis diene interaction involves the formation of a zwitterionic intermediate. Importantly, this intermediate is formed in two preferred conformations, which correspond to the endo and exo modes of approach of the reagents. Cyclization of these two identified conformations afforded the experimentally characterized endo and exo [2+4] cycloadducts. According to the calculations, the interconversion of the two conformers can either take place through a return to the pre-reaction complexes or it can occur by rotation through an intermediate conformation of lesser stability. In view of the stepwise character of the interaction, the possibility that the intermediate zwitterion is the result of the interaction between NBDF and the trans diene could not be excluded. Calculations carried out with the most stable and more populated s-trans conformer confirmed this idea and supported the role of the zwitterion in the overall interaction.

Synthesis and structures of spiro-σ-complexes based on 2-(2-benzylaminophenyl)-5,6-dimethylbenzimidazole

The reactions of 2-(2-benzylaminophenyl)-5,6-dimethylbenzimidazole with electrophilic 8-chloro-5,7-dinitroquinoline and 7-chloro-4,6-dinitrobenzofuroxan afforded two new bipolar spiro-σ-complexes. The structure of the complex prepared by the latter reaction was established by X-ray diffraction analysis. The activation parameters of the stereodynamic rearrangement of quinoline spirane were determined by dynamic NMR spectroscopy.

Synthesis and biological properties of nitrobenzoxadiazole derivatives as potential nitrogen(ii) oxide donors: SOX induction, toxicity, genotoxicity, and DNA protective activity in experiments using Escherichia coli-based lux biosensors

Dihetaryls containing superelectrophilic and π-excessive heterocycles were synthesized by the nucleophilic aromatic substitution and cycloaddition. The structures of the compounds and the mechanism of 1,3-N-oxide tautomerism were studied by NMR spectroscopy, X-ray diffraction, and quantum chemical methods. The ability of these compounds to initiate SOX induction, which is probably due to the in vivo generation of nitrogen(ii) oxide, was quantified using genetically engineered E. coli-based lux biosensors. 7-(1-Methylpyrrol-3-yl)-4,6-dinitrobenzofuroxan is the most active inducer, which is an order of magnitude more effective than nitroglycerin used as the reference compound. The absence of toxicity was established using the E. coli MG 1655 biosensor (pXen7-lux). The DNA protective effect of this leading compound was confirmed using the E. coli MG 1655 biosensor (pRecA-lux).

[3+2] Cycloaddition Reactions to Indolyl- and Pyrrolyl Derivatives of Dinitrobenzofurazan

The reactions of 4-chloro-5,7-dinitro-4-benzofurazan with indole and pyrrole derivatives, occurring by SNAr–SEAr mechanism, led to the formation of dihetaryls with intramolecular charge transfer. A method was developed for the annelation of pyrrole and dihydropyrrole ring to nitrobenzofurazan fragment by adding unstabilized azomethine ylide to the С=С bond of dinitrobenzofurazan. The structure of nitrobenzofurazan derivatives was studied by X-ray structural analysis, NMR spectroscopy, and quantum-chemical calculations using ab initio and DFT methods.

Ring opening and ring closure in an indolizine structure activated through SNAr coupling with superelectrophilic 4,6-dinitrobenzofuroxan, an unusual intramolecular oxygen transfer from a N-oxide functionality

Coupling of superelectrophilic 4,6-dinitrobenzofuroxan with a pi-excessive indolizine structure affords a strongly dipolar substitution product which undergoes a facile but unusual rearrangement induced by an intramolecular oxygen atom transfer from the N-oxide functionality of the DNBF moiety.

Synthesis and antiviral activity of bis-spirocyclic derivatives of rhodanine

Bis-spiro heterocycles containing spiro units at the 1,3-positions of the pyrrolizidine (isothiapyrrolizidine) moiety were synthesized by the reaction of unstabilized azomethine ylides, which were generated in situ from isatin and proline (isothiaproline), with hetarylidene-substituted rhodanines. Quantum chemical calculations of potential energy surface sections and descriptors controlling the regioselectivity of cycloaddition were carried out. For a number of compounds in vitro activity against the influenza virus A/California/07/09 (H1N1)pdm2009 was experimentally established.

Synthesis of the first 13-nitroaryl derivatives of 8-acetonylberberine

For the first time a method for the synthesis of 8-acetonylberberine 13-nitroaryl derivatives has been developed comprising a one-pot reaction of berberine, acetone, and neutral aromatic electrophiles (picryl chloride, 4-chloro-7-nitrobenzofurazan, 4-chloro-5,7-dinitrobenzofurazan). It was found that the reaction of 8-acetonylberberine with these chloronitroarenes does not lead to the formation of the target compounds.

Quantum-chemical and NMR study of nitrofuroxanoquinoline cycloaddition

Using DFT/B3LYP and ab initio RHF quantum-chemical calculations in the triple-zeta basis set 6-31++G** the endo and exo cycloaddition mechanism for the interaction of ethyl vinyl ether, trimethylsilyloxybutadiene, or cyclopentadiene with 5-nitro-7,8-furoxanoquinolines was studied in details. Considering that both in solutions and crystals nitrofuroxanoquinoline exists as an inseparable mixture of two N-oxide tautomers, all cycloaddition processes were studied for both of them. The studied mechanisms practically do not depend on the location of the exocyclic oxygen atom in nitrofuroxanoquinoline molecule. At the first step of all reactions the conjugated nitroarene fragments C=C–N=O react with nucleophilic reagents following the mechanism of endo-[4+2] cycloaddition with inverse electronic demand. Further (in the cases of trimethylsilyloxybutadiene and cyclopentadiene) endo-[4+2] cycloadducts recyclize spontaneously according to the mechanism of [3,3] sigmatropic rearrangement into more thermodynamically stable, experimentally detected endo-[2+4] cycloadducts. Both endo-[4+2] and endo-[2+4] cycloadducts obtained from cyclopentadiene and nitrofuroxanoquinoline have been experimentally isolated and characterized. For this case, the kinetic and activation parameters of [4+2] → [2+4] transformation have been studied by 1H NMR method, which have shown an excellent agreement with quantum-chemical results. In all cases the exo processes are one-step reactions, less favorable kinetically than their endo competitors.

Mechanism of Thiol-Induced Nitrogen(II) Oxide Donation by Furoxans: a Quantum-Chemical Study

Quantum-chemical calculations according to DFT with UB3LYP functional in the 6-311++G** basis set, and accounting for solvation effects by the polarized continuum method were used to study the mechanisms of thiol-induced fragmentation of unsubstituted and annulated furoxans with the elimination of nitrogen(II) oxide. A preference for NO formation according to the radical mechanism involving an attack by sulfanyl radical (HS˙) on the carbon atom bonded to the N-oxide group was demonstrated for all systems. Anionic mechanisms involving HS– anions were not feasible in any of the cases due to high endothermic effects.