P. G. Morozov

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.

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.

Cycloaddition of [3]dendralene derivatives to dinitrobenzofuroxan and nitrobenzodifuroxan

Abstract It has been shown experimentally (by NMR spectroscopy and X-ray structural analysis) and theoretically (by quantum-chemical calculations according to DFT with B3LYP/6-31G* basis set) that the cycloaddition of [3]dendralene derivatives to nitrobenzodifuroxan and dinitrobenzofuroxan occurs by a stepwise mechanism with a σ-complex as intermediate. It was shown that the cycloaddition steps occurring contrary to the Alder endo rule are characterized by significant global electrophilicity index differences for the reagents (Δω > 3.0 eV). The stages with Δω ≤ 3.0 eV occurred in accordance with the Alder endo rule as concerted processes. X-ray structural analysis and quantum-chemical calculations within the framework of AIM model identified intramolecular attraction forces between non-bonded atoms in the cycloadduct of phenyldendralene and nitrobenzodifuroxan.

Determination of the R ⇄ S enantiomerization barrier in 5,6-dihydrobenzoimidazo[1,2-c]quinazolines

Chiral imidazoquinazolines undergoing thermally induced reversible R ⇄ S enantiomerization have been synthesized by the interaction of 2-(o-aminophenyl)benzimidazoles with aldehydes and ketones. The benzimidazole fragment has been used for the first time as an indicator group in temperature-dependent 1H NMR spectra for determining the energy barrier of this rearrangement. The effects of nearby substituents on the kinetic and activation parameters, and on the recyclization mechanism have been investigated.

Synthesis of Spirocyclic Pyrrolizidineoxyindoles with a Furotropylidene Fragment by 1,3-Dipolar Cycloaddition

The 1,3-dipolar cycloaddition of the unstabilized azomethine ylides generated in situ from isatin and proline to the endocyclic C = C bond of the tropylidene ring is absolutely regio- and diastereoselective. The local electrophilicity of the dipolarophile and the local nucleophilicity of the azomethine ylide calculated by the B3LYP/6-31G** method are useful tools for predicting the regioselectivity of cycloaddition. The structure and the three-dimensional structure of the synthesized spiropyrrolizidineoxyindoles were established by correlation NMR spectroscopy and X-ray structural analysis.

The first dipolar spirocycle based on 10-(benzylamino)colchicine

We have synthesized the first dipolar spirocyclic σ-complex of Meisenheimer type from 10-(benzylamino)colchicine and trinitrobenzene. The chirality of colchicine moiety resulted in magnetic non-equivalence of protons in the trinitrophenyl ring, enabling their use as diastereotopic markers. The kinetic and activation parameters for the reversible degenerate recyclization of spirocycle were determined by a dynamic NMR method.