Mikhail A. Syroeshkin

Copper(I)-mediated synthesis of β-hydroxysulfones from styrenes and sulfonylhydrazides: an electrochemical mechanistic study

Copper(I) halides were used as mediators in the synthesis of β-hydroxysulfones via the oxysulfonylation of styrenes using sulfonylhydrazides. The feature of the developed process lies in the combination of a copper(I) salt with oxygen—the stoichiometric oxidant. Copper(II) species are responsible for the oxidation of sulfonylhydrazides, they are generated in small amounts in the O2/Cu(I)/Cu(II) redox system, which is formed during the reaction. The combination of these three components enables one to obtain in the case of α-methylstyrenes only β-hydroxysulfones and in the case of α-unsubstituted styrenes, β-hydroxysulfones as the main products and β-ketosulfones as the by-products. With good yields β-hydroxysulfones were prepared by reduction of the reaction mixture containing both products β-hydroxysulfones and β-ketosulfones with NaBH4. An electrochemical study revealed that the Cu(I)/Cu(II) pair can serve as an effective mediator of β-hydroxysulfones formation via redox processes.

Cyclic peroxides as promising anticancer agents: in vitro cytotoxicity study of synthetic ozonides and tetraoxanes on human prostate cancer cell lines

Synthetic ozonides and tetraoxanes were shown to have high cytotoxicity in vitro when tested on androgen-independent prostate cancer cell lines DU145 and PC3, which is in some cases was higher than that of doxorubicin, cisplatin, etoposide, artemisinin, and artesunate. Activity of ozonide stereoisomers differs from each other. This difference in activity and absence of correlation between activity of stereoisomers and their oxidative properties allow us to suggest existence of a quite specific mechanism of cytotoxicity of these endoperoxides different from a traditional mechanism based mainly on oxidative properties of peroxides.Graphical Abstract

Efficient electrochemical synthesis of pyrido[1,2-a]benzimidazoles

Electrochemical reduction of N-(2-nitroaryl)pyridinium chlorides in alcohol—dilute HCl mixtures gave pyrido[1,2-a]benzimidazoles in high yields in both divided and undivided cells. According to cyclic voltammetry measurements and DFT calculations (B3LYP/6-31+G(d)), the reaction involves intermediate formation of the corresponding hydroxylamine derivative followed by its heterocyclization.

Dimerization and protonation reactions of nitrosonitrobenzenes radical anions

The electrochemical behavior of 2-, 3-, and 4-nitrosonitrobenzenes (NNB) in DMF (with Bu4NClO4 suppoting salt) in the presence and in the absence of different proton donors (water, phenol, benzoic, acetic, chloroacetic, and sulfuric acids) is studied by the methods of cyclic voltammetry, chronoamperometry and also by electrolysis at the controlled potential. The electrochemical reduction of these compounds is shown to preferentially afford either monomeric (N-nitrophenylhydroxylamines) or dimeric (azoxy compounds) products, which is determined by the interplay between reactions of protonation and dimerization of NNB radical anions. The dimerization reactions proceed fast and reversibly to afford the corresponding dimeric dianions with the basicity much higher as compared with NNB radical anions as the result of which the monomeric products are formed in the presence of “strong” proton donors and the dimeric products form in the presence of “weak” proton donors. Like the effective rate of formation of dimeric products, the basicity of radical anions increases in the row 4- < 3- < 2-NNB.

Electrochemical reduction of N-(2-nitro-4-R-phenyl)pyridinium salts using redox-mediators

Electrochemical reduction of N-(2-nitroaryl)pyridinium chlorides was accomplished in acidic aqueous alcoholic medium in the galvanostatic mode using tin, titanium, vanadium, and iron chlorides as redox-mediators. The use of SnCl2 as a mediator catalyst made it possible to shorten the electrosynthesis time as compared to the direct electroreduction on an electrode and prepare the intramolecular cyclization products, viz., substituted pyrido[1,2-a]benzimidazoles, in high yield. The influence of the mediator nature and its amount, current density, temperature, cathode material, medium acidity, and the substrate structure on the efficiency of reductive heterocyclization of N-(2-nitroaryl)pyridinium salts was studied.

Iminoxyl radicals vs. tert-butylperoxyl radical in competitive oxidative C–O coupling with β-dicarbonyl compounds. Oxime ether formation prevails over Kharasch peroxidation

Oxidative coupling of oxime and β-dicarbonyl compounds dominates in a β-dicarbonyl compound/oxime/Cu(II)/t-BuOOH system; in the absence of oxime, oxidative coupling of t-BuOOH and a β-dicarbonyl compound (Kharasch peroxidation) takes place. The proposed conditions for oxidative coupling of oximes with dicarbonyl compounds require only catalytic amounts of copper salt and t-BuOOH serves as a terminal oxidant. The C–O coupling reaction proceeds via the formation of tert-butoxyl, tert-butylperoxyl and iminoxyl radicals. Apparently, tert-butylperoxyl radicals oxidize oxime into iminoxyl radical faster than they react with β-dicarbonyl compounds forming the Kharasch peroxidation product. Iminoxyl radicals are responsible for the formation of the target C–O coupling products; the yields are up to 77%.

Five Roads That Converge at the Cyclic Peroxy-Criegee Intermediates: BF3-Catalyzed Synthesis of β-Hydroperoxy-β-peroxylactones

We have discovered synthetic access to β-hydroperoxy-β-peroxylactones via BF3-catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals, with H2O2. Strikingly, independent of the choice of starting material, these reactions converge at the same β-hydroperoxy-β-peroxylactone products, i.e., the peroxy analogues of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger reaction. Computed thermodynamic parameters for the formation of the β-hydroperoxy-β-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the β-peroxylactones indeed correspond to a deep energy minimum that connects a variety of the interconverting oxygen-rich species at this combined potential energy surface. The target β-hydroperoxy-β-peroxylactones were synthesized from β-ketoesters, and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals were obtained in 30-96% yields. These reactions proceed under mild conditions and open synthetic access to a broad selection of β-hydroperoxy-β-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These β-peroxylactones are stable and can be useful for further synthetic transformations.

Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity

Twenty six peroxides belonging to bridged 1,2,4,5‐tetraoxanes, bridged 1,2,4‐trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for their in vitro antimalarial activity against Plasmodium falciparum (3D7) and for their cytotoxic activities against immortalized human normal fibroblast (CCD19Lu), liver (LO2), and lung (BEAS‐2B) cell lines as well as human liver (HepG2) and lung (A549) cancer‐cell lines. Synthetic ozonides were shown to have the highest cytotoxicity on HepG2 (IC50=0.19–0.59 μm), and some of these compounds selectively targeted liver cancer (selectivity index values for compounds 13 a and 14 a are 20 and 28, respectively) at levels that, in some cases, were higher than those of paclitaxel, artemisinin, and artesunic acid. In contrast some ozonides showed only moderate antimalarial activity against the chloroquine‐sensitive 3D7 strain of P. falciparum (IC50 from 2.76 to 24.2 μm; 12 b, IC50=2.76 μm; 13 a, IC50=20.14 μm; 14 a, IC50=6.32 μm). These results suggest that these derivatives have divergent mechanisms of action against cancer cells and malaria‐infected cells. A cyclic voltammetry study of the peroxides was performed, but most of the compounds did not show direct correlation in oxidative capacity–activity. Our findings offer a new source of antimalarial and anticancer agents through structural modification of peroxide compounds.

Corrigendum: Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity

On page 904, under the section ’In vitro activity against cancer and normal cell lines’, the sentences: “All cyclic peroxides showed better selectivity index (SI) values for lung A549 cancer cell lines than artemisinin, chloroquine, and paclitaxel (Table 2, Figures S3 and S4). The selectivity index of tetraoxane 4 was 540 times higher than that of the reference compound paclitaxel,” should instead be: “All cyclic peroxides showed better selectivity index (SI) values for lung A549 cancer cell lines than artemisinin and chloroquine (Table 2, Figures S3 and S4). The selectivity index of tetraoxane 4 was 54 times higher than that of the reference compound chloroquine.”

Hypervalent iodine compounds for anti-Markovnikov-type iodo-oxyimidation of vinylarenes

The iodo-oxyimidation of styrenes with the N-hydroxyimide/I2/hypervalent iodine oxidant system was proposed. Among the examined hypervalent iodine oxidants (PIDA, PIFA, IBX, DMP) PhI(OAc)2 proved to be the most effective; yields of iodo-oxyimides are 34–91%. A plausible reaction pathway includes the addition of an imide-N-oxyl radical to the double C=C bond and trapping of the resultant benzylic radical by iodine. It was shown that the iodine atom in the prepared iodo-oxyimides can be substituted by various nucleophiles.