Electrochemical Generation of Peroxy Radicals and Subsequent Peroxidation of 1,3-Dicarbonyls in an Undivided Cell.

The generation of peroxy radicals from hydroperoxides with subsequent selective peroxidation of 1,3-dicarbonyls in an undivided electrochemical cell under constant current conditions is reported. The method provides a variety of peroxy-containing barbituric acids and 4-hydroxy-2(5H)-furanones with yields of up to 74%. Only the combination of anodic and cathodic processes provides efficient peroxidation by generating a set of alkoxy and peroxy radicals. NaNO3 acts as both an electrolyte and a redox mediator of radical reactions.

C-O Coupling of Hydrazones with Diacetyliminoxyl Radical Leading to Azo Oxime Ethers-Novel Antifungal Agents.

Selective oxidative C-O coupling of hydrazones with diacetyliminoxyl is demonstrated, in which diacetyliminoxyl plays a dual role. It is an oxidant (hydrogen atom acceptor) and an O-partner for the oxidative coupling. The reaction is completed within 15-30 min at room temperature, is compatible with a broad scope of hydrazones, provides high yields in most cases, and requires no additives, which makes it robust and practical. The proposed reaction leads to the novel structural family of azo compounds, azo oxime ethers, which were discovered to be highly potent fungicides against a broad spectrum of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, Sclerotinia sclerotiorum).

Two Discoveries in One Crystal: σ-Type Oxime Radical as an Unforeseen Building Block in Molecular Magnetics and Its Spatial Structure.

In the present work, the study of the unusual interaction between copper hexafluoroacetylacetonate and the diacetyliminoxyl radical resulted in two discoveries from different fields: the determination of the oxime radical spatial structure and the introduction of an oxime radical into the field of molecular magnetic material design. Oxime radicals are key plausible intermediates in the processes of oxidative CH-functionalization and in the synthesis of functionalized isoxazolines from oximes. Due to the lack of X-ray diffraction data for oxime radicals, the knowledge about their structure is based mainly on indirect approaches, spectroscopic methods (electron paramagnetic resonance and IR), and quantum chemical calculations. The structure of the oxime radical was determined for the first time by stabilizing the diacetyliminoxyl radical in the form of its complex with copper (II) hexafluoroacetylacetonate (Cu(hfac)2), followed by single-crystal X-ray diffraction analysis. Although oxime radicals are known to undergo oxidative coupling with acetylacetonate ligands in transition-metal complexes, a complex is formed with intact hfac ligands. X-ray diffraction studies have shown that the oxime radical is coordinated with copper ions through the oxygen atoms of the carbonyl groups without the direct involvement of the C═N-O• radical moiety. The structure of the coordinated diacetyliminoxyl is in good agreement with the density functional theory (DFT) prediction for free diacetyliminoxyl due to the very weak interaction of the radical molecule with copper ions. Remarkably, both weak ferromagnetic and antiferromagnetic interactions between Cu (II) and oxime radicals have been revealed by modeling the temperature dependence of magnetic susceptibility and confirmed by DFT calculations, rendering diacetyliminoxyl a promising building block for the design of molecular magnets.

4-Nitropyrazolin-5-ones as Readily Available Fungicides of the Novel Structural Type for Crop Protection: Atom-Efficient Scalable Synthesis and Key Structural Features Responsible for Activity.

The development of new types of fungicides for agriculture and medicine is highly desirable due to the uprising fungal resistance against commonly used compounds. Herein, 4-substituted-4-nitropyrazolin-5-ones (nitropyrazolones) were proposed as highly active fungicides of the novel structural type. The first scalable and practical method for the nitropyrazolone synthesis was proposed, which is atom-efficient, is applicable for the multigram scale synthesis, and allows for production of a wide variety of nitropyrazolones with high yields and purity. The synthesized compounds demonstrated high fungicidal activity against the broad spectrum of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum). Their mycelium growth inhibiting activity was comparable or superior to that of kresoxim-methyl. In vitro activity against Staphyloccocus aureus, Candida albicans, and Aspergillus niger revealed that nitropyrazolones are promising candidates against human pathogens. The key factors for the manifestation of high fungicidal activity were established to be an aromatic substituent on the N1 atom and small substituents, such as methyl, at the C3 and C4 positions of the pyrazolone ring.

Stable and reactive diacetyliminoxyl radical in oxidative C-O coupling with ß-dicarbonyl compounds and their complexes.

As a rule, reactive free radicals used in organic synthesis are too labile to be isolated, whereas persistent radicals are inert and find limited synthetic application. In the present study, the unusually stable diacetyliminoxyl radical was presented as a "golden mean" between transient and stable unreactive radicals. It was successfully employed as a reagent for oxidative C-O coupling with ß-dicarbonyl compounds. Using this model radical the catalytic activity of acids, bases and transition metal ions in free-radical coupling was revealed.

Electrochemical Synthesis of Fluorinated Ketones from Enol Acetates and Sodium Perfluoroalkyl Sulfinates.

The electrochemical synthesis of fluorinated ketones from enol acetates and RfSO2Na in an undivided cell under constant current conditions was developed. The electrosynthesis proceeded via perfluoroalkyl radical generation from sodium perfluoroalkyl sulfinate followed by addition to the enol acetate and transformation of the resulting C radical to a fluorinated ketone. The method is applicable to a wide range of enol acetates and results in the desired products in yields of 20 to 85%.

Metal-Free Cross-Dehydrogenative C-O Coupling of Carbonyl Compounds with N-Hydroxyimides: Unexpected Selective Behavior of Highly Reactive Free Radicals at an Elevated Temperature.

Cross-dehydrogenative C-O coupling of N-hydroxyimides with ketones, esters, and carboxylic acids was achieved employing the di-tert-butyl peroxide as a source of free radicals and a dehydrogenating agent. The proposed method is experimentally simple and demonstrates the outstanding efficiency for the challenging CH substrates, such as unactivated esters and carboxylic acids. It was shown that N-hydroxyphthalimide drastically affects the oxidative properties of t-BuOOt-Bu by intercepting the t-BuO• radicals with the formation of phthalimide-N-oxyl radicals, a species responsible for both hydrogen atom abstraction from the CH reagent and the selective formation of the C-O coupling product by selective radical cross-recombination. The practical applicability of the developed method was exemplified by the single-stage synthesis of commercial reagent (known as Baran aminating reagent precursor) from isobutyric acid and N-hydroxysuccinimide, whereas in the standard synthetic approach, four stages are necessary.

Mild Nitration of Pyrazolin-5-ones by a Combination of Fe(NO3 )3 and NaNO2 : Discovery of a New Readily Available Class of Fungicides, 4-Nitropyrazolin-5-ones.

4-Nitropyrazolin-5-ones have been synthesized by the nitration of pyrazolin-5-ones at room temperature by employing the Fe(NO3 )3 /NaNO2 system. The method demonstrated selectivity towards the 4-position of pyrazolin-5-ones even in the presence of NPh and allyl substituents, which are sensitive to nitration. It was shown that other systems containing FeIII and nitrites, namely Fe(NO3 )3 /tBuONO, Fe(ClO4 )3 /NaNO2 , and Fe(ClO4 )3 /tBuONO, were also effective. Presumably, FeIII oxidizes the nitrite (NaNO2 or tBuONO) to form the NO2 free radical, which serves as the nitrating agent for pyrazolin-5-ones. The synthesized 4-nitropyrazolin-5-ones were discovered to be a new class of fungicides. Their in vitro activities against phytopathogenic fungi were found comparable or even superior to those of commercial fungicides (fluconazole, clotrimazole, triadimefon, and kresoxim-methyl). These results represent a promising starting point for the development of a new type of plant protection agents that can be easily synthesized from widely available reagents.

Electrochemically induced oxidative S-O coupling: synthesis of sulfonates from sulfonyl hydrazides and N-hydroxyimides or N-hydroxybenzotriazoles.

The process of oxidative S-O coupling under the action of electric current was developed. Aryl, hetaryl and alkyl sulfonyl hydrazides and N-hydroxy compounds (N-hydroxyimides and N-hydroxybenzotriazoles) are applied as starting reagents for the preparation of sulfonates. The reaction is carried out under constant current conditions in an experimentally convenient undivided electrochemical cell equipped with a graphite anode and a stainless steel cathode under a high current density (60 mA cm-2). NH4Br in this process acts as a supporting electrolyte and participates in the oxidation of the starting compounds to form a coupling product. The developed strategy represents a quite atom-efficient approach: one partner loses two nitrogen and three hydrogen atoms, while another one loses only one hydrogen atom. Cyclic voltammetry and the control experiment allowed us to propose possible reaction pathways: generated through anodic oxidation molecular bromine or its higher oxidation state derivatives oxidize the starting compounds to form reactive species, which couple to form the S-O bond.

Electrochemically Induced Intermolecular Cross-Dehydrogenative C-O Coupling of ß-Diketones and ß-Ketoesters with Carboxylic Acids.

The electrochemically induced cross-dehydrogenative C-O coupling of ß-diketones and ß-ketoesters (C-H reagents) with carboxylic acids (O-H reagents) was developed. An important feature of this reaction lies in the selective formation of intermolecular C-O coupling products in high yields, up to 92%, using DMSO as a solvent with a broad substrate scope in an undivided cell equipped with carbon and platinum electrodes at high current density. Electric current acts as a stoichiometric oxidant.

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

We have discovered synthetic access to ß-hydroperoxy-ß-peroxylactones via BF3-catalyzed cyclizations of a variety of acyclic precursors, ß-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 ß-hydroperoxy-ß-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 ß-hydroperoxy-ß-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the ß-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 ß-hydroperoxy-ß-peroxylactones were synthesized from ß-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 ß-hydroperoxy-ß-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These ß-peroxylactones are stable and can be useful for further synthetic transformations.

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.

Ozone-Free Synthesis of Ozonides: Assembling Bicyclic Structures from 1,5-Diketones and Hydrogen Peroxide.

Reactions of 1,5-diketones with H2O2 open an ozone-free approach to ozonides. Bridged ozonides are formed readily at room temperature in the presence of strong Brønsted or Lewis acids such as H2SO4, p-TsOH, HBF4, or BF3·Et2O. The expected bridged tetraoxanes, the products of double H2O2 addition, were not detected. This procedure is readily scalable to produce gram quantities of the ozonides. Bridged ozonides are stable and can be useful as building blocks for bioconjugation and further synthetic transformations. Although less stabilized by anomeric interactions than bis-peroxides, ozonides have an intrinsic advantage of having only one weak O-O bond. The role of the synergetic framework of anomeric effects in bis-peroxides is to overcome this intrinsic disadvantage. As the computational data have shown, this is only possible when all anomeric effects in bis-peroxides are activated to their fullest degree. Consequently, the cyclization selectivity is determined by the length of the bridge between the two carbonyl groups of the diketone. The generally large thermodynamic preference for the formation of cyclic bis-peroxides disappears when 1,5-diketones are used as the bis-cyclization precursors. Stereoelectronic analysis suggests that the reason for the bis-peroxide absence is the selective deactivation of anomeric effects in a [3.2.2]tetraoxanonane skeleton by a structural distortion imposed on the tetraoxacyclohexane subunit by the three-carbon bridge.

Interrupted Baeyer-Villiger Rearrangement: Building A Stereoelectronic Trap for the Criegee Intermediate.

The instability of hydroxy peroxyesters, the elusive Criegee intermediates of the Baeyer-Villiger rearrangement, can be alleviated by selective deactivation of the stereoelectronic effects that promote the 1,2-alkyl shift. Stable cyclic Criegee intermediates constrained within a five-membered ring can be prepared by mild reduction of the respective hydroperoxy peroxyesters (ß-hydroperoxy-ß-peroxylactones) which were formed in high yields in reaction of ß-ketoesters with BF3 ⋅Et2 O/H2 O2 .

A H2O2/HBr system - several directions but one choice: oxidation-bromination of secondary alcohols into mono- or dibromo ketones.

In this work we found that a H2O2-HBr(aq) system allows synthesis of α-monobromo ketones and α,α'-dibromo ketones from aliphatic and secondary benzylic alcohols with yields up to 91%. It is possible to selectively direct the process toward the formation of mono- or dibromo ketones by varying the amount of hydrogen peroxide and hydrobromic acid. The convenience of application, simple equipment, multifaceted reactivity, and compliance with green chemistry principles make the application of the H2O2-HBr(aq) system very attractive in laboratories and industry. The proposed oxidation-bromination process is selective in spite of known properties of ketones to be oxidized by the Baeyer-Villiger reaction or peroxidated with the formation of compounds with the O-O moiety in the presence of hydrogen peroxide and Bronsted acids.

Stereoelectronic Control in the Ozone-Free Synthesis of Ozonides.

The value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H2 O2 . The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H2 O2 were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.2]tetraoxanonanes by the three-carbon bridge leads to the partial deactivation of anomeric effects. The new procedure is readily scalable to produce gram quantities of the ozonides. This reaction enables the selective preparation of ozonides without the use of ozone.

Lanthanide-Catalyzed Oxyfunctionalization of 1,3-Diketones, Acetoacetic Esters, And Malonates by Oxidative C-O Coupling with Malonyl Peroxides.

The lanthanide-catalyzed oxidative C-O coupling of 1,3-dicarbonyl compounds with diacyl peroxides, specifically the cyclic malonyl peroxides, has been developed. An important feature of this new reaction concerns the advantageous role of the peroxide acting both as oxidant and reagent for C-O coupling. It is shown that lanthanide salts may be used in combination with peroxides for selective oxidative transformations. The vast range of lanthanide salts (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Y) catalyzes oxidative C-O coupling much more efficiently than other used Lewis and Bronsted acids. This oxidative cross-coupling protocol furnishes mono and double C-O coupling products chemo-selectively in high yields with a broad substrate scope. The double C-O coupling products may be hydrolyzed to vicinal tricarbonyl compounds, which are otherwise cumbersome to prepare. Based on the present experimental results, a nucleophilic substitution mechanism is proposed for the C-O coupling process in which the lanthanide metal ion serves as Lewis acid to activate the enol of the 1,3-dicarbonyl substrate. The side reactions-chlorination and hydroxylation of the 1,3-dicarbonyl partners-may be minimized under proper conditions.

Well-Known Mediators of Selective Oxidation with Unknown Electronic Structure: Metal-Free Generation and EPR Study of Imide-N-oxyl Radicals.

Nitroxyl radicals are widely used in chemistry, materials sciences, and biology. Imide-N-oxyl radicals are subclass of unique nitroxyl radicals that proved to be useful catalysts and mediators of selective oxidation and CH-functionalization. An efficient metal-free method was developed for the generation of imide-N-oxyl radicals from N-hydroxyimides at room temperature by the reaction with (diacetoxyiodo)benzene. The method allows for the production of high concentrations of free radicals and provides high resolution of their EPR spectra exhibiting the superhyperfine structure from benzene ring protons distant from the radical center. An analysis of the spectra shows that, regardless of the electronic effects of the substituents in the benzene ring, the superhyperfine coupling constant of an unpaired electron with the distant protons at positions 4 and 5 of the aromatic system is substantially greater than that with the protons at positions 3 and 6 that are closer to the N-oxyl radical center. This is indicative of an unusual character of the spin density distribution of the unpaired electron in substituted phthalimide-N-oxyl radicals. Understanding of the nature of the electron density distribution in imide-N-oxyl radicals may be useful for the development of commercial mediators of oxidation based on N-hydroxyimides.

Manganese triacetate as an efficient catalyst for bisperoxidation of styrenes.

A method was developed for the bisperoxidation of styrenes with tert-butyl hydroperoxide in the presence of a catalytic amount of manganese(III) acetate. It was shown that compounds of manganese in oxidation states 2, 4, and 7 also catalyze this reaction. The target [1,2-bis(tert-butylperoxy)ethyl]arenes were synthesized in yields from 46 to 75%.

Approach for the preparation of various classes of peroxides based on the reaction of triketones with H2O2: first examples of ozonide rearrangements.

The reaction of ß,δ-triketones with an ethereal solution of H2O2 catalyzed by heteropoly acids in the presence of a polar aprotic co-solvent proceeds via three pathways to form three classes of peroxides: tricyclic monoperoxides, bridged tetraoxanes, and a pair of stereoisomeric ozonides. The reaction is unusual in that produces bridged tetraoxanes and ozonides with one of the three carbonyl groups remaining intact. In the synthesis of bridged tetraoxanes, the peroxide ring is formed by the reaction of hydrogen peroxide with two carbonyl groups at the ß positions. The synthesis of ozonides from ketones and hydrogen peroxide is a unique process in which the ozonide ring is formed with the participation of two carbonyl groups at the δ positions. Rearrangements of ozonides were found for the first time after more than one century of their active investigation. Ozonides are interconverted with each other and rearranged into tricyclic monoperoxides, whereas ozonides and tricyclic monoperoxides are transformed into bridged tetraoxanes. The individual reaction products were isolated by column chromatography and characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. One representative of each class of peroxides was characterized by X-ray diffraction.