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).

The diacetyliminoxyl radical in oxidative functionalization of alkenes.

The intermolecular oxime radical addition to CC bonds was observed and studied for the first time. The diacetyliminoxyl radical was proposed as a model radical reagent for the study of oxime radical reactivity towards unsaturated substrates, which is important in the light of the active development of synthetic applications of oxime radicals. In the present work it was found that the diacetyliminoxyl radical reacts with vinylarenes and conjugated dienes to give radical addition products, whereas unconjugated alkenes can undergo radical addition or allylic hydrogen substitution by diacetyliminoxyl depending on the substrate structure. Remarkably, substituted alkenes give high yields of C-O coupling products despite the significant steric hindrance, whereas unsubstituted alkenes give lower yields of the C-O coupling products. The observed atypical C-O coupling yield dependence on the alkene structure was explained by the discovered ability of the diacetyliminoxyl radical to attack alkenes with the formation of a C-N bond instead of a C-O bond giving side products. This side process is not expected for sterically hindered alkenes due to lower steric availability of the N-atom in diacetyliminoxyl than that of the O-atom.

Free Radicals in the Queue: Selective Successive Addition of Azide and N-Oxyl Radicals to Alkenes.

The selective successive addition of azide (•N3) and N-oxyl radicals to alkenes is demonstrated, despite each of the two radicals being known to attack C═C bonds and the mixture of radical adducts possibly being expected. The proposed radical mechanism was supported by density functional theory calculations, electron paramagnetic resonance, and radical trapping experiments. The reaction proceeds at room temperature with the available reagents: NaN3, N-hydroxy compounds, and PhI(OAc)2 as the oxidant. The method can be applied for N-hydroxyimides, N-hydroxyamides, N-hydroxybenzotriazole, and oximes as N-oxyl radical precursors. Vinylarenes, aliphatic alkenes, and even electron-deficient methyl methacrylate were successfully functionalized.

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.

Heterogeneous Photocatalysis as a Potent Tool for Organic Synthesis: Cross-Dehydrogenative C-C Coupling of N-Heterocycles with Ethers Employing TiO2/N-Hydroxyphthalimide System under Visible Light.

Despite the obvious advantages of heterogeneous photocatalysts (availability, stability, recyclability, the ease of separation from products and safety) their application in organic synthesis faces serious challenges: generally low efficiency and selectivity compared to homogeneous photocatalytic systems. The development of strategies for improving the catalytic properties of semiconductor materials is the key to their introduction into organic synthesis. In the present work, a hybrid photocatalytic system involving both heterogeneous catalyst (TiO2) and homogeneous organocatalyst (N-hydroxyphthalimide, NHPI) was proposed for the cross-dehydrogenative C-C coupling of electron-deficient N-heterocycles with ethers employing t-BuOOH as the terminal oxidant. It should be noted that each of the catalysts is completely ineffective when used separately under visible light in this transformation. The occurrence of visible light absorption upon the interaction of NHPI with the TiO2 surface and the generation of reactive phthalimide-N-oxyl (PINO) radicals upon irradiation with visible light are considered to be the main factors determining the high catalytic efficiency. The proposed method is suitable for the coupling of π-deficient pyridine, quinoline, pyrazine, and quinoxaline heteroarenes with various non-activated ethers.

Redox-active molecules as organocatalysts for selective oxidative transformations - an unperceived organocatalysis field.

Organocatalysis is widely recognized as a key synthetic methodology in organic chemistry. It allows chemists to avoid the use of precious and (or) toxic metals by taking advantage of the catalytic activity of small and synthetically available molecules. Today, the term organocatalysis is mainly associated with redox-neutral asymmetric catalysis of C-C bond-forming processes, such as aldol reactions, Michael reactions, cycloaddition reactions, etc. Organophotoredox catalysis has emerged recently as another important catalysis type which has gained much attention and has been quite well-reviewed. At the same time, there are a significant number of other processes, especially oxidative, catalyzed by redox-active organic molecules in the ground state (without light excitation). Unfortunately, many of such processes are not associated in the literature with the organocatalysis field and thus many achievements are not fully consolidated and systematized. The present article is aimed at overviewing the current state-of-art and perspectives of oxidative organocatalysis by redox-active molecules with the emphasis on challenging chemo-, regio- and stereoselective CH-functionalization processes. The catalytic systems based on N-oxyl radicals, amines, thiols, oxaziridines, ketone/peroxide, quinones, and iodine(I/III) compounds are the most developed catalyst types which are covered here.

Decatungstate-Catalyzed Photochemical Synthesis of Enaminones from Vinyl Azides and Aldehydes.

Visible light-induced synthesis of enaminones from vinyl azides and aldehydes under decatungstate photocatalysis was developed. The reaction proceeds via acyl radical generation from aldehyde, followed by its addition to vinyl azide, nitrogen elimination, hydrogen atom abstraction by the intermediate iminyl radical, and tautomerization. Photochemical synthesis was efficiently conducted under both batch and flow conditions. The method can be applied to various vinyl azides and aldehydes and provides the desired products in 15-72% yields.

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.

Oxime radicals: generation, properties and application in organic synthesis.

N-Oxyl radicals (compounds with an N-O• fragment) represent one of the richest families of stable and persistent organic radicals with applications ranging from catalysis of selective oxidation processes and mechanistic studies to production of polymers, energy storage, magnetic materials design and spectroscopic studies of biological objects. Compared to other N-oxyl radicals, oxime radicals (or iminoxyl radicals) have been underestimated for a long time as useful intermediates for organic synthesis, despite the fact that their precursors, oximes, are extremely widespread and easily available organic compounds. Furthermore, oxime radicals are structurally exceptional. In these radicals, the N-O• fragment is connected to an organic moiety by a double bond, whereas all other classes of N-oxyl radicals contain an R2N-O• fragment with two single C-N bonds. Although oxime radicals have been known since 1964, their broad synthetic potential was not recognized until the last decade, when numerous selective reactions of oxidative cyclization, functionalization, and coupling mediated by iminoxyl radicals were discovered. This review is focused on the synthetic methods based on iminoxyl radicals developed in the last ten years and also contains some selected data on previous works regarding generation, structure, stability, and spectral properties of these N-oxyl radicals. The reactions of oxime radicals are classified into intermolecular (oxidation by oxime radicals, oxidative C-O coupling) and intramolecular. The majority of works are devoted to intramolecular reactions of oxime radicals. These reactions are classified into cyclizations involving C-H bond cleavage and cyclizations involving a double C=C bond cleavage.

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.

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.

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.

Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni.

Praziquantel is currently the only drug available to treat schistosomiasis. Since drug resistance would be a major barrier for the increasing global attempts to eliminate schistosomiasis as a public health problem, efforts should go hand in hand with the discovery of novel treatment options. Synthetic peroxides might offer a good direction since their antischistosomal activity has been demonstrated in the laboratory. We studied 19 bridged 1,2,4,5-tetraoxanes, 2 tricyclic monoperoxides, 11 bridged 1,2,4-trioxolanes, 12 silyl peroxides, and 4 hydroxylamine derivatives against newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Schistosomicidal compounds were tested for cytotoxicity followed by in vivo studies of the most promising compounds. Tricyclic monoperoxides, trioxolanes, and tetraoxanes revealed the highest in vitro activity against NTS (IC50s 0.4-20.2 µM) and adult schistosomes (IC50s 1.8-22.8 µM). Tetraoxanes showed higher cytotoxicity than antischistosomal activity. Selected trioxolane and tricyclic monoperoxides were tested in mice harboring an adult S. mansoni infection. The highest activity was observed for two trioxolanes, which showed moderate worm burden reductions (WBR) of 44.3% and 42.9% (p>0.05). Complexation of the compounds with ß-cyclodextrin with the aim to improve solubility and gastrointestinal absorption did not increase in vivo antischistosomal efficacy. The high in vitro antischistosomal activity of trioxolanes and tricyclic monoperoxides is a promising basis for future investigations, with the focus on improving in vivo efficacy.

Cross-dehydrogenative coupling for the intermolecular C-O bond formation.

The present review summarizes primary publications on the cross-dehydrogenative C-O coupling, with special emphasis on the studies published after 2000. The starting compound, which donates a carbon atom for the formation of a new C-O bond, is called the CH-reagent or the C-reagent, and the compound, an oxygen atom of which is involved in the new bond, is called the OH-reagent or the O-reagent. Alcohols and carboxylic acids are most commonly used as O-reagents; hydroxylamine derivatives, hydroperoxides, and sulfonic acids are employed less often. The cross-dehydrogenative C-O coupling reactions are carried out using different C-reagents, such as compounds containing directing functional groups (amide, heteroaromatic, oxime, and so on) and compounds with activated C-H bonds (aldehydes, alcohols, ketones, ethers, amines, amides, compounds containing the benzyl, allyl, or propargyl moiety). An analysis of the published data showed that the principles at the basis of a particular cross-dehydrogenative C-O coupling reaction are dictated mainly by the nature of the C-reagent. Hence, in the present review the data are classified according to the structures of C-reagents, and, in the second place, according to the type of oxidative systems. Besides the typical cross-dehydrogenative coupling reactions of CH- and OH-reagents, closely related C-H activation processes involving intermolecular C-O bond formation are discussed: acyloxylation reactions with ArI(O2CR)2 reagents and generation of O-reagents in situ from C-reagents (methylarenes, aldehydes, etc.).

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%.

Identification of antischistosomal leads by evaluating bridged 1,2,4,5-tetraoxanes, alphaperoxides, and tricyclic monoperoxides.

Although antischistosomal properties of peroxides were studied in recent years, systematic structure-activity relationships have not been conducted. We evaluated the antischistosomal potential of 64 peroxides belonging to bridged 1,2,4,5-tetraoxanes, alphaperoxides, and tricyclic monoperoxides. Thirty-nine compounds presented IC50 values <15 µM on newly transformed schistosomula. Active drugs featured phenyl-, adamantane-, or alkyl residues at the methylene bridge. Lower susceptibility was documented on adult schistosomes, with most hit compounds being tricyclic monoperoxides (IC50: 7.7-13.4 µM). A bridged 1,2,4,5-tetraoxane characterized by an adamantane residue showed the highest activity (IC50: 0.3 µM) on adult Schistosoma mansoni . Studies with hemin and heme supplemented medium indicated that antischistosomal activation of peroxides is not necessarily triggered by iron porphyrins. Two compounds (tricyclic monoperoxide; bridged 1,2,4,5-tetraoxane) revealed high worm burden reductions in the chronic (WBR: 75.4-82.8%) but only moderate activity in the juvenile (WBR: 18.9-43.1%) S. mansoni mouse model. Our results might serve as starting point for the preparation and evaluation of related derivatives.

Synthesis of 1-hydroperoxy-1'-alkoxyperoxides by the iodine-catalyzed reactions of geminal bishydroperoxides with acetals or enol ethers.

It was found that iodine-catalyzed reactions of geminal bishydroperoxides with acetals proceed with the replacement of only one alkoxy group by the peroxide group to give previously unknown structures of 1-hydroperoxy-1'-alkoxyperoxides in yields up to 64%. The same compounds are formed in the iodine-catalyzed reactions of geminal bishydroperoxides with enol ethers. The nature of the solvent has a decisive influence on the formation of 1-hydroperoxy-1'-alkoxyperoxides. In the series of Et(2)O, THF, EtOH, CHCl(3), CH(3)CN, and hexane, the best results were obtained with the use of Et(2)O or THF as the solvent.