Toward New Horizons in Verdazyl-Nitroxide High-Spin Systems: Thermally Robust Tetraradical with Quintet Ground State.

High-spin organic tetraradicals with significant intramolecular exchange interactions have high potential for advanced technological applications and fundamental research, but examples reported to date exhibit limited stability and processability. In this work, we designed the first tetraradical based on an oxoverdazyl core and nitronyl nitroxide radicals and successfully synthesized it using a palladium-catalyzed cross-coupling reaction of an oxoverdazyl radical bearing three iodo-phenylene moieties with a gold(I) nitronyl nitroxide-2-ide complex in the presence of a recently developed efficient catalytic system. The molecular and crystal structures of the tetraradical were confirmed by single crystal X-ray diffraction analysis. The tetraradical possesses good thermal stability with decomposition onset at ∼125 °C in an inert atmosphere; in a toluene solution upon prolonged heating at 90 °C in air, no decomposition was observed. The resulting unique verdazyl-nitroxide conjugate was thoroughly studied using a range of experimental and theoretical techniques, such as SQUID magnetometry of polycrystalline powders, EPR spectroscopy in various matrices, cyclic voltammetry, and high-level quantum chemical calculations. All collected data confirm the high thermal stability of the resulting tetraradical and quintet multiplicity of its ground state, which makes the synthesis of this important paramagnet a new milestone in the field of creating high-spin systems.

Structure and Dynamic Rearrangements of the Pt2dba3 and Pd2dba3 Complexes in Solution.

Although the tris(dibenzylideneacetone)diplatinum complex (Pt2dba3) is an important source of Pt(0) used in catalysis and materials science, its structure has not yet been fully elucidated. A thorough study of the three-dimensional structure of Pt2dba3 and its dynamic behavior in solution was carried out using NMR spectroscopy methods at a high field (600 MHz) and molecular modeling. The complex was shown to contain three dba ligands in the s-cis,s-trans, s-trans,s-cis, and s-trans,s-trans conformations, which are uniformly oriented around the Pt2 backbone. In solution, the Pt2dba3 and Pd2dba3 complexes undergo rapid dynamic rearrangements, as evidenced by the exchange between the signals of the olefin protons of various dba ligands in the EXSY NMR spectra. According to the experimental measurements, the activation energies of the rearrangements were estimated to be 19.9 ± 0.2 and 17.9 ± 0.2 kcal/mol for the platinum and palladium complexes, respectively. Three possible mechanisms for this chemical exchange process were considered within the framework of DFT calculations. According to the calculated data, M2dba3 complexes undergo fluxional isomerization involving successive rotations of the dihedral angles formed by the carbonyl group and the C═C bond. Dissociation of dba ligands does not occur within these processes.

The TaCl5-Mediated Reaction of Dimethyl 2-Phenylcyclopropane-1,1-dicarboxylate with Aromatic Aldehydes as a Route to Substituted Tetrahydronaphthalenes.

It is found that the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 2 equivalents each of aromatic aldehydes and TaCl5 in 1,2-dichloroethane at 23 °C for 24 h after hydrolysis gives substituted 4-phenyl-3,4-dihydronaphtalene-2,2(1H)-dicarboxylates in good yield. This represents a new type of reactions between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes, yielding chlorinated tetrahydronaphthalenes with a cis arrangement of the aryl and chlorine substituents in the cyclohexene moiety. A plausible reaction mechanism is proposed.

Formal High-Order Cycloadditions of Donor-Acceptor Cyclopropanes with Cycloheptatrienes.

Design of various cycloaddition / annulation processes is one of the most intriguing challenges during all time in the development of the donor-acceptor (D-A) cyclopropanes chemistry. In this work, a new missing class of formal high-order [6+n]-cycloaddition and annulation processes of D-A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D-A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was study in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2-zwitterionic complexes or 1,3-zwitterionic intermediates from starting D-A cyclopropanes, when other Lewis acids are ineffective and non-selective. New important examples of formal [6+2]-, [6+3]-, [6+4]-, [6+1]-, and [4+2]- cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself also can successfully act as a hydride anion donor which allows ionic hydrogenation of D-A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven-membered-based carbocycles has been developed.

Revealing the Mechanism of Combining Best Properties of Homogeneous and Heterogeneous Catalysis in Hybrid Pd/NHC Systems.

The formation of transient hybrid nanoscale metal species from homogeneous molecular precatalysts has been demonstrated by in situ NMR studies of catalytic reactions involving transition metals with N-heterocyclic carbene ligands (M/NHC). These hybrid structures provide benefits of both molecular complexes and nanoparticles, enhancing the activity, selectivity, flexibility, and regulation of active species. However, they are challenging to identify experimentally due to the unsuitability of standard methods used for homogeneous or heterogeneous catalysis. Utilizing a sophisticated solid-state NMR technique, we provide evidence for the formation of NHC-ligated catalytically active Pd nanoparticles (PdNPs) from Pd/NHC complexes during catalysis. The coordination of NHCs via C(NHC)-Pd bonding to the metal surface was first confirmed by observing the Knight shift in the 13C NMR spectrum of the frozen reaction mixture. Computational modeling revealed that as little as few NHC ligands are sufficient for complete ligation of the surface of the formed PdNPs. Catalytic experiments combined with in situ NMR studies confirmed the significant effect of surface covalently bound NHC ligands on the catalytic properties of the PdNPs formed by decomposition of the Pd/NHC complexes. This observation shows the crucial influence of NHC ligands on the activity and stability of nanoparticulate catalytic systems.

Synthesis of Cy5-Labelled C5-Alkynyl-modified cytidine triphosphates via Sonogashira coupling for DNA labelling.

New applications of palladium-catalyzed Sonogashira-type cross-coupling reaction between C5-halogenated 2'-deoxycytidine-5'-monophosphate and novel cyanine dyes with a terminal alkyne group have been developed. The present methodology allows to synthesize of fluorescently labeled C5-nucleoside triphosphates with different acetylene linkers between the fluorophore and pyrimidine base in good to excellent yields under mild reaction conditions. Modified 2'-deoxycytidine-5'-triphosphates were shown to be good substrates for DNA polymerases and were incorporated into the DNA by polymerase chain reaction.

Synthesis of the Indole-Based Inhibitors of Bacterial Cystathionine γ-Lyase NL1-NL3.

Bacterial cystathionine γ-lyase (bCSE) is the main producer of H2S in pathogenic bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, etc. The suppression of bCSE activity considerably enhances the sensitivity of bacteria to antibiotics. Convenient methods for the efficient synthesis of gram quantities of two selective indole-based bCSE inhibitors, namely (2-(6-bromo-1H-indol-1-yl)acetyl)glycine (NL1), 5-((6-bromo-1H-indol-1-yl)methyl)- 2-methylfuran-3-carboxylic acid (NL2), as well as a synthetic method for preparation 3-((6-(7-chlorobenzo[b]thiophen-2-yl)-1H-indol-1-yl)methyl)- 1H-pyrazole-5-carboxylic acid (NL3), have been developed. The syntheses are based on the use of 6-bromoindole as the main building block for all three inhibitors (NL1, NL2, and NL3), and the designed residues are assembled at the nitrogen atom of the 6-bromoindole core or by the substitution of the bromine atom in the case of NL3 using Pd-catalyzed cross-coupling. The developed and refined synthetic methods would be significant for the further biological screening of NL-series bCSE inhibitors and their derivatives.

Thermal Rearrangement of 5-(2-Hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines.

Some of the most important transformations in organic chemistry are rearrangement reactions, which play a crucial role in increasing synthetic efficiency and molecular complexity. The development of synthetic strategies involving rearrangement reactions, which can accomplish synthetic goals in a very efficient manner, has been an evergreen topic in the synthetic chemistry community. Xanthenes, pyridin-2(1H)-ones, and 1,6-naphthyridines have a wide range of biological activities. In this work, we propose the thermal rearrangement of 7,9-dihalogen-substituted 5-(2-hydroxy-6-oxocyclohexyl)-5H-chromeno[2,3-b]pyridines in DMSO. Previously unknown 5,7-dihalogenated 5-(2,3,4,9-tetrahydro-1H-xanthen-9-yl)-6-oxo-1,6-dihydropyridines and 10-(3,5-dihalogen-2-hydroxyphenyl)-5,6,7,8,9,10-hexahydrobenzo[b][1,6]naphthyridines were synthesized with excellent yields (90-99%). The investigation of the transformation using 1H-NMR monitoring made it possible to confirm the ANRORC mechanism. The structures of synthesized compounds were confirmed by 2D-NMR spectroscopy.

Inverse α-Effect as the Ariadne's Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities.

Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of ß,δ'-triketones, H2O2, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the "stereoelectronic frustration" of H2O2 and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

A Three-Component Synthesis of 3-Functionally Substituted 5,6-Dihydropyrrolo[2,1-a]isoquinolines.

Synthesis of novel C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines via a three-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal alkynes and CH-acids under microwave irradiation in dry acetonitrile is described. The method developed enables the obtainment of highly functionalized compounds with pharmacophore groups, which are potentially biologically active.

Lewis Acid-Catalyzed Formal (4+2)-Cycloaddition between Cross-Conjugated Azatrienes and Styrylmalonates: The Way to Functionalized Quinolizidine Precursors.

Quinolizidine and azaphenalene alkaloids are common in nature and exhibit a pharmaceutical activity, which stirs up increased interest in expanding the range of methods for the synthesis of the corresponding derivatives. In this work, we attempted to adapt our previously presented method for the synthesis of tetrahydropyridines to the preparation of potential precursors for these heterocycles as a separate development of a necessary intermediate stage. To this end, we studied the reactions of ß-styrylmalonates with N-protected cross-conjugated azatrienes in the presence of Sn(OTf)2. Moreover, the regioselectivity of the process involving unsymmetrically substituted azatrienes was estimated. The diene character of vinyltetrahydropyridines was studied in detail with the participation of PTAD. Finally, for the Ts-protected highly functionalized vinyltetrahydropyridines synthesized, a detosylation method to give new desired azadiene structures as precursors of the quinolizidine core was suggested.

Synthetic Optimizations for Gram-Scale Preparation of 1-O-Methyl d-Glycero-α-d-gluco-heptoside 7-Phosphate from d-Glucose.

Heptose phosphates-unique linkers between endotoxic lipid A and O-antigen in the bacterial membrane-are pathogen-associated molecular patterns recognized by the receptors of the innate immune system. Understanding the mechanisms of immune system activation is important for the development of therapeutic agents to combat infectious diseases and overcome antibiotic resistance. However, in practice, it is difficult to obtain a substantial amount of heptose phosphates for biological studies due to the narrow scope of the reported synthetic procedures. We have optimized and developed an inexpensive and convenient synthesis for the first performed gram-scale production of 1-O-methyl d-glycero-α-d-gluco-heptoside 7-phosphate from readily available d-glucose. Scaling up to such amounts of the product, we have increased the efficiency of the synthesis and reduced the number of steps of the classical route through the direct phosphorylation of the O6,O7-unprotected heptose. The refined method could be of practical value for further biological screening of heptose phosphate derivatives.

Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity.

The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the meta- and para-substituted substrates, the reaction involving ortho-derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its N-methyl analog compared to ortho or meta parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity.

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides.

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at -10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pKa units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C-O interaction with the two antiperiplanar C-O bonds. Due to the weakness of the complementary nO→σ*C-N donation from the peroxide oxygens (a consequence of "inverse α-effect"), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

Coupling of Styrylmalonates with Furan and Benzofuran Carbaldehydes: Synthesis and Chemistry of Substituted (4-Oxocyclopent-2-enyl)malonates.

On the basis of the reaction of ß-styrylmalonates with furfural derivatives in the presence of GaCl3 that occurs with opening of the furan ring, an efficient diastereoselective method for the synthesis of trisubstituted cyclopentenones containing a 1,4-diketone moiety was developed. The regularities of the reaction were studied, and a number of chemical reactions of the resulting substrates were carried out. A mechanism for the formation of substituted (4-oxo-2-arylcyclopent-2-enyl)malonates was suggested.

Reactions of Styrylmalonates with Aromatic Aldehydes: Detailed Synthetic and Mechanistic Studies.

Reactions of styrylmalonates with aromatic aldehydes in the presence of Lewis and Brønsted acids and their regularities have been studied in detail. Approaches to the synthesis of various polysubstituted 5,6-dihydropyran-2-ones, indenes, aryl-containing dienes and trienes, cyclopentadienes, and polycyclic lactones have been developed with chemo-, regio-, stereo-, and diastereoselectivity control. The mechanisms of these reactions were studied in depth using multinuclear NMR experiments, monitoring the reactions in the NMR tube, and 18O isotope labeling.

GaCl3-Mediated Cascade [2 + 4]-Cycloaddition/[4 + 2]-Annulation of Donor-Acceptor Cyclopropanes with Conjugated Dienes: Strategy for the Construction of Benzobicyclo[3.3.1]nonane Skeleton.

Structurally important benzobicyclo[3.3.1]nonane derivatives were synthesized by a gallium trichloride mediated reaction of readily available donor-acceptor cyclopropanes (DACs) with 1,3-dienes as a one-pot cascade ionic [2 + 4]-cycloaddition/Friedel-Crafts-type cyclization process. At the first stage, DACs act as sources of formal gallium 1,2-zwitterionic complexes to give 6-benzylcyclohex-3-ene-1,1-dicarboxylates that are converted under certain conditions in the presence of GaCl3 to give benzobicyclo[3.3.1]nonanes in 30-74% yields. The process is tolerant of varying substituents at different positions of the main framework. Further, potentially useful modifications of benzobicyclo[3.3.1]nonane derivatives are demonstrated. 2-Cyclopropylbutadiene reacts with DAC at higher temperature more deeply with cleavage of three-membered rings in both cyclopropane substrates, and twofold alkylation of the Ph-substituent at ortho- and meta-positions, that leads to a 1,2,7,8,9,10-hexahydro-6H-7,10a-methanocycloocta[cd]indene skeleton. Cyclopropane-1,1-diesters containing a bulky substituent in the ester group react with isoprene in a different way to give bicyclic lactones containing a 2-oxabicyclo[2.2.2]octan-3-one moiety.

"Cyclopropanation of Cyclopropanes": GaCl3-Mediated Ionic Cyclopropanation of Donor-Acceptor Cyclopropanes with Diazo Esters as a Route to Tetrasubstituted Activated Cyclopropanes.

A new ionic cyclopropanation process involving the addition of diazo esters to donor-acceptor cyclopropanes (DAC) activated by GaCl3 has been developed. The reactions occur via 1,2-zwitterionic gallium complexes with elimination of nitrogen in all cases to give 1,1,2,3-tetrasubstituted cyclopropanes as the main products. Also, a number of related processes with the formation of various polysubstituted cyclopropanes, alkenes, and cyclobutanes, including products of multiple diazo ester addition, have been developed. Obtained by the developed method tetrasubstituted cyclopropanes are activated cyclopropanes such as DAC and can be used for further synthesis in this capacity. Their new reaction with benzaldehyde promoted by TiCl4 and involving one of the additional functional groups has been demonstrated, which leads to five-membered lactones. The mechanisms of the occurring processes, as well as the structures and stereochemistry of a rich range of products formed, are discussed in detail.

Dumbbell-Shaped, Graft and Bottlebrush Polymers with All-Siloxane Nature: Synthetic Methodology, Thermal, and Rheological Behavior.

A methodology for synthesizing a wide range of dumbbell-shaped, graft and bottlebrush polymers with all-siloxane nature (without carbosilane linkers) is suggested. These macroarchitectures are synthesized from SiOH-containing compounds-silanol (Et3 SiOH) and siloxanol dendrons of the first and second generations, with various peripheral substituents (Me or Et)-and from linear siloxanes comprising terminal and internal SiH groups by the Piers-Rubinsztajn reaction. Products and key building blocks are obtained in yields up to 95%. These polymers are heat and frost-resistant siloxanes. As it turns out, the product physical properties are determined not only by the macromolecular structure, the linear chain length, the size and frequency of branched pendant, but also by the type of peripheral substituents-Me or Et-in the pendant. Thus, the viscosity of the graft polymers with branched pendant groups comprising peripheral Me-groups is more than ≈3-5 fold lower than that of analogous polymers with peripheral Et-groups.

Synthesis, Structure and Electrochemical Properties of Acetamide- and Caprolactam-Containing Silicon Catecholates.

Hexacoordinated heteroligand silicon catecholates, although being prospective as easily soluble compounds with high hydrolytic stability and diverse redox properties, have been insufficiently studied. The transesterification of 1-(trimethoxysilylmethyl)-2-oxohexahydroaze or N-methyl-N-(trimethoxysilylmethyl)acetamide by two equivalents of catechol derivatives in the presence of dicyclohexylamine afforded a series of target compounds in good yield. The complexes were characterized using elemental analysis, FTIR, 1H, 13C and 29Si NMR spectra, X-ray crystallography and cyclic voltammetry. X-ray diffraction confirmed that the silicon atom possesses the octahedral geometry of the SiCO5 polyhedron that remains unchanged in solution as it follows from 29Si NMR data. The compounds demonstrated up to three oxidation waves; and the reduction profile strongly depended on the nature of the substituents on a catecholate anion.