Sergey V Ryabukhin

• PhD
• Professor (Associate) at Taras Shevchenko National University of Kyiv

A set of Pd-containing composites was prepared by the deposition of Pd on the following carriers: polyaniline (PANI); PANI doped by H2SO4; Norit GSX activated carbon or Aerosil (SiO2) coated by PANI or by H2SO4-doped PANI; PANI after thermal treatment at 300 °C in an atmosphere of H2. One sample was also prepared by the in situ polymerization of an...

A novel efficient synthetic procedure for the synthesis of isatins found on careful analysis of serendipity results of unexpected products of aromatic nucleophilic substitution upon an attempt to introduce 6-fluoroisatins to the classic Pfitzinger reaction. Attentive analysis of these results led to elaborating the methodology for synthesizing elec...

Two-step α-methylation via enamination with subsequent reduction was investigated on various methylene-containing heterocyclic carbonyl compounds including lactams, lactones, thiolactones etc. Outcomes or enamination with Bredereck’s reagent and DMF-DMA were compared. Optimal enamination and reduction protocols regarding solubility, reactivity and...

An efficient method for the preparation of 6-azaindoles bearing 3-formyl functionality from commercially available substrates with (ortho-methyl)aminopyridine moiety is described. This transformation features a distinct, though broad, substrate scope, and simple experimental procedure and can easily be scaled up to 40 g of the target formyl derivat...

The practical rapid development of chemical leads for drug discovery strongly depends on scalable building block synthesis procedures. N-heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them...

Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration,...

2-Methyl benzothiazoles are widely used as key precursor for dyes, photosensitizers and fluorescent markers. Therefore, they are demanded in multigram and even kilogram amounts. Hereby, we propose a scalable single-step procedure for production of 2-alkylsubstituted benzothiazoles from corresponding bis-(2-nitrophenyl)-disulfides. Substrates contai...

Unusual amino acids have arisen as an indispensable instrument at the disposal of modern medicinal chemistry. While extensively exploited as building blocks in the search for new pharmaceuticals, their application goes far beyond and they are currently involved in the exploration of the structure and conformational mobility of peptides, modificatio...

A series of novel spirocyclic α-proline building blocks for drug discovery with a spiro conjunction in position 3 of pyrrolidine was prepared by means of two convenient and practical synthetic approaches. Both alternative routes utilize simple and easily available starting materials – cyclic ketones and esters – and comprise 6- and 7-steps, respect...

Scaffold hopping and three-dimensionality are one of dominating notions in contemporary drug discovery process. Following these concepts is a verified and generally robust avenue to improve the biological activity of a lead against a protein target, selectivity issues as well as ADMET properties. Unfortunately, the freedom of medicinal chemists to...

This study presents a scalable one-pot synthesis of 2,4-disubstituted-(1,3)thiazoles using diazoketones with thiosemicarbazide or thiourea, achieving high yields across various substrates. Thiazole derivatives demonstrate diverse biological activities (antibacterial, antiviral, anticancer, etc.) and applications in nanoelectronics and material scie...

This work highlights stellane's cage stability and derivatization opportunities. Using modern synthesis protocols, a di-verse range of building blocks were synthesized. Stellane's reactivity and chemical tolerance were rigorously evaluated across different reaction systems, demonstrating its promise as a bio-isosteric scaffold. It can be utilized i...

The practical rapid development of chemical leads for drug discovery is strongly dependent on scalable procedures for building block synthesis. N-heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions bet...

The scope and limitation of classical Biginelli reaction expanded to principally novel substrates: sulfamide and its monosubstituted analogues. The preparative procedure was optimized. The reasons for the unavailability of such...

A scalable and efficient synthesis of the 2-trifluoromethyl-3-trifluoroacetyl-6-azaindoles from 3-amino-4-methylpyridines under treatment with TFAA was disclosed. The reaction scope and limitation towards the pyridine and electrophilic components were investigated. Activation...

Actual problems of development of catalysts for hydrogenation of heterocyclic compounds by hydrogen are summarized and discussed. The scope of review covers composites of nanoparticles of platinum group metals and 3d metals for heterogeneous catalytic processes. Such problems include increase of catalyst activity, which is important for reduction o...

Numerous studies reported an association between GABA A R subunit genes and epilepsy, eating disorders, autism spectrum disorders, neurodevelopmental disorders, and bipolar disorders. This study was aimed to find some potential positive allosteric modulators and was performed by combining the in silico approach with further in vitro evaluation of i...

A set of 22 composites was prepared by pyrolysis of Cu2+ complexes with phenanthroline and 1,2-diaminobenzene, deposited on SiO2 (Aerosil). All composites contained Cu and carboneous components, while some of them additionally contained Cu2O or CuCl. According to the data of powder X-ray diffraction, the size of Cu nanoparticles was 20-37 nm. The p...

Herein, we present previously unavailable C(sp³)‐rich polycyclic hydrocarbon scaffolds that have the potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7]octane (bisno...

Modern organic chemistry is a titan supporting and reinforcing pharmaceutical, agricultural, food and material science products. Over the past decades, the organic compounds market has been evolving to meet all the research demands. In this regard, medicinal chemistry is especially dependent on available chemical space as subtle tuning of the molec...

The scope and limitation of classical Biginelli reaction expanded to principally novel substrates: sulfamide and its monosubstituted analogues. The preparative procedure was optimized. The reasons for the unavailability of such compounds earlier were determined. The relationship between the structure and stability of final compounds and the nature...

A scalable and efficient synthesis of the 2-trifluoromethyl-3-trifluoroacetyl-6-azaindoles from 3-amino-4-methylpyridines under treatment with TFAA was disclosed. The reaction scope and limitation towards the pyridine and electrophilic components were investigated. Examining the pyridine components using trifluoroacetic anhydride (TFAA) as a model...

Herein we present previously unavailable C(sp3)-rich polycyclic hydrocarbon scaffolds which have a potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7]octane (bisnora...

Herein we present previously unavailable C(sp3)-rich polycyclic hydrocarbon scaffolds which have a potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7]octane (bisnora...

A novel approach for a safe generation of the diazomethane-contained organic solution has been proposed using a serial flow reactor. The productivity of the diazomethane generation has reached 0.45 mol/h. Several chiral diazoketones have been prepared in quantities up to 150 g through the reaction of diazomethane with mixed anhydrides, generated in...

Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood dise...

A series of composites containing nanoparticles of NiO (from 1 to 10% by weight per Ni), deposited on NORIT charcoal, was prepared by the decomposition of the Ni0 complex Ni(cod)2 (cod = cis,cis-1,5-cyclooctadiene). Ni content in the composites was set by loading the appropriate quantities of the Ni(cod)2 precursor. The catalytic activity of the co...

Catalytic activity in arylzinc compound formation was studied for eight Co complexes with phosphines along with their redox properties for implementing the idea of rational design. It was found that Co(XantPhos)Cl2 and Co(N-XantPhos)Cl2 demonstrated distinct reversible CoII/CoI redox processes and acted as efficient catalysts of arylzinc compound f...

Catalytic borylations of sp³ C–H bonds occur with high selectivities for primary C–H bonds or secondary C–H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C–H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes...

The performance of a series of cobalt-based composites in catalytic amination of aromatic aldehydes by amines in the presence of hydrogen as well as hydrogenation of quinoline was studied. The composites were prepared by pyrolysis of CoII acetate, organic precursor (imidazole, 1,10-phenantroline, 1,2-diaminobenzene or melamine) deposited on aerosil...

An efficient chlorotrimethylsilane-promoted synthetic protocol for the preparation of functionalized fused β-trifluoromethyl pyridines by cyclization of electron-rich aminoheterocycles or substituted anilines with a trifluoromethyl vinamidinium salt was developed. The efficient and scalable approach for producing represented trifluoromethyl vinamid...

A series of seven palladium-containing composites, i.e., four Pd/C and three Pd(OH)2/C (Pearlman’s catalysts), was prepared using modified common approaches to deposition of Pd or hydrated PdO on charcoal. All the composites were tested in the catalytic hydrogenation of diene carboxylates with the isolated-ring scaffold, e.g., 5,6-dihydropyridine-1...

In this research, the oxidation of a series of benzoins, R-C(=O)-CH(OH)-R, where R = phenyl, 4-methoxyphenyl, 4-bromophenyl, and 2-naphthyl, by hydrogen peroxide in the presence of nanostructured HKUST-1 (suspension in acetonitrile/water mixture) was studied. The respective benzoic acids were the only products of the reactions. The initial average...

Aim. To share our experience when working with the Pd-catalyzed hydrogenation and discuss reactions occurred contrary to our expectations, as well as express our vision of the causes for such an unusual reactivity. Results and discussion. Catalysis is a key technology and among the central themes of both petrochemical and fine chemical industries....

New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.2 million compounds) was virtually screened accor...

Here, neuromodulatory effects of selective ACE2 inhibitors were investigated. Two different types of small molecule ligands for ACE2 inhibition were selected using chemical genetic approach, they were synthesized using developed chemical method and tested using presynaptic rat brain nerve terminals (synaptosomes). EBC-36032 (1 µM) increased in a do...

A set of building blocks based on the 4,5,6,7‐tetrahydro‐pyrazolo[1,5‐a]pyrazine scaffold is synthesized in a multigram scale in a cost‐efficient manner. The possibility of the introduction of different substituents, neutral or functionalized in different positions of pyrazole and/or piperazine rings, is shown. The efficacy of using NH‐pyrazole car...

Catalytic borylations of sp3 C–H bonds occur with high selectivities for primary C–H bonds or secondary C–H bonds that are activated by nearby electron-withdrawing substituents. The catalytic borylation at tertiary C–H bonds has not been observed. We describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes...

Physico‐chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem‐difluorinated cycloalkanes and compared to those of non‐fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the C...

The CF2 dragon reborn! The difluoromethylene dragon has evolved from difluorocyclopropanations (presented in a series of previous covers, see Adv. Synth. Catal., DOI: 201801304 and Eur. J. Org. Chem. 201900911) to the full strength of all other gem‐difluorocycloalkanes. In the Research Article by O. O. Grygorenko and co‐authors (DOI: 10.1002/chem.2...

A set of 20 composites was prepared by pyrolysis of Co²⁺ complexes with 1,10‐phenanthroline, melamine and 1,2‐diaminobenzene. These composites were tested as the catalysts for the hydrogenation of quinolines. As shown by powder X‐ray diffraction and TEM, the composited contained Co particles of several dozen nm sizes. The composition (elements cont...

We elaborate new models for ACE and ACE2 receptors with an excellent prediction power compared to previous models. We propose promising workflows for working with huge compound collections, thereby enabling us to discover optimized protocols for virtual screening management. The efficacy of elaborated roadmaps is demonstrated through the cost-effec...

A general approach to gem‐difluorocyclopropenes synthesis based on the reaction of alkynes with Ruppert‐Prakash reagent is reported. The proposed method is evaluated for the synthesis of a wide difluorocyclopropenes scope based on their bench lifespan and hydrolytic stability. The tolerance of the method for common functional groups was shown. Prev...

The ability to efficiently synthesize desired compounds can be a limiting factor for chemical space exploration in drug discovery. This ability is conditioned not only by the existence of well-studied synthetic protocols but also by the availability of corresponding reagents, so-called building blocks (BB). In this work, we present a detailed analy...

The ability to efficiently synthesize desired compounds can be a limiting factor for chemical space exploration in drug discovery. This ability is conditioned not only by the existence of well-studied synthetic protocols but also by the availability of corresponding reagents, so-called building blocks (BB). In this work, we present a detailed analy...

Here we present a new open-source toolkit for library design, called Synthons Interpreter or SynthI that allows merging those chemical space of the retrosynthetically generated fragments and the pool of available reagents into a single synthons space. Here synthons are defined as the actual fragments with valid valences and special labels, defining...

Here we present a new open-source toolkit for library design, called Synthons Interpreter or SynthI that allows merging those chemical space of the retrosynthetically generated fragments and the pool of available reagents into a single synthons space. Here synthons are defined as the actual fragments with valid valences and special labels, defining...

Here we present a new open-source toolkit for library design, called Synthons Interpreter or SynthI that allows merging those chemical space of the retrosynthetically generated fragments and the pool of available reagents into a single synthons space. Here synthons are defined as the actual fragments with valid valences and special labels, defining...

Here we present a new open-source toolkit for library design, called Synthons Interpreter or SynthI that allows merging those chemical space of the retrosynthetically generated fragments and the pool of available reagents into a single synthons space. Here synthons are defined as the actual fragments with valid valences and special labels, defining...

The third generation Buchwald precatalysts Pd(ABP)(Phos)(OMs) (also known as Phos Pd G3)) with XPhos and RuPhos were prepared in multigram scale by a modified procedure (ABP = fragment of C-deprotonated 2-aminobiphenyl, XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, RuPhos = 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, OMs⁻ =...

A homology model of Nav1.5, based mainly on the crystal structures of Nav1.2/1.5 was built, optimized and successfully inserted into the membrane bilayer. We applied steered and free MD simulation protocols for the visualization of the mechanism of Nav1.5 activation. We constrained dihedrals of S4 trigger to introduce a structural tension with furt...

The gem‐difluorocycloalkane family was extended to all possible regioisomers of the gem‐difluorocycloheptane, monofunctionalized by carboxilic‐, amino‐ or keto‐ group, that were synthesized on a multigram scale. The preparation of the corresponding building blocks was achieved from readily accessible starting materials either via six‐membered ring...

The new efficient, convenient protocol for the synthesis of heteroannelated 3-cyanopyridines and pyrimidines starting from diverse aminoheterocycles and 3,3-dimethoxy-2-formylpropionitrile sodium salt was elaborated. The advantages and improvements of the procedure compared to previously known methods were shown. The scope and limitations of the me...

The approaches to immobilization of metal-complex catalysts for organic processes of hydrogenation, alkene metathesis, and cross-coupling on silica and polymeric and other carriers are considered. The advantages and lack of modern approaches to the creation of such systems are analyzed. It was shown that the stability of the catalyst with immobiliz...

The microreview presents a comprehensive survey of application of [3-(dimethylamino)-2-(trifluoromethyl)prop-2-en-1-ylidene]dimethylazanium salts as efficient precursors for the synthesis of trifluoromethyl-substituted azaheterocycles. The current state of the art is presented by the most important recent examples (until the end of 2019).

[Figure not available: see fulltext.][Figure not available: see fulltext.]Different approaches and recent advances in methodologies for the synthesis of α-spirocyclic pyrrolidines are presented. The microreview covers the latest selected examples (2009–2019) on the synthesis of such compounds based on pyrrolidine ring construction. The advantages a...

A new, high yielding and practical synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole, key intermediates for important Medicinal and Agro Chemistry relevant building blocks, is developed. One step procedure for the regioisomeric mixture of target pyrazoles was proposed starting from 4-ethoxy-1,1,1-tri...

It is shown that a composite containing nickel nanoparticles and carboneous multi-layer graphene-like particles on aerosil, prepared by pyrolysis of deposited nickel complex with melamine, catalyzes hydrogenation of furfural to furfuryl alcohol as well as hydrogenation of quinoline to 1,2,3,4-tetrahydroquinoline. The highest yield of hydrogenation...

The reactivity of azomethines based on trifluoroacetaldehyde hydrate in the Castagnoli–Cushman reaction (CCR) was researched. The impact of the nature of anhydrides explored on the reaction route was determined. The preparative procedures for the synthesis of N-substituted (3R*,4R*)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxy...

In situ reduction of NiCl2 incorporated in porous coordination polymer MIL-101(Cr) by NaBH4 or reduction of PdCl2 incorporated in MIL-101(Cr) by H2 led to formation of NixB/MIL-101(Cr) and Pd/MIL-101(Cr) composites, respectively. Hydrogenation of quinoline at presence of these composites led to formation of 1,2,3,4-tetrahydroquinoline in more than...

The electrochemical Shono oxidation of Boc‐protected cyclic amines was revised. The conditions for scalable electrochemical synthesis of cyclic enecarbamates were found. The developed protocol included recycling of the full range of used reagents, favoring to E‐factor reduction according to Green Chemistry requirements. The method opened the way fo...

Drug discovery uses both natural product sources and synthetic organic chemistry to provide suitable starting points for further optimization. Producing such compounds in a time‐, quality‐, and cost‐efficient manner has become one of the most important applied tasks of the chemical sciences. Similarly, drug discovery has had an impact on the direct...

The possibility of deoxofluorination of β-keto esters using SF4 was investigated. The scope and limitation of the reaction were determined. The efficient method for the synthesis of β,β-difluorocarboxylic acids was elaborated based on the reaction. The set of mentioned acids, being the perspective building blocks for medicinal chemistry, were synth...

All pharmaceutical products contain organic molecules; the source may be a natural product or a fully synthetic molecule, or a combination of both. Thus, it follows that organic chemistry underpins both existing and upcoming pharmaceutical products. The reverse relationship has also affected organic synthesis, changing its landscape towards increas...

Base‐promoted cyclization of N‐Boc‐ω‐(4‐(chloromethyl)oxazol‐5‐yl)alkylamines led to the corresponding “dimerization” products containing fused 10‐, 12‐, and 14‐membered rings. Experimental data showed that the formation of these ring systems is favored over the corresponding 5‐/6‐/7‐membered ones, which was partially confirmed by DFT calculations;...

The Front Cover shows the “difluoro‐cyclopropanating dragon” (which has been already used to depict the CF3SiMe3 – the NaI system through the series of authors' previous works), who has aimed at new class of substrates, i.e. N‐vinylazoles, and thus reached a novel area of chemical space occupied by fluorinated cyclopropane derivatives. This method...

An efficient approach to the preparation of novel sp³-enriched 4,5-disubstituted oxazoles bearing a functional group at the C-4 position is described. The method commenced with synthesis of ethyl oxazole-4-carboxylates (13 examples, 63–99% yield), with subsequent function insertion to the heterocyclic core by late-stage functional group transformat...

An efficient approach towards introducing (cyclo)alkyl substituents at C‐2, C‐3 or C‐4 positions of the piperidine ring was described. The method relied on the straightforward two‐step reaction sequence based on the formal sp³–sp³ retrosynthetic disconnection. The procedure commenced with selective directed ortho metalation of 2‐ and 3‐bromopyridin...

Difluorocyclopropanation of N‐vinylazoles with the CF3SiMe3–NaI system was studied. It was found that N‐vinylpyrazoles could be transformed into the corresponding N‐difluorocyclopropyl‐substituted derivatives. The method was efficient on a 100 g scale and could be applied for the preparation of various functionalized regioisomeric pyrazole derivati...

An approach to the synthesis of 3-substituted piperidines bearing partially fluorinated alkyl groups was proposed. The method was based on the DAST-mediated nucleophilic fluorination of easily available 2-bromopyridin-3-yl alcohols and ketones affording 2-bromo-3-(1-fluoroalkyl)pyridines and 2-bromo-3-(1,1-difluoroalkyl)pyridines, respectively, fol...

The Front Cover shows piperidine derivatives depicted at the magical Rubik's cube, which is falling down from the chemical space to the dark woods of possible applications. This 3D puzzle symbolizes possibility to construct all isomeric (cyclo)alkylpiperidines – advanced sp3 enriched building blocks for drug discovery. Background photo by Andriy Ya...

Synthetic approaches toward multigram preparation of spirocyclic α,α-disubstituted pyrrolidines from readily available starting materials are discussed. It was shown that although a number of synthetic methodologies have been known to date, many of the title compounds remain hardly accessible. The most appropriate literature method (which relied on...

An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)¬cyclobutanone. Dissociation constants (pKa) and LogP values for 2,2-difluorocyclobutaneamin...

An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid-a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C1-binucleophile and the catalytic reduction of the pyridine ring as the key steps and al...