(Diazomethyl)dimethylphosphine Oxide - A Diazoalkane Reagent for [3+2] Cycloadditions.

A safe and efficient method for the in-situ preparation of (diazomethyl)dimethylphosphine oxide - a hereto unexplored diazoalkane reagent - is developed. The method is based on the diazotization of the corresponding P(O)Me2-substituted amine (readily available in multigram quantities) in non-aqueous media. The protocol provides the target product as ca. 1.5 M CHCl3 solution which is stable at -18 °C. The utility of the synthesized diazoalkane is illustrated by its [3+2] cycloaddition with electron-poor alkynes and alkenes providing the corresponding P(O)Me2-substituted pyrazoles and pyrazolines with moderate to good efficiency. In this view, the title compound represents and an important extension of medicinally relevant phosphine oxide reagents.

SNAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design.

The chemoselectivity of halo(het)arene sulfonyl halide aminations is studied thoroughly under parallel synthesis conditions, and the scope and limitations of the method are established. It is shown that SNAr-reactive sulfonyl halides typically undergo sulfonamide synthesis during the first step; the second amination is also possible provided that the SNAr-active center is sufficiently reactive. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper control. Further sulfur-fluoride exchange (SuFEx) is also possible, which can be especially valuable for some sulfonyl halide classes. The developed two-step parallel double amination protocol provides access to a 6.67-billion compound synthetically tractable REAL-type chemical space (76% expected synthesis success rate).

Organocatalytic Decarboxylative Borylation of Cyclopropane N-Hydroxyphthalimide Esters.

A convenient protocol for the two-step organocatalytic decarboxylative borylation of 1,1-disubstituted, 1,2-disubstituted, and bicyclic cyclopropane carboxylic acids via the corresponding N-hydroxyphthalimide esters is described, using tert-butyl or ethyl isonicotinate as an inexpensive and readily available catalyst. The scope of the method was demonstrated, being limited mainly by electron-poor substrates. The reaction sequence showed good scalability (up to 51.5 g) and excellent trans diastereoselectivity (for the case of 1,2-disubstituted substrates). Therefore, the proposed approach is a very promising alternative to other existing (i.e., metal-catalyzed) methods for borodecarboxylation.

Chemistry in Ukraine.

In this special issue, we highlight recent advances in chemical research by scientists in Ukraine, as well as by their compatriots and collaborators outside the country. Besides spotlighting their contributions, we see our task in fostering global partnerships and multi-, inter-, and trans-disciplinary collaborations, including much-needed co-funded projects and initiatives. The three decades of the renewed Ukraine independence have seen rather limited integration of Ukrainian (chemical) science into global research communities.[1] At the same time, the recent surge of collaborative science initiatives between European Union (EU) and Ukraine echoes the unfolding steps towards Ukraine's full research participation to the Horizon Europe Program. This recently implemented step opens enormous possibilities for Ukrainian researchers to apply for diverse EU research grants. Moreover, a number of journal special issues and collections were launched to highlight Ukrainian chemistry (i. e., by Chemistry of Heterocyclic Compounds[2] and ChemistrySelect[3] ). Other scientific initiatives include 'European Chemistry School for Ukrainians'[4] and 'Kharkiv Chemical Seminar'[5] as voluntary projects aimed at engaging Ukrainian scientists into European and international chemical research.

[3+2] Cycloaddition of Alkynyl Boronates and in†situ Generated Azomethine Ylide.

Scalable [3+2] cycloaddition of alkynyl boronates and in situ generated unstabilized azomethine ylide is reported for the first time. The selective formation of either 1 : 1 or 1 : 2 cycloaddition products was achieved by carefully optimizing the reaction conditions, mainly by controlling the reactant stoichiometry, catalyst loading, and internal temperature. The developed protocol tolerated many valuable functional groups, including TMS, protected alcohol (as ether or THP derivatives), or aldehyde (as acetal). Further common C-C and C-heteroatom bond-forming reactions, as well as scaled-up procedures demonstrate the utility of the prepared compounds as building blocks for organic synthesis and drug discovery.

Chemoselective Reactions of Functionalized Sulfonyl Halides.

Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2 F group - from amide and ester formation to directed ortho-lithiation and transition-metal-catalyzed cross-couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of "another click reaction". On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2 Cl moiety.

Insights into Modeling Approaches in Chemistry: Assessing Ligand-Protein Binding Thermodynamics Based on Rigid-Flexible Model Molecules.

In the field of chemistry, model compounds find extensive use for investigating complex objects. One prime example of such object is the protein-ligand supramolecular interaction. Prediction the enthalpic and entropic contribution to the free energy associated with this process, as well as the structural and dynamic characteristics of protein-ligand complexes poses considerable challenges. This review exemplifies modeling approaches used to study protein-ligand binding (PLB) thermodynamics by employing pairs of conformationally constrained/flexible model molecules. Strategically designing the model molecules can reduce the number of variables that influence thermodynamic parameters. This enables scientists to gain deeper insights into the enthalpy and entropy of PLB, which is relevant for medicinal chemistry and drug design. The model studies reviewed here demonstrate that rigidifying ligands may induce compensating changes in the enthalpy and entropy of binding. Some "rules of thumb" have started to emerge on how to minimize entropy-enthalpy compensation and design efficient rigidified or flexible ligands.

Bypassing Sulfonyl Halides: Synthesis of Sulfonamides from Other Sulfur-Containing Building Blocks.

This review disclosed synthetic approaches to sulfonyl amides from non-sulfonyl halogenated precursors. Known methods were systematized into groups and subgroups according to the type of starting organosulfur compound. Thiols, disulfides, and sulfonamides form a group of S(II)-containing precursors, which are used in oxidative amination reactions. An important and versatile group for oxidative amination is represented with S(IV)-containing compounds, i. e., sufinates, sulfinamides, DMSO, N-sulfinyl-O-(tert-butyl)hydroxylamine, etc. A series of S(VI)-containing precursors for amination reactions (except sulfonyl halides) include sulfonic acids, sulfonyl azides, thiosulfonates, and sulfones. All approaches are represented with the most prominent examples of the resulting sulfonamides, which could be obtained in high yields mostly via short reaction sequences. Promising electrochemical methods for the preparation of sulfonamides from thiols, disulfides, sulfonamides, sulfinic acid derivatives, and dimethyl sulfoxide under mild and green conditions are also highlighted.

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization.

Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.

Photochemical [2+2] Cycloaddition of Alkynyl Boronates.

A photochemical [2+2] cycloaddition of alkynyl boronates and maleimides is reported. The developed protocol provided 35-70 % yield of maleimide-derived cyclobutenyl boronates and demonstrated wide compatibility with various functional groups. The synthetic utility of the prepared building blocks was demonstrated for a range of transformations, including Suzuki cross-coupling, catalytic or metal-hydride reduction, oxidation, and cycloaddition reactions. With aryl-substituted alkynyl boronates, the products of double [2+2] cycloaddition were obtained predominantly. Using the developed protocol, a cyclobutene-derived analogue of Thalidomide was prepared in one step. Mechanistic studies supported the participation of the triplet-excited state maleimides and ground state alkynyl boronates in the key step of the process.

Mono- and Difluorinated Saturated Heterocyclic Amines for Drug Discovery: Systematic Study of Their Physicochemical Properties.

A comprehensive study of physicochemical properties (pKa , LogP, and intrinsic microsomal clearance) within the series of mono- and difluorinated azetidine, pyrrolidine, and piperidine derivatives was performed. While the number of fluorine atoms and their distance to the protonation center were the major factors defining the compound's basicity, both pKa and LogP values were affected considerably by the conformational preferences of the corresponding derivatives. For example, features of "Janus face" (facially polarized) cyclic compounds (i. e., unusually high hydrophilicity) were identified for cis-3,5-difluoropiperidine, preferring a diaxial conformation. Intrinsic microsomal clearance measurements demonstrated high metabolic stability of the compounds studied (with a single exception of the 3,3-difluoroazetidine derivative). According to pKa - LogP plots, the title compounds provide a valuable extension of the fluorine-containing (e. g., fluoroalkyl-substituted) saturated heterocyclic amine series as building blocks for rational optimization studies in early drug discovery.

Screening of Palladium/Charcoal Catalysts for Hydrogenation of Diene Carboxylates with Isolated-Rings (Hetero)aliphatic Scaffold.

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(2H)-carboxylates with 2-(alkoxycarbonyl)cyclopent-1-en-1-yl and hex-1-en-1-yl substituents at the C(4)-position. The performance of the composites was also studied via the hydrogenation of quinoline as a model reaction. The composites were characterized by transmission and scanning electron microscopy (TEM and SEM), powder X-ray diffraction, and low-temperature N2 adsorption. It was found that the composites containing Pd nanoparticles (NPs) of 5-40 nm size were the most efficient catalysts for the hydrogenation of dienes, providing the reduced products with up to 90% yields at p(H2) = 100 atm, T = 30 °C for 24 h. The method of Pd NPs formation had more effect on the catalyst performance than the size of the NPs. The catalytic performance of Pearlman's catalysts (Pd(OH)2/C) in the hydrogenation of dienes was comparable to or lower than the performance of the Pd/C systems, though the Pearlman's catalysts were more efficient in the hydrogenation of quinoline.

Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes.

An efficient approach to the synthesis of previously unavailable or hardly accessible 1,2-difunctionalized cyclobutanes (mostly with NH2/NHBoc, OH, SH, or SO2F groups attached to the carbocycle either directly or via a CH2 unit) relying on the divergent strategy is described. This class of compounds provides sp3-enriched and conformationally restricted building blocks that are of special demand for medicinal chemistry. The target compounds were prepared not only as pure racemic (±)-cis- and (±)-trans-diastereomers but in some cases also as single enantiomers. The developed procedures are readily scaled up and allow obtaining the target compounds on an up to hundred-gram scale. On the basis of the results of 20 X-ray diffraction experiments, structural characterization of the 1,2-difunctionalized cyclobutane core was performed using the extended Cremer-Pople puckering parameters and exit vector (EVP) plots.

C-C Coupling through Nitrogen Deletion: Application to Library Synthesis.

Invited for the cover of this issue are Oleksandr Grygorenko and his Ukrainian colleagues at Enamine Ltd., Taras Shevchenko National University of Kyiv, National Academy of Sciences of Ukraine, and ChemSpace, as well as Mark Levin at the University of Chicago. The image depicts application of a nitrogen-deleting anomeric amide to parallel C(sp3 )-C(sp3 ) coupling. Read the full text of the article at 10.1002/chem.202203470.

Metal-Free C-H Difluoromethylation of Imidazoles with the Ruppert-Prakash Reagent.

The reaction of trimethyl(trifluoromethyl)silane-tetrabutylammonium difluorotriphenylsilicate (CF3SiMe3-TBAT) with a series of imidazoles gives products of the formal difluorocarbene insertion into the C-H bond at the C-2 position (i.e., C-difluoromethylation). According to NMR spectra, the corresponding 2-(trimethylsilyl)difluoromethyl-substituted derivatives are likely formed as the intermediates in the reaction, and then, they slowly convert to 2-difluoromethyl-substituted imidazoles. Quantum chemical calculations of two plausible reaction mechanisms indicate that it proceeds through the intermediate imidazolide anion stabilized through the interaction with solvent molecules and counterions. In the first proposed mechanism, the anion reacts with difluorocarbene without an activation barrier, and then, the CF2 moiety of the adduct attacks the CF3SiMe3 molecule. After the elimination of the CF3 anion, 2-(trimethylsilyl)difluromethyl-substituted imidazole is formed. Another possible reaction pathway includes silylation of imidazolide anion at the N-3 atom, followed by the barrierless addition of difluorocarbene at the C-2 atom and then by 1,3-shift of the SiMe3 group from N-3 to the carbon atom of the CF2 moiety. Both proposed mechanisms do not include steps with high activation barriers.

C-C Coupling through Nitrogen Deletion: Application to Library Synthesis.

A protocol for parallel C(sp3 )-C(sp3 ) coupling of (hetero)aromatic aldehydes and (hetero)arylmethyl amines based on a reductive amination - "nitrogen deletion" reaction sequence has been developed. After preliminary validation experiments, an illustrative compound library of 25 members was prepared with 76 % synthetic efficiency. The estimated chemical space accessible by the proposed approach covers almost 600 000 representatives that are scarcely represented in current compound databases.

Advancing molecular graphs with descriptors for the prediction of chemical reaction yields.

Chemical yield is the percentage of the reactants converted to the desired products. Chemists use predictive algorithms to select high-yielding reactions and score synthesis routes, saving time and reagents. This study suggests a novel graph neural network architecture for chemical yield prediction. The network combines structural information about participants of the transformation as well as molecular and reaction-level descriptors. It works with incomplete chemical reactions and generates reactants-product atom mapping. We show that the network benefits from advanced information by comparing it with several machine learning models and molecular representations. Models included logistic regression, support vector machine, CatBoost, and Bidirectional Encoder Representations from Transformers. Molecular representations included extended-connectivity fingerprints, Morgan fingerprints, SMILESVec embeddings, and textual. Classification and regression objectives were assessed for each model and feature set. The goal of each classification model was to separate zero- and non-zero-yielding reactions. The models were trained and evaluated on a proprietary dataset of 10 reaction types. Also, the models were benchmarked on two public single reaction type datasets. The study was supplemented with analysis of data, results, and errors, as well as the impact of steric factors, side reactions, isolation, and purification efficiency. The supplementary code is available at https://github.com/SoftServeInc/yield-paper.

Challenges for chemistry in Ukraine after the war: Ukrainian science requires rebuilding and support.

The unprovoked Russian invasion has created considerable challenges for Ukrainian science. In this article, we discuss actions needed to support and rebuild Ukrainian science and educational systems. The proposed actions take into account past Ukrainian scientific achievements including developments in organic chemistry.

Impact of ß-perfluoroalkyl substitution of proline on the proteolytic stability of its peptide derivatives.

A series of all stereoisomers of ß-CF3 or ß-C2F5 substituted prolines and their dipeptide derivatives were synthesized. Mouse plasma stability assay was carried out to study the impact of fluoroalkyl substituents on the proteolytic stability of proline-derived peptides. The effect of the (R)-/(S)-configuration at the C-2 atom in combination with electronic and steric effects imposed by fluoroalkyl groups was addressed to rationalize the difference in the half-life stability of diastereomeric ß-CF3-Pro-Gly and ß-C2F5-Pro-Gly derivatives and compared to those of parent (S)-Pro-Gly and (R)-Pro-Gly dipeptides. The steric effect was predominant when the ß-CF3 or ß-C2F5 group was placed properly to create a spatial interference within the pockets of proteases, thereby protecting the substances from degradation (e.g., for cis-isomeric derivatives). Otherwise, a smaller electronic effect accelerating proteolysis was in charge (i.e., for the (2S,3S) isomers).

Fluorinated Cycloalkyl Building Blocks for Drug Discovery.

The review covers various aspects of fluorinated cycloalkyl (C3 -C7 ) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine-containing substrates, as well as some newer reactions like fluorination of non-activated and remotely activated C-H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.