Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space

Two novel solid reagents—1-sulfonimidoyl- and 1-sulfamimidoyl-3-methylimidazolium derivatives—for the synthesis of sulfonimidamides and imidosulfuric diamides, respectively, were developed. It is shown that these reagents are very effective in substitution reactions with various N- and O-nucleophiles; therefore, they significantly extend the accessibility to the chemical space covered by organosulfur(VI) compounds with S=N bonds. In addition, previously unknown imidosulfuric diamides with free imino nitrogen groups were prepared, and their physical and chemical properties were characterized (including molecular geometry, pK_a, Log P, microsomal stability, and reactivity towards typical electrophiles). Similar to other organosulfur(VI) derivatives with S=N bonds, these compounds can be considered as promising bioisosteres of amides, ureas, or sulfonamides.     

Saturated Boronic Acids,Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

This review discusses recent advances in the chemistry of saturated boronic acids, boronates, and trifluoroborates. Applications of the title compounds in the design of boron-containing drugs are surveyed, with special emphasis on α-amino boronic derivatives. A general overview of saturated boronic compounds as modern tools to construct C(sp³)−C and C(sp³)-heteroatom bonds is given, including recent developments in the Suzuki-Miyaura and Chan-Lam cross-couplings, single-electron-transfer processes including metallo- and organocatalytic photoredox reactions, and transformations of boron “ate” complexes. Finally, an attempt to summarize the current state of the art in the synthesis of saturated boronic acids, boronates, and trifluoroborates is made, with a brief mention of the “classical” methods (transmetallation of organolithium/magnesium reagents with boron species, anti-Markovnikov hydroboration of alkenes, and the modification of alkenyl boron compounds) and a special focus on recent methodologies (boronation of alkyl (pseudo)halides, derivatives of carboxylic acids, alcohols, and primary amines, boronative C−H activation, novel approaches to alkene hydroboration, and 1,2-metallate-type rearrangements).     

Acyl pyruvates as synthons in the Biginelli reaction

Chlorotrimethylsilane-promoted Biginelli-type reaction of ethyl 2,4-dioxo-4-phenylbutanoate, benzaldehyde, and various (thio)ureas is explored. The outcome of the reaction depends on the structure of the (thio)urea used and is strongly affected by the acceptor electronic properties of the COOEt substituent in the molecule of the starting β-dicarbonyl compound. The di- and tetrahydropyrimidine derivatives obtained possess two functional groups with orthogonal reactivity, and thus represent promising building blocks for drug discovery.     

Synthesis of azachromones and azachromanones

Chemistry of Heterocyclic Compounds - This minireview highlights known methods for the synthesis of azachromones and azachromanones, including the earliest and the latest examples of their...     

3-Fluoroalkyl (CF3, CHF2, CH2F) Cyclobutane-Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties

Synthesis and physicochemical characterization of all possible cis- and trans-1,3-disubstituted cyclobutane-derived amines and carboxylic acids bearing mono-, di- and trifluoromethyl groups at the C-3 position is disclosed. Tetramethylammonium fluoride (TMAF)- or morpholinosulfur trifluoride (Morph-DAST)-mediated nucleophilic fluorination of appropriate cis- and trans-diastereomeric substrates was used as the key step for the preparation of CH₂F- and CHF₂-substituted derivatives. To obtain the corresponding cis- and trans-isomeric CF₃-substituted derivatives, resolution of known 3-(trifluoromethyl)cyclobutanecarboxylic acid (obtained as a mixture of diastereomers) was applied. The proposed procedures were suitable for the preparation of corresponding fluoroalkyl-substituted cyclobutane-derived amines and carboxylic acids on up to 50 g scale. All 12 building blocks obtained were characterized by measuring dissociation constants (pK_a) and lipophilicities (LogP, for model derivatives) to evaluate the effect of the fluoroalkyl substituents on their physicochemical properties relevant to further drug discovery applications.     

Multigram Synthesis of α- and γ-((Hetera)cyclo)alkylpyridines through α-Arylation of (Hetero)aliphatic Nitriles

A systematic study on the S_nAr reaction of halogenated fluoropyridines and (hetero)aliphatic nitrile anions as an approach to the synthesis of functionalized pyridines bearing a (cyclo)alkyl or saturated heterocyclic substituent by is described. The scope of the method was demonstrated on a wide range of (hetero)aliphatic nitriles (including three- to six-membered cycloalkane derivatives and N-, O-, S-containing saturated heterocycles) and all isomeric halogenated 2-and 4-fluoropyridines. High chemo- and regioselectivity (i. e., exclusive substitution of the fluorine atom), as well as excellent scalability of the proposed reaction sequence were demonstrated (up to 450 g for the arylation step or up to 77 g of cycloalkylpyridine over two steps in a single run). The utility of the synthesized products was illustrated in the additional functional group transformations resulting in synthetically valuable pyridine-containing building blocks.     

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.     

Recyclizations of 3-formylchromones with binucleophiles

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