Dmitry Dar’in

Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)PdII Complexes

The reaction of cis-[PdCl2(CNXyl)2] (Xyl = 2,6-Me2C6H3) with various 1,3-thiazol- and 1,3,4-thiadiazol-2-amines in chloroform gives a mixture of two regioisomeric binuclear diaminocarbene complexes. For 1,3-thiazol-2-amines the isomeric ratio depends on the reaction conditions and kinetically (KRs) or thermodynamically (TRs) controlled regioisomers were obtained at room temperature and on heating, respectively. In CHCl3 solutions, the isomers are subject to reversible isomerization accompanied by the cleavage of Pd-N and C-N bonds in the carbene fragment XylNCN(R)Xyl. Results of DFT calculations followed by the topological analysis of the electron density distribution within the formalism of Baders theory (AIM method) reveal that in CHCl3 solution the relative stability of the regioisomers (ΔGexp = 1.2 kcal/mol; ΔGcalcd = 3.2 kcal/mol) is determined by the energy difference between two types of the intramolecular chalcogen bonds, viz. S···Cl in KRs (2.8-3.0 kcal/mol) and S···N in TRs (4.6-5.3 kcal/mol). In the case of the 1,3,4-thiadiazol-2-amines, the regioisomers are formed in approximately equal amounts and, accordingly, the energy difference between these species is only 0.1 kcal/mol in terms of ΔGexp (ΔGcalcd = 2.1 kcal/mol). The regioisomers were characterized by elemental analyses (C, H, N), HRESI+-MS and FTIR, 1D (1H, 13C{1H}) and 2D (1H,1H-COSY, 1H,1H-NOESY, 1H,13C-HSQC, 1H,13C-HMBC) NMR spectroscopies, and structures of six complexes (three KRs and three TRs) were elucidated by single-crystal X-ray diffraction.

New Heterocyclic Product Space for the Castagnoli–Cushman Three-Component Reaction

Significant expansion of heterocyclic product space accessible by the Castagnoli-Cushman reaction (CCR) has been achieved via the use of glutaric anhydride analogues containing endocyclic substitutions with oxygen, nitrogen, and sulfur. Incorporation of these heteroatoms in the anhydrides backbone results in enhanced reactivity and generally lower temperatures that are required for the reactions to go to completion. These findings are particularly significant in light of the CCR recently recognized as an efficient tool for lead-oriented synthesis.

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

A series of 15 benzene-fused hexahydropyrrolo[1,2-b]isoquinolonic acids with substantial degree of steric encumbrance has been prepared via a novel variant of the Castagnoli–Cushman reaction of homophthalic anhydride (HPA) and various indolenines. The employment of a special kind of a cyclic imine component reaction allowed, for the first time, isolating a Mannich-type adduct between HPA and an imine component which has been postulated but never obtained in similar reactions.

Skeletal Diversity in Combinatorial Fashion: A New Format for the Castagnoli–Cushman Reaction

A new format for the Castagnoli-Cushman reaction of structurally diverse dicarboxylic acids, amines, and aldehydes in the presence of acetic anhydride as dehydrating agent is described. The reaction is distinctly amenable to parallel format: the combinatorial array of 180 reactions delivered 157 products of >85% purity without chromatographic purification (of this number, 143 compounds had >94% purity). The new method offers a convenient preparation of the skeletally and peripherally diverse, lead- and druglike γ- and δ-lactam carboxylic acids with high diastereoselectivity in combinatorial fashion.

Lucky Switcheroo: Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII

A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N1 (as in the earlier reported series) to C2. Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitors lipophilic periphery in the nearby hydrophobic pocket. The robustness of the docking simulations was tested and confirmed by molecular dynamics simulations.

Mechanism of generation of closo-decaborato amidrazones. Intramolecular non-covalent B–H⋯π(Ph) interaction determines stabilization of the configuration around the amidrazone CN bond

Three types of N(H)-nucleophiles, viz. hydrazine, acetyl hydrazide, and a set of hydrazones, were used to study the nucleophilic addition to the CN group of the 2-propanenitrilium closo-decaborate cluster (Ph3PCH2Ph)[B10H9NCEt], giving N-closo-decaborato amidrazones. A systematic mechanistic study of the nucleophilic addition is provided and included detailed synthetic, crystallographic, computational and kinetic work. As a result, two possible mechanisms have been proposed, which consist of firstly a consecutive incorporation of two Nu(H) nucleophiles, with the second responsible for a subsequent rapid proton exchange. The second possible mechanism assumes a pre-formation of a dinuclear [Nu(H)]2 species which subsequently proceeds with the nucleophilic attack on the boron cluster. The activation parameters for hydrazones indicate a small dependence on bond formation [ΔH‡ = 6.8–15 kJ mol−1], but significantly negative entropies of activation [ΔS‡ ranges from −139 to −164 J K−1 mol−1] with the latter contributing some 70–80% of the total Gibbs free energy of activation, ΔG‡. In the X-ray structure of (Z)-(Ph3PCH2Ph)[B10H9N(H)C(Et)NHNCPh2], very rare intramolecular non-covalent B–H⋯π(Ph) interactions were detected and studied by DFT calculations (M06-2x/6-311++G** level of theory) and topological analysis of the electron density distribution within the framework of Baders theory (QTAIM method). The estimated strength of these non-covalent interactions is 0.8–1.4 kcal mol−1.

Gold-Catalyzed Hydrohydrazidation of Terminal Alkynes

Facile gold-catalyzed hydrohydrazidation of alkynes with various hydrazides R2CONHNH2 (R = Alk or Ar; including those with an additional nucleophilic moiety) in the presence of Ph3PAuNTf2 (6 mol %) leading to a wide range of substituted keto- N-acylhydrazones (18 examples) in excellent to good yields (99-66%) is reported. This novel metal-catalyzed coupling proceeds under mild conditions (chlorobenzene, 60 °C), exhibits high functional group tolerance, and is insensitive to the electronic and steric effects of the substituents in the reactants.

Bicyclic Piperazine Mimetics of the Peptide β-Turn Assembled via the Castagnoli–Cushman Reaction

5-Oxopiperazine-2-carboxamides and respective carboxylic acids (obtained by the Castagnoli-Cushman reaction of protected iminodiacetic anhydride) were converted into cis- and trans-configured bicyclic piperazines containing two stereogenic centers. The latter are not only well-established mimetics of peptide β-turn but also attractive, high-Fsp3 cores for drug design in general. The methodology was applied to the preparation of ring-expanded version of bicyclic piperazines not described in the literature.

Spontaneous formation of tricyclic lactones following the Castagnoli–Cushman reaction

Castagnoli–Cushman reaction of imines derived from 2-chloropyridine-3-carboxaldehyde with a cyclic anhydride (4-(methylsulfonyl)-morpholine-2,6-dione) conducted at 110°C in DMF over 1 h, as expected, led to a mixture of trans- and cis-configured carboxylic acids. However, the latter underwent a spontaneous intramolecular reaction of the carboxylic functionality onto the labile nearby 2-chloropyridine moiety to give the respective tricyclic lactones in 17–23% yield, along with 41–68% yield of the uncyclized trans-configured products (isolated as methyl esters).