Attractive and repulsive forces in a crystal of [Rb(18-crown-6)][SbCl6] under high pressure.

The compression behavior of [Rb(18-crown-6)][SbCl6] crystal under pressure up to 2.16 (3) GPa was investigated in a diamond anvil cell (DAC) using a mixture of pentane-isopentane (1:4) as the pressure-transmitting fluid. The compound crystallizes in trigonal space group R3 and no phase transition was observed in the indicated pressure range. The low value of pressure bulk modulus [9.1 (5) GPa] found in this crystal is a characteristic of soft materials with predominant dispersive and electrostatic interaction forces. The nonlinear relationship between unit-cell parameters under high pressure is attributed to the influence of reduced intermolecular H...Cl contacts under pressure over 0.73 GPa. It also explains the high compression efficiency of [Rb(18-crown-6)][SbCl6] crystals at relatively low pressures, resulting in a significant shift of the Rb atom to the center of the crown ether cavity. At pressures above 0.9 GPa, steric repulsion forces begin to play a remarkable role, since an increasing number of interatomic H...Cl and H...H contacts become shorter than the sum of their van der Waals (vdW) radii. Below 0.9 GPa, both unit-cell parameter dependences (P-a and P-c) exhibit hysteresis upon pressure release, demonstrating their influence on the disordered model of Rb atoms. The void reduction under pressure also demonstrates two linear sections with the inflection point at 0.9 GPa. Compression of the crystal is accompanied by a significant decrease in the volume of the voids, leading to the rapid approach of Rb atoms to the center of the crown ether cavity. For the Rb atom to penetrate into the center of the crown ether cavity in [Rb(18-crown-6)][SbCl6], it is necessary to apply a pressure of about 2.5 GPa to disrupt the balance of atomic forces in the crystal. This sample serves as a compression model demonstrating the influence of both attractive and repulsive forces on the change in unit-cell parameters under pressure.

Multigram Synthesis of Dimethyl Stellane-1,5-Dicarboxylate as a Key Precursor for ortho-Benzene Mimics.

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 (bisnoradamantane or stellane) 1,5-dicarboxylic acid derivatives. X-ray crystallographic analysis of the stellane 1,5-dicarboxylic acid dimethyl ester has revealed that this scaffold is an optimal saturated isostere for ortho-disubstituted benzene where substituents exhibit in-plane topology. The synthetic protocol is based on the oxidative cyclization of dimethyl octahydropentalene-2,5-dicarboxylate (DMOD) through lithiation followed by I2 oxidation. The reaction outcome is determined by the stereochemistry of the substrate. While the endo,endo cis-DMOD, exclusively gives the "unwanted" Claisen cyclization product, the exo,endo cis- and exo,exo cis- stereoisomers afford the desired stellane 1,5-dicarboxylic acid dimethyl ester quantitatively. DFT computations have revealed that the reaction proceeds via the dianion of dimethyl octahydropentalene-2,5-dicarboxylate, which undergoes SET oxidation by I2 to form a radical anion. The subsequent cyclization followed by a second SET oxidation gives the desired stellane derivative.

Straightforward Synthesis of Halopyridine Aldehydes via Diaminomethylation.

A novel two-step method for formylation of fluoropyridines with silylformamidine Me3 SiC(=NMe)NMe2 (1) under catalyst-free conditions was developed. A series of all possible 18 fluoropyridines featuring one to four fluorine atoms were subjected to the reaction with 1 existing in equilibrium with its carbenic form Me2 NC(:)N(Me)SiMe3 (1'). Among them, 12 fluoropyridines were shown to react via C-H insertion. The reaction proceeded either at ß- or γ-positions affording the corresponding aminals. The more fluorine atoms in pyridines, the easier the reaction proceeded. We also hypothesized that the pyridines in which the fluorine was substituted by other halogens would react in a similar manner. To test the hypothesis, a set of 3,5-disubstituted pyridines with various combination of halogen atoms was prepared. 3,5-Difluoropyridine was taken as a compound for comparison. All the pyridines in the series also reacted likewise. In most cases, hydrolysis of the aminals afforded the corresponding aldehydes. As DFT calculations indicate, the reaction mechanism includes deprotonation of pyridine by 1' as a strong base and the following rearrangement of the formed tight ionic pair to the final product. An alternative reaction pathway involving addition of 1' to the pyridine carbon with the following hydrogen transfer via a three-membered transition state structure required much higher activation energy.

Redox Behavior of Cobalt-Phosphine Complexes vs Their Catalytic Activity in Organozinc Compound Formation: Background for Mechanistic Investigations.

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 formation. Meanwhile, for Co(DPEphos)Cl2, Co(dppf)Cl2, Co(dppb)Cl2, Co(PPh3)2Cl2, and Co(XantPhos)(Piv)2 (the latter one without the addition of LiCl), reversible redox processes were not observed. These catalysts did not act efficiently for the model process of organozinc compound formation. Co4(dppe)5Cl8 was the only exception, explained by a completely different structure (CoP4Cl and CoPCl3) of donor sets instead of CoP2X2 (X = Cl or O). The stability of complexes in tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) solutions was studied by UV-vis spectroscopy. Previously unknown X-ray structures for Co(XantPhos)(Piv)2, Co(N-XantPhos)Cl2, and {Co(DMF)6}{(CoCl3)2(dppb)} were determined. The use of pivalate counterions instead of chloride for Co(XantPhos)2+ led to a significant (ca. 20 times) increase of the kinetic solubility in THF compared to Co(XantPhos)Cl2, preserving high catalytic productivity upon the addition of LiCl. This allowed the latter to be efficiently used in combination with LiCl as the catalyst for arylzinc compound formation on a 2 g scale. The data obtained in this work can be regarded as experimental confirmation of the first and last stages of the plausible reaction pathway of arylzinc compound formation, involving CoII → CoI and CoI → CoII transformations, which could be a significant framework for further mechanistic investigations.

Gradual evolution of hydrogen-bonding patterns with the carbamoylcyanonitrosomethanide anion in a series of aliphatic diammonium salts.

Developing the structures of organic materials that rely on the hydrogen bonding of multifunctional substrates is often complicated due to a competition between various possible motifs. In this context, the illustrative case of the carbamoylcyanonitrosomethanide anion, [ONC(CN)-C(O)NH2]-, suggests sufficient control over the crystal lattice with a set of supramolecular synthons, which are specific to all the present nitroso, carbamoyl and cyano groups. The structures of the carbamoylcyanonitrosomethanide salts of ethane-1,2-diammonium, C2H10N22+·2C3H2N3O2-, (1), piperazine-1,4-diium, C4H12N22+·2C3H2N3O2-, (2), butane-1,4-diammonium, C4H14N22+·2C3H2N3O2-, (3), and hexane-1,6-diammonium, C6H18N22+·2C3H2N3O2-, (4), reveal two- and three-dimensional hydrogen-bonded frameworks governed by a set of site-selective interactions. The strongest N-H...O hydrogen bonds [N...O = 2.6842 (17)-2.8718 (17) Å, mean 2.776 (2) Å] are associated with the polarized ammonium N-H donors and nitroso O-atom acceptors, which sustain invariant motifs in the form of nitroso/ammonium dimers. Subtle structural changes within this series of compounds concern the rupture of some weaker interactions, i.e. mutual hydrogen bonds of the carbamoyl groups in (1)-(3) [N...O = 2.910 (2)-2.9909 (18) Å; mean 2.950 (2) Å] and carbamoyl/nitrile hydrogen bonds in (1), (2) and (4) [N...N = 2.936 (2)-3.003 (3) Å, mean 2.977 (2) Å], providing a gradual evolution of the hydrogen-bonding pattern. A hierarchy of the synthons involving three different groups could be applicable to supramolecular synthesis with polyfunctional methanide species, suggesting also a degree of control over layered and interpenetrated hydrogen-bonded networks.

Trifluoromethyl Vinamidinium Salt as a Promising Precursor for Fused ß-Trifluoromethyl Pyridines.

An efficient chlorotrimethylsilane-promoted synthetic protocol for the preparation of functionalized fused ß-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 vinamidinium salt demonstrated huge prospects for further use. The structure specificities of the trifluoromethyl vinamidinium salt and their impact on the reaction progress were determined. The procedure's scope and alternative ways of the reaction were investigated. The possibility of increasing the reaction scale up to 50 g and further modification of obtained products was shown. A minilibrary of potential fragments for 19F NMR-based fragment-based drug discovery (FBDD) was synthesized.

Synthesis and separation of diastereomeric N-(1-phenylethyl)amides of inherently chiral hydroxydibenzoyloxy-calix[4]arene acetic acids.

A preparative method for the synthesis of optically pure N-(1-phenylethyl)amides of inherently chiral (cR)- and (cS)-dibenzoyloxy-calix[4]arene acetic acids has been developed. Their absolute stereochemical configuration was determined by X-ray diffraction analysis.

Crystal structure of tetra-kis-(µ-4-benzyl-4H-1,2,4-triazole-κ2 N 1:N 2)tetra-fluoridodi-µ2-oxido-dioxidodisilver(I)divanadium(V).

The crystal structure of the title compound, [Ag2(VO2F2)2(C9H9N3)4], is presented. The mol-ecular complex is based on the heterobimetallic AgI-VV fragment {AgI 2(VVO2F2)2(tr)4} supported by four 1,2,4-triazole ligands [4-benzyl-(4H-1,2,4-triazol-4-yl)]. The triazole functional group demonstrates homo- and heterometallic connectivity (Ag-Ag and Ag-V) of the metal centers through the [-NN-] double and single bridges, respectively. The vanadium atom possesses a distorted trigonal-bipyramidal coordination environment [VO2F2N] with the Reedijk structural parameter τ = 0.59. In the crystal, C-H⋯O and C-H⋯F hydrogen bonds as well as C-H⋯π contacts are observed involving the organic ligands and the vanadium oxofluoride anions. A Hirshfeld surface analysis of the hydrogen-bonding inter-actions is also described.

A stereochemical journey around spirocyclic glutamic acid analogs.

A practical divergent synthetic approach is reported for the library of regio- and stereoisomers of glutamic acid analogs built on the spiro[3.3]heptane scaffold. Formation of the spirocyclic scaffold was achieved starting from a common precursor - an O-silylated 2-(hydroxymethyl)cyclobutanone derivative. Its olefination required using the titanium-based Tebbe protocol since the standard Wittig reaction did not work with this particular substrate. The construction of the second cyclobutane ring of the spirocyclic system was achieved through either subsequent dichloroketene addition or Meinwald oxirane rearrangement as the key synthetic steps, depending on the substitution patterns in the target compounds (1,6- or 1,5-, respectively). Further modified Strecker reaction of the resulting racemic spirocyclic ketones with the Ellman's sulfinamide as a chiral auxiliary had low to moderate diastereoselectivity; nevertheless, all stereoisomers were isolated in pure form via chromatographic separation, and their absolute configuration was confirmed by X-ray crystallography. Members of the library were tested for the inhibitory activity against H. pylori glutamate racemase.

Latent Nucleophilic Carbenes.

Using DFT and ab initio calculations, we demonstrate that noncyclic formamidines can undergo thermal rearrangement into their isomeric aminocarbenes under rather mild conditions. We synthesized the silylformamidine, for which the lowest activation energy in this process was predicted. Experimental studies proved it to serve as a very reactive nucleophilic carbene. The reactions with acetylenes, benzenes, and trifluoromethane proceeded via insertion into sp, sp2, and sp3 CH bonds. The carbene also reacted with the functional groups, such as CHO, COR, and CN at double or triple bonds, displaying high mobility of the trimethylsilyl group. The obtained silylformamidine can be considered as a latent nucleophilic carbene. It can be prepared in bulk quantities, stored, and used when the need arises. Calculation results predict similar behavior for some other silylated formamidines and related compounds.

Hydrogen-bonding landscape of the carbamoyl-cyano-nitro-somethanide anion in the crystal structure of its ammonium salt.

The structure of the title salt, ammonium carbamoyl-cyano-nitro-somethanide, NH4 +·C3H2N3O2 -, features the co-existence of different hydrogen-bonding patterns, which are specific to each of the three functional groups (nitroso, carbamoyl and cyano) of the methanide anion. The nitroso O-atoms accept as many as three N-H⋯O bonds from the ammonium cations [N⋯O = 2.688 (3)-3.000 (3) Å] to form chains of fused rhombs [(NH4)(O)2]. The most prominent bonds of the carbamoyl groups are mutual and they yield 21 helices [N⋯O = 2.903 (2) Å], whereas the cyano N-atoms accept hydrogen bonds from sterically less accessible carbamoyl H-atoms [N⋯N = 3.004 (3) Å]. Two weaker NH4 +⋯O=C bonds [N⋯O = 3.021 (2), 3.017 (2) Å] complete the hydrogen-bonded environment of the carbamoyl groups. A Hirshfeld surface analysis indicates that the most important inter-actions are overwhelmingly O⋯H/H⋯O and N⋯H/H⋯N, in total accounting for 64.1% of the contacts for the individual anions. The relatively simple scheme of these inter-actions allows the delineation of the supra-molecular synthons, which may be applicable to crystal engineering of hydrogen-bonded solids containing polyfunctional methanide anions.

The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones - an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones.

A regioselective method for the synthesis of 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones - close structural analogs of naturally occurring vasicinone alkaloids - is described. The procedure is based on PIFA-initiated oxidative 5-exo-trig cyclization of 2-(3-butenyl)quinazolin-4(3Н)-ones, in turn prepared by thermal cyclocondensation of the corresponding 2-(pent-4-enamido)benzamides. The products obtained have a good natural product likeness (NPL) score and therefore can be useful for the design of natural product-like compound libraries.

Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-Cycloaddition.

A general approach to bicyclic fused pyrrolidines via [3 + 2]-cycloaddition between nonstabilized azomethyne ylide and endocyclic electron-deficient alkenes was elaborated. "Push-pull" alkenes and CF3-alkenes did not react with the azomethyne ylide under the previously reported conditions, and we developed a superior protocol (LiF, 140 °C, no solvent). Among obtained products were medchem-relevant bicyclic sulfones, monofluoro-, difluoro-, and trifluoromethyl-substituted pyrrolidines. This approach not only allowed preparation of novel molecules but also significantly simplified synthesis of the existing ones (e.g., sofinicline).

Third Generation Buchwald Precatalysts with XPhos and RuPhos: Multigram Scale Synthesis, Solvent-Dependent Isomerization of XPhos Pd G3 and Quality Control by 1H- and 31P-NMR Spectroscopy.

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- = CH3SO3-). The 1H- and 31P-NMR spectra of the title complexes and some impurities, measured by various 1D and 2D techniques, were analyzed in detail. The solvent-dependent isomerization of Pd(ABP)(XPhos)(OMs) was studied by NMR, and the X-ray structures of two isomers were determined. The impurities in precatalysts, such as Pd(ABP)(HABP)(OMs) (HABP-neutral 2-aminobiphenyl coordinated to Pd2+ in N-monodentate mode) and PdCl2(XPhos)2, were identified and characterized by single crystal X-ray diffraction. A simple method for the quick quality control (QC) of the precatalysts, suitable for routine use, was proposed. The method was based on the assessment of the impurity content on the basis of the 1H-NMR spectra analysis.

Selective α-Methylation of Ketones.

The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of enaminones with further diastereoselective and functional groups tolerant hydrogenation to α-methylketones are developed. The scope and limitations of the proposed methodology are discussed. The advantages compared to known procedures are demonstrated. The unexpected role of acetone in the hydrogenation is suggested. The evaluation of the method for both early building block synthesis and late-stage CH-functionalization is shown. The elaborate procedures' preparability and scalability are demonstrated by the synthesis of several α-methyl ketones up to 100 g amount.

Halogen-containing heteroaromatic carbenes of the 1,2,4-triazole series and their transformations.

A series of new stable halogenated carbenes, 1-tert-butyl-3,4-diaryl-1,2,4-triazol-5-ylidenes, has been synthesized. According to quantum chemical calculations, 4-(2,3,4-trifluorophenyl)-substituted 1-tert-butyl-3,4-diaryl-1,2,4-triazol-5-ylidene is the least basic in comparison with the known sterically open stable heteroaromatic carbenes. Upon heating in organic solvents these carbenes undergo a tandem induced reaction thereby forming 5-amidino-1,2,4-triazoles. The interaction of carbenes with benzylidenemalononitrile, propanesultone and phenyl isothiocyanate results in zwitterionic compounds of the 1,2,4-triazole series. The data for X-ray diffraction study of 1-tert-butyl-3-phenyl-4-(2,4-difluorophenyl)-1,2,4-triazol-5-ylidene, its protonated salt, complex with copper(i) iodide, related complex of 1-tert-butyl-3-phenyl-4-(2-trifluoromethylphenyl)-1,2,4-triazol-5-ylidene, and adduct of 1-tert-butyl-3-phenyl-4-(4-bromophenyl)-1,2,4-triazol-5-ylidene and propansultone are given.

Crystal structure of tetra-kis-[µ-3-carboxy-1-(1,2,4-triazol-4-yl)adamantane-κ2 N 1:N 2]tetra-fluoridodi-µ2-oxido-dioxidodisilver(I)divanadium(V) tetra-hydrate.

The crystal structure of the title mol-ecular complex, [Ag2{VO2F2}2(C13H17N3O2)4]·4H2O, supported by the heterofunctional ligand tr-ad-COOH [1-(1,2,4-triazol-4-yl)-3-carb-oxy-adamantane] is reported. Four 1,2,4-triazole groups of the ligand link two AgI atoms, as well as AgI and VV centres, forming the heterobimetallic coordination cluster {AgI 2(VVO2F2)2(tr)4}. VV exists as a vanadium oxofluoride anion and possesses a distorted trigonal-bipyramidal coordination environment [VO2F2N]. A carb-oxy-lic acid functional group of the ligand stays in a neutral form and is involved in hydrogen bonding with solvent water mol-ecules and VO2F2 - ions of adjacent mol-ecules. The extended hydrogen-bonding network is responsible for the crystal packing in the structure.

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold.

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 allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.

On the Border between Low-Nuclearity and One-Dimensional Solids: A Unique Interplay of 1,2,4-Triazolyl-Based {CuII5(OH)2} Clusters and MoVI-Oxide Matrix.

A pentanuclear CuII5-hydroxo cluster possessing an unusual linear-shaped configuration was formed and crystallized under hydrothermal conditions as a result of the unique cooperation of bridging 1,2,4-triazole ligand ( trans-1,4-cyclohexanediyl-4,4'-bi(1,2,4-triazole) ( tr2 cy)), MoVI-oxide, and CuSO4. This structural motif can be rationalized by assuming in situ generation of {Cu2Mo6O22}4- anions, which represent heteroleptic derivatives of γ-type [Mo8O26]4- further interlinked by [Cu3(OH)2]4+ cations through [ N- N] bridges. The framework structure of the resulting compound [Cu5(OH)2( tr2 cy)2Mo6O22]·6H2O (1) is thus built up from neutral heterometallic {Cu5(OH)2Mo6O22} n layers pillared with tetradentate tr2 cy. Quantum-chemical calculations demonstrate that the exclusive site of the parent γ-[Mo8O26]4- cluster into which CuII inserts corresponds with the site that has the lowest defect ("MoO2 vacancy") formation energy, demonstrating how the local metal-polyoxomolybdate chemistry can express itself in the final crystal structure. Magnetic susceptibility measurements of 1 show strong antiferromagnetic coupling within the Cu5 chain with exchange parameters J1 = -500(40) K (-348(28) cm-1), J2 = -350(10) K (-243(7) cm-1) and g = 2.32(2), χ2 = 6.5 × 10-4. Periodic quantum-chemical calculations reproduce the antiferromagnetic character of 1 and connect it with an effective ligand-mediated spin coupling mechanism that comes about from the favorable structural arrangement between the Cu centers and the OH-, O2-, and tr2 cy bridging ligands.

Exploration of a Variety of Copper Molybdate Coordination Hybrids Based on a Flexible Bis(1,2,4-triazole) Ligand: A Look through the Composition-Space Diagram.

We investigated the coordination ability of the bis(1,2,4-triazolyl) module, tr2pr = 1,3-bis(1,2,4-triazol-4-yl)propane, toward the engineering of solid-state structures of copper polyoxomolybdates utilizing a composition space diagram approach. Different binding modes of the ligand including [N-N]-bridging and N-terminal coordination and the existence of favorable conformation forms (anti/anti, gauche/anti, and gauche/gauche) resulted in varieties of mixed metal CuI/MoVI and CuII/MoVI coordination polymers prepared under hydrothermal conditions. The composition space analysis employed was aimed at both the development of new coordination solids and their crystallization fields through systematic changes of the reagent ratios [copper(II) and molybdenum(VI) oxide precursors and the tr2pr ligand]. Nine coordination compounds were synthesized and structurally characterized. The diverse coordination architectures of the compounds are composed of cationic fragments such as [CuII3(µ2-OH)2(µ2-tr)2]4+, [CuII3(µ2-tr)6]6+, [CuII2(µ2-tr)3]4+, etc., connected to polymeric arrays by anionic species (molybdate MoO42-, isomeric α-, δ-, and ß-octamolybdates {Mo8O26}4- or {Mo8O28H2}6-). The inorganic copper(I,II)/molybdenum(VI) oxide matrix itself forms discrete or low-dimensional subtopological motifs (0D, 1D, or 2D), while the organic spacers interconnect them into higher-dimensional networks. The 3D coordination hybrids show moderate thermal stability up to 230-250 °C, while for the 2D compounds, the stability of the framework is distinctly lower (∼190 °C). The magnetic properties of the most representative samples were investigated. The magnetic interactions were rationalized in terms of analyzing the planes of the magnetic orbitals.