Study on medium ring heterocycles: synthesis and structure of novel condensed pyrazolo[1,4]diazocinones including single enantiomers

By means of a base-catalysed ring enlargement of triazapentalenoindenes resulting from diasteroselective anhydride-induced ring transformation of chiral aminoalcohol-derived zwitterionic 2,3-dihydroimidazo[2,1-a]phthalazinium-olates, a series of pyrazolo[1,5-d][1,4]diazocin-7(6H)-ones with central and conformational chirality were obtained in enantiomerically pure form. The possible reasons of the characteristic substrate- and reagent-dependency observed for the diasteroselective ring transformations of the zwitterions were interpreted in terms of the relative energetics of the crucial alternative imidazolinium intermediates disclosed by B3LYP/6-31G(d,p) calculations. The trans-annular opening of three epimeric pairs of triazapentalenoindanones afforded identical pyrazolodiazonine products. This finding suggests that the primarily formed diastereomers, having different asymmetric conformations but the same element of central chirality, undergo ring inversions in one- and two steps, respectively, involved in pathways previously established for the facile racemisation of pyrazolodiazocines with conformational chirality and hydrogen- or methyl-substituent at C1-position. The ring enlargement of triazapentalenoindanones resulted from butyric anhydride-mediated ring transformation of zwitterions with symmetrical substitution pattern afforded highly rigid 1-ethylpyrazolodiazocines in racemic form potentially separable without thermal racemisation. The constitution, conformation and relative configuration of the novel compounds were determined by ¹H-, ¹³C- and ¹⁵N-NMR methods including 2D-HSQC, 2D-HMBC and DNOE measurements and the structure of a pyrazolodiazocine was supported by single crystal X-ray diffraction.     

In situ generated rhodium‐based catalyst for addition of phenylboronic acid to aldehydes

New 1,3‐dialkylperhydrobenzimidazolinium and 1,3‐dialkylimidazolinium salts ( 2,4 ) as NHC precursors have been synthesized and characterized. These salts in combination with [RhCl(COD)]₂ provided active catalysts for the addition of phenylboronic acid to aldehydes under mild conditions. The in situ prepared three‐component system [RhCl(COD)]₂/imidazolinium salts ( 2,4 ) and KOBu^t catalyse the addition of phenylboronic acid to sterically hindered aldehydes affording the corresponding arylated secondary alcohols in good yields. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:461–465, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20132     

Estimation of the hydration of polar groups of α-amino acids by differential scanning calorimetry

The heat capacity of hydration of zwitterions derived from aliphatic amino acids depends linearly on the surface area of the amino acid side radicals accessible to water molecules with the slopeb = 2.35±0.11 J mol^–1 K^–1 Å^–2 at 298 K. The linear correlation between hydration heat capacities of zwitterions of aliphatic amino acids and the corresponding aliphatic alcohols with a coefficient of approximately unity confirms the assumption that hydrophobic hydration does not depend on the nature of the surrounding groups. Using the assumption that the hydration of hydrocarbon radicals is independent of the neighboring groups, theb value has been used to calculate the contributions of polar groups. The contributions of OH, COON, and CONH groups of the side radicals in polar amino acids in the zwitterion form are close to zero; in the case of organic nonionic molecules, these contributions are negative. The increments for polar groups obtained for the zwitterions can be used for the calculation of the heat capacities of proteins and polypeptides incorporating charged amino acid residues. The difference between hydrophilic and hydrophobic hydration mechanisms is manifested not only as different magnitudes and signs of heat capacities and temperature coefficients but also in the fact that the neighboring polar (charged) groups have an effect on hydrophilic hydration but have no effect on hydrophobic hydration.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2237–2242, September, 1996.     

Tailor-made synthesis of various backbone-substituted imidazolinium salts by triflic anhydride mediated intramolecular cyclisation

We have found a Tf(2)O-mediated intramolecular cyclization reaction and have revealed an intriguing stereoselectivity and a regioselectivity during the preparation of intermediate alcohols, which allow for the tailor-made synthesis of various backbone-substituted imidazolinium salts, and structurally specific syn-4,5-disubstituted imidazolinium salts.     

Structural characterization of <Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>′-bis(2-methoxyethyl) -4,5-bis(2,4,6-trimethylphenyl)imidazolinium hexafluorophosphate

The crystal and molecular structure of the N,N′-bis(2-methoxyethyl)-4,5-bis(2,4,6-trimethylphenyl)- imidazolinium hexafluorophosphate, which is the first example of 1,3- and 4,5-disubstituted imidazolinium salts, have been determined and characterized by X-ray single crystal diffraction technique,¹H, ¹³C, ³¹P and ¹⁹F NMR spectroscopy. The compound, C₂₇H₃₉N₂O₂ ⁺·PF₆ ^?, crystallizes in the orthorhombic space group Pba2 with a = 15.8139(4) Å, b = 22.9346(7) Å, c = 8.069(3) Å. Two charge-assisted C–H\(\cdots\)F type crystal packing interactions between the imidazolinium C–H bonds and the F atoms of hexafluorophosphate counteranions build up zigzag chains along a-axis of the unit cell and indicate that the C–H bonds of the imidazolinium ring are also polarized. In addition, the title salt was modeled by DFT calculations in order to verify charge transfer mechanism observed in its imidazolinium ring.     

Thermal analysis study of imidazolinium and some benzimid azolium salts by TG

The imidazolinium and benzimidazolium bromide salts with pentafluor substituents on N atom were synthesized. The structures of imidazolinium and benzimidazolium bromide salts obtained were conformed by ¹H and ¹³C NMR, ¹⁹F NMR and elemental analysis. It was found that pyrolytic decomposition occurs with melting in salts. The imidazolinium and benzimidazolium bromide salts were studied by TG-DTG and DTA from ambient temperature to 1000°C in nitrogen atmosphere. The decomposition occurred mainly in one stage and the values of activation energy E, frequency factor A, reaction order n, enthalpy change ΔH ^#, entropy change ΔS ^# and Gibbs free energy ΔG ^#, of the thermal decomposition were calculated by means of Coats-Redfern (CR), MacCallum-Tanner (MC) and van Krevelen (vK) methods. The activation energy value obtained by CR and MC methods were in good agreement with each other while those obtained by vK were found to be 10–12 kJ mol⁻¹ larger.     

四氢叶酸辅酶模型1, 2, 3-三取代咪唑啉盐的质谱裂解行为

讨论了１,２,３－不对称取代咪唑啉盐各种离子的生成途径以及取代基对裂解方式的影响并分析了该类化合物的主要裂解方式。在所有中的均ｍ／ｚ＝１２７（１＾＋）的离子峰和有机正离子Ａ峰存在,表明化合物１和２均有机正离子和碘离子形成的盐。化合物１和２的质谱有相似的裂解方式;有机正离子发生失掉氮原子上的一个取代基而保留咪唑啉环产生Ｄ,Ｅ,Ｆ离子的裂解方式。更重要的是咪唑啉环有相同的裂解方式：Ｃ＾２－Ｎ＾３键和Ｃ     

Robust and Electron‐Rich cis‐Palladium(II) Complexes with Phosphine and Carbene Ligands as Catalytic Precursors in Suzuki Coupling Reactions

A new imidazolinium ligand precursor [L²H]Cl ( 2 ) was prepared in 86 % yield. Compared with its imidazolium counterpart, [L¹H]Cl ( 1 ), 2 is very sensitive to moisture and can undergo ring‐opening reactions very readily. Palladium complexes with the ring‐opened products from imidazolinium salts were isolated and characterized by X‐ray crystallography. Theoretical studies confirmed that the imidazolinium salt has a higher propensity for the ring‐opening reaction than the imidazolium counterpart. New mixed phosphine/carbene palladium complexes, cis‐[PdCl₂(L)(PR₃)] (L=L¹ and L²; R=Ph, Cy), were successfully prepared. These complexes are highly robust as revealed by variable‐temperature NMR spectroscopic studies and thermal gravimetric analysis. The structural and electronic properties of the new complexes on varying the carbene group (imidazol‐2‐ylidene group (unsaturated carbene) vs. imidazolin‐2‐ylidene (saturated carbene)) and the phosphine group (PPh₃ vs. PCy₃) were studied in detail by X‐ray crystallography, X‐ray photoelectron spectroscopy, and theoretical calculations. The catalytic study reveals that cis‐[PdCl₂(L²)(PCy₃)] is a competent Pd^II precatalyst for Suzuki coupling reactions, in which unreactive aryl chlorides can be applied as substrates.     

The dipole approach in ion-interaction chromatography of zwitterions

Summary The chromatographic behavior of zwitterions in Ion-interaction chromatography (IIC) is, investigated theoretically for the first time. The modification of the stationary phase in the presence of Ion-interaction reagent (IIR), and adsorption competition between test analytes and IIR for inner layer sites are shown theoretically to change the partition coefficient for zwitterions. Experimental results from the literature concerning retention behavior of zwitterions in IIC, were used to test the new thermodynamic theory. Very reasonable estimates of (i) ΔG ^o values for the IIR adsorption onto the stationary phase (II) total ligand concentration, and (iii) dipolar moments validate the present thermodynamic model for the IIC of zwitterionic analytes. Retention equations are compared to those which can be obtained, if the net charge of the analyte is zero, from the most important retention models in IIC. None of them is able to explain, even in a qualitative way, the retention behavior of zwitterions in IIC whereas, the present model is quantitatively able to do this.     

Recent advances of Pd-π-allyl zwitterions in cycloaddition reactions

Palladium-catalyzed cycloaddition reactions via Pd-π-allyl zwitterions have been established as significant synthetic transformations to enable numerous carbon- or heterocycles compounds that are key constituents of various biologically active natural products and pharmaceuticals. In addition to the well-known Pd-π-allyl zwitterions, including palladium-trimethylenemethane and Pd-1,3/1,4-zwitterions, chemists have recently discovered new applications of several long ago reported but less-studied Pd-π-allyl zwitterions, which can straightforwardly and efficiently construct novel cyclic architectures. Meanwhile, some impressive newly designed zwitterions have been also developed. Those zwitterions are diverse and can serve as transient and highly reactive intermediates for the subsequent cyclization with various acceptors. In this review, we highlight recent advances in applications of these two types of zwitterions in the synthesis of complex polycyclics and medium-sized cyclic compounds.     

Liver‐Targeted Small‐Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell‐free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography ¹⁸F‐isotopologue validated our liver‐targeting approach.     

Self-assembly and gel formation processes in an aqueous solution of L-cysteine and silver nitrate

The experimental and theoretical study of self-assembly and gel formation processes in an aqueous solution of L-cysteine and silver nitrate (CSS) is performed. A method to obtain CSS-based hydrogel is described. Its characteristic feature is the formation of a spatial gel network at a low concentration of the dispersed phase (～0.01%) and the thixotropic behavior. The experimental examination of this system provides the formulation of a phenomenological model of the gel formation. Based on it, an atomistic computer model is made to verify our assumptions. It is shown that due to the formation of donor-acceptor sulfur-silver bonds there form clusters from silver mercaptide (SM) zwitterions, from which in turn filamentous aggregates form. An analysis of the molecular configurations formed shows that the filamentous aggregates are stabilized by the interaction of 3 ?NH ₃ ⁺ and ?C(O)O^? groups belonging to SM zwitterions in the composition of the neighboring clusters. The obtained conclusions underlie the mesoscopic model based on which we managed to illustrate the processes of generation and growth of filamentous aggregates in large spatial scales.     

Kinetic determination of alcohols and their binary mixtures with a stopped-flow spectrophotometric technique

The kinetic method described for the determination of a single alcohol (? 5 X 10^-4 M), or of a binary mixture of alcohols in aqueous solution is based on fast oxidation by silver(II), monitored spectrophotometrically by using a stopped-flow technique. Mixtures of alcohols having rate constants differing by a factor of ?3 can be resolved. The lower limit of determination is ca. 5 × 10^-4 M.     

Water sorption in poly(ammonium sulfopropylbetaines). II. Sorption isotherms

Water sorption by four amorphous acrylic and methacrylic poly(zwitterions) bearing ammonium sulfopropylbetaine side groups () was studied at a constant temperature of 23°C and over a broad range of water activity (0.14-0.90). Whatever the physical state of the hydrated polymer, glassy or viscoelastic, water diffusion is Fickian (average diffusion coefficient D?_s in the range 2-16 × 10^?8 cm² s^?1), and the sorption isotherms may be quantitatively analyzed according to the Guggenheim-Anderson-De Boer amended BET equation for multilayer sorption processes. The number of sitebound water molecules per monomeric unit is in the range 1.5–2.0, and apparently there is no great energy difference between direct site binding and indirect binding in the successive solvation layers. The polymer-water interaction parameter (?0.6 < χ Flory < 0.6) is an increasing function of the water content of the hydrated poly(zwitterions) over the whole composition range (water volume fraction < 0.5), without any clear transition from the glassy to the viscoelastic state. Clustering of water molecules (Zimm-Lundberg theory) is never observed, even at high water content. Because of the charged structure of their dipolar units, the poly(zwitterions) show a water sorption process similar to that of the corresponding poly(electrolytes) of the tetra-alkylammonium sulfonate type. © 1992 John Wiley & Sons, Inc.     

Sorption of nicotinic and isonicotinic acids by the strongly basic anion exchanger АВ-17-8

Thermodynamics and kinetics of sorption with the participation of nicotinic and isonicotinic acids on the strongly basic anion exchanger АВ-17-8 were studied. According to calorimetric measurements, partial (differential) heat of sorption was estimated for anions and zwitterions of pyridinecarboxylic acids upon sorption by the OH-form of the anion exchanger AB-17-8 at 298K. Sorption of zwitterions of pyridinecarboxylic acids by the OH-form of the strongly basic anion exchanger can be presented as the process that involves independent reactions of ion exchange, dissociation of pyridinecarboxylic acid, and neutralization. The kinetics of sorption on the strongly basic anion exchanger with the participation of nicotinic and isonicotinic acids is shown to be controlled by the slow diffusion of the components in the polymer phase. For the organic anion in the phase of the anion exchanger АВ-17-8, the diffusion coefficient is equal to (1.3±0.4)?10^–12 m² s^–1.     

Zwitterionic species from deprotonation of η6-arene-η5-cyclopentadienyliron cations and their reactions as nucleophiles

A variety of η⁶-arene-η⁵-cyclopentadienyliron cations in which the arene ligand has an α-carbon substituent containing one or more hydrogens can be deprotonated with base to give the corresponding neutral zwitterionic species. These zwitterions can react in situ as nucleaphiles with different substrates such as CH₃I, other organic halides. CO₂ and CS₂ to give a wide range of synthetic applications.     

Lignin-type, α,β-unsaturated aldehydes of lignin-type in organic solvents

A 1:1 reaction of [HO(CH₂)₃]₃P with 4-hydroxy-3-methoxy-cinnamaldehyde (coniferaldehyde) or 3,5-dimethoxy-4-hydroxycinnamaldehyde (sinapaldehyde) in acetone at room temperature affords phosphonium zwitterions of the type R₃P⁺CH(4-O^?-Ar)CH₂CHO; other phosphines [R = Et, n-Bu, (CH₂)₂CN, and p-Tol] do not react under the same conditions. In alcohols R??OH(D) [R?? = CD₃, Et, (CD₃)₂CD, s-Bu, HOCH₂CH₂], the above phosphines (except the cyano-derivative) and those where R = i-Pr, Cy, Me₂Ph, MePh₂ do react within an equilibrium established between the reactants and the zwitterion-hemiacetal products R₃P⁺CH(4-O^?-Ar)CH₂CH(OH)(OR??) that are formed as a mixture of two diastereomers. The nature of the phosphine and the alcohol affects the equilibrium and the diastereomeric ratio.     

Highly Efficient Kinetic Resolution of Aryl-Alkenyl Alcohols by Ru-Catalyzed Hydrogen Transfer

No matter through asymmetric reduction of ketones or kinetic resolution of secondary alcohols, enantioselective synthesis of the corresponding secondary alcohols is challenging when the two groups attached to the prochiral or chiral centers are spatially or electronically similar. For examples, dialkyl (sp³ vs. sp³), diaryl (sp² vs. sp²), and aryl-alkenyl (sp² vs. sp²) alcohols are difficult to produce with high enantioselectivities. By exploiting our recently developed Ru-catalysts of minimal stereogenicity, we reported herein a highly efficient kinetic resolution of aryl-alkenyl alcohols through hydrogen transfer. This method enabled such versatile chiral building blocks for organic synthesis as allylic alcohols, to be readily accessed with excellent enantiomeric excesses at practically useful conversions.     

Piperazine‐ and DABCO‐bridged dinuclear N‐heterocyclic carbene palladium complexes: synthesis,structure and application to Hiyama coupling reaction

Four dinuclear N ‐heterocyclic carbene (NHC) palladium complexes were prepared by reaction of imidazolinium salts, PdCl₂ and bridging ligands (piperazine and DABCO) in one pot or by direct cleavage of the chloro‐bridged dimeric compounds [Pd(μ ‐Cl)(Cl)(NHC)]₂ with bridging ligands. All of the complexes were fully characterized using ¹H NMR, ¹³C NMR, high‐resolution mass and infrared spectroscopies, elemental analysis and single‐crystal X‐ray diffraction. The catalytic activities of the obtained palladium catalysts towards Hiyama coupling of aryl chlorides with phenyltrimethoxysilane were investigated and the results showed that the dinuclear palladium complexes were considerably active for the coupling reaction. Copyright © 2016 John Wiley & Sons, Ltd.     

Chiral N-heterocyclic carbene ligands based on a biisoquinoline template

New chiral imidazolinium salts with tunable steric features, based on a biisoquinoline template, have been developed and structurally characterised using single crystal X-ray crystallography. The trans PdI(2)(NHC)(2) complex was prepared by reaction of the parent H(4) imidazolinium salt with Pd(OAc)(2) in the presence of NaI, and the solid state structure determined by X-ray crystallography. The rigid, chiral, biisoquinoline geometry of the H(4) imidazolinium salt was found to be maintained upon ligand complexation. The sterically unencumbered parent biisoquinoline ligand has been found to give high conversion with modest enantioselectivity in the copper-catalysed asymmetric addition of diethylzinc to cyclohexenone.