Thermal and photoinduced radical cascade annulation using aryl isonitriles: An approach to quinoline-derived benzophosphole oxides.

Herein, we present a radical cascade addition cyclization sequence to access quinoline-based benzophosphole oxides from ortho-alkynylated aromatic phosphine oxides using various aryl isonitriles as radical acceptors and inexpensive tert-butyl-hydroperoxide (TBHP) as a terminal oxidant in the presence of a catalytic amount of silver acetate. Alternatively, the same cascade can be realized through a sustainable photochemical approach utilizing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as an organic photocatalyst at room temperature. The introduced modular approach shows broad functional group tolerance and offers straightforward access to complex P,N-containing polyheterocyclic arenes. These novel π-extended benzophosphole oxides exhibit interesting photophysical and electrochemical properties such as absorption in the visible region, emission and reversible reduction at low potentials, which makes them promising for potential materials science applications. The photophysical properties can further be tuned by addition of external Lewis and Brønsted acids.

Towards Optimized Bioavailability of 99mTc-Labeled Barbiturates for Non-invasive Imaging of Matrix Metalloproteinase Activity.

INTRODUCTION: Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo. METHODS: Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo. Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry. RESULTS: We prepared three new 99mTc-labeled MMP inhibitors, bearing either a glycine ([99mTc]MEA39), lysine ([99mTc]MEA61), or the ligand HYNIC with the ionic co-ligand TPPTS ([99mTc]MEA223) yielding gradually increasing hydrophilicity. [99mTc]MEA39 and [99mTc]MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [99mTc]MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [99mTc]MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images. CONCLUSION: Introduction of HYNIC/TPPTS into the barbiturate lead structure ([99mTc]MEA223) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model.

Ligand-controlled and nanoconfinement-boosted luminescence employing Pt(ii) and Pd(ii) complexes: from color-tunable aggregation-enhanced dual emitters towards self-referenced oxygen reporters.

In this work, we describe the synthesis, structural and photophysical characterization of four novel Pd(ii) and Pt(ii) complexes bearing tetradentate luminophoric ligands with high photoluminescence quantum yields (Φ L) and long excited state lifetimes (τ) at room temperature, where the results were interpreted by means of DFT calculations. Incorporation of fluorine atoms into the tetradentate ligand favors aggregation and thereby, a shortened average distance between the metal centers, which provides accessibility to metal-metal-to-ligand charge-transfer (3MMLCT) excimers acting as red-shifted energy traps if compared with the monomeric entities. This supramolecular approach provides an elegant way to enable room-temperature phosphorescence from Pd(ii) complexes, which are otherwise quenched by a thermal population of dissociative states due to a lower ligand field splitting. Encapsulation of these complexes in 100 nm-sized aminated polystyrene nanoparticles enables concentration-controlled aggregation-enhanced dual emission. This phenomenon facilitates the tunability of the absorption and emission colors while providing a rigidified environment supporting an enhanced Φ L up to about 80% and extended τ exceeding 100 µs. Additionally, these nanoarrays constitute rare examples for self-referenced oxygen reporters, since the phosphorescence of the aggregates is insensitive to external influences, whereas the monomeric species drop in luminescence lifetime and intensity with increasing triplet molecular dioxygen concentrations (diffusion-controlled quenching).

Nickel(II) complexes based on dithiolate-polyamine binary ligand systems: crystal structures, hirshfeld surface analysis, theoretical study, and catalytic activity study on photocatalytic hydrogen generation.

To ascertain the influence of binary ligand systems [1,1-dicyanoethylene-2,2-dithiolate (i-mnt-2) and polyamine {tetraen = tris(2-aminoethyl)amine, tren = diethylene triamine and opda = o-phenylenediamine}] on the coordination modes of the Ni(ii) metal center and resulting supramolecular architectures, a series of nickel(ii) thiolate complexes [Ni(tetraen)(i-mnt)](DMSO) (1), [Ni2(tren)2(i-mnt)2] (2), and [Ni2(i-mnt)2(opda)2]n (3) have been synthesized in high yield in one step in water and structurally characterized by single crystal X-ray crystallography and spectroscopic techniques. X-ray diffraction studies disclose the diverse i-mnt-2 coordination to the Ni+2 center in the presence of active polyamine ligands, forming a slightly distorted octahedral geometry (NiN4S2) in 1, square planar (NiS4) and distorted octahedral geometries (NiN6) in the bimetallic co-crystallized aggregate of cationic [Ni(tren)2]+2 and anionic [Ni(i-mnt)2]-2 in 2, and a one dimensional (1D) polymeric chain along the [100] axis in 3, having consecutive square planar (NiS4) and octahedral (NiN6) coordination kernels. The N-HO, N-HS, N-HN, N-HS, N-HN, and N-HO type hydrogen bonds stabilize the supramolecular assemblies in 1, 2, and 3 respectively imparting interesting graph-set-motifs. The molecular Hirshfeld surface analyses (HS) and 2D fingerprint plots were utilized for decoding all types of non-covalent contacts in the crystal networks. Atomic HS analysis of the Ni+2 centers reveals significant Ni-N metal-ligand interactions compared to Ni-S interactions. We have also studied the unorthodox interactions observed in the solid state structures of 1-3 by QTAIM and NBO analyses. Moreover, all the complexes proved to be highly active water reduction co-catalysts (WRC) in a photo-catalytic hydrogen evolution process involving iridium photosensitizers, wherein 2 and 3 having a square planar arrangement around the nickel center(s) - were found to be the most active ones, achieving 1000 and 1119 turnover numbers (TON), respectively.

Fe-Catalyzed Anaerobic Mukaiyama-Type Hydration of Alkenes using Nitroarenes.

Hydration of alkenes using first row transition metals (Fe, Co, Mn) under oxygen atmosphere (Mukaiyama-type hydration) is highly practical for alkene functionalization in complex synthesis. Different hydration protocols have been developed, however, control of the stereoselectivity remains a challenge. Herein, highly diastereoselective Fe-catalyzed anaerobic Markovnikov-selective hydration of alkenes using nitroarenes as oxygenation reagents is reported. The nitro moiety is not well explored in radical chemistry and nitroarenes are known to suppress free radical processes. Our findings show the potential of cheap nitroarenes as oxygen donors in radical transformations. Secondary and tertiary alcohols were prepared with excellent Markovnikov-selectivity. The method features large functional group tolerance and is also applicable for late-stage chemical functionalization. The anaerobic protocol outperforms existing hydration methodology in terms of reaction efficiency and selectivity.

10-(4-Phenylpiperazine-1-carbonyl)acridin-9(10H)-ones and related compounds: Synthesis, antiproliferative activity and inhibition of tubulin polymerization.

As part of our continuing search for potent inhibitors of tubulin polymerization, two novel series of 42 10-(4-phenylpiperazine-1-carbonyl)acridin-9(10H)-ones and N-benzoylated acridones were synthesized on the basis of a retrosynthetic approach. All newly synthesized compounds were tested for antiproliferative activity and interaction with tubulin. Several analogs potently inhibited tumor cell growth. Among the compounds tested, 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)acridin-9(10H)-one (17c) exhibited excellent growth inhibitory effects on 93 tumor cell lines, with an average GI50 value of 5.4 nM. We were able to show that the strong cytotoxic effects are caused by disruption of tubulin polymerization, as supported by the EBI (N,N'-Ethylenebis(iodoacetamide)) assay and the fact that the most potent inhibitors of cancer cell growth turned out to be the most efficacious tubulin polymerization inhibitors. Potencies were nearly comparable or superior to those of the antimitotic reference compounds. Closely related to this, the most active analogs inhibited cell cycling at the G2/M phase at concentrations down to 30 nM and induced apoptosis in K562 leukemia cells. We believe that our work not only proves the excellent suitability of the acridone scaffold for the design of potent tubulin polymerization inhibitors but also enables synthetic access to further potentially interesting N-acylated acridones.

C3 -Symmetric Tricyclo[2.2.1.02,6 ]heptane-3,5,7-triol.

A straightforward access to a hitherto unknown C3 -symmetric tricyclic triol both in racemic and enantiopure forms has been developed. Treatment of 7-tert-butoxynorbornadiene with peroxycarboxylic acids provided mixtures of C1 - and C3 -symmetric 3,5,7-triacyloxynortricyclenes via transannular π-cyclization and replacement of the tert-butoxy group. By refluxing in formic acid, the C1 -symmetric esters were converted to the C3 -symmetric formate. Hydrolysis gave diastereoisomeric triols, which were separated by recrystallization. Enantiomer resolution via diastereoisomeric tri(O-methylmandelates) delivered the target triols on a gram scale. The pure enantiomers are useful as core units of dopants for liquid crystals.

Synthesis, Physico-chemical Characterization, Crystal Structure and Influence on Microbial and Tumor Cells of Some Co(II) Complexes with 5,7-Dimethyl-1,2,4-triazolo[1,5-a]pyrimidine.

Three complexes, namely [Co(dmtp)2(OH2)4][CoCl4] (1), [Co(dmtp)2Cl2] (2) and [Co(dmtp)2(OH2)4]Cl2∙2H2O (3) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine), were synthesized and characterized by spectral (IR, UV-Vis-NIR), and magnetic measurements at room temperature, as well as single crystal X-ray diffraction. Complex (1) crystallizes in monoclinic system (space group C2/c), complex (2) adopts an orthorhombic system (space group Pbca), and complex (3) crystallizes in triclinic system (space group P1). Various types of extended hydrogen bonds and π-π interactions provide a supramolecular architecture for all complexes. All species were evaluated for antimicrobial activity towards planktonic and biofilm-embedded microbial cells and influence on HEp-2 cell viability, cellular cycle and gene expression.

1,3,5-Triazapentadienes by Nucleophilic Addition to 1,3- and 1,4-Dinitriles-Sterically Constrained Examples by Incorporation into Cyclic Peripheries: Synthesis, Aggregation, and Photophysical Properties.

1,3,5-Triazapentadienes usually show U- or twisted S-shaped conformations along the N-C-N-C-N skeleton due to dominating n/π* interactions. If, however, the 1,3,5-triazapentadiene unit is part of a ring, its W conformation might be restricted to the plane. Here, we describe the synthesis of 13 new 1,3,5-triazapentadienes 10-12, which are sterically restrained by incorporation into six- or seven-membered ring systems, by addition of a lithiated primary amine or hydrazine 5 to a dinitrile 7, 8, or 9 with the two cyano groups in 1,3 or 1,4 distance. These novel compounds show very strong tendency for aggregation due to hydrogen bonding, especially to form homodimers as seen from X-ray data in the solid state. Additional hydrogen bonding generates also linear chains in the crystal. Several of the new compounds show fluorescence in solution. Quantum chemical DFT calculations were used for evaluation of the dimerization energies and for interpretation of the photophysical properties.

3-Alkylperoxy-3-cyano-oxindoles from 2-Cyano-2-diazo-N-phenyl-acetamides via Cyclizing Carbene Insertion and Subsequent Radical Oxidation.

A transition-metal-free one-pot sequence for the synthesis of 3-peroxy-substituted oxindoles from readily prepared 2-cyano-2-diazo-acetamides is reported. The two-step tandem process includes a highly efficient thermal intramolecular C-H-carbene insertion followed by a tetrabutylammonium iodide (TBAI) catalyzed radical C3-peroxy-functionalization. The protocol provides easy access to a new class of 3-cyano-3-peroxy-disubstituted oxindoles. Useful transformations to amides and alcohols are demonstrated.

Hydroalumination of Ketenimines and Subsequent Reactions with Heterocumulenes: Synthesis of Unsaturated Amide Derivatives and 1,3-Diimines.

The series of differently substituted ketenimines 1 was hydroluminated using di-iso-butyl aluminum hydride. For the sterically congested ketenimine 1a, preferred hydroalumination of the C═N-bond was proven by X-ray crystallography (compound 5a). In situ treatment of the hydroaluminated ketenimines 5 with various heterocumulenes like carbodiimides, isocycanates, isothiocyanates and ketenimines as electrophiles and subsequent hydrolytic workup resulted in novel enamine derived amide species in case of N-attack (sterically less hindered ketenimines) under formation of a new C-N-bond or in 1,3-diimines by C-C-bond-formation in case of bulky substituents at the ketenimine-nitrogen atom. Furthermore, domino reactions with more than 1 equiv of the electrophile or by subsequent addition of two different electrophiles are possible and lead to polyfunctional amide derivatives of the biuret type which are otherwise not easily accessible.

Fluorescent benzene-centered mono-, bis- and tris-triazapentadiene-boron complexes.

A series of novel benzene centered mono-, bis- and tris-1,3,5-triazapentadiene ligands was synthesized and investigated with respect to their reactivity towards triphenylborane. The resulting blue-fluorescent boron complexes with a six-membered ring chelate structure show excellent thermal and chemical stability. All title compounds were completely characterized including X-ray diffraction studies for and . Whereas the absorption spectra of all three classes of compounds are similar, the fluorescence spectra show distinct differences. Thus, the emission spectra of show Stokes shifts of 4100-6700 cm(-1) with low quantum yields both in solution and in the solid state. However, the more bulky compounds show markedly larger molar extinction coefficients and smaller bathochromic shifts compared to . For all compounds, we observe significantly more intense red-shifted fluorescence in the solid state compared to that in dichloromethane solutions. For the interpretation of the absorption properties TD-DFT studies were performed based on DFT geometry optimizations.

Radical aminooxygenation of alkenes with N-fluoro-benzenesulfonimide (NFSI) and TEMPONa.

Reaction of various alkenes with commercially available N-fluorobenzenesulfonimide (NFSI) and TEMPONa provides the corresponding aminooxygenation products in moderate to good yields. Single electron transfer from readily generated TEMPONa to NFSI allows for clean generation of the corresponding bissulfonylamidyl radical along with TEMPO. N-radical addition to an alkene and subsequent TEMPO trapping provides the corresponding aminooxygenation product.

Preparation of phenanthrenes from ortho-amino-biphenyls and alkynes via base-promoted homolytic aromatic substitution.

A transition-metal-free phenanthrene synthesis starting from readily accessible ortho-amino-biaryls is presented. The biarylamines are in situ transformed into the corresponding diazonium salts which upon single electron reduction give the corresponding aryl radicals. Addition to an alkyne and subsequent base promoted homolytic aromatic substitution (BHAS) provide phenanthrenes in moderate to good yields.

Tuning the structural and photophysical properties of cationic Pt(II) complexes bearing neutral bis(triazolyl)pyridine ligands.

The emission properties of a series of cationic Pt(II) complexes bearing neutral tridentate 2,6-bis-(1H-1,2,3-triazol-5-yl)pyridine and monoanionic ancillary ligands (Cl(-) or CN(-)) are described. By varying the substitution pattern on the 1,2,3-triazole moieties of the tridentate luminophore and the nature of the ancillary ligand, we were able to tune the intermolecular interactions between the complexes and therefore the electronic interactions between the metal centers. Indeed, all the compounds possessing Cl(-) as ancillary ligand are nonluminescent at room temperature, while the complexes containing CN(-) are luminescent. Interestingly, the π-accepting nature of this ancillary ligand induces Pt(II)-Pt(II) interactions irrespectively of bulky substitution patterns on the tridentate ligand.

Phosphine-catalyzed dearomatizing [3+2] annulations of isoquinolinium methylides with allenes.

A phosphine-catalyzed dearomatizing [3+2] annulation of isoquinolinium methylides with allenoates or allenones yields highly functionalized pyrroloisoquinolines with high regioselectivity and in viable yields.

Stereospecific formal [3+2] dipolar cycloaddition of cyclopropanes with nitrosoarenes: an approach to isoxazolidines.

The MgBr2-catalyzed formal [3+2] cycloaddition of donor-acceptor activated cyclopropanes with nitrosoarenes offers a novel approach to various structurally diverse isoxazolidines. The reactions, which are experimentally easy to conduct, occur with complete stereospecificity and perfect control of regioselectivity. Product isoxazolidines can be readily transformed into α-amino lactones by reductive or decarboxylative N-O cleavage and subsequent lactonisation, and the N-aryl bond cleavage is also possible under oxidative conditions.

6-Phosphorylated phenanthridines from 2-isocyanobiphenyls via radical C-P and C-C bond formation.

A C-P bond and a C-C bond are formed in the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and commercially available P-radical precursors. The radical cascade reaction comprises addition of an oxidatively generated P-centered radical to the isonitrile functionality and subsequent homolytic aromatic substitution. Various 6-phosphorylated phenanthridines are formed in moderate to excellent yield. In contrast to the currently intensively investigated direct arene phosphorylation, the arene core is constructed with concomitant phosphorylation using this approach.

Synthesis of dihydrobenzo[b]furans by diastereoselective acyloxyarylation.

A highly diastereoselective synthesis of 2-aryl-3-acyloxy-2,3-dihydrobenzofurans by palladium-catalyzed acyloxyarylation involving dearomatization of benzofurans with arylboronic acids and carboxylic acids occurring under mild conditions has been developed.

Highly enantioselective synthesis of chiral 7-ring O- and N-heterocycles by a one-pot nitro-Michael-cyclization tandem reaction.

A concise enantioselective approach to synthesise medium-sized 7-ring O- and N-heterocycles has been developed. The synthetic strategy relies on an organocatalytic nitro-Michael-nitrile oxide cycloaddition tandem reaction, leading to the corresponding chiral benzoxe- and benzazepine derivatives containing an additional fused dihydroisoxazoline ring in good yields and excellent enantioselectivities (up to 97% ee).