Phenol-benzoxazolone bioisosteres of GluN2B-NMDA receptor antagonists: Unexpected rearrangement during reductive alkylation with phenylcyclohexanone.

Negative allosteric modulators of N-methyl- d-aspartate receptors containing the GluN2B subunit represent promising drug candidates for the treatment of various neurological disorders including stroke, epilepsy, and Parkinson's disease. To increase the bioavailability and GluN2B affinity, the phenol of the potent benzazepine-based inhibitor, WMS-1410 (3), was replaced bioisosterically by a benzoxazolone moiety and the phenylbutyl side chain was conformationally restricted in a phenylcyclohexyl substituent. A four-step, one-pot procedure transformed the oxazolo-benzazepine 7 into the phenylcyclohexyl derivative 11. The same protocol was applied to the methylated analog 12, which unexpectedly led to ring-contracted oxazolo-isoquinolines 18. This rearrangement was explained by the additional methyl moiety in the 8-position inhibiting the formation of the planar intermediate iminium ion with phenylcyclohexanone. The allyl protective group of 11 and 18 was removed with RhCl3 and HCl to obtain the tricyclic compounds 5 and 19 without substituent at the oxazolone ring. The structures of the rearranged products 18 and 19 were elucidated by X-ray crystal structure analysis. The oxazolo-isoquinoline trans-18 with allyl moiety (Ki = 89 nM) and the oxazolo-benzazepine 5 without substituent at the oxazolone ring (Ki = 114 nM) showed GluN2B affinity in the same range as the lead compound 3. In two-electrode voltage clamp measurements, 5 displayed only weak inhibitory activity.

Ir(III) Cyclometalated Complexes Containing Phenylphenanthridine Ligands with Different Substitutions: Effects on the Electrochemiluminescence Properties.

A family of neutral bis-cyclometalated Ir(III) complexes based on phenanthridine (phent) derivates as cyclometalating ligands and picolinate as an ancillary ligand are described. The influence of extended conjugation, rigidity, and hydrophobicity as well as the electronic nature of the substituents were investigated in relation to the photoluminescence, PL, and electrochemiluminescence, ECL, properties. A significant increase of ECL in aqueous media is observed upon extension of the aromatic system or by substituting the phenyl with a dibenzofurane moiety, in compounds 2 and 3, respectively. Under real immunoassay conditions, these complexes achieve up to 4-fold higher ECL efficiency than the commercial ruthenium standard. These values, among the highest reported in the literature under these conditions, confirm the potential of iridium complexes as alternative labels in commercial instruments.

Shedding Light on the Interactions of Hydrocarbon Ester Substituents upon Formation of Dimeric Titanium(IV) Triscatecholates in DMSO Solution.

The dissociation of hierarchically formed dimeric triple lithium bridged triscatecholate titanium(IV) helicates with hydrocarbyl esters as side groups is systematically investigated in DMSO. Primary alkyl, alkenyl, alkynyl as well as benzyl esters are studied in order to minimize steric effects close to the helicate core. The 1 H NMR dimerization constants for the monomer-dimer equilibrium show some solvent dependent influence of the side chains on the dimer stability. In the dimer, the ability of the hydrocarbyl ester groups to aggregate minimizes their contacts with the solvent molecules. Due to this, most solvophobic alkyl groups show the highest dimerization tendency followed by alkenyls, alkynyls and finally benzyls. Furthermore, trends within the different groups of compounds can be observed. For example, the dimer is destabilized by internal double or triple bonds due to π-π repulsion. A strong indication for solvent supported London dispersion interaction between the ester side groups is found by observation of an even/odd alternation of dimerization constants within the series of n-alkyls, n-Ω-alkenyls or n-Ω-alkynyls. This corresponds to the interaction of the parent hydrocarbons, as documented by an even/odd melting point alternation.

Oxadiazole-substituted naphtho[2,3-b]thiophene-4,9-diones as potent inhibitors of keratinocyte hyperproliferation. Structure-activity relationships of the tricyclic quinone skeleton and the oxadiazole substituent.

Novel analogues of oxadiazole-substituted naphtho[2,3-b]thiophene-4,9-diones were synthesized in which the tricyclic quinone skeleton was systematically replaced with simpler moieties, such as structures with fewer rings and open-chain forms, while the oxadiazole ring was maintained. In addition, variants of the original 1,2,4-oxadiazole ring were explored. Overall, the complete three-ring quinone was essential for potent suppression of human keratinocyte hyperproliferation, whereas analogous anthraquinones were inactive. Also, the oxadiazole ring per se was not sufficient to elicit activity. However, rearrangement of the heteroatom positions in the oxadiazole ring resulted in highly potent inhibitors with compound 24b being the most potent analogue of this series showing an IC50 in the nanomolar range. Furthermore, experiments in isolated enzymatic assays as well as in the keratinocyte-based hyperproliferation assay did not support a major role of redox cycling in the mode of action of the compounds.

Diastereoselective anodic hetero- and homo-coupling of menthol-, 8-methylmenthol- and 8-phenylmenthol-2-alkylmalonates.

Diastereoselective radical coupling was achieved with chiral auxiliaries. The radicals were generated by anodic decarboxylation of five malonic acid derivatives. These were prepared from benzyl malonates and four menthol auxiliaries. Coelectrolyses with 3,3-dimethylbutanoic acid in methanol at platinum electrodes in an undivided cell afforded hetero-coupling products in 22-69% yield with a diastereoselectivity ranging from 5 to 65% de. Electrolyses without a coacid led to diastereomeric homo-coupling products in 21-50% yield with ratios of diastereomers being 1.17:2.00:0.81 to 7.03:2.00. The stereochemistry of the new stereogenic centers was confirmed by X-ray structure analysis and 13C NMR data.

Crystal structure of (1S*,2R*)-7-benz-yloxy-2-methyl-3-tosyl-2,3,4,5-tetra-hydro-1H-3-benz-azepin-1-ol: elucidation of the relative configuration of potent allosteric GluN2B selective NMDA receptor antagonists.

In the title compound, C25H27NO4S, which crystallized as a racemate, the relative configuration of the adjacent OH and CH3 groups on the azepine ring is trans. The seven-membered azepin ring has a chair-like conformation. The planar aromatic rings of the benzyl and tosyl-ate moiety are inclined to the planar 3-benzazepine ring by 78.39 (15) and 77.03 (14)°, respectively, and to each another by 13.82 (15)°. In the crystal, mol-ecules are linked via O-H⋯O and C-H⋯O hydrogen bonds, forming double-stranded chains along the a-axis direction. The chains are linked via C-H⋯π inter-actions, forming a three-dimensional architecture.

Novel GluN2B selective NMDA receptor antagonists: relative configuration of 7-meth-oxy-2-methyl-2,3,4,5-tetra-hydro-1H-3-benzazepin-1-ols.

The title compounds, C22H29NO2 (3) and C22H29NO2 (4) [systematic names: (1S*,2R*)-7-meth-oxy-2-methyl-3-(4-phenyl-but-yl)-2,3,4,5-tetra-hydro-1H-3-benzazepin-1-ol and (1R*,2R*)-7-meth-oxy-2-methyl-3-(4-phenyl-but-yl)-2,3,4,5-tetra-hydro-1H-3-benzazepin-1-ol, are diastereomers with the relative configuration of the adjacent hydroxyl and methyl groups at the seven-membered azepine ring being trans in (3) and cis in (4). In the crystals the orientation of these groups is -anti-periplanar (3) and +syn-clinal (4). In both cases, the crystals studied proved to be of a racemic mixture, with relative configurations (R*,S*)-3 and (R*,R*)-4. In both compounds, the seven-membered azepine ring has a chair-like conformation, and the 4-phenyl-butyl side chain adopts a extended conformation in (R*,S*)-3, but a twisted conformation in (R*,R*)-4. In the crystal of (S*,R*)-3, mol-ecules are linked via C-H⋯O hydrogen bonds, forming slabs parallel to the ac plane. In the crystal of (R*,R*)-4, mol-ecules are linked via O-H⋯N hydrogen bonds, forming chains propagating along the c-axis direction. The chains are linked by C-H⋯O hydrogen bonds, forming slabs parallel to the ac plane.

Neutral Mononuclear Copper(I) Complexes: Synthesis, Crystal Structures, and Photophysical Properties.

Neutral green-emitting four-coordinate Cu(I) complexes with general formula POPCu(NN), where POP = bis[2-(diphenylphosphino)phenyl]ether and NN = substituted 2-pyridine-1,2,4-triazole ligands, were synthesized. The crystal structures of (POPCuMeCN)(+)(PF6)(-) (1), POPCuPhPtp (2a, PhPtp = 2-(5-phenyl-2H-[1,2,4]triazol-3-yl)-pyridine), and POPCu(3,5-2FPhPtp) (2d, 3,5-2FPhPtp = 2-(5-(3,5-difluorophenyl)-2H-1,2,4-triazol-3-yl)pyridine) were determined by single-crystal X-ray diffraction analysis. The electronic and photophysical properties of the complexes were examined by UV-vis, steady-state, and time-resolved spectroscopy. At room temperature, weak emission was observed in solution, while in the solid state, all complexes exhibit intense green emission with quantum yield up to 0.54. The electronic and photophysical properties were further supported by calculation performed at the (time-dependent) density functional theory level. One of the complexes was also tested as dopant in electroluminescent devices.

Planar Chiral, Ferrocene-Stabilized Silicon Cations.

The preparation of a series of planar chiral, ferrocenyl-substituted hydrosilanes as precursors of ferrocene-stabilized silicon cations is described. These molecules also feature stereogenicity at the silicon atom. The generation and (29)Si NMR spectroscopic characterization of the corresponding silicon cations is reported, and problems arising from interactions of the electron-deficient silicon atom and adjacent C(sp(3))-H bonds or aromatic π donors are discussed. These issues are overcome by tethering another substituent at the silicon atom to the ferrocene backbone. The resulting annulation also imparts conformational rigidity and steric hindrance in such a way that the central chirality at the silicon atom is set with complete diastereocontrol. These chiral Lewis acid catalysts were then tested in difficult Diels-Alder reactions, but no enantioinduction was seen.

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.

[((Cl)Im(Dipp))P=P(Dipp)][GaCl4]: a polarized, cationic diphosphene.

The reaction of the neutral diphosphanide [((Cl)Im(Dipp))P-P(Cl)(Dipp)] (6) ((Cl)Im(Dipp) = 4,5-dichloro-1,3-bis(Dipp)-imidazol-2-yl; Dipp = 2,6-di-iso-propylphenyl) with methyl triflate (MeOTf) leads to the formation of cationic diphosphane [((Cl)Im(Dipp))(Me)P-P(Cl)(Dipp)](+) (8+) in a stereoselective methylation. In contrast, reacting with the Lewis acid GaCl3 yields cationic diphosphene [((Cl)Im(Dipp))P=P(Dipp)](+) (7+), which is explained by a low P-Cl bond dissociation energy. The significantly polarized P=P double bond in 7+ allows for its utilization as an acceptor for nucleophiles - the reaction with Cl(-) regenerates diphosphanide and the reaction with PMe3 gives cation [((Cl)Im(Dipp))P-P(PMe3)(Dipp)] (9+). In depth DFT investigation provides detailed insights into the bonding situation of the reported compounds.

Conformationally restricted κ-opioid receptor agonists: Synthesis and pharmacological evaluation of diastereoisomeric and enantiomeric decahydroquinoxalines.

All diastereoisomeric decahydroquinoxalines representing conformationally restricted analogs of κ agonists U-50,488 and GR-89,696 have been prepared. Cis/trans configured compound 7 is by far the highest binding diastereoisomer with a Ki of 0.35 nM. Racemates 4, 6, and 7 were separated into enantiomers. (+)-(4aR,5S,8aS)-Configured enantiomer 7b was identified as a high affinity (Ki=0.25 nM) κ ligand with high selectivity over µ and δ receptors. It acts as full agonist with an EC50 value of 2.0 nM in the [(35)S]GTPγS assay, while enantiomer 7a showed an EC50 value of 1000 nM.

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.

Asymmetric synthesis of 3-substituted tetrahydro-2-benzazepines.

The enantiomerically and diastereomerically pure tricyclic oxazolidine cis-10 was prepared in a five step synthesis starting with 1-bromo-2-iodobenzene. Me3SiCN and allylSiMe3 reacted with cis-10 in the presence of TiCl4 to form the nitrile (3S)-11 and the allyl derivative (3S)-12 with high diastereoselectivity. The hydrogenolytic removal of the chiral auxiliary failed, since the endocyclic benzyl-N-bond was cleaved simultaneously. Therefore the N-(hydroxyethyl)amide of (3S)-12 was transformed into the enamide 27, which was hydrolyzed to afford the secondary amide 28. The enamide strategy to remove the chiral auxiliary from (3S)-11 led to complete racemization due to fast deprotonation in α-position of the cyano moiety. Two pairs of enantiomers 30a-b/ent-30a-b with prototypical σ substituents at the N-atom were prepared. The low σ1 affinity of the tetrahydro-2-benzazepines (ent-30b, Ki = 407 nM) is attributed to the short distance between the two lipophilic aromatic moieties.

Diastereoselective Synthesis of Cyclic Five-Membered trans,trans-Configured Nitrodiols by Double Henry Reaction of 1,4-Dialdehydes.

Conformationally constrained perhydroquinoxalines 4 show high κ receptor affinity, selectivity over related receptors and full agonistic activity. Since the κ affinity can be correlated with the dihedral angle of the ethylenediamine pharmacophore (4a: 55°/71°), the dihedral angles of the postulated cyclopentane derivative 5a (73°/84°) and indane derivative 6a (77°/81°) were calculated. The first step of the synthesis represents a double Henry reaction of 1,4-dialdehydes 8 and 10 with nitromethane, leading predominantly to the trans,trans-configured nitrodiols 9 and 11. X-ray crystal structure analyses of 9 and 11 led to dihedral angles O2 N−C−C−OH of 73.4 and 88.3°, respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a.

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.

Luminescent copper(I) halide and pseudohalide phenanthroline complexes revisited: simple structures, complicated excited state behavior.

We have synthesized a series of luminescent trigonal [CuX(dtbphen)] (X = I (), Br (), Cl (), CN (), dtbphen = 2,9-di-tert-butylphenanthroline) and tetrahedral [Cu2(µ-I)2(L)2] (L = phenanthroline (), 2,9-dimethylphenanthroline ()) copper diimine complexes. Bearing in mind the chemical simplicity of this class of long-known Cu(i) phenanthroline compounds, it is surprising that they exhibit non-trivial photophysical properties, which have not been fully recognized. They display broad XMLCT absorption between ca. 450-600 nm, and the broad emission between ca. 550-850 nm in the solid state occurring with lifetimes on the µs timescale indicates phosphorescence, although the energetic overlap between excitation and emission suggests thermally activated delayed fluorescence (TADF) from S1. In line with the latter assumption, low temperature measurements of in the solid state show an energetic separation of emission and excitation. However, a counter-intuitive decrease of emission intensity and simultaneous increase of the emission lifetime at low temperatures are observed for , which indicates two triplet states also being involved. Our DFT and TD-DFT calculations show that emission from the lowest excited triplet state T1 is of (3)LMXCT nature, separated by only ca. 0.16 eV from S1. Low temperature photophysical measurements at 77 K in a glassy matrix of in 2-Me-THF and of in the solid state are in agreement with the theoretical results, revealing in addition that π-interactions in the solid state also greatly influence the photophysical properties, making a clear conclusion towards TADF ambiguous. This study suggests that other related simple and long-known Cu(i) systems may exhibit a similar, more complex excited state behavior than previously appreciated, involving several emitting states and important intermolecular interactions.

Preparation of dithienylphospholes by 1,1-carboboration.

In this study the scope of the 1,1-carboboration reaction was extended to the preparation of mixed heterole-based conjugated π-systems. Two arylbis(alkynyl)phosphane starting materials 2 were synthesized bearing two thiophene isomers at the alkyne units and the bulky tipp-substituent (tipp=2,4,6-triisopropylphenyl) at the phosphorous atom. The bis(thienylethynyl)phosphanes 2 were converted into the corresponding 2,5-thienyl-substituted 3-borylphospholes 4 in a double 1,1-carboboration reaction sequence employing the strongly electrophilic B(C6 F5 )3 reagent under mild reaction conditions. Subsequent Suzuki-Miyaura type cross-coupling yielded the corresponding 3-phenylphospholes 7 in a one-pot procedure from phosphanes 2 in high yields. Phospholes 7 were converted into the respective phosphole oxides 8. A photophysical characterization of derivatives 7 and 8 was carried out. The results presented here demonstrate the suitability of the 1,1-carboboration reaction for the preparation of phosphole-/thiophene-based, light-emitting systems.

Influence of the substitution and conformation of C--H-bond-based bis-triazole acceptors in anion-binding catalysis.

A study on the key parameters involved in the anion-binding process and catalytic activity of the new family of CH-bond-based, anion-binding bis-triazole catalysts BisTri was carried out. The effects of substitution at the side arms and the central backbone structure of the catalyst were investigated. Electron-deficient 3,5-bis(trifluoromethyl)phenyl groups at the side arms led to the most strongly bound structures. The evaluation of differently shaped anions showed remarkable binding selectivity of the BisTri derivatives for the chloride anion. Examination of various nucleophiles in a model catalytic alkylation reaction suggested a more complex mechanism than the expected SN 1, in which the nucleophiles also participate partially in activation of the electrophile. DFT calculations were performed to investigate the relationship between the catalyst conformation and the binding affinity. Finally, in silico design and identification of a new, more efficient BisTri catalyst was accomplished.

Synthesis and pharmacological evaluation of like- and unlike-configured tetrahydro-2-benzazepines with the α-substituted benzyl moiety in the 5-position.

A large set of tetrahydro-2-benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-benzazepines with various binding sites of the NMDA receptor were not observed.