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.

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.

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.

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.

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.

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.

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.

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.

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.

Stereocontrol in dinuclear triple lithium-bridged titanium(IV) complexes: solving some stereochemical mysteries.

Compounds 1 a-f-H2 form "monomeric" triscatecholate titanium(IV) complexes [Ti(1 a-f)3](2-), which in the presence of Li cations are in equilibrium with the triple lithium-bridged "dimers" [Li3(Ti(1 a-f)3)2](-). The equilibrium strongly depends on the donor ability of the solvent. Usually, in solvents with high donor ability, the stereochemically labile monomer is preferred, whereas in nondonor solvents, the dimer is the major species. In the latter, the stereochemistry at the complex units is "locked". The configuration at the titanium(IV) triscatecholates is influenced by addition of chiral ammonium countercations. In this case, the induced stereochemical information at the monomer is transferred to the dimer. Alternatively, the configuration at the metal complexes can be controlled by enantiomerically pure ester side chains. Due to the different orientation of the ester groups in the monomer or dimer, opposite configurations of the triscatecholates were observed by circular dichroism (CD) spectroscopy for [Ti(1 c-e)3](2-) or [Li3(Ti(1 c-e)3)2](-). A surprising exception was found for the dimer [Li3(Ti(1 f)3)2](-). Herein, the dimer is the dominating species in weak donor (methanol), as well as strong donor (DMSO), solvents. This is due to the bulkiness of the ester substituent destabilizing the monomer. Due to the size of the substituent in [Li3(Ti(1 f)3)2](-) the esters have to adopt an unusual conformation in the dimer resulting in a stereocontrol of the small methyl group. Following this, opposite stereocontrol mechanisms were observed for the central metal-complex units of [Li3(Ti(1 c-e)3)2](-) or [Li3(Ti(1 f)3)2](-).

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.

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.

Indirect "no-bond" ³¹P···³¹P spin-spin couplings in P,P-[3]ferrocenophanes: insights from solid-state NMR spectroscopy and DFT calculations.

No-bond (31)P-(31)P indirect dipolar couplings, which arise from the transmission of nuclear spin polarization through interaction of proximal nonbonded electron pairs have been investigated in the solid state for a series of closely related substituted P,P-[3]ferrocenophanes and model systems. Through variation and combination of ligands (phenyl, cyclohexyl, isopropyl) at the two phosphorus sites, the P···P distances in these compounds can be varied from 3.49 to 4.06 Å. Thus, the distance dependence of the indirect no-bond coupling constant J(nb) can be studied in a series of closely related compounds. One- and two-dimensional solid-state NMR experiments serve to establish the character of these couplings and to measure the isotropic coupling constants J(iso), which were found to range between 12 and 250 Hz. To develop an understanding of the magnitude of J(nb) in terms of molecular structure, their dependences on intramolecular internuclear distances and relative orbital orientations is discussed by DFT-calculations on suitable models. In agreement with the literature the dependence of J(nb) on the P···P distance is found to be exponential; however, the steepness of this curve is highly dependent on the internuclear equilibrium distance. For a quantitative description, the off-diagonal elements of the expectation value of the Kohn-Sham-Fock operator in the LMO basis for the LMOs of the two phosphorus lone-pairs is proposed. This parameter correlates linearly with the calculated J(nb) values and possesses the same distance-dependence. In addition, the simulations indicate a distinct dependence of J(nb) on the dihedral angle defined by the two C-P bonds providing ligation to the molecular backbone. For disordered materials or those featuring multiple sites, conformers, and/or polymorphism, a new double-quantum NMR method termed DQ-DRENAR can be used to conveniently measure internuclear (31)P-(31)P distances. If conducted on compounds with known P···P distances, such measurements can also serve to estimate the magnitude of the anisotropy ΔJ of these no-bond indirect spin-spin couplings. The DFT results suggest that in the present series of compounds the magnitude of ΔJ is strongly correlated with that of the isotropic component, as both parameters have analogous distance dependences. While our studies indicate a sizable J-anisotropy for the model compound 1,8-bis(diphenylphosphino)napthalene (ΔJ ~ -70 Hz), the corresponding values for the P,P-[3]ferrocenophanes are significantly smaller, affecting their DQ-DRENAR curves only in a minor way. Based on the above insights, the structural aspects of conformational disorder and polymorphism observed in some of the P,P-[3]ferrocenophanes are discussed.

Noninteracting, vicinal frustrated P/B-Lewis pair at the norbornane framework: synthesis, characterization, and reactions.

Hydroboration of dimesitylnorbornenylphosphane with Piers' borane [HB(C6F5)2] gave the frustrated Lewis pair (FLP) 4 in good yield. It has the -PMes2 Lewis base attached at the 2-endo position and the -B(C6F5)2 group 3-exo oriented at the norbornane framework. The vicinal FLP 4 was shown by X-ray diffraction and by spectroscopy to be a rare example of an intramolecular noninteracting pair of a Lewis acid and Lewis base functionality. The FLP 4 rapidly splits dihydrogen heterolytically at ambient temperature to yield the phosphonium/hydrido borate zwitterion 5. It adds to the carbonyl group of benzaldehyde and to carbon dioxide to yield the adducts 6 and 7, respectively. Compounds 5-7 were characterized by X-ray diffraction. Compound 4 adds to the S═O function of sulfur dioxide to give a pair of diastereomeric heterocyclic six-membered ring products due to the newly formed sulfur chirality center, annulated with the norbornane skeleton, which were investigated by (31)P/(11)B single and double resonance solid state NMR experiments. Compound 8 was also characterized by X-ray diffraction. The FLP 4 undergoes a clean N,N-addition to nitric oxide (NO) to give a norbornane annulated five-membered heterocyclic persistent FLP-NO aminoxyl radical 12 (characterized, e.g., by X-ray diffraction and EPR spectroscopy). Additionally, the FLP radical was characterized by (1)H solid state NMR spectroscopy. The radical 12 undergoes a H-atom abstraction reaction with 1,4-cyclohexadiene to yield the respective diamagnetic FLP-NOH product 13, which was also characterized by X-ray diffraction and solid state NMR spectroscopy.

Modification and unexpected reactivity of 2-borylbenzaldimines: acylated and silylated derivatives as well as dimeric compounds.

Various novel N-alkyl and N-benzyl 2-borylbenzaldimines 3 were prepared by condensation of 2-(dimesitylboryl)benzaldehyde (1) with amines. Further functionalization of compound 3e was possible by deprotonation and subsequent regioselective reaction with electrophiles to give compounds 4. Applying similar conditions to 3a led to the unexpected formation of hitherto unknown dimeric compounds (5 and 6). All structural types were fully characterized, including by X-ray diffraction (XRD). Furthermore, quantum chemical calculations on the SCS-MP2 and DFT levels gave insights into the reaction mechanisms and the stereoselectivity. The B/N bonding situation in these molecules was analyzed using Wiberg bond indices. Preliminary UV-vis and fluorescence measurements indicate that the substitution reaction leading to compounds 4 can be utilized to tune the photophysical properties of these compounds.

Fluorescent modular boron systems based on NNN- and ONO-tridentate ligands: self-assembly and cell imaging.

We have synthesized a series of new fluorescent boron systems 1a-c and 2a-d based on nitrogen (NNN) or nitrogen and oxygen (ONO)-containing tridentate ligands. These novel dyes are characterized by high thermal and chemical stability. They show large Stokes shifts (mostly above 3200 cm(-1)) and quantum yields in solution and in the solid state up to 40%. The easy, modular synthesis facilitates the convenient variation of the axial substituent on the central boron atom, allowing the functionalization of this dye for biochemical use. Introducing a long alkyl chain with a phenyl spacer at this axial position enables the self-assembly of the boron compound 2d to form a fluorescent vesicle, which is able to encapsulate small molecules such as sulforhodamine. Additionally, boron compound 2d was found to serve as a dye for cell imaging since it has the capability of binding to the nuclear membranes of HeLa cells. With phospholipids such as DOPC, giant unilamelar vesicles (GUV) are formed. These results demonstrate the wide applicability of this new boron system in supramolecular and medicinal chemistry.

O-tert-butyldiphenylsilyl coumarin and dicoumarol: a case toward selective sensing of F- ions in organic and aqueous environments.

O-tert-Butyldiphenylsilyl coumarin 1 and 2 dicoumarol have been synthesized and their anion binding properties have been examined in organic and aqueous organic solvents. Compound 1 senses F(-) selectively over the other anions examined in CHCl3 by exhibiting a greater increase in emission. In contrast, compound 2 shows similar selectivity in CHCl3 giving ratiometric change in emission as well as color. In addition, both 1 and 2 are capable of detecting F(-) in water ensuing the cleavage of Si-O bonds. They also show cell permeability and demonstrate their abilities to detect F(-) in a living system.

Iridium(III) emitters based on 1,4-disubstituted-1H-1,2,3-triazoles as cyclometalating ligand: synthesis, characterization, and electroluminescent devices.

A series of blue and blue-green emitters based on neutral bis- and tris-cyclometalated Ir(III) complexes with 1-benzyl-4-(2,6-difluorophenyl)-1H-1,2,3-triazole (dfptrBn) as cyclometalating ligand is reported. The bis-cyclometalated complexes of the type [Ir(dfptrBn)(2)(L(^)X)] with different ancillary ligands, L(^)X = picolinate (pic) (2) or 2-(5-(perfluorophenyl)-2H-1,2,4-triazol-3-yl)pyridine (pytrF(5)) (3), are described and their photophysical properties compared with the analogous complexes containing the archetypal 2-(2,4-difluorophenyl)pyridinato (dfppy) as cyclometaled ligand (C(^)N). Complex 2 exhibits a marked solvatochromic behavior, from 475 nm in toluene to 534 nm in formamide, due to the strong MLCT character of its emissive excited state. Complex 3 displays a true-blue emission, narrower in the visible part than FIrpic. In addition, the homoleptic complex [Ir(dfprBn)(3)] (4) and the heteroleptic compounds with mixed arylpyridine/aryltriazole ligands, [Ir(dfptrBn)(2)(C(^)N)] (C(^)N = 2-phenylpyridinato (ppy) (5) or dfppy (6)), have been synthesized and fully characterized. The facial (fac) complex fac-4 is emissive at 77 K showing a deep-blue emission, but it is not luminescent in solution at room temperature similarly to their phenylpyrazole counterparts. However, the fac isomers, fac-5 and fac-6, are highly emissive in solution and thin films, reaching emission quantum yields of 76%, with emission colors in the blue to blue-green region. The photophysical properties for all complexes have been rationalized by means of quantum-chemical calculations. In addition, we constructed electroluminescent devices, organic light-emitting diodes (OLEDs) by sublimation of fac-6, and by solution processed polymer-based devices (PLEDs) using complexes fac-5 or fac-6 as dopants.