Structure-property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives.

Presented here is the design, synthesis, and study of a variety of novel hydrogen-bonding-capable π-conjugated N-heteroacenes, 1,4-dihydropyrazino[2,3-b]quinoxaline-2,3-diones (DPQDs). The DPQDs were accessed from the corresponding weakly hydrogen-bonding dicyanopyrazinoquinoxaline (DCPQ) suspensions with excess potassium hydroxide, resulting in moderate to good yields. Both families of compounds were analyzed by UV-vis and NMR spectroscopy, where the consequences of hydrogen bonding capability could be assessed through the structure-property studies. Conversion of the DCPQs into hydrogen-bonding capable DPQDs results in modulation of frontier MO energies, higher molar extinction coefficients, enhanced crystallinity, and on-average higher thermal stability (where in some cases the 5% weight loss temperature is increased by up to 100 °C). Single crystal X-ray diffraction data could be obtained for three DPQDs. One reveals pairwise hydrogen bonding in the solid state as well as a herringbone packing arrangement rendering it a promising candidate for additional studies in the context of organic optoelectronic devices.

Hydrogen Peroxide Modifies Aß-Membrane Interactions with Implications for Aß40 Aggregation.

Alzheimer's disease (AD) is pathologically characterized by the formation of extracellular senile plaques, predominately comprised of aggregated ß-amyloid (Aß), deposited in the brain. Aß aggregation can result in a myriad of distinct aggregate species, from soluble oligomers to insoluble fibrils. Aß strongly interacts with membranes, which can be linked to a variety of potential toxic mechanisms associated with AD. Oxidative damage accompanies the formation of Aß aggregates, with a 10-50% proportion of Aß aggregates being oxidized in vivo. Hydrogen peroxide (H2O2) is a reactive oxygen species implicated in a number of neurodegenerative diseases. Recent evidence has demonstrated that the H2O2 concentration fluctuates rapidly in the brain, resulting in large concentration spikes, especially in the synaptic cleft. Here, the impact of environmental H2O2 on Aß aggregation in the presence and absence of lipid membranes is investigated. Aß40 was exposed to H2O2, resulting in the selective oxidation of methionine 35 (Met35) to produce Aß40Met35[O]. While oxidation mildly reduced the rate of Aß aggregation and produced a distinct fibril morphology at high H2O2 concentrations, H2O2 had a much more pronounced impact on Aß aggregation in the presence of total brain lipid extract vesicles. The impact of H2O2 on Aß aggregation in the presence of lipids was associated with a reduced affinity of Aß for the vesicle surface. However, this reduced vesicle affinity was predominately associated with lipid peroxidation rather than Aß oxidation.

Photoluminescence of Seven-Coordinate Zirconium and Hafnium Complexes with 2,2'-Pyridylpyrrolide Ligands.

Luminescent seven-coordinated zirconium and hafnium complexes bearing three mono-anionic 2,2'-pyridylpyrrolide ligands and one chloride were synthesized. Solid-state structures and the dynamic behaviors in solution were probed by X-ray crystallography and variable temperature 1 H NMR experiments, respectively. Absorption spectroscopy and time-dependent density functional theory (TD-DFT) calculations supported a hybrid of ligand-to-metal charge transfer (LMCT)/ligand-to-ligand charge transfer (LLCT) for the visible light absorption band. The complexes (Me PMPMe )3 MCl (M=Zr, Hf, Me PMPMe =3,5-dimethyl-2-(2-pyridyl)pyrrolide) are emissive in solution at room temperature upon irradiation with visible light due to a combination of phosphorescence and fluorescence characterized by excited state lifetimes in the µs and low to sub-ns timescale, respectively. Electrochemical experiments revealed that the zirconium complex possesses a reversible redox event under highly reducing condition (-2.29 V vs. Fc+/0 ).

Reactivity of Pyridine Dipyrrolide Iron(II) Complexes with Organic Azides: C-H Amination and Iron Tetrazene Formation.

Reaction of (MesPDPPh)Fe(thf) (H2MesPDPPh = 2,6-bis(5-(2,4,6-trimethylphenyl)-3-phenyl-1H-pyrrol-2-yl)pyridine) with organic azides has been studied. The identity of the azide substituent had a profound impact on the transformation type and nature of the observed products. Reaction with aromatic p-tolyl azide, N3Tol, resulted in exclusive formation of the corresponding iron tetrazene complex (MesPDPPh)Fe(N4Tol2). In contrast, the use of bulky 1-adamantyl azide led to clean intramolecular C-H amination of one of the benzylic C-H bonds of a mesityl substituent on the pyridine dipyrrolide, PDP, supporting ligand. The smaller aliphatic substituent in benzyl azide allowed for the isolation of two different compounds from distinct reaction pathways. One product is the result of double C-H amination of the PDP ligand via nitrene transfer, while the second one contains a dibenzyltetrazene and a benzaldimine ligand. All isolated complexes were characterized using a combination of X-ray crystallography, solid state magnetic susceptibility measurements, 1H NMR and 57Fe Mössbauer spectroscopy, and density functional theory (DFT), and their electronic structures were elucidated. Potential electronic structures for putative iron(IV) imido or iron(III) imidyl radical complexes were explored via DFT calculations.

Synthesis of the tricyclic indole alkaloids, dilemmaones A and B.

Dilemmaones A-C are naturally occurring tricyclic indole alkaloids possessing a unique hydroxymethylene or methoxymethylene substituent at the C2 position of the indole core and a C6-C7 fused cyclopentanone. Dilemmaone B has been prepared in 5 steps from 5-methylindan-1-one, and dilemmaone A has been prepared in 3 steps from a common precursor, 6-bromo-5-methyl-7-nitroindan-1-one. In both syntheses, key steps include a Kosugi-Migita-Stille cross coupling and a reductive cyclization using hydrogen gas and a transition metal catalyst.

Synthesis of new cyano-substituted analogues of Tröger's bases from bromo-derivatives. A stereochemical dependence of long-range (n JHH , n = 4, 5, and 6) proton-proton and proton-carbon (n JCH , n = 1, 2, 3, 4, and 5) coupling constants of these compounds.

A free-catalyst microwave-assisted cyanation of brominated Tröger's base derivatives (2a-f) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds (3a-e, I) in very good yields. Complete assignment of 1 H and 13 C chemical shifts of 2a-f, I and 3a-d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton-proton coupling constants n JHH (n = 4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the 1 H NMR spectrum and comparing it to the experimental spectrum. The excitation-sculptured indirect-detection experiment (EXSIDE) and 1 H-15 N CIGARAD-HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long-range carbon-proton coupling constants n JCH (n = 2, 3, and 4) and for assignment of 15 N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6-31G(d,p), 6-311G(d,p), and 6-311 + G(d,p) basis sets. For calculation of 1 H and 13 C chemical shifts, n JHH (n = 2, 3, 4, 5, and 6), and n JCH (n = 1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long-range n JHH (n = 4, 5, and 6) and n JCH (n = 1, 2, 3, 4, and 5) have been found in bromo-substituted analogues of Tröger's bases.

Synthesis of Molecular Nanohoops Bearing a Tetrahydro[6]cycloparaphenylene Fused to a Hydrogenated or a Bithiophene-Inserted Cycloparaphenylene.

A synthetic pathway to a molecule bearing two molecular nanohoops, including a tetrahydro[6]cycloparaphenylene (4H[6]CPP) fused through two 1,4-dimethoxybenzene units to a 4H[10]CPP, was developed. Similarly, a molecule containing a 4H[6]CPP fused through two 1,4-dimethoxybenzene units to a molecular nanohoop bearing a [6]CPP inserted with two 2,2'-bithiophene-5,5'-diyl groups was synthesized. The Diels-Alder reactions of two (E,E)-1,4-diaryl-1,3-butadienes with 1,4-benzoquinone and the Ni-mediated homocoupling reactions are the key steps for the construction of macrocyclic ring structures. Oxidative aromatization with DDQ converted a hydrogenated system to a fully aromatized nanohoop with 10 aromatic units, including a [6]CPP inserted with two 2,2'-bithiophene-5,5'-diyl groups. The UV-vis and fluorescence spectra of the fused two-hoop systems were investigated.

Synthesis of a Cyclophane Bearing Two Benz[a]anthracene Units Connected at the 5 and 7 Positions with Two Naphth-1,4-diyl Groups.

A synthetic pathway to a cyclophane bearing two benz[a]anthracene units connected at the 5 and 7 positions through two naphth-1,4-diyl groups was developed, and its structure was confirmed by X-ray structure analysis. Because of structural constraints, the two naphthyl groups are distorted from planarity and the bonds connecting them to the benz[a]anthracene units are bent significantly. The UV-vis and fluorescence spectra of the cyclophane are red-shifted from those of 7-(1-naphthalenyl)benz[a]anthracene, which is the corresponding monomeric polycyclic aromatic hydrocarbon.

Highly Efficient and Stereoselective Thioallylation of Alkynes: Possible Gold Redox Catalysis with No Need for a Strong Oxidant.

Stereoselective thioallylation of alkynes under possible gold redox catalysis was accomplished with high efficiency (as low as 0.1 % catalyst loading, up to 99 % yield) and broad substrate scope (various alkynes, inter- and intramolecular fashion). The gold(I) catalyst acts as both a π-acid for alkyne activation and a redox catalyst for AuI/III coupling, whereas the sulfonium cation generated in situ functions as a mild oxidant. This novel methodology provides an exciting system for gold redox catalysis without the need for a strong oxidant.

Investigations on Gold-Catalyzed Thioalkyne Activation Toward Facile Synthesis of Ketene Dithioacetals.

Nucleophilic addition to thioalkynes was investigated under various catalytic conditions with gold(I) complexes being identified as the optimal catalysts. Structural evaluation of the product revealed an unexpected cis-addition, arising from a gold-associated thioketene intermediate. Based on this interesting mechanistic insight, a gold(I)-catalyzed thioether addition to thioalkynes was developed as a novel approach to prepare ketene dithioacetals with good yields and high efficiency.

Synthesis of Partially Hydrogenated Cycloparaphenylenes with Bent and Fused Structures Bearing Armchair Carbon Nanotube-like Connections.

The Diels-Alder reactions between 2 equiv of (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene and 1,4-benzoquinone led to the formation of a key intermediate with all four 4-bromophenyl substituents cis to one another. The subsequent nickel-mediated homocoupling reactions then produced partially hydrogenated cycloparaphenylenes, including a molecule bearing two units of tetrahydro[6]cycloparaphenylene (4H[6]CPP) fused together through two 1,4-dimethoxybenzene units in an armchair (6,6)carbon nanotube-like connection. Similarly, two 6H[9]CPPs were connected through three 1,4-dimethoxybenzene units in an armchair (9,9)carbon nanotube-like arrangement. A bent 8H[12]CPP and a bent 12H[18]CPP, which were fused intramolecularly with two and three 1,4-dimethoxybenzene units, respectively, to create the bent structures, were likewise synthesized. A molecule containing a bent 8H[12]CPP fused to a 4H[6]CPP was likewise constructed. The structures of these partially hydrogenated CPPs were established by X-ray structure analysis, NMR spectroscopy, and additional independent synthetic pathways.

Synthesis and Characterization of Functionalized [12]Cycloparaphenylenes Containing Four Alternating Biphenyl and Naphthyl Units.

Functionalized [12]cycloparaphenylenes ([12]CPPs) containing four alternating biphenyl and naphthyl units were synthesized. A macrocyclic furan-containing CPP precursor was used for the Diels-Alder reaction with the parent benzyne or 3,6-dimethoxybenzyne to form the corresponding macrocyclic carbon frameworks. The subsequent reductive deoxygenation of the Diels-Alder adducts with Fe2(CO)9 followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone produced the functionalized [12]CPPs. The effect of macrocyclic ring size on the reaction rate of oxidative aromatization was investigated.

Synthesis of Cycloparaphenylenes Bearing Furan-2,5-diyl or 2,2'-Bifuran-5,5'-diyl Units in the Macrocyclic Structures.

Synthetic pathways to furan-containing cycloparaphenylenes (CPPs) as molecular nanohoops bearing 10, 12, and 15 aromatic units including furan-2,5-diyl or 2,2'-bifuran-5,5'-diyl units have been developed. The X-ray structures of a partially hydrogenated bifuran-containing CPP precursor and the corresponding fully aromatized bifuran-containing CPP were obtained to allow the determination of their conformational arrangements in the crystal lattice. The optical and electrochemical properties of the furan-containing CPPs were investigated.

Double Palladium Catalyzed Reductive Cyclizations. Synthesis of 2,2'-, 2,3'-, and 3,3'-Bi-1H-indoles, Indolo[3,2-b]indoles, and Indolo[2,3-b]indoles.

A palladium catalyzed, carbon monoxide mediated, double reductive cyclization of 1,4-, 1,3-, and 2,3-bis(2-nitroaryl)-1,3-butadienes to afford 2,2'-, 2,3'-, and 3,3'-biindoles, respectively, was developed. In contrast, reductive cyclizations of 1,2-bis(2-nitroaryl)ethenes were nonselective, affording mixtures of monocyclized indoles, indolo[3,2-b]indole, indolo[1,2-c]quinazolin-6(5H)-ones, and 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones. Nonselective product formation was also observed from reductive cyclization of 1,1-bis(2-nitroaryl)ethenes, producing indolo[2,3-b]indoles and indolo[2,3-c]quinolin-6-ones. Carbon monoxide insertion to give the carbonyl containing products was the major or sole reaction path starting from 1,1- or 1,2-bis(2-nitroaryl)ethenes.

Regioselective Amine-Borane Cyclization: Towards the Synthesis of 1,2-BN-3-Cyclohexene by Copper-Assisted Triazole/Gold Catalysis.

The combination of triazole/gold (TA-Au) and Cu(OTf)2 is identified as the optimal catalytic system for promoting intramolecular hydroboration for the synthesis of a six-membered cyclic amine-borane. Excellent yields (up to 95 %) and regioselectivities (5-exo vs. 6-endo) were achieved through catalyst control and sequential dilution. Good functional-group tolerance was attained, thus allowing the preparation of highly functionalized cyclic amine-borane substrates, which could not be achieved using other methods. Deuterium-labeling studies support the involvement of a hydride addition to a gold-activated alkyne with subsequent C-B bond formation.

Synergistic Gold and Iron Dual Catalysis: Preferred Radical Addition toward Vinyl-Gold Intermediate over Alkene.

A dual catalytic approach enlisting gold and iron synergy is described. This method offers readily access to substituted heterocycle aldehydes via oxygen radical addition to vinyl-gold intermediates under Fe catalyst assistance. This system shows good functional group compatibility for the generation of substituted oxazole, indole, and benzofuran aldehydes. Mechanistic evidence greatly supports selective radical addition to an activated vinyl-Au double bond over alkene. This unique discovery offers a new avenue with great potential to further extend the synthetic power and versatility of gold catalysis.

Total synthesis of the tetracyclic indole alkaloid ht-13-B.

An expedient synthesis corroborating the proposed structure of the tetracyclic indole alkaloid ht-13-B is presented. Key synthetic steps include acyliminium ion allylation, a Mitsunobu reaction, a palladium-catalyzed Stille-Kelly cross coupling reaction, and a carbon monoxide-mediated palladium-catalyzed reductive N-heterocyclization. The chiral centers are ultimately derived from commercially available trans-4-hydroxy-l-proline.

Ligand-Assisted Gold-Catalyzed Cross-Coupling with Aryldiazonium Salts: Redox Gold Catalysis without an External Oxidant.

Gold-catalyzed C(sp)-C(sp(2)) and C(sp(2))-C(sp(2)) cross-coupling reactions are accomplished with aryldiazonium salts as the coupling partner. With the assistance of bpy ligand, gold(I) species were oxidized to gold(III) by diazonium without any external oxidants. Monitoring the reaction with NMR and ESI-MS provided strong evidence for the nitrogen extrusion followed by Au(III) reductive elimination as the key step.

Gold-catalyzed oxidative cross-coupling of terminal alkynes: selective synthesis of unsymmetrical 1,3-diynes.

Gold-catalyzed oxidative cross-coupling of alkynes to unsymmetrical diynes has been achieved for the first time. A N,N-ligand (1,10-Phen) and PhI(OAc)2 were identified as crucial factors to promote this transformation, giving the desired cross-coupled conjugated diynes in excellent heteroselectivity (>10:1), in good to excellent yields, and with large substrate tolerability.

Asymmetric synthesis of substituted NH-piperidines from chiral amines.

Previously, we reported an efficient asymmetric synthesis of substituted piperidines through an exocyclic chirality induced nitroalkene/amine/enone (NAE) condensation reaction. An effective protecting group strategy was developed herein to achieve enantiopure piperidines (yields up to 92%) with complete chirality retention (ee > 95%). A simple derivatization of the obtained piperidines gave thiourea catalysts, indicating the strong potential of this method for producing new amine-based dual functional organocatalysts for future development.