5-N-Arylaminothiazoles with pyridyl groups and their first-row transition metal complexes: synthesis, photophysical properties, and Zn sensing.

A series of 5-N-arylaminothiazoles were synthesized with facile diversity-oriented synthesis from readily available starting materials via the reaction of thioamide dianions and thioformamides. The introduction of various substituents at the 2-position of a thiazole ring (i.e., 2-pyridyl, 4-methylpyridyl, and phenyl groups) and on the nitrogen atom (i.e., p-tolyl and phenyl groups) significantly influenced the absorption and emission spectra of the isolated compounds. X-ray analysis confirmed that the substituents at the amino site were twisted from a thiazole ring, while the formation of its nickel complex showed dinuclear metal complexes bridged with chlorine atoms. Moreover, the formation of zinc-thiazole complexes showed enhanced emission properties in solution and noticeable emission in a solid state. In addition, thiazole-bridged dypyrromethene type ligands showed high selectivity toward Zn+2, which make them good candidates for zinc sensing.

Stereoselective Transesterification of P-Chirogenic Hydroxybinaphthyl Phosphinates.

The substitution reaction of phosphinates with a binaphthyloxy group at the phosphorus atom with lithium alkoxides proceeded with good to high efficiencies to give P-chirogenic phosphinates with a high enantiomeric ratio. As alcohols, primary, secondary, and tertiary alcohols could be used, and the use of tert-butyl alcohol yielded the products with a higher enantiomeric ratio. A substrate with two different alkyl groups on the phosphorus atom could also participate in the substitution reaction to give the corresponding products in good yields with excellent selectivity. The molecular structures of one of the substrates and the corresponding products, determined by X-ray analyses, proved that the substitution reaction at the phosphorus atom proceeded with inversion of the absolute configuration. The usefulness of the reaction was demonstrated by using it to prepare a drug candidate for Duchenne muscular dystrophy. Finally, thionation of the resulting phosphinates was carried out to form P-chirogenic phosphinothioates.

Boron complexes of thiazole-bridged 1,5-bidentate nitrogen ligands: synthesis and acid-responsive photophysical properties.

Boron complexes of 1,5-bidentate nitrogen ligands with a thiazole linker were synthesized by the halogenation of 5-H thiazoles followed by Buchwald-Hartwig amination and complexation with BF3·Et2O. These boron complexes showed a large Stokes shift of up to 125 nm, which is in marked contrast to that observed for ordinary BODIPYs. The absorption and emission spectra of the boron complexes were almost independent of the substituents in the complexes as well as the solvents used for the measurement. The nitrogen atom of the pyridyl group attached to the thiazole ring acted as a Lewis base which accepted Lewis and Brønsted acids to lead to a prominent red-shift of the absorption bands. Addition of tris(pentafluorophenyl)borane, B(C6F5)3, to the boron complex led to a significant red-shift of the absorption band. Likewise, addition of triflic acid (TfOH) and trifluoroacetic acid (TFA) resulted in the emergence of a new absorption band at a longer wavelength accompanied by fluorescence quenching phenomena. DFT calculations show that the energy gap between HOMO and LUMO of the complex significantly decreases after protonation of the nitrogen atom in the acceptor unit of the boron complex.

Hormetic Effects of Binaphthyl Phosphonothioates as Pro-oxidants and Antioxidants.

Organophosphorous compounds with such a wide variety in structure, application, and biochemical activities include pesticides, herbicides, nerve agents, medicines, reagents in organic chemistry, and additives for polymers. Binaphthyl phosphono-, phosphorothioates, and their derivatives, are useful chiral catalysts for various asymmetric reactions and are expected to act as heavy metal scavengers. In this study, we aimed to evaluate the neurotoxicity and biochemical properties of a new series of binaphthyl phosphonothioates called KK compounds using the mouse hippocampal HT22 cells. Despite negligible structural difference, the compounds exhibited differential general cytotoxic activity which was independent of acetylcholine esterase inhibition; on the other hand, all compounds tested prevented endogenous oxidative stress by suppressing generation of reactive oxygen species. Among them, KK397, KK387, KK410, and KK421 showed hormesis, i.e., biphasic dose responses to endogenous oxidative stress, characterized by beneficial effect at low dose and toxic effect at high dose. At cytotoxic concentrations, these compounds were potent radical generators and activated intracellular signaling molecules such as the p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, growth arrest- and DNA damage-inducible gene 153, X-box binding protein 1, and heme oxygenase 1, which are preferentially activated by cell stress-inducing signals, including oxidative and endoplasmic reticulum stress. These findings indicated that novel binaphthyl phosphonothioates can exhibit multiple biochemical properties, functioning as antioxidants and/or pro-oxidants, depending on the concentration, and chemical modification of binaphthyl organophosphorus compounds endowed them with unique characteristics and multiple beneficial functions.

Chemoselective and Stereoselective Alcoholysis of Binaphthyl Phosphonothioates: Straightforward Access to Both Stereoisomers of Biologically Relevant P-Stereogenic Phosphonothioates.

P-Stereogenic phosphonothioates have attracted great attention due to their potent biological activities as analogues of phosphoric acids and phosphorothioates. We demonstrate here straightforward access to P-stereogenic phosphonothioates through the use of binaphthyl phosphonothioates as a chiral template. The first-step alcoholysis of binaphthyl phosphonothioates proceeded via a transfer of the axial chirality of a binaphthyl group to the central chirality of a phosphorus atom to give only monoalcohol adducts with moderate to excellent diastereoselectivities. Further alcoholysis of the obtained products in the presence of a small excess of alcohol and base proceeded with complete elimination of a binaphthyl group to give the corresponding P-stereogenic phosphonothioates with high enantiomeric excess. A DFT study of the reaction mechanisms in first-step alcoholysis indicated that the coordination of a sulfur atom to a sodium cation is the key factor in controlling the diastereoselectivities. This method can be applied to prepare both stereoisomers of a G6P analogue with high diastereomeric purity.

A Modular Approach to Phosphorescent π-Extended Heteroacenes.

A modular route to previously inaccessible classes of ring-fused π-extended heteroacenes bearing the heavy inorganic element tellurium (Te) is presented. These new materials can be viewed as n-doped analogs of molecular graphene subunits that exhibit color tunable visible light phosphorescence in the solid state and in the presence of air. The general mechanism of phosphorescence in these systems was probed experimentally and computationally via time-dependent density functional theory (TD-DFT). The incorporation of Te into π-extended oligoacene frameworks was achieved by an efficient Zr/Te transmetalation protocol; related zirconium-element exchange reactions have been used to prepare both electron-rich and electron-deficient heterocycles containing different elements from throughout the p-block. Therefore, the current study provides a clear path to incorporate inorganic elements into heteroacenes of greater complexity and side group selectivity compared to existing synthetic routes.

Synthesis of Chiral Selenazolines from N-Acyloxazolidinones via a Selenative Rearrangement of Chiral Cyclic Skeletons.

A synthetic route to chiral selenazolines from readily available N-acyloxazolidinones via a selenative rearrangement of a chiral cyclic skeleton is reported. The reaction proceeds in the presence of elemental selenium, a hydrochlorosilane, and an amine. Although the stability of the obtained selenazoline products is relatively low, a wide range of selenazolines was successfully prepared.

The Construction and Application of C=S Bonds.

The current section presents an overview of the fundamental aspects of thiocarbonyl compounds, such as thioaldehydes and thioketones. Firstly, a theoretical approach and a physical-organic experimental approach disclose their properties. Secondly, their synthetic reactions are introduced. Finally, a focus is given to their synthetic applications, including nucleophilic and electrophilic reactions, as well as concerted reactions.

Selenolactams as Synthetic Intermediates for the Synthesis of Polycyclic Amines via Seleno-Claisen Rearrangements.

A highly diastereoselective α-allylation of selenolactams with allyl halides is reported. DFT analyses and experimental observations suggested that this reaction proceeds via a Se-allylation of the eneselenolates of the lactams followed by a seleno-Claisen rearrangement. The thus-obtained products could be efficiently transformed into polycyclic amines using a previously developed sequential addition of organometallic reagents and ring-closing metathesis.

Hydrolysis of Phosphonothioates with a Binaphthyl Group: P-Stereogenic O-Binaphthyl Phosphonothioic Acids and Their Use as Optically Active Ligands and Chiral Discriminating Agents.

The hydrolysis of phosphonothioates with a binaphthyl group afforded the first example of O-(2'-hydroxy)binaphthyl phosphonothioic acids in good to high yields and >95:5 diastereoselectivity. The reaction proceeds via an axis-to-center chirality-transfer reaction. The ability of these acids to act as chiral molecular auxiliaries was demonstrated by using them as optically active ligands for the asymmetric ethylation of benzaldehyde and as a chiral discriminating agent for chiral aliphatic amines.

Employing BINOL-Phosphoroselenoyl Chloride for Selective Inositol Phosphorylation and Synthesis of Glycosyl Inositol Phospholipid from Entamoeba histolytica.

The chemical synthesis of glycosyl inositol phospholipids from Entamoeba histolytica is reported. The key feature of this synthesis is a regioselective phosphorylation reaction that occurs through desymmetrization of a myo-inositol derivative with phosphoroselenoyl chloride. A new protecting-group strategy was developed that utilizes allyl and alloc groups to synthesize complex glycolipids bearing unsaturated lipids. These developments provided an efficient synthetic route for various complex inositol phospholipids and their analogues. Furthermore, the binding affinity of the synthetic inositol phospholipids with mouse CD1d molecules has been evaluated, as well as the immunostimulatory activity.

Experimental and Theoretical Examination of the Radical Cations Obtained from the Chemical and Electrochemical Oxidation of 5-Aminothiazoles.

Chemical or electrochemical one-electron oxidation of 5-N-arylaminothiazoles was found to afford stable radical cations. For chemical oxidation, 1 equivalent of [(4-BrC6H4)3N][SbCl6] (Magic Blue, MB) was added to CH2Cl2 solutions of the thiazoles, and the thus-obtained radicals showed light absorption in the near-infrared region. Electrochemical oxidation also led to bathochromic shifts in the absorption bands, and the obtained spectra were similar to those derived from the chemically oxidized species. These radicals afforded electron paramagnetic resonance (EPR) spectra that are consistent with the notion of stable nitrogen radicals (half-life≤385 h). The EPR spectrum of a thiazole containing 4-dimethylaminophenyl groups on the nitrogen atom at the 5-position changed significantly upon adding >3 equivalents of MB. Details of the electronic structures of the experimentally obtained radical cations were generated from theoretical calculations.

Imidazo[1,5-a]pyridin-3-ylidenes as π-accepting carbene ligands: substituent effects on properties of N-heterocyclic carbenes.

Various 1-substituted-imidazo[1,5-a]pyridin-3-ylidenes were prepared and characterized. The fundamental character and the effects of substituents on the imidazo[1,5-a]pyridine backbone on the electronic character of carbenes were evaluated using rhodium complexes and selenium adducts. 13C NMR chemical shifts of carbene carbons in imidazo[1,5-a]pyridin-3-ylidene and 1H and 13C NMR spectra of olefin moieties trans to the carbene in Rh(nhc)(cod)Cl complexes shifted relatively downfield compared to those for the corresponding complexes bearing conventional N-heterocyclic carbenes (NHCs). The IR peak of the trans-carbonyl moiety of Rh(nhc)(CO)2Cl complexes appeared at a higher wavenumber than for conventional NHCs. These observations suggest that imidazo[1,5-a]pyridin-3-ylidene ligands have strong π-accepting character. Rh(nhc)(CO)2Cl complexes were further characterized by X-ray diffraction analyses. To obtain further insight into the electronic character of imidazo[1,5-a]pyridin-3-ylidenes, selenoureas were prepared. We found that a combination of both the 77Se NMR chemical shift and 1JC-Se coupling constant of C-Se bonds are appropriate for a rigorous evaluation of the electronic characters of imidazo[1,5-a]pyridin-3-ylidenes, but did not correspond to those for conventional NHCs. DFT calculations for imidazo[1,5-a]pyridin-3-ylidenes revealed that a hybrid accepting orbital comprised of a vacant p-orbital of carbene and a π* orbital of the pyridine ring newly occurred to result in significantly increased π-accepting character. Finally, the strong π-accepting character of the ligand was demonstrated by the Rh-catalyzed polymerization of phenylacetylene.

Acid-Responsive Absorption and Emission of 5-N-Arylaminothiazoles: Emission of White Light from a Single Fluorescent Dye and a Lewis Acid.

The front cover artwork is provided by the group of Toshiaki Murai at Gifu University (Japan). The image shows structures of the key compounds and the change of the fluorescence. Although electron-donating and -accepting groups are not in the same plane, they show relatively strong fluorescence from blue to orange. For more details, read the full text of the Communication at 10.1002/open.201600059.

Acid-Responsive Absorption and Emission of 5-N-Arylaminothiazoles: Emission of White Light from a Single Fluorescent Dye and a Lewis Acid.

Solutions of 5-N-arylaminothiazoles containing pyridyl groups exhibited clear halochromism and halofluorism upon addition of Brønsted and Lewis acids. The addition of triflic acid to solutions of 5-N-arylaminothiazoles in Et2O induced bathochromic shifts of the absorption and emission bands. DFT calculations suggested that the spectral changes arise from the protonation of the pyridyl group of the thiazoles in Et2O. Single-crystal X-ray diffraction analysis of a thiazole and its protonated form revealed the change of the conformation around the thiazole ring. The emission of white light was accomplished from a single fluorescent dye by adjusting the ratio of dye and B(C6F5)3, whereby the International Commission on Illumination coordinates showed a linear change from blue to orange.

Sequential Deprotonation-Alkylation of Binaphthyloxy-Substituted Phosphonochalcogenoates: Chiral Tri- and Tetrasubstituted Carbon Centers Adjacent to a Phosphorus Atom.

Sequential deprotonation and alkylation of 1,1'-binaphthyloxy-substituted phosphonoselenoates and phosphonates resulted in the diastereoselective formation of chiral tri- and tetrasubstituted carbon centers adjacent to a phosphorus atom.

Sequential Addition Reaction of Sulfanylmethyllithiums and Grignard Reagents to Thioformamides Leading to the Formation of 2-Phenyl-2-sulfanylethyl Tertiary Amines.

The reaction of sulfanylmethyllithiums generated from benzylsulfanes and n-BuLi with N,N-dimethylthioformamide followed by the addition of Grignard reagents gave 2-phenyl-2-sulfanyl tertiary amines in moderate to good yields. A range of Grignard reagents involving primary alkyl, aryl, vinyl, and alkynyl Grignard reagents were used. Two carbon-carbon bond-forming reactions were achieved through a one-pot reaction. The reaction showed good to high diastereoselectivity, particularly with alkynyl Grignard reagents.

Direct C-H Bond Arylation of Thienyl Thioamides Catalyzed by Pd-Phenanthroline Complexes.

A direct C-H bond arylation method for thienyl thioamides catalyzed by [Pd(phen)2](PF6)2 was developed. This reaction selectively afforded 2-monoarylated products, while the corresponding amide thiophene derivatives furnished 2,5-diarylated products. Mechanistic studies revealed that a Pd(II)-bisthioamide complex should be the active species for the reaction of thienyl thioamides in the presence of catalytic amounts of [Pd(phen)2](PF6)2. Similar to the reaction with amides, the reaction with thioamides selectively generated the 2,5-diarylated products when a preformed Pd(phen)PhI complex was used.

5-N-Arylaminothiazoles as Highly Twisted Fluorescent Monocyclic Heterocycles: Synthesis and Characterization.

A series of 5-N-arylaminothiazoles was prepared by reacting thioamide dianions derived from secondary thioamides with thioformamides, followed by sequential oxidation with iodine. X-ray analyses demonstrated that they adopt structures that are highly twisted from planar conformations. Their orientations were tuned by the steric and/or electronic interactions of the substituents at their 2-, 4-, and 5-positions. The 5-aminothiazoles exhibited a range of fluorescent emissions, from blue to orange. Although the absorption spectra were independent of the polarity of the solvent, fluorescent emissions were influenced by the polarity of the solvent: in more polar solvents, the emissions were red-shifted. These phenomena were examined in terms of Lippert-Mataga plots and the change in the dipole moment between the ground and excited states. They also exhibited emissions in the solid state, again from blue to orange. Cyclic voltammetry of the 5-aminothiazoles showed reversible waves of one-electron oxidation. The half-potential of the oxidation was reduced by the introduction of electron-donating groups to the phenyl groups on the nitrogen atom at the 5-position. DFT calculations were carried out to determine the energy levels of the HOMO and LUMO. Finally, the results of TG-DTA showed that they are thermally stable.

α-Hydroxy and α-Oxo Selenoamides: Synthesis via Nucleophilic Selenocarbamoylation of Carbonyl Compounds and Characterization.

Carbonyl compounds were added to selenocarbamoyllithiums to generate α-hydroxy and α-oxo selenoamides. Their conformations were determined by X-ray analyses. These compounds adopted conformations that were almost identical to those of ordinary amides. Unlike the consistency of the chemical shifts of the C═Se groups of the selenoamides in (13)C NMR spectra and the (1)J coupling constants of the C═Se groups, the substituents far from the selenium atom influenced the chemical shifts in (77)Se NMR.