Cyclization-Carbonylation of 2-Alkynyl Primary Benzamides using p-Benzoquinone under Neutral Conditions.

A palladium-catalyzed cyclization-carbonylation of 2-alkynyl primary benzamides 1 afforded methyl 3-substituted 1-methoxyisoquinoline-4-carboxylates 6 in good to moderate yields. In the case of mesylate 1r, 12 was obtained directly via a cyclization-carbonylation-cyclization cascade. Compounds 6 were converted to isoquinolin-1(2H)-ones 8 in good yields under microwave irradiation. In the case of the mesylate 6q, tricyclic isoquinolinone 10 was obtained in good yield. The reactions of thiophene-2-carboxamide derivatives also proceeded well.

A sequential reaction of picolinamide with benzaldehydes promoted by Pd(TFA)2: rapid access to 4,5-disubstituted 2-(pyridin-2-yl)oxazoles in n-octane.

We developed a synthetic method for obtaining 4,5-disubstituted 2-(pyridin-2-yl)oxazoles from picolinamide and aldehydes by employing Pd(TFA)2 as the catalyst in n-octane. This cascade reaction involves the condensation of picolinamide and two aldehyde molecules promoted by trifluoroacetic acid (TFA) generated in situ from Pd(TFA)2. This one-pot protocol provides rapid access to synthetically valuable triaryloxazoles from readily available starting materials under mild conditions. An 18O labeling study revealed that this tandem reaction proceeded via a different reaction mechanism compared to the Robinson-Gabriel oxazole synthesis.

Conformational Control of [2]Rotaxane by Hydrogen Bond.

A series of [2]rotaxanes with various functional groups in the axle component was synthesized by the oxidative dimerization of alkynes, which is mediated by a macrocyclic phenanthroline-Cu complex. The rotaxanes were fully characterized by spectroscopic methods, and the structure of a rotaxane was determined by X-ray crystallographic analysis. The interaction between the ring component and the axle component was studied in detail to understand the conformation of the rotaxanes. The presence of the hydrogen bond between the phenanthroline moiety in the macrocyclic component and the acidic proton in the axle component influenced the conformation of rotaxane.

Dehydrative amination of benzhydrols with electron-withdrawing group-substituted 2-aminopyridines utilizing Au(III)/TPPMS catalyst system in water.

We report a method for gold(III)/sodium diphenylphosphinobenzene-3-sulfonate (TPPMS)-catalyzed direct amination of benzhydrols using 2-aminopyridines with poor nucleophilic character in water. Various functional groups such as electron-withdrawing nitro, cyano and halogen groups were tolerated well to form the desired N-benzylated 2-aminopyridine compounds. On the basis of mechanistic studies including kinetic profiles, Hammett study and isotope effects, we propose a pathway in which a Lewis acidic gold cation species activates the sp3 C-O bond of the alcohol in the rate-determining step.

Synthesis and Systematic Structural Analysis of Cationic Half-Sandwich Ruthenium Chalcogenocarbonyl Complexes.

Although the chemistry of transition-metal complexes with carbonyl (CO) and thiocarbonyl (CS) ligands has been well developed, their heavier analogues, namely selenocarbonyl (CSe) and tellurocarbonyl (CTe) complexes remain scarce. The limited availability of such CSe and CTe complexes has so far hampered our understanding of the differences between such chalcogenocarbonyl (CE: E=O, S, Se, Te) ligands. Herein, we report the synthesis and properties of a series of cationic half-sandwich ruthenium CE complexes of the type [CpRu(CE)(H2 IMes)(CNCH2 Ts)][BArF 4 ] (Cp=η5 -C5 H5 - ; H2 IMes=1,3-dimesitylimidazolin-2-ylidene; ArF =3,5-(CF3 )2 C6 H3 ). A combination of X-ray diffraction analyses, NMR spectroscopic analyses, and DFT calculations revealed an increasing π-accepting ability of the CE ligands in the order O

Synthesis and chiroptical properties of cylindrical macrocycles comprising two calix[3]aramide moieties.

Calix[3]aramide-based cylindrical macrocycles were synthesized by the one-step amide coupling reaction of a monomer containing two meta-alkylaminobenzoic acid units linked by para-phenylene bridges. The major products included a meso-form and an enantiomeric pair, with stereochemistry derived from the direction of the amide bonds and their fixed conformation. Mirror-image ECD, VCD, and CPL spectra were observed in the enantiomeric pair and the absolute structure was determined by comparing measured and calculated ECD and VCD spectra.

[Identification of Descarbonsildenafil in an Adulterated Dietary Supplement and Evaluation of Its Inhibitory Activity for Phosphodiesterase Type 5 (PDE5)].

Some illegal dietary supplements contain phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, for exerting "therapeutic" effects in erectile dysfunction. This is apparently dangerous, and thus, should be appropriately regulated. Identification of descarbonsildenafil was first reported in Singapore in a coffee sample labeled to exert male sexual performance enhancement effects. However, it is unclear whether the compound possesses PDE5 inhibitory activity. We encountered during our survey of dietary supplements, a sexual enhancement product commercially available in Tokyo, in which a peak presumed to be of descarbonsildenafil was detected by LC-UV and electrospray ionization-tandem MS (ESI-MS/MS). The compound was isolated and identified as descarbonsildenafil with liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS), NMR, and X-ray crystal structural analysis. In addition, descarbonsildenafil showed PDE5 inhibitory activity in PDE5 inhibition assay, and its IC50 value for PDE5A1 was found to be 30 nmol/L. The results of INADEQUATE NMR and X-ray crystal structural analysis in this study provide information for the identification of descarbonsildenafil. Since this study indicates that this compound is a PDE5 inhibitor having adequate activity, it is regulated as a drug component in Japan.

Asymmetric Cyclizative Dimerization of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst.

The first example of an asymmetric cyclization-dimerization of (ortho-alkynyl phenyl) (methoxymethyl) sulfides with a palladium(II) bisoxazoline (box) catalyst has been developed. The box ligand enhances the alkynophilicity of benzothienyl palladium(II) intermediate A and thus promotes coordination of the second alkyne substrate, leading to the dimerization. The characteristic properties of the box ligand were supported by density functional theory (DFT) calculations of the intermediate. Axially chiral bibenzothiophenes were obtained in good yields with good enantioselectivities.

Gold(III)-Catalyzed Decarboxylative C3-Benzylation of Indole-3-carboxylic Acids with Benzylic Alcohols in Water.

A strategy for the gold(III)-catalyzed decarboxylative coupling reaction of indole-3-carboxylic acids with benzylic alcohols has been developed. This cascade reaction is devised as a straightforward and efficient synthetic route for 3-benzylindoles in moderate to excellent yields (50-93%). A Hammett study of the protodecarboxylation gives a negative ρ value, suggesting that there is a buildup of positive charge on the indole ring in the transition state. Furthermore, comparison of initial rates in H2O and in D2O reveals an observed kinetic solvent isotope effect (KSIE = 2.7). This simple protocol, which affords the desired products with CO2 and water as the coproducts, can be achieved under mild conditions without the need for base or other additives in water.

Synthesis, Structures, and Properties of Hexapole Helicenes: Assembling Six [5]Helicene Substructures into Highly Twisted Aromatic Systems.

Hexapole helicenes 1, which contain six [5]helicene substructures, were synthesized by Pd-catalyzed [2+2+2]cycloadditions of aryne precursor 6. Among the possible 20 stereoisomers, which include ten pairs of enantiomers, HH-1 was obtained selectively. Density functional theory (DFT) calculations identified HH-1 as the second most stable isomer that quantitatively isomerizes under thermal conditions into the most stable isomer (HH-2). Both enantiomers of HH-2 can be separated by chiral HPLC. Single-crystal X-ray diffraction analyses revealed a saddle-like structure for (P,M,P,P,M,P) HH-1 and a propeller-like structure for (P,M,P,M,P,M) HH-2. Because of the helical assembly and the resulting steric repulsion, the structure of HH-1 is significantly distorted and exhibits the largest twisting angle reported so far (up to 35.7° per benzene unit). Electrochemical studies and DFT calculations indicated a narrow HOMO-LUMO gap on account of the extended π-system. Kinetic studies of the isomerization from HH-1 to HH-2 and the racemization of enantiomerically pure HH-2 were conducted based on 1H NMR spectroscopy, HPLC analysis, and DFT calculations.

Synthesis and Shuttling Behavior of [2]Rotaxanes with a Pyrrole Moiety.

We synthesized [2]rotaxanes with a pyrrole moiety from a [2]rotaxane with a 1,3-diynyl moiety. The conversion of the 1,3-diynyl moiety of the axle component to the pyrrole moiety was accomplished by a Cu-mediated cycloaddition of anilines. The cycloaddition reaction was accelerated when the [2]rotaxane was used as the substrate. The effect of the structure of the pyrrole moiety on the rate of the shuttling was studied.

Cationic palladium(ii)-catalyzed dehydrative nucleophilic substitutions of benzhydryl alcohols with electron-deficient benzenethiols in water.

An efficient direct nucleophilic substitution of benzhydryl alcohols with electron-deficient benzenethiols using cationic Pd(ii) catalysts as Lewis acids in water is reported. Atom economical and environmentally benign protocols afford S-benzylated products in moderate to excellent yields. Commercially available Pd(MeCN)4(OTf)2, PdCl2(MeCN)2, and Na2PdCl4 are highly efficient catalysts. Notably, this simple protocol can be achieved without any other additives such as acids, bases, or external ligands. A Hammett study on the rate constants of S-benzylation by using various substituted benzhydryl alcohols yielded negative ρ values, suggesting that there is a build-up of positive charge in the transition state.

Direct substitution of benzylic alcohols with electron-deficient benzenethiols viaπ-benzylpalladium(ii) in water.

An efficient and environmentally benign method for the direct nucleophilic substitution of benzylic alcohols with electron-deficient benzenethiols in water is developed. π-Benzylpalladium(ii) cation complexes show high catalytic activity for S-benzylation, which provides a mechanistic alternative to the borrowing hydrogen methodology. Hammett studies on the rate constants of S-benzylation by various substituted alcohols show good correlation between log(kX/kH) and the σ value of the respective substituents. From the slope, negative ρ values are obtained, suggesting that there is a build-up of positive charge in the transition state. Water plays an important role in the catalytic system for sp(3) C-O bond activation and stabilization of the activated Pd(ii) cation species.

Enantioselective desymmetrization of FTY720.

A method for enantioselective desymmetrization of N-Ac and N-Boc-FTY720 by nonenzymatic asymmetric acylation was developed. Effective enantioselective monobenzoylation using benzoyl chloride in the presence of the tetraphenylbisoxazoline (L2)-CuCl2 complex gave the desired products 3a and 3b in 52-62% yield with 64% ee.

Hg2+-trapping beads: Hg2+-specific recognition through thymine-Hg(II)-thymine base pairing.

Mercury pollution poses a severe threat to human health. To remove Hg(2+) from contaminated water, we synthesized Hg(2+)-trapping beads that include oligo-thymidine functionalities that can form thymine-Hg(II)-thymine base pairs on the solid support. The beads can selectively trap Hg(2+) even in the presence of other metal cations. More interestingly, Hg(2+)-trapping efficiency was higher in the presence of the co-existing cations. Thus, the developed Hg(2+)-trapping beads can capture Hg(2+) without affecting the mineral balance of water so much. The Hg(2+)-trapping beads presented here show promise for removing Hg(2+) from environmental water.

Organocatalytic functionalization of heteroaromatic N-oxides with C-nucleophiles using in situ generated onium amide bases.

Organocatalytic functionalization of heteroaromatic N-oxides was investigated using in situ generated onium amide bases, and C-nucleophiles were efficiently introduced by the sequential addition-elimination reaction under metal-free conditions, affording 2-substituted nitrogen heteroaromatics generally in good to high yields.

Synthesis of the Proposed Structure of Mohangic Acid C.

The proposed structure of mohangic acid C (3) was stereoselectively synthesized via a catalytic asymmetric aldol reaction to install a p-aminoacetophenone moiety, Marshall propargylation furnishing two stereocenters, and Cu-mediated Stille-type coupling to construct the whole framework of 3.

Synthesis, crystal structure, and properties of methyl-substituted coronene amide analogue.

A coronene amide analogue was synthesized in six steps using an improved method at the final biarylation step. The key to the progress of palladium-mediated biarylation involved the introduction of three methyl groups to suppress the undesired reaction and the use of tri-tert-butylphosphine as the ligand for palladium. Single-crystal X-ray analysis revealed that the core unit of the coronene analogue has a non-planar structure.

Dicationic oligotelluroxane or mononuclear telluronium cation? Elucidation of the true catalytic species and activation mechanism of the benzylic carbon-halogen bond.

The application of diaryltelluronium cations as chalcogen bonding organocatalysts was investigated for the Ritter-like reaction using time-course NMR analysis. The resistance to water of dicationic oligotelluroxanes differed depending on the oligomer chain length and counter anions. The activation mechanism of the substrate was discussed based on DFT calculations.

Water-promoted dehydrative coupling of 2-aminopyridines in heptane via a borrowing hydrogen strategy.

A synthetic method for dehydrative N-benzylation promoted by water molecules in heptane using a π-benzylpalladium system has been developed. The presence of water significantly accelerates carbon-nitrogen bond formation, which is accomplished in an atom-economical process to afford the corresponding N-monobenzylated products. A crossover experiment afforded H/D scrambled products, which is consistent with a borrowing hydrogen mechanism. Kinetic isotope effect measurements revealed that benzylic carbon-hydrogen bond cleavage was the rate-determining step.