Carbofunctionalization of Terminal Alkynes via Rhodium Catalysis Enabling Formations of Four Different Bonds.

Described here is the oxygenative carbofunctionalization of terminal alkynes mediated by combined rhodium catalysis that enables regioselective quadruple formation of C-C, C-H, C-O, and C-heteroatom bonds. Mechanistic studies suggest that a disubstituted rhodium vinylidene complex is generated upon C-C bond formation at the terminal alkyne with tethered electrophiles such as alkyl halides, aldehydes, imines, and Michael acceptors. Subsequent intermolecular transfer oxygenation of the rhodium vinylidene with pyridine N-oxide generates a rhodium-complexed ketene intermediate that reacts with a variety of heteroatom nucleophiles to give rise to cyclic carboxylic acid derivatives.

Dicarboxylate-containing and fully substituted ferrocene with rapid dissolvability, high solubility, good stability, and moderate formal potential for mediated electrochemical detection.

An electron mediator with rapid dissolvability and high solubility in aqueous electrolyte solutions is essential for point-of-care testing based on mediated electrochemical detection. However, most ferrocenyl (Fc) compounds have slow dissolvability and poor solubility owing to high hydrophobicity of the Fc backbone. Moreover, many Fc compounds have poor stability and nonoptimal formal potential (). Herein, we present an Fc compound, Fc8m2c, which exhibits rapid dissolvability, high solubility, good stability, and moderate along with its high electron-mediation rate. The of Fc8m2c (0.17 V vs. Ag/AgCl) is tuned by two electron-withdrawing acyl substituents and eight electron-donating methyl substituents. Two pendant carboxylate groups of Fc8m2c allow for rapid dissolvability and high solubility (0.63 M in water), whereas full substitution in its two cyclopentadienyl ligands facilitates good chemical stability against decomposition in the presence of dissolved O2 and ambient light. A moderate enables the application of a potential of 0.07 V at which electrochemical background currents are low and also contributes toward resisting the decomposition of both Fc8m2c and Fc8m2c+. Fc8m2c provides a high electron-mediation rate constant (2.4 × 106 M-1 s-1) in glucose detection using glucose dehydrogenase. When Fc8m2c is applied to a glucose sensor, the calculated detection limit is ∼0.1 mM with a measurement period of 5 s. Considering that the normal concentration of glucose in serum is between 3.9 and 6.6 mM, the detection limit is sufficiently low. These results show that Fc8m2c is an excellent electron-mediator candidate for sensitive and rapid glucose detection.

Adding functions to pyridines.

Chemical reactions break a pyridine ring to allow its modification.

Nondirected Pd-catalyzed aerobic C-H alkenylation of ruthenocene and ferrocene.

Pd-catalyzed alkenylations of metallocenes via C-H activation were developed using electronically tunable pyrazolonaphthyridine (PzNPy) ligands. Ferrocene was alkenylated using the most electron-deficient ligand in the series, whereas the less reactive ruthenocene needed balancing of the electrophilicity and stability of catalysts. Various alkenes were installed, allowing fine-tuning of redox potentials.

Di(Thioether Sulfonate)-Substituted Quinolinedione as a Rapidly Dissoluble and Stable Electron Mediator and Its Application in Sensitive Biosensors.

The commonly required properties of diffusive electron mediators for point-of-care testing are rapid dissolubility, high stability, and moderate formal potential in aqueous solutions. Inspired by nature, various quinone-containing electron mediators have been developed; however, satisfying all these requirements remains a challenge. Herein, a strategic design toward quinones incorporating sulfonated thioether and nitrogen-containing heteroarene moieties as solubilizing, stabilizing, and formal potential-modulating groups is reported. A systematic investigation reveals that di(thioether sulfonate)-substituted quinoline-1,4-dione (QLS) and quinoxaline-1,4-dione (QXS) display water solubilities of ≈1 m and are rapidly dissoluble. By finely balancing the electron-donating effect of the thioethers and the electron-withdrawing effect of the nitrogen atom, formal potentials suitable for electrochemical biosensors are achieved with QLS and QXS (-0.15 and -0.09 V vs Ag/AgCl, respectively, at pH 7.4). QLS is stable for >1 d in PBS (pH 7.4) and for 1 h in tris buffer (pH 9.0), which is sufficient for point-of-care testing. Furthermore, QLS, with its high electron mediation ability, is successfully used in biosensors for sensitive detection of glucose and parathyroid hormone, demonstrating detection limits of ≈0.3 × 10-3 m and ≈2 pg mL-1 , respectively. This strategy produces organic electron mediators exhibiting rapid dissolution and high stability, and will find broad application beyond quinone-based biosensors.

Transition-Metal-Catalyzed Divergent C-H Functionalization of Five-Membered Heteroarenes.

Conversion of common reactants to diverse products is a key objective of organic syntheses. Recent developments in transition-metal-catalyzed C-H functionalization have increased the interest in such conversions. Both the position of functionalization and the type of the substituent can be varied, allowing systematic diversification of common structural cores. Because five-membered heteroarenes (pyrazole, imidazole, thiazole, pyrrole, and thiophene) are ubiquitous in pharmaceuticals and organic functional materials, the selective C-H functionalization of these heterocyclic cores facilitates both the optimization of their physicochemical properties and streamlining of their preparation. In addition, the parent forms of these heterocycles are more readily available and inexpensive than any other derivatives of their families. Hence, their nondirected C-H functionalization is highly desirable. Although various regioselective reactions have been developed, many of them target the most reactive site; hence, except for some extensively studied arylation reactions, regiodivergent functionalization of two or more sites has been limited.This Account summarizes our work on the regiodivergent, nondirected C-H functionalization of five-membered heteroarenes with alkenes and alkynes. These unsaturated hydrocarbons are readily available, and all the composing atoms can be incorporated into products with high atom efficiency. Furthermore, the installed alkenyl groups can be transformed to other useful functional groups. To achieve comparable selectivity to that observed in the traditional reactions of these heteroarenes with highly electrophilic reagents and strong bases, a transition metal catalytic system was carefully devised with a more streamlined synthesis. A judicious choice of metals, ligands, acid and base additives, and solvents orchestrates divergent transformations using electronic and steric effects of the heteroarenes. Although C-H cleavage is a rate- and site-selectivity-determining step in most cases, the subsequent steps involving the formation of C-C bonds are often more critical than the other steps. For the C-H cleavage step, modulating the electronic properties of catalysts to make them electrophilic allows preferential alkenylation at the nucleophilic position. In addition, the presence of an internal base that can be exploited for concerted metalation-deprotonation of the acidic C-H bond offers alternative regioselectivity. Furthermore, we developed our own ligand system based on a conformationally rigid pyrazolonaphthyridine scaffold that enables aerobic C-H alkenylation reactions with steric control. We showed that the electronic and steric effects of heteroarenes can be further extended to chemodivergent reactions with norbornene derivatives. Depending on whether the palladacycle is formed, heteroarenes selectively undergo 1:2 annulation with norbornene derivatives and three-component reactions with other azoles through the Pd-norbornene adducts or Catellani and 2:1 annulation reactions through the palladacycle intermediates.Other research groups have also contributed to the development of divergent reactions, in investigations ranging from the pioneering studies in the early days of research on C-H functionalization to recent studies with new ligands. We have also discussed these studies in context. These approaches provide access to many heteroarenes with systematically varied substituents. We believe that new ligand systems and mechanistic insights gained through these studies will enrich fields beyond C-H functionalization of five-membered heteroarenes.

Sterically controlled C-H alkenylation of pyrroles and thiophenes.

Pd-catalyzed C-H alkenylations targeting the least hindered position of N-alkyl pyrroles and 3-substituted thiophenes, as opposed to electronically controlled approaches, are developed. The steric demand and stable bidentate binding mode of the pyrazolonaphthyridine ligand are key to the success of these sterically controlled alkenylations using oxygen as an oxidant.

Synthesis of Bidentate Nitrogen Ligands by Rh-Catalyzed C-H Annulation and Their Application to Pd-Catalyzed Aerobic C-H Alkenylation.

A new class of bidentate ligands was prepared by a modular approach involving Rh-catalyzed C-H annulation reactions. The resulting conformationally constrained ligands enabled the Pd-catalyzed C-H alkenylation at electron-rich and sterically less hindered positions of electron-rich arenes while promoting the facile oxidation of Pd(0) intermediates by oxygen. This newly introduced ligand class is complementary to the ligands developed for Pd-catalyzed oxidative reactions and may find broad application in transition-metal-catalyzed reactions.

Effects of Meridian Acupressure on Stress, Fatigue, Anxiety, and Self-Efficacy of Shiftwork Nurses in South Korea.

Shiftwork nurses experience physical and psychological health problems related to shift work. This study aimed to examine the effects of Meridian acupressure on stress, fatigue, anxiety, and self-efficacy of shiftwork nurses in South Korea. A quasi-experimental pretest-posttest control group design was employed. Study participants were a total of 59 shiftwork nurses (intervention group: n = 29, control group: n = 30) in S hospital, Seoul, South Korea. The study was conducted at nurse stations in S hospital. Meridian acupressure as intervention was conducted for a total of 15 min on six Meridian acupressure points (GV 20, GB 12, GB 21, LI 11, SI 3, KI 1), 2 min 30 s (10 times for 15 s at a time) on each Meridian point. Measures were the stress scale, fatigue scale, State Anxiety Inventory, and self-efficacy scale, in Korean. Data were collected from July to August 2018. There were significant differences in the degrees of stress, fatigue, and anxiety of shiftwork nurses between the two groups. Meridian acupressure significantly decreased stress, fatigue, and anxiety of shiftwork nurses. This study provides preliminary evidence that Meridian acupressure was an effective intervention. Meridian acupressure could be applied to shiftwork nurses in various clinical situations.

Interference-Free Duplex Detection of Total and Active Enzyme Concentrations at a Single Working Electrode.

The duplex detection of both total and active enzyme concentrations without interferences at a single working electrode is challenging, especially when two different assays are combined. It is also challenging to obtain two different redox-cycling reactions without interference. Here, we present a simple but sensitive combined assay that is based on two redox-cycling reactions using two incubation periods and applied potentials at a single electrode. The assay combines an immunoassay for the determination of the total enzyme (total prostate-specific antigen, tPSA) concentration with a protease assay for the determination of the active enzyme (free PSA, fPSA) concentration. The immunoassay label and fPSA that are affinity-bound to the electrode are used for high sensitivity and specificity in the protease assay as well as the immunoassay. In the immunoassay, electrochemical-enzymatic (EN) redox cycling involving ferrocenemethanol is obtained at 0.1 V versus Ag/AgCl without incubation before the proteolytically released 4-amino-1-naphthol is generated. In the protease assay, EN redox cycling involving 4-amino-1-naphthol is obtained at 0.0 V after 30 min of incubation without ferrocenemethanol electro-oxidation. The detection procedure is almost the same as common electrochemical sandwich-type immunoassays, although the two different assays are combined. The duplex detection in buffer and serum is highly interference-free, specific, and sensitive. The detection limits for tPSA and fPSA are approximately 10 and 1 pg/mL, respectively.

Divergent Strategies for the π-Extension of Heteroaryl Halides Using Norbornadiene as an Acetylene Synthon.

Pd-catalyzed multicomponent coupling reactions of five-membered heteroaryl halides and norbornadiene (NBD) were developed. Either direct addition of (benzo)azoles or 2:1 annulation was achieved depending on the propensity of the intermediate complex to undergo palladacycle formation, determined by the nature and substitution pattern of the heteroarene. The obtained exo- and cis-diheteroaryl norbornenes underwent epimerization and retro-Diels-Alder reactions to afford the corresponding trans-isomers and π-extended heteroaromatic systems, respectively, demonstrating the versatility of NBD as an acetylene synthon.

Enantioselective total synthesis of (+)-ieodomycin A, (+)-ieodomycin B, and their three stereoisomers.

We describe a divergent and enantioselective total synthesis of (+)-ieodomycin A and (+)-ieodomycin B with three stereoisomers. The main advantage of the present synthesis is the late-stage elaboration of the side chain, which would afford a wide range of structurally diverse analogs with interesting bioactivities.

Transition-metal-catalyzed C-H functionalization of pyrazoles.

This review describes recent advances in transition-metal-catalyzed C-H functionalization reactions of pyrazoles to form new C-C and C-heteroatom bonds on the pyrazole ring. In contrast to traditional cross-coupling reactions that require pre-functionalized pyrazoles, direct C-H functionalization reactions provide access to a wide range of functionalized pyrazoles in a single step. Various strategies are presented and the efficiency and regioselectivity are described with respect to the types of functional groups that are installed.

Synthesis of Redox-Active Phenanthrene-Fused Heteroarenes by Palladium-Catalyzed C-H Annulation.

Pd-catalyzed C-H annulation reactions of halo- and aryl-heteroarenes were developed using readily available o-bromobiaryls and o-dibromoaryls, respectively. A variety of five-membered heteroarenes rapidly provided the corresponding phenanthrene-fused heteroarenes, which led to the identification of phenanthro-pyrazole and thiazole as new, stable -2 V redox couples. The flexible syntheses and tunability of the redox potentials of these azole-fused phenanthrenes over a wide range are expected to facilitate their application as redox-active organic functional materials.

Regio- and Stereoselective Synthesis of Thiazole-Containing Triarylethylenes by Hydroarylation of Alkynes.

Thiazole-containing π-conjugated moieties are important structural units in the development of new electronic and photochromic materials. We have developed a Pd-catalyzed syn-hydroarylation reaction of diaryl alkynes with thiazoles that provides access to thiazole-containing triarylethylenes. Pd(II) complexes derived from Pd(0) species and carboxylic acids facilitated C-H functionalization of the unsubstituted thiazole with high C5 selectivity. The catalytic system was also compatible with other azoles, such as oxazoles and a pyrazole, allowing the stereoselective syntheses of various trisubstituted olefins.

Use of a Phosphatase-Like DT-Diaphorase Label for the Detection of Outer Membrane Vesicles.

DT-diaphorase (DT-D) is known to mainly catalyze the two-electron reduction of quinones and nitro(so) compounds. Detection of Gram-negative bacterial outer membrane vesicles (OMVs) that contain pyrogenic lipopolysaccharides (LPSs, also called endotoxins) is required for evaluating the toxic effects of analytical samples. Here, we report that DT-D has a high dephosphorylation activity: DT-D catalyzes reductive dephosphorylation of a phosphate-containing substrate in the presence of NADH. We also report that sensitive and simple OMV detection is possible with a sandwich-type electrochemical immunosensor using DT-D and two identical LPS-binding antibodies as a catalytic label and two sandwich probes, respectively. The absorbance change in a solution containing 4-nitrophenyl phosphate indicates that dephosphorylation occurs in the presence of both DT-D and NADH. Among the three phosphate-containing substrates [4-aminophenyl phosphate, ascorbic acid phosphate, and 1-amino-2-naphthyl phosphate (ANP)] that can be converted into electrochemically active products after dephosphorylation, ANP shows the highest electrochemical signal-to-background ratio, because (i) the dephosphorylation of ANP by DT-D is fast, (ii) the electrochemical oxidation of the dephosphorylated product (1-amino-2-naphthol, AN) is rapid, even at a bare indium-tin oxide electrode, and (iii) two redox cycling processes significantly increase the electrochemical signal. The two redox cycling processes include an electrochemical-enzymatic redox cycling and an electrochemical-chemical redox cycling. The electrochemical signal in a neutral buffer (tris buffer, pH 7.5) is comparable to that in a basic buffer (tris buffer, pH 9.5). When the immunosensor is applied to the detection of OMV from Escherichia coli, the detection limit is found to be 8 ng/mL. This detection strategy is highly promising for the detection of biomaterials, including other extracellular vesicles.

Regioselective C-H alkenylation of imidazoles and its application to the synthesis of unsymmetrically substituted benzimidazoles.

A palladium-catalyzed C-H alkenylation of imidazoles has been developed. High C5 selectivity was achieved for C2-unsubstituted and C2-substituted imidazoles using oxygen and copper(ii) acetate, respectively, as oxidants. The obtained products were applied to benzannulation through a sequence involving transposition of N-alkyl groups to give C4-alkenyl imidazoles, alkenylation, thermal 6π-electrocyclization, and oxidation, affording unsymmetrically substituted benzimidazoles.

C-H Alkenylation of Pyrroles by Electronically Matching Ligand Control.

Directing group and substrate control strategies have frequently been employed for the regioselective C-H alkenylation of acid- and oxidant-sensitive pyrrole heterocycles. We developed an undirected, aerobic strategy for the C-H alkenylation of N-alkylpyrroles by ligand control. For C2-alkenylation of electron-rich N-alkylpyrroles, an electrophilic palladium catalyst derived from Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF) was used. Alternatively, a combination of Pd(OAc)2 and a mono-protected amino acid ligand, Ac-Val-OH, was useful for C5-alkenylation of N-alkylpyrroles possessing electron-withdrawing groups at the C2 position. This approach based on the electronic effects of heterocycles and catalysts can rapidly provide a wide range of alkenyl pyrroles from readily available N-alkylpyrroles and alkenes.

Ligand-controlled Regiodivergent C-H Alkenylation of Pyrazoles and its Application to the Synthesis of Indazoles.

Regioselective C4-, C5-, and di-alkenylations of pyrazoles were achieved. An electrophilic Pd catalyst generated by trifluoroacetic acid (TFA) and 4,5-diazafluoren-9-one (DAF) leads to C4-alkenylation, whereas KOAc and mono-protected amino acid (MPAA) ligand Ac-Val-OH give C5-alkenylation. A combination of palladium acetate, silver carbonate, and pivalic acid affords dialkenylation products. Annulation through sequential alkenylation, thermal 6π-electrocyclization, and oxidation gives functionalized indazoles. This comprehensive strategy greatly expands the range of readily accessible pyrazole and indazole derivatives, enabling useful regiodivergent C-H functionalization of pyrazoles and other heteroaromatic systems.

Immunosensor Employing Stable, Solid 1-Amino-2-naphthyl Phosphate and Ammonia-Borane toward Ultrasensitive and Simple Point-of-Care Testing.

Biosensors for ultrasensitive point-of-care testing require dried reagents with long-term stability and a high signal-to-background ratio. Although ortho-substituted diaromatic dihydroxy and aminohydroxy compounds undergo fast redox reactions, they are not used as electrochemical signaling species because they are readily oxidized and polymerized by dissolved oxygen. In this report, stable, solid 1-amino-2-naphthyl phosphate (1A2N-P) and ammonia-borane (H3N-BH3) are respectively employed as a substrate for alkaline phosphatase (ALP) and a reductant for electrochemical-chemical (EC) redox cycling. ALP converts 1A2N-P to 1-amino-2-naphthol (1A2N), which is then employed in EC redox cycling using H3N-BH3. The oxidation and polymerization of 1A2N by dissolved oxygen is significantly prevented in the presence of H3N-BH3. The electrochemical measurement is performed without modification of indium-tin oxide (ITO) electrodes with electrocatalytic materials. For comparison, nine aromatic dihydroxy and aminohydroxy compounds, including 1A2N, are evaluated to achieve fast EC redox cycling, and four strong reductants, including H3N-BH3, are evaluated to achieve a low background level. The combination of 1A2N and H3N-BH3 allows the achievement of a very high signal-to-background ratio. When the newly developed combination is applied to the detection of creatine kinase-MB (CK-MB), the detection limit for CK-MB is ∼80 fg/mL, indicating that the combination allows ultrasensitive detection. The concentrations of CK-MB in clinical serum samples, determined using the developed system, are in good agreement with the concentrations obtained using a commercial instrument. Thus, the use of stable, solid 1A2N-P and H3N-BH3 along with bare ITO electrodes is highly promising for ultrasensitive and simple point-of-care testing.