Recent Developments in Reactions and Catalysis of Protic Pyrazole Complexes.

Protic pyrazoles (N-unsubstituted pyrazoles) have been versatile ligands in various fields, such as materials chemistry and homogeneous catalysis, owing to their proton-responsive nature. This review provides an overview of the reactivities of protic pyrazole complexes. The coordination chemistry of pincer-type 2,6-bis(1H-pyrazol-3-yl)pyridines is first surveyed as a class of compounds for which significant advances have made in the last decade. The stoichiometric reactivities of protic pyrazole complexes with inorganic nitrogenous compounds are then described, which possibly relates to the inorganic nitrogen cycle in nature. The last part of this article is devoted to outlining the catalytic application of protic pyrazole complexes, emphasizing the mechanistic aspect. The role of the NH group in the protic pyrazole ligand and resulting metal-ligand cooperation in these transformations are discussed.

Asymmetric Transfer Hydrogenative Amination of Benzylic Ketones Catalyzed by Cp*Ir(III) Complexes Bearing a Chiral N-(2-Picolyl)sulfonamidato Ligand.

A convenient asymmetric reductive amination of benzylic ketones (α-arylated ketones) catalyzed by newly designed Cp*Ir complexes bearing a chiral N-(2-picolyl)sulfonamidato ligand was developed. Using readily available ß-amino alcohols as chiral aminating agents, a range of benzo-fused and acyclic ketones were successfully reduced with formic acid in methanol at 40 °C to afford amines with favorable chemo- and diastereoselectivities. The amino alcohol-derived chiral auxiliary was easily removed by mild periodic oxidants, leading to optically active primary ß-arylamines without erosion of the optical purity (up to 97% ee). The excellent catalytic performance was retained even upon lowering the amount of catalyst to a substrate/catalyst (S/C) ratio of 20,000, and the amination could be performed on a large scale exceeding 100 g. The precise hydride transfer to iminium species generated from the ketonic substrate and the chiral amine counterpart was suggested by the mechanistic studies on stoichiometric reactions of isolable hydridoiridium complexes and model intermediates such as N,O-acetal, enamine, and iminium compounds.

Complexes Bearing Protic N-Heterocyclic Carbene Ligands.

Complexes bearing protic N-heterocyclic carbenes (protic NHCs, pNHCs), defined as cyclic carbenes stabilized by two heteroatoms including at least one NH group, have been less explored in comparison to the conventional N,N'-disubstituted NHCs. The small and reactive NH group of the pNHCs differentiates this class of compounds from the classical NR,NR-NHCs with regard to their properties and reactivity. While the free pNHCs have so far eluded isolation due to isomerization to the azole tautomer, a significant number of transition-metal pNHC complexes have by now been prepared by a variety of methods. This article reviews the coordination chemistry of the pNHCs. Synthetic approaches toward complexes of pNHCs are first described, followed by a discussion of the properties and reactivity of pNHC complexes with emphasis on the Brønsted-acidic nature of the NH wingtip. Involvement of the pNHC ligands in catalytically active intermediates and in cooperative catalysis is also discussed.

A Strategy toward Cyclic Topologies Based on the Dynamic Behavior of a Bis(hindered amino)disulfide Linker.

A simple and efficient method to generate macrocyclic structures has been developed based on the dynamic behavior of the linker bis(2,2,6,6-tetramethylpiperidin-1-yl)disulfide (BiTEMPS). The prime linear structure was transformed into a (macro)cycle using the following sequence: 1) thiol-ene reaction with a BiTEMPS derivative to afford the linear precursor, then 2) an entropy-driven transformation induced by diluting and heating. The radicals generated from BiTEMPS upon heating are highly tolerant toward a variety of chemical species, including oxygen and olefins, but they exhibit high reactivity in exchange reactions, which can be applied to the topology transformation of various skeletons. The advantages of the present method, namely, its procedural simplicity and substrate versatility, are demonstrated by the gram-scale synthesis of cyclic compounds with low and relatively high molecular weight.

Cleavage of N-H Bond of Ammonia via Metal-Ligand Cooperation Enables Rational Design of a Conceptually New Noyori-Ikariya Catalyst.

The asymmetric transfer hydrogenation (ATH) of ketones/imines with Noyori-Ikariya catalyst represents an important reaction in both academia and fine chemical industry. The method allows for the preparation of chiral secondary alcohols/amines with very good to excellent optical purities. Remarkably, the same chiral Noyori-Ikariya complex is also a precatalyst for a wide range of other chemo- and stereoselective reductive and oxidative transformations. Among them are enantioselective sulfonamidation of acrylates (intramolecular aza-Michael reaction) and carboxylation of indoles with CO2. Development of these catalytic reactions has been inspired by the realized cleavage of the N-H bond of sulfonamides and indoles by the 16e- amido derivative of the 18e- precatalyst via metal-ligand cooperation (MLC). This paper summarizes our efforts to investigate N-H bond cleavage of gaseous ammonia in solution via MLC and reports the serendipitous discovery of a new class of chiral tridentate κ3[ N, N', N″] Ru and Ir metallacycles, derivatives of the famous M-FsDPEN catalysts (M = Ru, Ir). The protonation of these metallacycles by strong acids containing weakly coordinating (chiral) anions generates ionic complexes, which were identified as conceptually novel Noyori-Ikariya precatalysts. For example, the ATH of aromatic ketones with some of these complexes proceeds with up to 99% ee.

Metal-ligand cooperative C-O bond cleavage of propargylic alcohol with protic pyrazole complexes of ruthenium.

The C-O bond cleavage of a propargylic alcohol, 1,1-dimethyl-3-phenylprop-2-yn-1-ol (3), by metal-ligand cooperation was investigated. The reactions of a naphthalene complex [CpRu(η6-C10H8)]PF6 (Cp = η5-C5H5) with 5-R-3-(pyrid-2-yl)pyrazoles (R-LH; R = Ph, CF3) in acetonitrile afforded the starting metal-ligand bifunctional ruthenium complexes [CpRu(R-LH)(MeCN)]PF6 (1a, R = Ph; 1b, R = CF3) featuring an N-N chelate protic pyrazole. The treatment of the CF3-substituted pyrazole complex 1b with 3 in 1,2-dichloroethane at 50 °C resulted in the formation of the η3-butadienyl complex 5. Meanwhile, the corresponding reaction of the phenylpyrazole complex 1a in 1,4-dioxane at 90 °C gave the N-allenylmethylpyrazole complex 6. The C-O and C-H bond cleavage of 3 in these reactions can be ascribed to the metal-ligand cooperation: initial formation of an η3-propargyl complex assisted by NHO hydrogen bonding and following C-H deprotonation by the neighboring pyrazolato ligand. On the other hand, in boiling methanol, the protic pyrazole complex 1a catalyzed the C-O bond cleavage of 3, which resulted in catalytic isomerization of 3 to an α,ß-unsaturated enone, 3-methyl-1-phenylbut-2-en-1-one (8). The control experiments using non-protic and isocyanide ruthenium complexes indicated that both a labile nitrile ligand on the metal and the protic cooperating ligand are crucial for the catalysis.

Reductive Amination of Ketonic Compounds Catalyzed by Cp*Ir(III) Complexes Bearing a Picolinamidato Ligand.

Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low temperature and exhibits excellent chemoselectivity toward primary amines.

Protic N-Heterocyclic Carbene Versus Pyrazole: Rigorous Comparison of Proton- and Electron-Donating Abilities in a Pincer-Type Framework.

Evaluation of the acidity of proton-responsive ligands such as protic N-heterocyclic carbenes (NHCs) bearing an NH-wingtip provides a key to understanding the metal-ligand cooperation in enzymatic and artificial catalysis. Here, we design a CNN pincer-type ruthenium complex 2 bearing protic NHC and isoelectronic pyrazole units in a symmetrical skeleton, to compare their acidities and electron-donating abilities. The synthesis is achieved by direct C-H metalation of 2-(imidazol-1-yl)-6-(pyrazol-3-yl)pyridine with [RuCl2 (PPh3 )3 ]. 15 N-Labeling experiments confirm that deprotonation of 2 occurs first at the pyrazole side, indicating clearly that the protic pyrazole is more acidic than the NHC group. The electrochemical measurements as well as derivatization to carbonyl complexes demonstrate that the protic NHC is more electron-donating than pyrazole in both protonated and deprotonated forms.

Structural Analysis and Inclusion Mechanism of Native and Permethylated α-Cyclodextrin-Based Rotaxanes Containing Alkylene Axles.

Native α-cyclodextrin- (α-CD) and permethylated α-CD (PMeCD)-based rotaxanes with various short alkylene chains as axles can be synthesized through a urea end-capping method. Native α-CD tends to form [3]- or [5]pseudorotaxanes and not [2]- or [4]pseudorotaxanes, which indicates that the coupled CDs act as a single fragment. End-capping reactions of the pseudorotaxanes with C18 and C24 axle lengths do not occur because the axle termini are covered by the densely stacked CDs. The number of PMeCDs on the pseudorotaxane is flexible and mainly depends on the axle length. Peracetylated α-CD (PAcCD)-based rotaxanes are synthesized through O-acetylation of the α-CD-based rotaxanes without any decomposition of the rotaxanated structures. The structures of PMeCD-based [3]- and [4]rotaxanes, and the molecular dynamics calculations on [3]pseudorotaxanes, indicate that the tail face of PMeCDs is regularly directed toward the axle termini. On the basis of the results obtained, it can be concluded that the directions and numbers of CDs in rotaxanes containing short alkylene chains depend on 1) the interactions between CDs, 2) the length of the alkylene axle, and 3) the interactions between the axle end and tail face of the CD.

Protic Ruthenium Tris(pyrazol-3-ylmethyl)amine Complexes Featuring a Hydrogen-Bonding Network in the Second Coordination Sphere.

We synthesized ruthenium complexes bearing a tris(pyrazol-3-ylmethyl)amine ligand LH3 and revealed that this tripodal ligand allows predictable accumulation of three proton-delivering NH groups around a coordination site. The Brønsted acidity of the NH groups in LH3 led to the formation of multiple hydrogen bonds with the substrate ligand and deprotonation. The chlorido complex ligated by LH3 catalyzed disproportionation of 1,2-diphenylhydrazine.

Smartphone-assisted prehospital medical information system for analyzing data on prehospital stroke care.

BACKGROUND AND PURPOSE: Optimizing prehospital stroke care is important because effective treatments for acute stroke require a narrow therapeutic time window. We developed a smartphone-assisted prehospital medical information system (SPMIS) to facilitate research on prehospital stroke care. METHODS: Prehospital medical information was input into the SPMIS application installed on smartphones by emergency medical staff, sent to a server through the Internet, and connected with in-hospital information. Using SPMIS, we analyzed data on 914 patients transferred to our institution by ambulance between April 2012 and March 2013. RESULTS: The data analyzed were the sensitivity and specificity of the prehospital diagnosis and prehospital stroke scale and the relationship between prehospital vital signs and forms of stroke. These analyses could be performed semiautomatically in a few hours. CONCLUSIONS: SPMIS enabled us to analyze the prehospital information of patients with stroke in a short time with little effort. More large-scale studies on prehospital stroke care will become feasible using SPMIS, which may lead to advances in stroke treatment.

Unsymmetrical pincer-type ruthenium complex containing ß-protic pyrazole and N-heterocyclic carbene arms: comparison of Brønsted acidity of NH groups in second coordination sphere.

A reaction of a 2-(imidazol-1-yl)methyl-6-(pyrazol-3-yl)pyridine with [RuCl2 (PPh3 )3 ] resulted in tautomerization of the imidazole unit to afford the unsymmetrical pincer-type ruthenium complex 2 containing a protic pyrazole and N-heterocyclic carbene (NHC) arms. Deprotonation of 2 with one equivalent of a base led to the formation of the NHC-pyrazolato complex 3, indicating that the protic NHC arm is less acidic. When 2 was treated with two equivalents of a base under H2 or in 2-propanol, the hydrido complex 4 containing protic NHC and pyrazolato groups was obtained through metal-ligand cooperation.

Cyclodextrin-based size-complementary [3]rotaxanes: selective synthesis and specific dissociation.

α-Cyclodextrin (CD)-based size-complementary [3]rotaxanes with alkylene axles were prepared in one-pot by end-capping reactions with aryl isocyanates in water. The selective formation of [3]rotaxane with a head-to-head regularity was indicated by the X-ray structural analyses. Thermal degradation of the [3]rotaxanes bearing appropriate end groups proceeded by stepwise dissociation to yield not only the original components but also [2]rotaxanes. From the kinetic profiles of the deslippage, it turned out that the maximum yield of [2]rotaxane was estimated to be 94 %. Thermodynamic studies and NOESY analyses of such rotaxanes revealed that [2]rotaxanes are specially stabilized, and that the dissociation capability of the [3]rotaxanes to the components can be adjusted by controlling the structure of the end groups, direction of the CD groups, and length of the alkylene axle.

Asymmetric Reductive Amination of α-Keto Acids Using Ir-Based Hydrogen Transfer Catalysts: An Access to Unprotected Unnatural α-Amino Acids.

A direct asymmetric reductive amination of α-keto acids catalyzed by Cp*Ir complexes bearing a chiral N-(2-picolyl)sulfonamidato ligand is described. The combined use of optically active 2-phenyglycinol as an aminating agent is effective for the chemo- and stereoselective transfer hydrogenation using formic acid. The subsequent elimination of the hydroxyethyl moiety by orthoperiodic acid can afford various unprotected α-amino acids in satisfactory isolated yields (20 examples) with excellent optical purities (up to >99% ee).

N-N bond cleavage of hydrazines with a multiproton-responsive pincer-type iron complex.

N-N bond cleavage of hydrazines on transition metals is of considerable importance in understanding the mechanism of biological nitrogen fixation under ambient conditions. We found that a metal-ligand-bifunctional complex of iron with a pincer-type ligand bearing two proton-responsive pyrazole arms catalyzes the disproportionation of hydrazine into ammonia and dinitrogen. The NH groups in the pyrazole ligands and hydrazines are crucial for the reaction, which most likely occurs through multiple and bidirectional proton-coupled electron transfer between the iron complex and hydrazine. The multiproton-responsive pincer-type ligand also stabilizes the intermediate diazene complex through a hydrogen-bonding network, as revealed by structural characterization of a κ(1)N-phenylhydrazine complex.

Information accountability and usability: are there any connections?

Availability of health information is rapidly increasing and the expansion and proliferation of health information is inevitable. The Electronic Healthcare Record, Electronic Medical Record and Personal Health Record are at the core of this trend and are required for appropriate and practicable exchange and sharing of health information. However, it is becoming increasingly recognized that it is essential to preserve patient privacy and information security when utilising sensitive information for clinical, management and administrative processes. Furthermore, the usability of emerging healthcare applications is also becoming a growing concern. This paper proposes a novel approach for integrating consideration of information accountability with a perspective from usability engineering that can be applied when developing healthcare information technology applications. A social networking user case in the healthcare information exchange will be presented in the context of our approach.

Proposal of diagnostic process model for computer based diagnosis.

We aim at making a diagnosis support system that can be put to practical use. We proposed a diagnostic process model based on simple knowledge which can be gleaned from textbooks. We defined clinical finding (CF) as a general concept for patient's symptom or findings etc., whose value is expressed by Boolean. We call the combination of several CFs a "CF pattern", and a set of CF patterns with concomitant diseases "case base". We consider diagnosis as a process of searching an instance from the case base whose CF pattern is concomitant with that of a patient. The diseases which have the same CF pattern are candidates for diagnosis. Then we select a CF which is present in part of the candidates and check whether it is present or absent in the patient in order to narrow down the candidates. Because the case base does not exist in reality, the probability of CF pattern is calculated by the product of CF occurrence rate assuming that occurrence of CF is independent. Therefore the knowledge required for diagnosis is frequency of disease under sex and age group and CF-disease relation (CF and its occurrence rate in the disease). By processing these two types of knowledge, diagnosis can be made.